U.S. patent application number 10/395502 was filed with the patent office on 2003-10-23 for combination therapy comprising glucose reabsorption inhibitors and ppar modulators.
Invention is credited to Bussolari, Jacqueline C., Chen, Xiaoli, Conway, Bruce R., Demarest, Keith T., Ross, Hamishi N.M., Severino, Rafael.
Application Number | 20030199557 10/395502 |
Document ID | / |
Family ID | 23077253 |
Filed Date | 2003-10-23 |
United States Patent
Application |
20030199557 |
Kind Code |
A1 |
Bussolari, Jacqueline C. ;
et al. |
October 23, 2003 |
Combination therapy comprising glucose reabsorption inhibitors and
PPAR modulators
Abstract
Combination therapy comprising PPAR modulators and glucose
reabsorption inhibitors useful for the treatment of diabetes and
Syndrome X are disclosed.
Inventors: |
Bussolari, Jacqueline C.;
(Skillman, NJ) ; Chen, Xiaoli; (Belle Mead,
NJ) ; Conway, Bruce R.; (Doylestown, PA) ;
Demarest, Keith T.; (Flemington, NJ) ; Ross, Hamishi
N.M.; (Far Hills, NJ) ; Severino, Rafael;
(Madrid, ES) |
Correspondence
Address: |
AUDLEY A. CIAMPORCERO JR.
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
23077253 |
Appl. No.: |
10/395502 |
Filed: |
March 24, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10395502 |
Mar 24, 2003 |
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10115827 |
Apr 3, 2002 |
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60281429 |
Apr 4, 2001 |
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Current U.S.
Class: |
514/342 ;
514/369 |
Current CPC
Class: |
A61K 31/31 20130101;
A61P 3/10 20180101; A61K 31/4439 20130101; A61K 31/7034 20130101;
A61P 43/00 20180101; A61K 31/427 20130101; A61K 31/426 20130101;
A61K 31/31 20130101; A61K 2300/00 20130101; A61K 31/426 20130101;
A61K 2300/00 20130101; A61K 31/427 20130101; A61K 2300/00 20130101;
A61K 31/4439 20130101; A61K 2300/00 20130101; A61K 31/7034
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/342 ;
514/369 |
International
Class: |
A61K 031/4439; A61K
031/426 |
Claims
What is claimed is:
1. A method for treating diabetes, Syndrome X, or associated
symptoms or complications in a subject, said method comprising (a)
administering to said subject a jointly effective amount of a
glucose reabsorption inhibitor; and (b) administering to said
subject a jointly effective amount of a PPAR modulator, said
co-administration being in any order and the combined jointly
effective amounts providing the desired therapeutic effect.
2. The method of claim 1, wherein the PPAR modulator is a
PPAR.gamma. agonist.
3. The method of claim 1, wherein the PPAR modulator is a
thiazolidinedione or a non-thiazolidinedione insulin
sensitizer.
4. The method of claim 1, wherein the PPAR modulator is selected
from (a) rosiglitazone; (b) pioglitazone; (c) troglitazone; (d)
isaglitazone; (e) 5-BTZD; (f) JT-501; (g) KRP-297; (h) Farglitazar;
(i) Risarestat; (j) YM 440; (k) NN 2344; (l) NN 622; (m)
AR-H039242; (n) Fenofibrate; and (o) bexarotene.
5. The method of claim 1, wherein the diabetes or Syndrome X, or
associated symptoms or complications thereof is selected from IDDM,
NIDDM, IGT, IFG, obesity, nephropathy, neuropathy, retinopathy,
atherosclerosis, polycystic ovary syndrome, hypertension, ischemia,
stroke, heart disease, irritable bowel disorder, inflammation, and
cataracts.
6. The method of claim 1 or 2, wherein the diabetes or Syndrome X,
or associated symptoms or complication thereof is IDDM.
7. The method of claim 1 or 2, wherein the diabetes or Syndrome X,
or associated symptoms or complications thereof is NIDDM.
8. The method of claim 1 or 2, wherein the diabetes or Syndrome X,
or associated symptoms or complications thereof is IGT or IFG.
9. The method of claim 1 or 2, further comprising administering to
said subject a jointly effective amount of a third antidiabetic
agent.
10. The method of claim 9, wherein the third antidiabetic agent is
selected from (aa) insulins, (bb) insulin analogues; (cc) insulin
secretion modulators, and (dd) insulin secretagogues.
11. The method of claim 10, wherein the diabetes or Syndrome X, or
associated symptoms or complications thereof is IDDM.
12. The method of claim 1 or 2, wherein the glucose reabsorption
inhibitor is an SGLT inhibitor.
13. The method of claim 12, wherein the glucose reabsorption
inhibitor is an SGLT1 inhibitor.
14. The method of claim 12, wherein the glucose reabsorption
inhibitor is an SGLT2 inhibitor.
15. The method of claim 12, wherein the glucose reabsorption
inhibitor is selected from a dihydrochalcone, a propiophenone and a
derivative thereof.
16. The method of claim 15, wherein the glucose reabsorption
inhibitor is a compound of Formula (V) 10or an optical isomer,
enantiomer, diastereomer, racemate or racemic mixture thereof,
ester, prodrug form, or a pharmaceutically acceptable salt thereof,
wherein Ar is aryl or heteroaryl; OX is an optionally protected
hydroxy group; Y is hydrogen or alkyl; and Z is glucopyranosyl
wherein one or more hydroxy groups thereof may optionally be
substituted with one or more groups selected from
.alpha.-D-glucopyranosyl, alkanoyl, alkoxycarbonyl, and substituted
alkyl.
17. The method of claim 16, wherein the glucose reabsorption
inhibitor is a compound of Formula (IV) 11wherein Ar is an aryl
group, R.sup.1 is hydrogen atom or an acyl group, R.sup.2 is
hydrogen atom, an acyl group or .alpha.-D-glucopyranosyl group, or
R' and R2 may combine together to form a substituted methylene
group, R.sup.3 and R.sup.4 are each hydrogen atom or an acyl group,
and OR.sup.5 is a protected or unprotected hydroxy group or a lower
alkoxy group.
18. The method of claim 16, wherein the glucose reabsorption
inhibitor is a compound of Formula (III) 12wherein R' is a lower
alkanoyl group, and R" is a hydrogen atom, or R' is a hydrogen
atom, and R" is a lower alkoxycarbonyl group.
19. The method of claim 16, wherein the glucose reabsorption
inhibitor is a compound of Formula (II) 13wherein X is an oxygen
atom, a sulfur atom or a methylene group, OY is a protected or
unprotected hydroxy group, Z is a .beta.-D-glucopyranosyl group or
4-O-(.alpha.-D-glucopyranosyl)-.bet- a.-D-glucopyranosyl group
wherein one or more hydroxy groups of these groups may optionally
be acylated, and the dotted line means the presence or absence of a
double bond.
20. The method of claim 16, wherein the glucose reabsorption
inhibitor is a compound of Formula (I) 14wherein OX is a hydroxy
group which may optionally be protected, Y is a lower alkyl group,
and Z is a .beta.-D-glucopyranosyl group wherein one or more
hydroxy groups may optionally be protected.
21. The method of claim 20, wherein the glucose reabsorption
inhibitor is T-1095 or T-1095A 15with one or more hydroxyl or diol
protecting groups, or a pharmaceutically acceptable salt
thereof.
22. The method of claim 20, wherein the glucose reabsorption
inhibitor is T-1095 or T-1095A, 16or an optical isomer, enantiomer,
diastereomer, racemate or racemic mixture thereof, ester, prodrug
form, or a pharmaceutically acceptable salt thereof.
23. The method of claim 20 wherein the glucose reabsorption
inhibitor is T-1095 or T-1095A with one or more hydroxyl or diol
protecting groups, or an optical isomer, enantiomer, diastereomer,
racemate or racemic mixture thereof, ester, prodrug form, or a
pharmaceutically acceptable salt thereof.
24. The method of claim 23 wherein the glucose reabsorption
inhibitor is T-1095.
25. The method of claim 23 wherein the glucose reabsorption
inhibitor is T-1095A.
26. The method of claim 23, wherein the jointly effective amount of
T-1095 or T-1095A is an amount sufficient to reduce the plasma
glucose excursion following a meal.
27. A method for inhibiting the onset of diabetes or Syndrome X, or
associated symptoms or complications thereof in a subject, said
method comprising (a) administering to said subject a jointly
effective amount of a glucose reabsorption inhibitor; and (b)
administering to said subject a jointly effective amount of a PPAR
modulator, said co-administration being in any order and the
combined jointly effective amounts providing the desired
prophylactic effect.
28. The method of claim 27, wherein said onset is from a
prediabetic state to NIDDM.
29. A pharmaceutical composition comprising a glucose reabsorption
inhibitor, a PPAR modulator, and a pharmaceutically acceptable
carrier.
30. The pharmaceutical composition of claim 29, wherein the PPAR
modulator is a PPAR.gamma. agonist.
31. The pharmaceutical composition of claim 29, wherein the PPAR
modulator is selected from (a) rosiglitazone; (b) pioglitazone; (c)
troglitazone; (d) isaglitazone; (e) 5-BTZD; (f JT-501; (g) KRP-297;
(h) Farglitazar; (i) Risarestat; (j) YM 440; (k) NN 2344; (l) NN
622; (m) AR-H039242; (n) Fenofibrate; and (o) bexarotene.
32. The pharmaceutical composition of claim 29, wherein the glucose
reabsorption inhibitor is an SGLT inhibitor.
33. The pharmaceutical composition of claim 32, wherein the glucose
reabsorption inhibitor is an SGLT1 inhibitor.
34. The pharmaceutical composition of claim 32, wherein the glucose
reabsorption inhibitor is an SGLT2 inhibitor.
35. The pharmaceutical composition of claim 32, wherein the glucose
reabsorption inhibitor is selected from a dihydrochalcone, a
propiophenone and a derivative thereof.
36. The pharmaceutical composition of claim 35, wherein the glucose
reabsorption inhibitor is a compound of Formula (V) 17or an optical
isomer, enantiomer, diastereomer, racemate or racemic mixture
thereof, ester, prodrug form, or a pharmaceutically acceptable salt
thereof, wherein Ar is aryl or heteroaryl; OX is an optionally
protected hydroxy group;, Y is hydrogen or alkyl; and Z is
glucopyranosyl wherein one or more hydroxy groups thereof may
optionally be substituted with one or more groups selected from
.alpha.-D-glucopyranosyl, alkanoyl, alkoxycarbonyl, and substituted
alkyl.
37. The pharmaceutical composition of claim 36, wherein the glucose
reabsorption inhibitor is a compound of Formula (I) 18wherein OX is
a hydroxy group which may optionally be protected, Y is a lower
alkyl group, and Z is a .beta.-D-glucopyranosyl group wherein one
or more hydroxy groups may optionally be protected.
38. The pharmaceutical composition of claim 37, wherein the glucose
reabsorption inhibitor is T-1095 or T-1095A, optionally having one
or more hydroxyl or diol protecting groups, or an optical isomer,
enantiomer, diastereomer, racemate or racemic mixture thereof,
ester, prodrug form, or a pharmaceutically acceptable salt
thereof.
39. A process for formulating a pharmaceutical composition,
comprising formulating together a glucose reabsorption inhibitor, a
PPAR modulator that increases insulin sensitivity, and a
pharmaceutically acceptable carrier.
40. The process of claim 39, wherein the PPAR modulator is a
PPAR.gamma. agonist.
41. The process of claim 39, wherein the glucose reabsorption
inhibitor is an SGLT inhibitor.
42. The process of claim 41, wherein the glucose reabsorption
inhibitor is an SGLT1 inhibitor.
43. The process of claim 41, wherein the glucose reabsorption
inhibitor is an SGLT2 inhibitor.
44. The process of claim 41, wherein the glucose reabsorption
inhibitor is selected from a dihydrochalcone, a propiophenone and a
derivative thereof.
45. The process of claim 44, wherein the glucose reabsorption
inhibitor is a compound of Formula (V) 19or an optical isomer,
enantiomer, diastereomer, racemate or racemic mixture thereof,
ester, prodrug form, or a pharmaceutically acceptable salt thereof,
wherein Ar is aryl or heteroaryl; OX is an optionally protected
hydroxy group; Y is hydrogen or alkyl; and Z is glucopyranosyl
wherein one or more hydroxy groups thereof may optionally be
substituted with one or more groups selected from
.alpha.-D-glucopyranosyl, alkanoyl, alkoxycarbonyl, and substituted
alkyl.
46. The process of claim 45, wherein the glucose reabsorption
inhibitor is a compound of Formula (I) 20wherein OX is a hydroxy
group which may optionally be protected, Y is a lower alkyl group,
and Z is a .beta.-D-glucopyranosyl group wherein one or more
hydroxy groups may optionally be protected.
47. The process of claim 46, wherein the glucose reabsorption
inhibitor is T-1095 or T-1095A, optionally having one or more
hydroxyl or diol protecting groups, or an optical isomer,
enantiomer, diastereomer, racemate or racemic mixture thereof,
ester, prodrug form, or a pharmaceutically acceptable salt
thereof.
48. A process for making a pharmaceutical composition comprising
mixing one or more glucose reabsorption inhibitors in combination
with a PPAR modulator for the preparation of a medicament for
treating a condition selected from IDDM, NIDDM, IGT, IFG, obesity,
nephropathy, neuropathy, retinopathy, atherosclerosis, polycystic
ovary syndrome, hypertension, ischemia, stroke, heart disease,
irritable bowel disorder, inflammation, and cataracts.
49. The process of claim 48, wherein the PPAR modulator is a
PPAR.gamma. agonist.
50. The process of claim 49, wherein the PPAR modulator is selected
from (a) rosiglitazone; (b) pioglitazone; (c) troglitazone; (d)
isaglitazone; (e) 5-BTZD; (e JT-501; (g) KRP-297; (h) Farglitazar;
(i) Risarestat; (j) YM 440; (k) NN 2344; (l) NN 622; (m)
AR-H039242; (n) Fenofibrate; and (o) bexarotene.
51. The process of claim 48, wherein the glucose reabsorption
inhibitor is an SGLT inhibitor.
52. The process of claim 51, wherein the glucose reabsorption
inhibitor is an SGLT1 inhibitor.
53. The process of claim 51, wherein the glucose reabsorption
inhibitor is an SGLT2 inhibitor.
54. The process of claim 51, wherein the glucose reabsorption
inhibitor is selected from a dihydrochalcone, a propiophenone, and
a derivative thereof.
55. The process of claim 54, wherein the glucose reabsorption
inhibitor is a compound of Formula (V) 21or an optical isomer,
enantiomer, diastereomer, racemate or racemic mixture thereof,
ester, prodrug form, or a pharmaceutically acceptable salt thereof,
wherein Ar is aryl or heteroaryl; OX is an optionally protected
hydroxy group; Y is hydrogen or alkyl; and Z is glucopyranosyl
wherein one or more hydroxy groups thereof may optionally be
substituted with one or more groups selected from
.alpha.-D-glucopyranosyl, alkanoyl, alkoxycarbonyl, and substituted
alkyl.
56. The process of claim 55, wherein the glucose reabsorption
inhibitor is a compound of Formula (I) 22wherein OX is a hydroxy
group which may optionally be protected, Y is a lower alkyl group,
and Z is a .beta.-D-glucopyranosyl group wherein one or more
hydroxy groups may optionally be protected.
57. The process of claim 56, wherein the glucose reabsorption
inhibitor is T-1095 or T-1095A, optionally having one or more
hydroxyl or diol protecting groups, or an optical isomer,
enantiomer, diastereomer, racemate or racemic mixture thereof,
ester, prodrug form, or a pharmaceutically acceptable salt
thereof.
58. A method for inhibiting the progression of a prediabetic state
in a subject to a diabetic condition, comprising (a) administering
to said subject a jointly effective amount of a glucose
reabsorption inhibitor; and (b) administering to said subject a
jointly effective amount of a PPAR modulator, said
co-administration being in any order and the combined jointly
effective amounts providing the desired inhibiting effect.
59. The method of claim 58 wherein said state is IGT or IFG.
60. The method of claim 58 wherein said inhibiting of the
progression of a prediabetic condition is prevention of the
progression of a prediabetic state to a diabetic condition.
61. The method of claim 60 wherein the PPAR modulator is a
PPAR.gamma. agonist.
62. The method of claim 61 wherein the PPAR modulator is selected
from (a) rosiglitazone; (b) pioglitazone; (c) troglitazone; (d)
isaglitazone; (e) 5-BTZD; (f) JT-501; (g) KRP-297; (h) Farglitazar;
(i) Risarestat; (j) YM 440; (k) NN 2344; (1) NN 622; (m)
AR-H039242; (n) Fenofibrate; and (o) bexarotene.
63. The method of claim 61 wherein the glucose reabsorption
inhibitor is an SGLT inhibitor.
64. The method of claim 61 wherein the glucose reabsorption
inhibitor is selected from a dihydrochalcone, a propiophenone and a
derivative thereof.
65. The method of claim 64, wherein the glucose reabsorption
inhibitor is a compound of Formula (V) 23or an optical isomer,
enantiomer, diastereomer, racemate or racemic mixture thereof,
ester, prodrug form, or a pharmaceutically acceptable salt thereof,
wherein Ar is aryl or heteroaryl; OX is an optionally protected
hydroxy group; Y is hydrogen or alkyl; and Z is glucopyranosyl
wherein one or more hydroxy groups thereof may optionally be
substituted with one or more groups selected from
.alpha.-D-glucopyranosyl, alkanoyl, alkoxycarbonyl, and substituted
alkyl.
66. The method of claim 68, wherein the glucose reabsorption
inhibitor is a compound of Formula (I) 24wherein OX is a hydroxy
group which may optionally be protected, Y is a lower alkyl group,
and Z is a .beta.-D-glucopyranosyl group wherein one or more
hydroxy groups may optionally be protected.
67. The method of claim 66, wherein the glucose reabsorption
inhibitor is T-1095 or T-1095A, optionally having one or more
hydroxyl or diol protecting groups, or an optical isomer,
enantiomer, diastereomer, racemate or racemic mixture thereof,
ester, prodrug form, or a pharmaceutically acceptable salt thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from the provisional
application U.S. Ser. No. 60/281,429 filed on Apr. 4, 2001, our
Docket Number ORT-1409, which application is incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] This invention relates to methods and compositions for the
treatment or prophylaxis of diabetes and Syndrome X.
BACKGROUND OF THE INVENTION
[0003] Diabetes is a chronic disorder affecting carbohydrate, fat
and protein metabolism in animals.
[0004] Type I diabetes mellitus, which comprises approximately 10%
of all diabetes cases, was previously referred to as
insulin-dependent diabetes mellitus ("IDDM") or juvenile-onset
diabetes. This disease is characterized by a progressive loss of
insulin secretory function by beta cells of the pancreas. This
characteristic is also shared by non-idiopathic, or "secondary",
diabetes having its origins in pancreatic disease. Type I diabetes
mellitus is associated with the following clinical signs or
symptoms: persistently elevated plasma glucose concentration or
hyperglycemia; polyuria; polydipsia and/or hyperphagia; chronic
microvascular complications such as retinopathy, nephropathy and
neuropathy; and macrovascular complications such as hyperlipidemia
and hypertension which can lead to blindness, end-stage renal
disease, limb amputation and myocardial infarction.
[0005] Type II diabetes mellitus (non-insulin-dependent diabetes
mellitus or NIDDM) is a metabolic disorder involving the
dysregulation of glucose metabolism and impaired insulin
sensitivity. Type II diabetes mellitus usually develops in
adulthood and is associated with the body's inability to utilize or
make sufficient insulin. In addition to the insulin resistance
observed in the target tissues, patients suffering from type II
diabetes mellitus have a relative insulin deficiency--that is,
patients have lower than predicted insulin levels for a given
plasma glucose concentration. Type II diabetes mellitus is
characterized by the following clinical signs or symptoms:
persistently elevated plasma glucose concentration or
hyperglycemia; polyuria; polydipsia and/or hyperphagia; chronic
microvascular complications such as retinopathy, nephropathy and
neuropathy; and macrovascular complications such as hyperlipidemia
and hypertension which can lead to blindness, end-stage renal
disease, limb amputation and myocardial infarction.
[0006] Syndrome X, also termed Insulin Resistance Syndrome (IRS),
Metabolic Syndrome, or Metabolic Syndrome X, is recognized in some
2% of diagnostic coronary catheterizations. Often disabling, it
presents symptoms or risk factors for the development of Type II
diabetes mellitus and cardiovascular disease, including impaired
glucose tolerance (IGT), impaired fasting glucose (IFG),
hyperinsulinemia, insulin resistance, dyslipidemia (e.g., high
triglycerides, low HDL), hypertension and obesity.
[0007] Therapy for IDDM patients has consistently focused on
administration of exogenous insulin, which may be derived from
various sources (e.g., human, bovine, porcine insulin). The use of
heterologous species material gives rise to formation of
anti-insulin antibodies which have activity-limiting effects and
result in progressive requirements for larger doses in order to
achieve desired hypoglycemic effects.
[0008] Typical treatment of Type II diabetes mellitus focuses on
maintaining the blood glucose level as near to normal as possible
with lifestyle modification relating to diet and exercise, and when
necessary, the treatment with anti-diabetic agents, insulin or a
combination thereof. NIDDM that cannot be controlled by dietary
management is treated with oral antidiabetic agents.
[0009] Although insulin resistance is not always treated in all
Syndrome X patients, those who exhibit a prediabetic state (e.g.,
IGT, IFG), where fasting glucose levels may be higher than normal
but not at the diabetes diagnostic criterion, is treated in some
countries (e.g., Germany) with metformin to prevent diabetes. The
anti-diabetic agents may be combined with pharmacological agents
for the treatment of the concomitant co-morbidities (e.g.,
antihypertensives for hypertension, hypolipidemic agents for
lipidemia).
[0010] First-line therapies typically include metformin and
sulfonylureas as well as thiazolidinediones. Metformin monotherapy
is a first line choice, particularly for treating type II diabetic
patients who are also obese and/or dyslipidemic. Lack of an
appropriate response to metformin is often followed by treatment
with metformin in combination with sulfonylureas,
thiazolidinediones, or insulin. Sulfonylurea monotherapy (including
all generations of drugs) is also a common first line treatment
option. Another first line therapy choice may be
thiazolidinediones. Alpha glucosidase inhibitors are also used as
first and second line therapies. Patients who do not respond
appropriately to oral anti-diabetic monotherapy, are given
combinations of the above-mentioned agents. When glycemic control
cannot be maintained with oral antidiabetics alone, insulin therapy
is used either as a monotherapy, or in combination with oral
antidiabetic agents.
[0011] One recent development in treating hyperglycemia is focused
on excretion of excessive glucose directly into urine. Specific
inhibitors of SGLTs have been shown to increase the excretion of
glucose in urine and lower blood glucose levels in rodent models of
IDDM and NIDDM.
SUMMARY OF THE INVENTION
[0012] The present invention features methods and compositions for
the treatment or prophylaxis of diabetes, Syndrome X, or associated
symptoms or complications. The invention provides a method for
treating diabetes or Syndrome X, or associated symptoms or
complications, in a subject afflicted with such a condition, said
method comprising administering one or more glucose reabsorption
inhibitors, and administering one or more PPAR modulator for the
treatment of diabetes or Syndrome X, or associated symptoms or
complications.
[0013] One aspect of the invention-features a pharmaceutical
composition comprising a glucose reabsorption inhibitor, a PPAR
modulator, and a pharmaceutically acceptable carrier. The invention
also provides a process for formulating a pharmaceutical
composition, comprising formulating together a glucose reabsorption
inhibitor, a PPAR modulator, and a pharmaceutically acceptable
carrier.
[0014] An embodiment of the invention is a method for treating
diabetes or Syndrome X, or associated symptoms or complications
thereof in a subject, said method comprising administering to said
subject a jointly effective amount of a glucose reabsorption
inhibitor and administering to said subject a jointly effective
amount, of a PPAR modulator, said combined administration providing
the desired therapeutic effect.
[0015] Another embodiment of the invention is a method for
inhibiting the onset of diabetes or Syndrome X, or associated
symptoms or complications thereof in a subject, said method
comprising administering to said subject a jointly effective dose
of a glucose reabsorption inhibitor and administering to said
subject a jointly effective amount of a PPAR modulator, said
combined administration providing the desired prophylactic
effect.
[0016] In the disclosed methods, the diabetes or Syndrome X, or
associated symptoms or complications thereof, is selected from
IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy,
retinopathy, atherosclerosis, polycystic ovary syndrome or
polycystic ovarian syndrome, hypertension, ischemia, stroke, heart
disease, irritable bowel disorder, inflammation, and cataracts.
[0017] Also included in the invention is the use of one or more
glucose reabsorption inhibitors in combination with one or more
PPAR modulators for the preparation of a medicament for treating a
condition selected from IDDM, NIDDM, IGT, IFG, obesity,
nephropathy, neuropathy, retinopathy, atherosclerosis, polycystic
ovary syndrome or polycystic ovarian syndrome, hypertension,
ischemia, stroke, heart disease, irritable bowel disorder,
inflammation, and cataracts.
[0018] Other features and advantages of the invention will become
apparent from the detailed disclosure, the examples, and the
appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 shows the effect of 11 day dosing of rosiglitazone,
with and without 100 mpk (mg/kg body weight) T-1095, on plasma
triglycerides in db/db mice. The horizontal axis represents the
amount of rosiglitazone used (with and without T-1095), while the
vertical axis represents the level of plasma triglycerides.
[0020] FIG. 2 shows the effect of 11 day dosing of rosiglitazone,
with and without T-1095 (100 mpk), on plasma glucose in db/db mice.
The horizontal axis represents the amount of rosiglitazone used
(with and without T-1095), while the vertical axis represents the
level of plasma glucose.
[0021] FIG. 3 shows effect of 11 day dosing of rosiglitazone, with
and without T-1095, on plasma insulin in db/db mice. The horizontal
axis represents the amount of rosiglitazone used (with and without
T-1095), while the vertical axis represents the level of plasma
insulin.
[0022] FIG. 4 shows effect of rosiglitazone, with and without
T-1095, on liver weight in db/db mice. The horizontal axis
represents the amount of rosiglitazone used (with and without
T-1095), while the vertical axis represents the liver weight.
[0023] FIG. 5 shows effect of 11 day dosing of rosiglitazone, with
and without T-1095, on body weight change in db/db mice. The
horizontal axis represents the amount of rosiglitazone used (with
and without T-1095), while the vertical axis represents the change
in body weight.
[0024] FIG. 6 shows effect of 11 day dosing of T-1095, with and
without rosiglitazone, on liver weight in db/db mice. The
horizontal axis represents the amount of T-1095 used (with and
without rosiglitazone), while the vertical axis represents the
liver weight.
[0025] FIG. 7 shows effect of 11 day dosing of T-1095, with and
without rosiglitazone, on body weight change in db/db mice. The
horizontal axis represents the amount of T-1095 used (with and
without rosiglitazone), while the vertical axis represents the
change in body weight.
DETAILED DESCRIPTION OF THE INVENTION
[0026] All diabetics, regardless of their genetic and environmental
backgrounds, have in common an apparent lack of insulin or
inadequate insulin function. Because transfer of glucose from the
blood into muscle and fatty tissue is insulin dependent, diabetics
lack the ability to utilize glucose adequately, which leads to
undesired accumulation of glucose in the blood (hyperglycemia).
Chronic hyperglycemia leads to decrease in insulin secretion and
contributes to increased insulin resistance, and as a result, the
blood glucose concentration is increased so that diabetes is
self-exacerbated (Diabetologia, 1985, "Hyperglycaemia as an inducer
as well as a consequence of impaired isle cell function and insulin
resistance: implications for the management of diabetes", Vol. 28,
p.119); Diabetes Cares, 1990, Vol. 13, No. 6, "Glucose Toxicity",
pp. 610-630). Therefore, by treating hyperglycemia, the
aforementioned self-exacerbating cycle is interrupted so that the
prophylaxis or treatment of diabetes is made possible.
[0027] U.S. Pat. No. 6,153,632 to R. Rieveley discloses a method
and composition stated to be for the treatment of diabetes mellitus
(Type I, Impaired Glucose Tolerance ["IGT"] and Type II), which
incorporates a therapeutic amount of one or more insulin
sensitizers along with one or more of an orally ingested insulin,
an injected insulin, a sulfonylurea, a biguanide or an
alpha-glucosidase inhibitor for the treatment of diabetes
mellitus.
[0028] According to one aspect, the invention features the
combination of a PPAR modulator, preferably a PPAR .delta. agonist,
and an SGLT inhibitor, preferably an SGLT 2 inhibitor or a
selective SGLT 2 inhibitor.
[0029] A. Terms
[0030] Some terms are defined below and by their usage throughout
this disclosure.
[0031] Unless otherwise noted, "alkyl" and "alkoxy" as used herein,
whether used alone or as part of a substituent group, include
straight, cyclic, and branched-chain alkyl having 1 to 8 carbon
atoms, or any number within this range. For example, alkyl radicals
include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, t-butyl, 2-butenyl, 2-butynyl, n-pentyl,
3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl,
2-hexyl and 2-methylpentyl. Alkoxy radicals are oxygen ethers
formed from the previously described straight or branched chain
alkyl groups. The alkyl and alkoxy group may be independently
substituted with one to five, preferably one to three groups
selected from halogen (F, Cl, Br, I), oxo, OH, amino, carboxyl, and
alkoxy. The alkyl and alkoxy group may also be independently linked
to one or more PEG radicals (polyethylene glycol).
[0032] The term "acyl" as used herein, whether used alone or as
part of a substituent group, means an organic radical having 2 to 6
carbon atoms (branched or straight chain) derived from an organic
acid by removal of the hydroxyl group. The acyl group is, for
example, an optionally substituted C.sub.2-20 alkanoyl group, a
lower alkoxy-lower alkanoyl group, an optionally substituted lower
alkoxycarbonyl group, an optionally substituted benzoyl group, an
optionally substituted phenoxycarbonyl group, or an amino acid
residue which is obtained by removing a hydroxy group from the
carboxyl group of a corresponding amino acid (wherein amino groups
and/or carboxyl groups in said residue may be protected by a
conventional protecting group). The term "Ac" as used herein,
whether used alone or as part of a substituent group, means
acetyl.
[0033] "Aryl" is a carbocyclic aromatic radical including, but not
limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic
aromatic radical may be substituted by independent replacement of 1
to 3 of the hydrogen atoms thereon with halogen, OH, CN, mercapto,
nitro, amino, cyano, optionally substituted C.sub.1-C.sub.8-alkyl,
optionally substituted alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkyl-amino, di(C.sub.1-C.sub.8-alkyl)amino, formyl,
carboxyl, alkoxycarbonyl, alkoxycarbonyloxy, alkanoyloxy, phenyl,
carbamoyl, carboxamide, di-lower alkylcarbamoyloxy,
phenoxycarbonyloxy group, lower alkylenedioxy, benzoyloxy,
alkyl-CO--O--, alkyl-O--CO--, --CONH.sub.2, alkyl-O--CO--O--, or
alkyl-CO--NH--. Illustrative aryl radicals include, for example,
phenyl, naphthyl, biphenyl, indene 1
[0034] indane 2
[0035] fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl,
carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl,
hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl,
methoxyethylphenyl, acetamidophenyl, tolyl, xylyl,
dimethylcarbamylphenyl and the like. "Ph" or "PH" denotes
phenyl.
[0036] The term "heteroaryl" as used herein represents a stable
five or six-membered monocyclic or bicyclic aromatic ring system
which consists of carbon atoms and from one to three heteroatoms
selected from N, O and S. The heteroaryl group may be attached at
any heteroatom or carbon atom, which results in the creation of a
stable structure. Examples of heteroaryl groups include, but are
not limited to benzofuranyl, benzothiophenyl, pyridinyl, pyrazinyl,
pyridazinyl, pyrimidinyl, thiophenyl, furanyl, imidazolyl,
isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl,
triazolyl, benzimidazolyl, benzofuranyl, benzothienyl,
benzisoxazolyl, benzoxazolyl, benzopyrazolyl, indolyl,
benzothiazolyl, benzothiadiazolyl, benzotriazolyl or quinolinyl.
Preferred heteroaryl groups include pyridinyl, thiophenyl, furanyl,
and quinolinyl. When the heteroaryl group is substituted, the
heteroaryl group may have one to three substituents which are
independently selected from halogen, OH, CN, mercapto, nitro,
amino, cyano, optionally substituted C.sub.1-C.sub.8-alkyl,
optionally substituted alkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkyl-amino, di(C.sub.1-C.sub.8-alkyl)amino, formyl,
carboxyl, alkoxycarbonyl, alkoxycarbonyloxy, alkanoyloxy, phenyl,
carbamoyl, carboxamide, di-lower alkylcarbamoyloxy,
phenoxycarbonyloxy group, lower alkylenedioxy, benzoyloxy,
alkyl-CO--O--, alkyl-O--CO--, --CONH.sub.2, alkyl-O--CO--O--, or
alkyl-CO--NH--.
[0037] The terms "heterocycle," "heterocyclic," and "heterocyclyl"
refer to an optionally substituted, fully or partially saturated
cyclic group which is, for example, a 4- to 7-membered monocyclic,
7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring
system, which has at least one heteroatom in at least one carbon
atom containing ring. Each ring of the heterocyclic group
containing a heteroatom may have 1, 2, or 3 heteroatoms selected
from nitrogen atoms, oxygen atoms, and sulfur atoms, where the
nitrogen and sulfur heteroatoms may also optionally be oxidized.
The nitrogen atoms may optionally be quaternized. The heterocyclic
group may be attached at any heteroatom or carbon atom.
[0038] Exemplary monocyclic heterocyclic groups include
pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl;
oxazolyl; oxazolidinyl; isoxazolinyl; thiazolidinyl;
isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl;
2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl;
4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl;
tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl;
thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane;
dioxanyl; thietanyl; thiiranyl; and the like. Exemplary bicyclic
heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl;
dihydroisoindolyl; dihydroquinazolinyl (such as
3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl;
dihydrobenzothienyl; dihydrobenzothiopyranyl;
dihydrobenzothiopyranyl sulfone; dihydrobenzopyranyl; indolinyl;
isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and
the like. When the heteroaryl group is substituted, the
heterocyclyl may be independently substituted with one to five,
preferably one to three groups selected from halogen, OH, CN,
mercapto, nitro, amino, cyano, optionally substituted
C.sub.1-C.sub.8-alkyl, optionally substituted alkoxy, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkyl-amino,
di(Cl-C.sub.8-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,
alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide,
di-lower alkylcarbamoyloxy, phenoxycarbonyloxy group, lower
alkylenedioxy, benzoyloxy, alkyl-CO--O--, alkyl-O--CO--,
--CONH.sub.2, alkyl-O--CO--O--, or alkyl-CO--NH--.
[0039] The term "composition" is intended to encompass a product
comprising the specified ingredients in the specified amounts, as
well as any product which results, directly or indirectly, from
combinations of the specified ingredients in the specified
amounts.
[0040] The term "combined administration" includes
co-administration wherein: 1) the two or more agents are
administered to a subject at substantially similar times; and 2)
the two or more agents are administered to a subject at different
times, at independent intervals which may or may not overlap or
coincide.
[0041] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who is the object of
treatment, observation or experiment.
[0042] The term "PPAR modulator," as used herein, refers to
peroxisome proliferator-activated receptor agonists, partial
agonists, and antagonists. The modulator may, selectively or
preferentially, affect PPAR alpha, PPAR gamma, or both receptors.
Preferably the modulator increases insulin sensitivity. According
to one aspect, the modulator is a PPAR gamma agonist.
[0043] Diabetes, Syndrome X, and associated symptoms or
complications include such conditions as IDDM, NIDDM, IGT, IFG,
obesity, nephropathy, neuropathy, retinopathy, atherosclerosis,
polycystic ovary syndrome, polycystic ovarian syndrome,
hypertension, ischemia, stroke, heart disease, irritable bowel
disorder, inflammation, and cataracts. Examples of a prediabetic
state include IGT and IFG.
[0044] Methods are known in the art for determining effective doses
for therapeutic and prophylactic purposes for the disclosed
pharmaceutical compositions or the disclosed drug combinations,
whether or not formulated in the same composition. For therapeutic
purposes, the term "jointly effective amount" as used herein, means
that amount of each active compound or pharmaceutical agent, alone
or in combination, that elicits the biological or medicinal
response in a tissue system, animal or human that is being sought
by a researcher, veterinarian, medical doctor or other clinician,
which includes alleviation of the symptoms of the disease or
disorder being treated. For prophylactic purposes (i.e., inhibiting
the onset or progression of a disorder), the term "jointly
effective amount" refers to that amount of each active compound or
pharmaceutical agent, alone or in combination, that inhibits in a
subject the onset or progression of a disorder as being sought by a
researcher, veterinarian, medical doctor or other clinician, the
delaying of which disorder is mediated by the modulation of glucose
reabsorption activity or PPAR activity or both. Thus, the present
invention provides combinations of two or more drugs wherein, for
example, (a) each drug is administered in an independently
therapeutically or prophylactically effective amount; (b) at least
one drug in the combination is administered in an amount that is
sub-therapeutic or sub-prophylactic if administered alone, but is
therapeutic or prophylactic when administered in combination with
the second or additional drugs according to the invention; or (c)
both drugs are administered in an amount that is sub-therapeutic or
sub-prophylactic if administered alone, but are therapeutic or
prophylactic when administered together.
[0045] The term "protecting groups" refer to those moieties known
in the art that are used to mask functional groups; protecting
groups may be removed during subsequent synthetic transformations
or by metabolic or other in vivo administration conditions. During
any of the processes for preparation of the compounds of the
present invention, it may be necessary and/or desirable to protect
sensitive or reactive groups on any of the molecules concerned.
This may be achieved by means of conventional protecting groups,
such as those described in Protective Groups in Organic Chemistry,
ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P.
G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition,
John Wiley & Sons, 1999. The protecting groups may be removed
at a convenient subsequent stage using methods known in the art.
Examples of hydroxyl and diol protecting groups are provided
below.
[0046] Protection for the hydroxyl group includes methyl ethers,
substituted methyl ethers, substituted ethyl ethers, substitute
benzyl ethers, and silyl ethers.
[0047] Substituted Methyl Ethers
[0048] Examples of substituted methyl ethers include
methyoxymethyl, methylthiomethyl, t-butylthiomethyl,
(phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,
p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl,
t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,
2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,
tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,
1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,
4-methoxytetrahydrothiop- yranyl, 4-methoxytetrahydrothiopyranyl
S,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,
1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and
2,3,3a,4,5,6,7,7a-octahydro--
7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.
[0049] Substituted Ethyl Ethers
[0050] Examples of substituted ethyl ethers include 1-ethoxyethyl,
1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyeth- yl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, benzyl, and polyethyleneglycol
ethers.
[0051] Substituted Benzyl Ethers
[0052] Examples of substituted benzyl ethers include
p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,
p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-
and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,
p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
.alpha.-naphthyldiphenylmethyl, p-methoxyphenyidiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxy)phenyldiphenylmethyl,
4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4"-tris(levulinoyloxyphenyl)methyl,
4,4',4"-tris(benzoyloxyphenyl)me- thyl,
3-(/midazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,
1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
[0053] Silyl Ethers
[0054] Examples of silyl ethers include trimethylsilyl,
triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl,
diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl,
t-butyidiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl,
triphenylsilyl, diphenylmethylsilyl, and
t-butylmethoxyphenylsilyl.
[0055] Esters
[0056] In addition to ethers, a hydroxyl group may be protected as
an ester. Examples of esters include formate, benzoylformate,
acetate, chloroacetate, dichloroacetate, trichloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate,
3-phenylpropionate, 4-oxopentanoate(levulinate),
4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate,
4-methoxycrotonate, benzoate, p-phenylbenzoate,
2,4,6-trimethylbenzoate(mesitoate), and polyethyleneglycol
esters.
[0057] Carbonates
[0058] Examples of carbonates include methyl, 9-fluorenylmethyl,
ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,
2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl,
vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl
thiocarbonate, 4-ethoxy-1-naphthyl, methyl dithiocarbonate, and
polyethyleneglycol carbonates.
[0059] Assisted Cleavage
[0060] Examples of assisted cleavage include 2-iodobenzoate,
4-azidobutyrate, 4-nitro-4-methylpentanoate,
o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate,
2-(methylthiomethoxy)ethyl carbonate,
4-(methylthiomethoxy)butyrate, and
2-(methylthiomethoxymethyl)benzoate.
[0061] Miscellaneous Esters
[0062] Examples of miscellaneous esters include
2,6-dichloro-4-methylpheno- xyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(
1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),
o-(methoxycarbonyl)benzoate, p-P-benzoate, .alpha.-naphthoate,
nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate,
N-phenylcarbamate, borate, dimethylphosphinothioyl, and
2,4-dinitrophenylsulfenate
[0063] Sulfonates
[0064] Examples of sulfonates include sulfate;
methanesulfonate(mesylate), benzylsulfonate, and tosylate.
[0065] Protection for 1,2- and 1,3-Diols
[0066] Cyclic Acetals and Ketals
[0067] Examples of cyclic acetals and ketals include methylene,
ethylidene, 1-t-butylethylidene, 1-phenylethylidene,
(4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene,
acetonide(isopropylidene), cyclopentylidene, cyclohexylidene,
cycloheptylidene, benzylidene, p-methoxybenzylidene,
2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and
2-nitrobenzylidene.
[0068] Cyclic Ortho Esters
[0069] Examples of cyclic ortho esters include methoxymethylene,
ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,
1-ethoxyethylidine, 1,2-dimethoxyethylidene,
.alpha.-methoxybenzylidene, 1-(N,N-dimethylamino)ethylidene
derivative, .alpha.-(N,N-dimethylamino)be- nzylidene derivative,
and 2-oxacyclopentylidene.
[0070] Silyl Derivatives
[0071] Examples of silyl derivatives include di-t-butylsilylene
group, and 1,3-(1,1, 3,3-tetraisopropyidisiloxanylidene)
derivative.
[0072] B. Glucose Reabsorption Inhibitors
[0073] One method of treating hyperglycemia is to excrete excessive
glucose directly into urine so that the blood glucose concentration
is normalized. For example, sodium-glucose cotransporters (SGLTs),
primarily found in chorionic membrane of the intestine and the
kidney, are a family of proteins actively involved in the normal
process of glucose absorption. Among them, SGLT1 is present in
intestinal and renal epithelial cells (Lee et al., 1994), whereas
SGLT2 is found in the epithelium of the kidney (You et al., 1995,
MacKenzie et al., 1994). Glucose absorption in the intestine is
primarily mediated by SGLT1, a high-affinity low-capacity
transporter with a Na.sup.+:glucose transport ratio of 2:1. SGLT2,
also known as SAAT1, transports Na.sup.+ and glucose at a ratio of
1:1 and functions as a low-affinity high-capacity transporter.
These SGLTs are characterized in Table 1:
1TABLE 1 Preferred K.sub.m* TmG** K.sub.m* ISOFORM TISSUE
Stoichiometry Substrate in vitro in vitro in vivo SGLT1 Sm.
Intestine 2:1 D-glucose 0.1 nd nd D-galactose Kidney (S1, S3) 2:1
D-glucose 0.39 7.9 0.3 D-galactose SGLT2 Kidney (S3) 1:1 D-glucose
1.64 83 6 (SAAT1) *(mM) for D-glucose **Maximal transport rate
pmol/min/mm
[0074] Renal reabsorption of glucose is mediated by SGLT1 and SGLT2
(Silverman et al., 1992; Deetjen et al., 1995). Plasma glucose is
filtered in the glomerulus and is transepithelially reabsorbed in
the proximal tubules. SGLT1 and SGLT2 are located in the apical
plasma membranes of the epithelium and derive their energy from the
inward sodium gradient created by the Na.sup.+/K.sup.+ ATPase pumps
located on the basolateral membrane. Once reabsorbed, the elevated
cytosolic glucose is then transported to the interstitial space by
facilitated glucose transports (GLUT1 and GLUT2). Therefore,
inhibition of SGLTs reduces plasma glucose through suppression of
glucose reabsorption in the kidney. A therapeutically or
prophylactically effective amount of an SGLT inhibitor, such as
that sufficient to increase urine glucose excretion, or to decrease
plasma glucose, in a subject by a desired amount per day, can be
readily determined using methods established in the art. Recently,
it has been found that phlorizin, a natural glycoside present in
barks and stems of Rosaceae (e.g., apple, pear, etc.), inhibits
Na.sup.+-glucose co-transporters located in chorionic membrane of
the intestine and the kidney. By inhibiting Na.sup.+-glucose
co-transporter activity, phlorizin inhibits the renal tubular
glucose reabsorption and promotes the excretion of glucose so that
the glucose level in a plasma is controlled at a normal level for a
long time via subcutaneous daily administration (Journal of
Clinical Investigation, 1987, Vol. 79, p. 1510).
[0075] JP 8-347406, filed Dec. 26,1996, and U.S. Pat. Nos.
5,767,094, 5,830,873, and 6,048,842 (all to Tanabe Seiyaku Co.,
Ltd.) disclose propiophenone derivatives having hypoglycemic
activity by inhibiting sodium-glucose cotransporter activity.
JP2762903, JP2795162, JP2906978, and U.S. Pat. Nos. 5,424,406 and
5,731,292, all to Tanabe Seiyaku Co., Ltd., disclose
dihydrochalcone derivatives having hypoglycemic activity based on
the urine glucose increasing activity thereof.
[0076] In particular, U.S. Pat. No. 6048842 discloses a compound,
or a pharmaceutically acceptable salt thereof, useful for treatment
and/or prophylaxis of diabetes, which has the structure of Formula
I: 3
[0077] wherein OX is a hydroxy group which may optionally be
protected, Y is a lower alkyl group, and Z is a
.beta.-D-glucopyranosyl group wherein one or more hydroxy groups
may optionally be protected.
[0078] Where OX of Formula I is a protected hydroxy group, the
protecting group may be any protecting group which can be a
protecting group for a phenolic hydroxy group, for example, a lower
alkoxy-lower alkyl group such as, methoxymethyl group; an allyl
group; and an acyl group such as a lower alkanoyl group, a lower
alkoxy-lower alkanoyl group, a lower alkoxycarbonyl group, a lower
alkoxy-lower alkoxycarbonyl group, an arylcarbonyl group (e.g.,
benzoyl group). Among these protecting groups, preferable ones are
an acyl group such as a lower alkanoyl group, a lower alkoxy-lower
alkanoyl group, a lower alkoxycarbonyl group, a lower alkoxy-lower
alkoxycarbonyl group, and especially preferable ones are a lower
alkanoyl group, and a lower alkoxycarbonyl group.
[0079] Where Z of Formula I is a .beta.-D-glucopyranosyl group
wherein one or more hydroxy groups are protected, the protecting
group may be any conventional protecting groups for hydroxy group
which can easily be removed by a conventional method such as
acid-treatment, hydrolysis, reduction, etc. The
.beta.-D-glucopyranosyl group wherein one or more hydroxy groups
are protected by the above-mentioned protecting groups may be
selected from (i) a .beta.-D-glucopyranosyl group wherein one or
more hydroxy groups are acylated, (ii) a .beta.-D-glucopyranosyl
group wherein two hydroxy groups combine to form a 1-lower
alkoxy-lower alkylidenedioxy group, a benzylidenedioxy group, a
phosphinicodioxy group, or a carbonyldioxy group together with the
protecting groups thereof, and (iii) a .beta.-D-glucopyranosyl
group wherein one or two hydroxy groups are acylated, and the other
two hydroxy groups combine to form a 1-lower alkoxy-lower
alkylidenedioxy group, a benzylidenedioxy group, a phosphinicodioxy
group, or a carbonyldioxy group together with the protecting groups
thereof. However, the protecting groups for the hydroxy groups of
the .beta.-D-glucopyranosyl group should not be construed to be
limited to the above protecting groups, and may be any ones which
can be removed after administering the present compound into the
living body and give the hydroxy groups of the
.beta.-D-glucopyranosyl group, or can promote the absorption of the
desired compound into the living body, or make it more easy to
administer the present compound into the living body, or can
increase the solubility in oil and/or water of the present
compound.
[0080] When the hydroxy group of the .beta.-D-glucopyranosyl group
is acylated, the acyl group is preferably a lower alkanoyl group, a
lower alkoxy-lower alkanoyl group, a lower alkoxycarbonyl group, a
lower alkoxy-lower alkoxycarbonyl group, or an arylcarbonyl group
(e.g., benzoyl group), or an amino acid residue which is obtained
by removing a hydroxy group from the carboxyl group of a
corresponding amino acid (wherein amino groups and/or carboxyl
groups and/or hydroxy groups in said residue may be protected by a
conventional protecting group). The amino acid residue includes a
group which is obtained by removing a hydroxy group from the
carboxyl group of a natural amino acid such as aspartic acid,
glutamic acid, glutamine, serine, sarcosine, proline,
phenylalanine, leucine, isoleucine, glycine, tryptophan, cysteine,
histidine, tyrosine, or valine, or an antipode thereof, or a
racemic compound thereof.
[0081] When Z is a .beta.-D-glucopyranosyl group wherein two
hydroxy groups of the .beta.-D-glucopyranosyl group combine to form
a 1-lower alkoxy-lower alkylidenedioxy group, a benzylidenedioxy
group, a phosphinicodioxy group, or a carbonyldioxy group together
with the protecting groups thereof, said .beta.-D-glucopyranosyl
group may be a .beta.-D-glucopyranosyl group wherein the 4- and
6-hydroxy groups of the .beta.-D-glucopyranosyl group combine to
form a 1-lower alkoxy-lower alkylidenedioxy group, a
benzylidenedioxy group, a phosphinicodioxy group, or a
carbonyldioxy group together with the protecting groups thereof.
Such .beta.-D-glucopyranosyl group has one of the following two
formulae: 4
[0082] wherein one of R.sup.7 and R.sup.8 is a hydrogen atom or a
lower alkyl group, and the other is a lower alkoxy group, or one of
R.sup.7 and R.sup.8 is a hydrogen atom, and the other is a phenyl
group, or R.sup.7 and R.sup.8 combine to form an oxo group.
[0083] When two hydroxy groups of the .beta.-D-glucopyranosyl group
combine to form a 1-lower alkoxy-lower alkylidenedioxy group
together with the protecting groups thereof, the 1-lower
alkoxy-lower alkylidenedioxy group is preferably a 1-lower
alkoxyethylidenedioxy group, and more preferably a
1-methoxyethylidenedioxy group or a 1-ethoxyethylidenedioxy
group.
[0084] Y of Formula I is preferably an alkyl group having 1 to 4
carbon atoms, more preferably a methyl group or an ethyl group.
[0085] The propiophenone derivatives of Formula I or a
pharmaceutically acceptable salt thereof include an intramolecular
salt thereof, or a solvate or hydrate thereof, as well.
[0086] In addition, U.S. Pat. No. 5,830,873 discloses a compound,
or a pharmaceutically acceptable salt thereof, useful for treatment
and/or prophylaxis of diabetes which has the structure of Formula
II: 5
[0087] wherein X is an oxygen atom, a sulfur atom or a methylene
group, OY is a protected or unprotected hydroxy group, Z is a
.beta.-D-glucopyranosyl group or
4-O-(.alpha.-D-glucopyranosyl)-.beta.-D-- glucopyranosyl group
wherein one or more hydroxy groups of these groups may optionally
be acylated, and the dotted line means the presence or absence of a
double bond.
[0088] Furthermore, U.S. Pat. No. 5,767,094 discloses a compound,
or a pharmaceutically acceptable salt thereof, useful for treatment
and/or prophylaxis of diabetes which has the structure of Formula
III: 6
[0089] wherein R' is a lower alkanoyl group, and R" is a hydrogen
atom, or R' is a hydrogen atom, and R" is a lower alkoxycarbonyl
group.
[0090] Furthermore, U.S. Pat. Nos. 5,424,406 and 5,731,292 disclose
a compound, or a pharmaceutically acceptable salt thereof, useful
for treatment and/or prophylaxis of diabetes which has the
structure of Formula IV: 7
[0091] wherein Ar is an aryl group, R.sup.1 is hydrogen atom or an
acyl group, R.sup.2 is hydrogen atom, an acyl group or
.alpha.-D-glucopyranosy- l group, or R.sup.1 and R.sup.2 may
combine together to form a substituted methylene group, R.sup.3 and
R.sup.4 are each hydrogen atom or an acyl group, and OR.sup.5 is a
protected or unprotected hydroxy group or a lower alkoxy group.
[0092] Other SGLT inhibitors include alkyl- and phenyl-glucosides,
1-5-isoquinolinesulfonyl)-2-methylpiperazine-HCl (indirectly via
protein kinase C), p-chloromercuribenzoate (PCMB),
N,N'-dicyclohexylcarbodiimide (DCCD), copper and cadmium ions, and
trivalent lanthanides.
[0093] The compounds of formulae I, II, III, IV, and V may be
prepared by the processes disclosed in U.S. Pat. Nos. 5,424,406,
5,731,292, 5,767,094, 5,830,873, and 6,048,842.
[0094] C. PPAR Modulators
[0095] Thiazolidinediones (TZD's) and non-thiazolidinediones
insulin sensitizers decrease peripheral insulin resistance by
enhancing the effects of insulin at target organs and tissues.
These drugs are known to bind and activate the nuclear receptor
peroxisome proliferator-activated receptor-gamma (PPAR.gamma.)
which increases transcription of specific insulin-responsive genes.
Examples of PPAR-gamma agonists are thiazolidinediones such as:
[0096] (1) rosiglitazone
(2,4-thiazolidinedione,5-((4-(2-(methyl-2-pyridin-
ylamino)ethoxy)phenyl)methyl)-, (Z)-2-butenedioate (1:1) or
5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidined-
ione, known as AVANDIA; also known as BRL 49653, BRL 49653C, BRL
49653c, SB 210232, or rosiglitazone maleate);
[0097] (2) pioglitazone(2,4-thiazolidinedione,
5-((4-(2-(5-ethyl-2-pyridin- yl)ethoxy)phenyl)methyl)-,
monohydrochloride, (+-)- or
5-((4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl)methy)-2,4-thiazolidinedione,
known as ACTOS, ZACTOS, or GLUSTIN; also known as AD 4833, U 72107,
U 72107A, U 72107E, pioglitazone hydrochloride (USAN));
[0098] (3) troglitazone
(5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-
-2H-1-benzopyran-2-yl)methoxy)phenyl)methyl)-2,4-thiazolidinedione,
known as NOSCAL, REZULIN, ROMOZIN, or PRELAY; also known as CI 991,
CS 045, GR 92132, GR 92132X);
[0099] (4) isaglitazone
((+)-5-[[6-[(2-fluorophenyl)methoxy]-2-naphthaleny-
l]methyl]-2,4-thiazolidinedione or
5-((6-((2-fluorophenyl)methoxy)-2-napht-
halenyl)methyl)-2,4-thiazolidinedione or
5-(6-(2-fluorobenzyloxy)naphthale-
n-2-ylmethyl)thiazolidine-2,4-dione, also known as MCC-555 or
netoglitazone or neoglitazone); and
[0100] (5) 5-BTZD.
[0101] Additionally, the non-thiazolidinediones that act as
insulin-sensitizing agents include, but are not limited to:
[0102] (1) JT-501 (JTT 501, PNU-1827, PNU-716-MET-0096, or PNU
182716: isoxazolidine-3,5-dione,
4-((4-(2-phenyl-5-methyl)-1,3-oxazolyl)ethylphen-
yl-4)methyl-);
[0103] (2) KRP-297
(5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-(tr-
ifluoromethyl)benzyl)benzamide or
5-((2,4-dioxo-5-thiazolidinyl)methyl)-2--
methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide); and
[0104] (3) Farglitazar (L-tyrosine,
N-(2-benzoylphenyl)-o-(2-(5-methyl-2-p- henyl-4-oxazolyl)ethyl)- or
N-(2-benzoylphenyl)-O-(2-(5-methyl-2-phenyl-4--
oxazolyl)ethyl)-L-tyrosine, or GW2570 or GI-262570).
[0105] Other agents have also been shown to have PPAR modulator
activity such as PPAR.gamma., SPPAR.gamma., and/or
PPAR.alpha./.delta. agonist activity. Examples are listed
below:
[0106] (1) AD 5075;
[0107] (2) R 119702
((+-)-5-(4-(5-methoxy-1H-benzimidazol-2-ylmethoxy)benz-
yl)thiazolin-2,4-dionehydrochloride, or CI 1037 or CS 011);
[0108] (3) CLX-0940 (peroxisome proliferator-activated receptor
alpha-agonist/peroxisome proliferator-activated receptor gamma
agonist);
[0109] (4) LR-90
(2,5,5-tris(4-chlorophenyl)-1,3-dioxane-2-carboxylic acid, PPAR
.alpha./.gamma. agonist);
[0110] (5) Tularik (PPAR .gamma. agonist);
[0111] (6) CLX-0921 (PPAR .gamma. agonist);
[0112] (7) CGP-52608 (PPAR agonist);
[0113] (8) GW-409890 (PPAR agonist);
[0114] (9) GW-7845 (PPAR agonist);
[0115] (10) L-764406 (PPAR agonist);
[0116] (11) LG-101280 (PPAR agonist);
[0117] (12) LM-4156 (PPAR agonist);
[0118] (13) Risarestat (CT-112);
[0119] (14) YM 440 (PPAR agonist);
[0120] (15) AR-H049020 (PPAR agonist);
[0121] (16) GW 0072
(4-(4-((2S,5S)-5-(2-(bis(phenylmethyl)amino)-2-oxoethy-
l)-2-heptyl-4-oxo-3-thiazo lidinyl)butyl)benzoic acid);
[0122] (17) GW 409544 (GW-544 or GW-409544);
[0123] (18) NN 2344 (DRF 2593);
[0124] (19) NN 622 (DRF 2725);
[0125] (20) AR-H039242 (AZ-242);
[0126] (21) GW 9820 (fibrate);
[0127] (22) GW 1929
(N-(2-benzoylphenyl)-O-(2-(methyl-2-pyridinylamino)eth-
yl)-L-tyrosine, known as GW 2331, PPAR .alpha./.gamma.
agonist);
[0128] (23) SB 219994
((S)-4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha-(-
2,2,2-trifluoroethoxy)benzen epropanoic acid or
3-(4-(2-(N-(2-benzoxazolyl-
)-N-methylamino)ethoxy)phenyl)-2(S)-(2,2,2-trifluoroethoxy)propionic
acid or benzenepropanoic
acid,4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha-(2-
,2,2-trifluoroethoxy)-, (alpha S)-, PPAR .alpha./.gamma.
agonist);
[0129] (24) L-796449 (PPAR .alpha./.gamma. agonist);
[0130] (25) Fenofibrate (propanoic acid,
2-[4-(4-chlorobenzoyl)phenoxy]-2-- methyl-, 1-methylethyl ester,
known as TRICOR, LIPCOR, LIPANTIL, LIPIDIL MICRO PPAR .alpha.
agonist);
[0131] (26) GW-9578 (PPAR .alpha. agonist);
[0132] (27) GW-2433 (PPAR .alpha./.gamma. agonist);
[0133] (28) GW-0207 (PPAR .gamma. agonist);
[0134] (29) LG-100641 (PPAR .gamma. agonist);
[0135] (30) LY-300512 (PPAR .gamma. agonist);
[0136] (31) NID525-209 (NID-525);
[0137] (32) VDO-52 (VDO-52);
[0138] (33) LG 100754 (peroxisome proliferator-activated receptor
agonist);
[0139] (34) LY-510929 (peroxisome proliferator-activated receptor
agonist);
[0140] (35) bexarotene
(4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-n- aphthalenyl)
ethenyl) benzoic acid, known as TARGRETIN, TARGRETYN, TARGREXIN;
also known as LGD 1069, LG 100069, LG 1069, LDG 1069, LG 69, RO
264455); and
[0141] (36) GW-1536 (PPAR .alpha./.gamma. agonist).
[0142] Preferred examples of PPAR modulators include
thiazolidinediones and non-thiazolidinediones insulin sensitizers,
which decrease peripheral insulin resistance by enhancing the
effects of insulin at target organs and tissues. These drugs
primarily bind and activate the nuclear receptor peroxisome
proliferator-activated receptor-gamma (PPAR.gamma.) which increases
transcription of specific insulin-responsive genes. Examples of
PPAR-gamma agonists are the thiazolidinediones such as
rosiglitazone (Avandia or BRL-49653), pioglitazone (Actos),
troglitazone (Rezulin), and isaglitazone (known as MCC-555; it may
also be referred to as neoglitazone). Additionally, the
non-thiazolidinediones that act as insulin sensitizing drugs
include, but are not limited to, JT-501, KRP-297, and
GW2570/GI-262570.
[0143] D. Additional Antidiabetic Agents
[0144] Antidiabetic agents that can be used as a third antidiabetic
agent according to the invention include, but are not limited
to:
[0145] (A) Retinoid-X receptor (RXR) modulators, also insulin
sensitizing drugs, which include, but are not limited to:
[0146] (1) bexarotene
(4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-na-
phthalenyl)ethenyl)benzoic acid, known as TARGRETIN, TARGRETYN,
TARGREXIN; also known as LGD 1069, LG 100069, LG 1069, LDG 1069, LG
69, RO 264455);
[0147] (2) 9-cis-retinoic acid;
[0148] (3) AGN-4326 (also known as ALRT-4204, AGN-4204, ALRT-326,
ALRT-324, or LGD 1324);
[0149] (4) LGD 1324 (ALRT 324);
[0150] (5) LG 100754;
[0151] (6) LY-510929;
[0152] (7) LGD 1268
(6-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphth-7--
ylcycloprop-1-yl)nicotinic acid, known as ALRT 268 or LG 100268);
and
[0153] (8) LG 100264.
[0154] (B) Other insulin sensitizing agents include, but are not
limited to:
[0155] (1) INS-1 (D-chiro inositol or
D-1,2,3,4,5,6-hexahydroxycyclohexane- );
[0156] (2) protein tyrosine phosphatase 1 B (PTP-1B)
inhibitors;
[0157] (3) glycogen synthase kinase-3 (GSK3) inhibitors;
[0158] (4) beta 3 adrenoceptor agonists such as ZD 2079
((R)-N-(2-(4-(carboxymethyl)phenoxy)ethyl)-N-(2-hydroxy-2-phenethyl)ammon-
ium chloride, also known as ICI D 2079) or AZ 40140;
[0159] (5) glycogen phosphorylase inhibitors;
[0160] (6) fructose-1,6-bisphosphatase inhibitors;
[0161] (7) chromic picolinate, vanadyl sulfate (vanadium
oxysulfate);
[0162] (8) KP 102 (organo-vanadium compound);
[0163] (9) chromic polynicotinate;
[0164] (10) potassium channel agonist NN 414;
[0165] (11) YM 268 (5,5'-methylene-bis
(1,4-phenylene)bismethylenebis(thia- zolidine-2,4-dione);
[0166] (12) TS971;
[0167] (13) T 174
((+-)-5-(2,4-dioxothiazolidin-5-ylmethyl)-2-(2-naphthylm-
ethyl)benzoxazole);
[0168] (14) SDZ PGU 693
((+)-trans-2(S-((4-chlorophenoxy)methyl)-7alpha-(3-
,4-dichlorophenyl)tetrahydropyrrolo(2,1-b)oxazol-5(6H)-one);
[0169] (15) S 15261
((-)-4-(2-((9H-fluoren-9-ylacetyl)amino)ethyl)benzoic acid
2-((2-methoxy-2-(3-(trifluoromethyl)phenyl)ethyl)amino)ethyl
ester);
[0170] (16) AZM 134 (Alizyme);
[0171] (17) ARIAD;
[0172] (18) R 102380;
[0173] (19) PNU 140975 (1-(hydrazinoiminomethyl)hydrazino)acetic
acid;
[0174] (20) PNU 106817 (2-(hydrazinoiminomethyl)hydrazino)acetic
acid;
[0175] (21) NC 2100
(5-((7-(phenylmethoxy)-3-quinolinyl)methyl)-2,4-thiazo-
lidinedione;
[0176] (22) MXC 3255;
[0177] (23) MBX 102;
[0178] (24) ALT 4037;
[0179] (25) AM 454;
[0180] (26) JTP 20993
(2-(4-(2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)benzyl- )-malonic
acid dimethyl diester);
[0181] (27) Dexlipotam (5(R)-(1,2-dithiolan-3-yl)pentanoic acid,
also known as (R)-alpha lipoic acid or (R)-thioctic acid);
[0182] (28) BM 170744 (2,2-Dichloro-12-(p-chlorophenyl)dodecanoic
acid);
[0183] (29) BM 152054
(5-(4-(2-(5-methyl-2-(2-thienyl)oxazol-4-yl)ethoxy)b-
enzothien-7-ylmethyl) thiazolidine-2,4-dione);
[0184] (30) BM 131258
(5-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzot-
hien-7-ylmethyl)thiazolidine-2, 4-dione);
[0185] (31) CRE 16336 (EML 16336);
[0186] (32) HQL 975
(3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)--
2(S)-(propylamino)propionic acid);
[0187] (33) DRF 2189
(5-((4-(2-(1-Indolyl)ethoxy)phenyl)methyl)thiazolidin-
e-2,4-dione);
[0188] (34) DRF 554158;
[0189] (35) DRF-NPCC;
[0190] (36) CLX 0100, CLX 0101, CLX 0900, or CLX 0901;
[0191] (37) IkappaB Kinase (IKK B) Inhibitors
[0192] (38) mitogen-activated protein kinase (MAPK) inhibitors p38
MAPK Stimulators
[0193] (39) phosphatidyl-inositide triphosphate
[0194] (40) insulin recycling receptor inhibitors
[0195] (41) glucose transporter 4 modulators
[0196] (42) TNF-.alpha. antagonists
[0197] (43) plasma cell differentiation antigen-1 (PC-1)
Antagonists
[0198] (44) adipocyte lipid-binding protein (ALBP/aP2)
inhibitors
[0199] (45) phosphoglycans
[0200] (46) Galparan;
[0201] (47) Receptron;
[0202] (48) islet cell maturation factor;
[0203] (49) insulin potentiating factor (IPF or insulin
potentiating factor-1);
[0204] (50) somatomedin C coupled with binding protein (also known
as IGF-BP3, IGF-BP3, SomatoKine);
[0205] (51) Diab II (known as V-411) or Glucanin, produced by
Biotech Holdings Ltd. or Volque Pharmaceutical;
[0206] (52) glucose-6 phosphatase inhibitors;
[0207] (53) fatty acid glucose transport protein;
[0208] (54) glucocorticoid receptor antagonists; and
[0209] (55) glutamine:fructose-6-phosphate amidotransferase (GFAT)
modulators.
[0210] (C) Biguanides, which decrease liver glucose production and
increases the uptake of glucose. Examples include metformin such
as:
[0211] (1) 1,1-dimethylbiguanide (e.g., Metformin-DepoMed,
Metformin-Biovail Corporation, or METFORMIN GR (metformin gastric
retention polymer)); and
[0212] (2) metformin hydrochloride (N,N-dimethylimidodicarbonimidic
diamide monohydrochloride, also known as LA 6023, BMS 207150,
GLUCOPHAGE, or GLUCOPHAGE XR.
[0213] (D) Alpha-glucosidase inhibitors, which inhibit
alpha-glucosidase. Alpha-glucosidase converts fructose to glucose,
thereby delaying the digestion of carbohydrates. The undigested
carbohydrates are subsequently broken down in the gut, reducing the
post-prandial glucose peak. Examples include, but are not limited
to:
[0214] (1) acarbose (D-glucose,
O-4,6-dideoxy-4-(((1S-(1alpha,4alpha,5beta-
,6alpha))-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl)
amino)-alpha-D-glucopyranosyl-(1-4)-O-alpha-D-glucopyranosyl-(1-4)-,
also known as AG-5421, Bay-g-542, BAY-g-542, GLUCOBAY, PRECOSE,
GLUCOR, PRANDASE, GLUMIDA, or ASCAROSE);
[0215] (2) Miglitol (3,4,5-piperidinetriol,
1-(2-hydroxyethyl)-2-(hydroxym- ethyl)-, (2R (2alpha, 3beta,
4alpha, 5beta))- or (2R,3R,4R,5S)-1-(2-hydrox-
yethyl)-2-(hydroxymethyl-3,4,5-piperidinetriol, also known as BAY
1099, BAY M 1099, BAY-m-1099, BAYGLITOL, DIASTABOL, GLYSET,
MIGLIBAY, MITOLBAY, PLUMAROL);
[0216] (3) CKD-711
(0-4-deoxy-4-((2,3-epoxy-3-hydroxymethyl-4,5,6-trihydro-
xycyclohexane-1-yl)amino)-alpha-b-glucopyranosyl-(1-4)-alpha-D-glucopyrano-
syl-(1-4)-D-glucopyranose);
[0217] (4) emiglitate
(4-(2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymeth-
yl)-1-piperidinyl)ethoxy benzoic acid ethyl ester, also known as
BAY o 1248 or MKC 542);
[0218] (5) MOR 14 (3,4,5-piperidinetriol,
2-(hydroxymethyl)-1-methyl-, (2R-(2alpha,3beta,4alpha,5beta))-,
also known as N-methyldeoxynojirimycin or N-methylmoranoline);
and
[0219] (6) Voglibose
(3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)ami-
no)-2-C-(hydroxymethyl)-D-epi-inositol or
D-epi-Inositol,3,4-dideoxy-4-((2-
-hydroxy-1-(hydroxymethyl)ethyl)amino)-2-C-(hydroxymethyl)-, also
known as A 71100, AO 128, BASEN, GLUSTAT, VOGLISTAT.
[0220] (E) Insulins include regular or short-acting,
intermediate-acting, and long-acting insulins, non-injectable or
inhaled insulin, tissue selective insulin, glucophosphokinin
(D-chiroinositol), insulin analogues such as insulin molecules with
minor differences in the natural amino acid sequence and small
molecule mimics of insulin (insulin mimetics), and endosome
modulators. Examples include, but are not limited to:
[0221] (1) Biota;
[0222] (2) LP 100;
[0223] (3) (SP-5-21)-oxobis
(1-pyrrolidinecarbodithioato-S,S')vanadium,
[0224] (4) insulin aspart (human insulin (28B-L-aspartic acid) or
B28-Asp-insulin, also known as insulin X14, INA-X14, NOVORAPID,
NOVOMIX, or NOVOLOG);
[0225] (5) insulin detemir (Human
29B-(N6-(1-oxotetradecyl)-L-lysine)-(1A-- 21A), (1 B-29B)-Insulin
or NN 304);
[0226] (6) insulin lispro ("28B-L-lysine-29B-L-proline human
insulin, or Lys(B28), Pro(B29) human insulin analog, also known as
lys-pro insulin, LY 275585, HUMALOG, HUMALOG MIX 75/25, or HUMALOG
MIX 50/50);
[0227] (7) insulin glargine (human (A21-glycine, B31-arginine,
B32-arginine) insulin HOE 901, also known as LANTUS,
OPTISULIN);
[0228] (8) Insulin Zinc Suspension, extended (Ultralente), also
known as HUMULIN U or ULTRALENTE;
[0229] (9) Insulin Zinc suspension (Lente), a 70% crystalline and
30% amorphous insulin suspension, also known as LENTE ILETIN II,
HUMULIN L, or NOVOLIN L;
[0230] (10) HUMULIN 50/50 (50% isophane insulin and 50% insulin
injection);
[0231] (11) HUMULIN 70/30 (70% isophane insulin NPH and 30% insulin
injection), also known as NOVOLIN 70/30, NOVOLIN 70/30 PenFill,
NOVOLIN 70/30 Prefilled;
[0232] (12) insulin isophane suspension such as NPH ILETIN II,
NOVOLIN N, NOVOLIN N PenFill, NOVOLIN N Prefilled, HUMULIN N;
[0233] (13) regular insulin injection such as ILETIN II Regular,
NOVOLIN R, VELOSULIN BR, NOVOLIN R PenFill, NOVOLIN R Prefilled,
HUMULIN R, or Regular U-500 (Concentrated);
[0234] (14) ARIAD;
[0235] (15) LY 197535;
[0236] (16) L-783281; and
[0237] (17) TE-17411.
[0238] (F) Insulin secretion modulators such as:
[0239] (1) glucagon-like peptide-1 (GLP-1) and its mimetics;
[0240] (2) glucose-insulinotropic peptide (GIP) and its
mimetics;
[0241] (3) exendin and its mimetics;
[0242] (4) dipeptyl protease (DPP or DPPIV) inhibitors such as
[0243] (4a) DPP-728 or LAF 237
(2-pyrrolidinecarbonitrile,1-(((2-((5-cyano-
-2-pyridinyl)amino)ethyl)amino)acetyl), known as NVP-DPP-728,
DPP-728A, LAF-237);
[0244] (4b) P 3298 or P32/98 (di-(3N-((2S,
3S)-2-amino-3-methyl-pentanoyl)- -1,3-thiazolidine)fumarate);
[0245] (4c) TSL 225
(tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxyli- c
acid);
[0246] (4d) Valine pyrrolidide (valpyr);
[0247] (4e) 1-aminoalkylisoquinolinone-4-carboxylates and analogues
thereof;
[0248] (4f) SDZ 272-070 (1-(L-Valyl)pyrrolidine);
[0249] (4g) TMC-2A, TMC-2B, or TMC-2C;
[0250] (4h) Dipeptide nitriles (2-cyanopyrrolodides);
[0251] (4i) CD26 inhibitors; and
[0252] (4j) SDZ 274-444;
[0253] (5) glucagon antagonists such as AY-279955; and
[0254] (6) amylin agonists which include, but are not limited to,
pramlintide (AC-137, Symlin, tripro-amylin or pramlintide
acetate).
[0255] (G) Insulin secretagogues, which increase insulin production
by stimulating pancreatic beta cells, such as:
[0256] (1) asmitiglinide ((2
(S)-cis)-octahydro-gamma-oxo-alpha-(phenylmet-
hyl)-2H-isoindole-2-butanoic acid, calcium salt, also known as
mituglimide calcium hydrate, KAD 1229, or S 21403);
[0257] (2) Ro 34563;
[0258] (3) nateglinide
(trans-N-((4-(1-methylethyl)cyclohexyl)carbonyl)-D-- phenylalanine,
also known as A 4166, AY 4166, YM 026, FOX 988, DJN 608, SDZ
DJN608, STARLIX, STARSIS, FASTIC, TRAZEC);
[0259] (4) JTT 608 (trans-4-methyl-gamma-oxocyclohexanebutanoic
acid);
[0260] (5) sulfonylureas such as:
[0261] (5a) chlorpropamide
(1-[(p-chlorophenyl)sulfonyl]-3-propylurea, also known as
DIABINESE);
[0262] (5b) tolazamide (TOLINASE or TOLANASE);
[0263] (5c) tolbutamide (ORINASE or RASTINON);
[0264] (5d) glyburide
(1-[[p-[2-(5-chloro-o-anisamido)ethyl]phenyl]sulfony-
l]-3-cyclohexylurea, also known as Glibenclamide, DIABETA,
MICRONASE, GLYNASE PresTab, or DAONIL);
[0265] (5e) glipizide
(1-cyclohexyl-3-[[p-[2-(5-ethylpyrazinecarboxamido)e-
thyl]phenyl]sulfonyl]urea, also known as GLUCOTROL, GLUCOTROL XL,
MINODIAB, or GLIBENESE);
[0266] (5f) glimepiride (1H-pyrrole-1-carboxamide,
3-ethyl-2,5-dihydro-4-m-
ethyl-N-[2-[4-[[[[(4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl-
lethyl]-2-oxo-, trans-, also known as Hoe-490 or AMARYL);
[0267] (5g) acetohexamide (DYMELOR);
[0268] (5h) gliclazide (DIAMICRON);
[0269] (5i) glipentide (STATICUM);
[0270] (5j) gliquidone (GLURENORM); and
[0271] (5k) glisolamide (DIABENOR);
[0272] (6) K.sup.+ channel blockers including, but not limited to,
meglitinides such as
[0273] (6a) Repaglinide
((S)-2-ethoxy-4-(2-((3-methyl-1-(2-(1-piperidinyl)-
phenyl)butyl)amino)-2-oxoethyl)benzoic acid, also known as AGEE
623, AGEE 623 ZW, NN 623, PRANDIN, or NovoNorm);
[0274] (6b) imidazolines; and
[0275] (6c) .alpha.-2 adrenoceptor antagonists;
[0276] (7) pituitary adenylate cyclase activating polypeptide
(PAcAP);
[0277] (8) vasoactive intestinal peptide (VIP);
[0278] (9) amino acid analogs; and
[0279] (10) glucokinase activators.
[0280] (H) Growth Factors such as:
[0281] (1) insulin-like growth factors (IGF-1, IGF-2);
[0282] (2) small molecule neurotrophins;
[0283] (3) somatostatin;
[0284] (4) growth hormone-releasing peptide (GHRP);
[0285] (5) growth hormone-releasing factor (GHRF); and
[0286] (6) human growth hormone fragments.
[0287] (I) Immunomodulators such as:
[0288] (1) vaccines;
[0289] (2) T-cell inhibitors
[0290] (3) monoclonal antibodies;
[0291] (4) interleukin-1 (IL-1) antagonists; and
[0292] (5) BDNF.
[0293] (J) Other antidiabetic agents:
[0294] (1) rHu-Glucagon;
[0295] (2) DHEA analogs;
[0296] (3) carnitine palmitoyl transferase (CPT) inhibitors;
[0297] (4) islet neurogenesis;
[0298] (5) pancreatic .beta. amyloid inhibitors; and
[0299] (6) UCP (uncoupling protein)-2 and UCP-3 modulators.
[0300] In addition, a second PPAR modulator, as described above in
Section C, may also be utilized as a third antidiabetic agent,
provided that it is different from the first PPAR modulator.
[0301] E. Combinations
[0302] The invention features a combination therapy method
comprising administering a glucose reabsorption inhibitor, such as
an SGLT inhibitor, and administering a PPAR modulator for the
treatment of diabetes or Syndrome X, or associated symptoms or
complications thereof. The demonstrated efficacy of SGLT inhibitors
in numerous models of NIDDM validates the utility of this drug
alone for the treatment of NIDDM in humans. Since glucose
reabsorption inhibitors have a mechanism of action distinct from
that of PPAR modulators, the disclosed combination with PPAR
modulators has the advantage of reducing the amount of either drug
necessary to achieve combined therapeutic or pharmaceutical
efficacy, relative to the use of either drug alone, thereby
reducing one or more adverse side-effects, which often include
weight gain, edema, cardiac hypertrophy, hepatohypertrophy,
hypoglycemia, or hepatotoxicity, or any combination thereof.
[0303] The invention provides a method for treating diabetes or
Syndrome X, or associated symptoms or complications thereof in a
subject, said method comprising administering to said subject a
jointly effective amount of a glucose reabsorption inhibitor in
combination with a jointly effective amount of a PPAR modulator. In
one aspect of the invention, the PPAR modulator is a PPAR agonist
that increases insulin sensitivity in the subject. In another
aspect of the invention, the PPAR modulator is a PPAR antagonist
that increases insulin sensitivity in the subject. Methods to
determine the insulin sensitizing activity of an agent are well
known in the art. For example, an insulin sensitizer can increase
glucose tolerance in a subject in an oral glucose tolerance
test.
[0304] This invention also provides a pharmaceutical composition
comprising one or more glucose reabsorption inhibitors, one or more
PPAR modulators, and a pharmaceutically acceptable carrier. In one
aspect of the invention, the PPAR modulator is a PPAR agonist that
increases insulin sensitivity in the subject. In another aspect of
the invention, the PPAR modulator is a PPAR antagonist that
increases insulin sensitivity in the subject.
[0305] In particular, the glucose reabsorption inhibitor is a SGLT1
and/or SGLT2 inhibitor. More particularly, the glucose reabsorption
inhibitor is selected from a propiophenone, a dihydrochalcone, and
a derivative thereof.
[0306] Specifically, the glucose reabsorption inhibitor is a
compound of Formula V: 8
[0307] wherein
[0308] Ar is aryl or heteroaryl;
[0309] OX is an optionally protected hydroxy group;
[0310] Y is hydrogen or alkyl; and
[0311] Z is glucopyranosyl wherein one or more hydroxy groups
thereof may optionally be substituted with one or more groups
selected from .alpha.-D-glucopyranosyl, alkanoyl, alkoxycarbonyl,
and substituted alkyl.
[0312] Preferably, Z is .beta.-D-glucopyranosyl.
[0313] A preferred group of compounds of Formula V are compounds of
Formula I wherein substituents are as described in U.S. Pat. No.
6,048,842, particularly claims 2 through 10.
[0314] A preferred group of compounds of Formula V are compounds of
Formula II wherein substituents are as described in U.S. Pat. NO.
5,830,873, particularly claims 2 through 8 and 13 through 16.
[0315] A preferred group of compounds of Formula V are compounds of
Formula III wherein substituents are as described in U.S. Pat. No.
5,767,094, particularly claims 2, 3, 8, and 9.
[0316] A preferred group of compounds of Formula V are compounds of
Formula IV wherein substituents are as described in U.S Pat. No.
U.S. Pat. Nos. 5,731,292 and 5,424,406, particularly claims 4
through 13 of U.S. Pat. No. 5,731,292 and claims 6 through 13 and
15 through 18 of U.S. Pat. No. 5,424,406.
[0317] Preferably, the glucose reabsorption inhibitor is selected
from T-1095 and T-1095A: 9
[0318] T-1095A is a selective and potent inhibitor of SGLT in the
kidney. T-1095 is a pro-drug and converted to its active form
T-1095A in the liver. Oral administration of T-1095 has been shown
to suppress elevated blood glucose levels by enhancing the
excretion of glucose in rodent models of IDDM and NIDDM. Treatment
for 3 weeks to 6 months with T-1095 reduced both fed and fasting
blood glucose levels and HbA1c in diabetic rodent models
(streptozotocin (STZ)-induced diabetic rat, yellow KK mice, db/db
mice, Zucker Diabetic Fatty rats and GK rats). In addition, there
was a decrease in the hyperinsulinemia, hypertriglyceridemia, and
the development of microalbuminuria in the yellow KK mice and other
diabetic mice models. The results of oral glucose tolerance test
and hyperinsulinemic euglycemic clamp studies revealed the
improvement of glucose tolerance and the reduction of insulin
resistance. There was no observed sign of adding weight, infection
in the urinary tracts, electrolyte imbalance in plasma, changes in
food intake, acute hypoglycemic shock nor pathological changes in
the kidney during treatment with T-1095. The presence of the
carbonate may impart SGLT selectivity. For the intestinal SGLT-1,
T-1095A is a better substrate than T-1095. The prodrug is
hydrolysed in vivo to yield T-1095A, which is also a better
substrate for the inhibition of SGLT-2 in the kidney.
[0319] T-1095 or T-1095A may be protected with one or more hydroxyl
or diol protecting groups, examples of which are listed above in
Section A.
[0320] For use in medicine, the salt or salts of the compounds of
Formula I, II, III, IV, or V refer to non-toxic pharmaceutically
acceptable salts. Other salts may, however, be useful in the
preparation of compounds according to this invention or of their
pharmaceutically acceptable salts. Representative organic or
inorganic acids include, but are not limited to, hydrochloric,
hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric,
acetic, propionic, glycolic, lactic, succinic, maleic, fumaric,
malic, tartaric, citric, benzoic, mandelic, methanesulfonic,
hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic,
2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,
salicylic, saccharinic or trifluoroacetic acid. Representative
basic/cationic salts include, but are not limited to, benzathine,
chloroprocaine, choline, diethanolamine, ethylenediamine,
meglumine, procaine, aluminum, calcium, lithium, magnesium,
potassium, sodium, or zinc. The compounds of Formula I, II, III,
IV, or V, or a pharmaceutically acceptable salt thereof, may
include an intramolecular salt thereof, or a solvate or hydrate
thereof.
[0321] F. Administration, Formulation, and Dosages
[0322] The utility of the disclosed compounds, compositions, and
combinations to treat disorders in glucose and lipid metabolism can
be determined according to the procedures well known in the art
(see the references listed below), as well as all the procedures
described in U.S. Pat. Nos. 5,424,406, 5,731,292, 5,767,094,
5,830,873, and 6,048,842, which are incorporated herein by
reference. The compound may be administered to a patient by any
conventional route of administration, including, but not limited
to, intravenous, oral, subcutaneous, intramuscular, intradermal and
parenteral administration. Preferably, formulations are for oral
administration.
[0323] The present invention also provides pharmaceutical
compositions comprising one or more glucose reabsorption inhibitors
and one or more PPAR modulators in association with a
pharmaceutically acceptable carrier.
[0324] The daily dosage of the products may be varied over a wide
range from 1 to 1000 mg per adult human per day. For oral
administration, the compositions are preferably provided in the
form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0,
10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 or 500 milligrams of the
active ingredient for the symptomatic adjustment of the dosage to
the patient to be treated. The compounds may be administered on a
regimen of 1 to 2 times per day. The dosages, however, may be
varied depending upon the requirement of the patients, the severity
of the condition being treated and the compound being employed. The
use of either daily administration or post-periodic dosing may be
employed. Preferably these compositions are in unit dosage forms
such as tablets, pills, capsules, powders, granules, sterile
parenteral solutions or suspensions, metered aerosol or liquid
sprays, drops, ampoules, auto-injector devices or suppositories;
for oral parenteral, intranasal, sublingual or rectal
administration, or for administration by inhalation or
insufflation. Alternatively, the composition may be presented in a
form suitable for once-weekly or once-monthly administration; for
example, an insoluble salt of the active compound, such as the
decanoate salt, may be adapted to provide a depot preparation for
intramuscular injection. For preparing solid compositions such as
tablets, the principal active ingredient or ingredients are mixed
with a pharmaceutical carrier, e.g. conventional tableting
ingredients such as corn starch, lactose, sucrose, sorbitol, talc,
stearic acid, magnesium stearate, dicalcium phosphate or gums, and
other pharmaceutical diluents, e.g. water, to form a solid
preformulation composition containing a homogeneous mixture of one
or more glucose reabsorption inhibitors and one or more PPAR
modulators, or a pharmaceutically acceptable salt thereof. When
referring to these preformulation compositions as homogeneous, it
is meant that the active ingredient or ingredients are dispersed
evenly throughout the composition so that the composition may be
readily subdivided into equally effective dosage forms such as
tablets, pills and capsules. This solid preformulation composition
is then subdivided into unit dosage forms of the type described
above containing from 0.1 to about 500 mg of the active ingredient
or ingredients of the present invention. The tablets or pills of
the novel composition can be coated or otherwise compounded to
provide a dosage form affording the advantage of prolonged action.
For example, the tablet or pill can comprise an inner dosage and an
outer dosage component, the latter being in the form of an envelope
over the former. The two components can be separated by an enteric
layer which serves to resist disintegration in the stomach and
permits the inner component to pass intact into the duodenum or to
be delayed in release. A variety of material can be used for such
enteric layers or coatings, such materials including a number of
polymeric acids with such materials as shellac, cetyl alcohol and
cellulose acetate.
[0325] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include, aqueous solutions, suitably flavoured syrups,
aqueous or oil suspensions, and flavoured emulsions with edible
oils such as cottonseed oil, sesame oil, coconut oil or peanut oil,
as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions, include
synthetic and natural gums such as tragacanth, acacia, alginate,
dextran, sodium carboxymethylcellulose, methylcellulose,
polyvinyl-pyrrolidone or gelatin. The liquid forms in suitably
flavored suspending or dispersing agents may also include the
synthetic and natural gums, for example, tragacanth, acacia,
methyl-cellulose and the like. For parenteral administration,
sterile suspensions and solutions are desired. Isotonic
preparations which generally contain suitable preservatives are
employed when intravenous administration is desired.
[0326] Advantageously, the combinations of one or more glucose
reabsorption inhibitors and one or more PPAR modulators of the
present invention may be administered in a single daily dose, or
the total daily dosage may be administered in divided doses of two,
three or four times daily. Furthermore, one or more glucose
reabsorption inhibitors and/or one or more PPAR modulators
according to the present invention can be administered in
intranasal form via topical use of suitable intranasal vehicles, or
via transdermal skin patches well known to those of ordinary skill
in that art. To be administered in the form of a transdermal
delivery system, the dosage administration will, of course, be
continuous rather than intermittent throughout the dosage
regimen.
[0327] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. Moreover, when desired or
necessary, suitable binders; lubricants, disintegrating agents and
coloring agents can also be incorporated into the mixture. Suitable
binders include, without limitation, starch, gelatin, natural
sugars such as glucose or beta-lactose, corn sweeteners, natural
and synthetic gums such as acacia, tragacanth or sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite,
xanthan gum and the like.
[0328] Wherein the present invention is directed to the
administration of a combination, the compounds may be
co-administered simultaneously, sequentially, or in a single
pharmaceutical composition. Where the compounds are administered
separately, the number of dosages of each compound given per day,
may not necessarily be the same, e.g. where one compound may have a
greater duration of activity, and will therefore, be administered
less frequently.
[0329] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound used, the strength of the preparation, the mode of
administration, and the advancement of the disease condition. In
addition, factors associated with the particular patient being
treated, including patient age, weight, diet and time of
administration, will result in the need to adjust dosages.
[0330] The novel compositions of the present invention can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes can be formed from a variety of
lipids, including but not limited to amphipathic lipids such as
phosphatidylcholines, sphingomyelins, phosphatidylethanolamines,
phophatidylcholines, cardiolipins, phosphatidylserines,
phosphatidylglycerols, phosphatidic acids, phosphatidylinositols,
diacyl trimethylammonium propanes, diacyl dimethylammonium
propanes, and stearylamine, neutral lipids such as triglycerides,
and combinations thereof. They may either contain cholesterol or
may be cholesterol-free.
[0331] From Formula V and other disclosed formulae it is evident
that some compounds in the compositions of the invention may have
one or more asymmetric carbon atoms in their structure. It is
intended that the present invention include within its scope the
stereochemically pure isomeric forms of the compounds as well as
their racemates. Stereochemically pure isomeric forms may be
obtained by the application of art known principles.
Diastereoisomers may be separated by physical separation methods
such as fractional crystallization and chromatographic techniques,
and enantiomers may be separated from each other by the selective
crystallization of the diastereomeric salts with optically active
acids or bases or by chiral chromatography. Pure stereoisomers may
also be prepared synthetically from appropriate stereochemically
pure starting materials, or by using stereospecific reactions.
[0332] Some compounds in the compositions of the present invention
may have various individual isomers, such as trans and cis, and
various alpha and beta attachments (below and above the plane of
the drawing). In addition, where the processes for the preparation
of the compounds according to the invention give rise to mixture of
stereoisomers, these isomers may be separated by conventional
techniques such as preparative chromatography. The compounds may be
prepared as a single stereoisomer or in racemic form as a mixture
of some possible stereoisomers. The non-racemic forms may be
obtained by either synthesis or resolution. The compounds may, for
example, be resolved into their components enantiomers by standard
techniques, such as the formation of diastereomeric pairs by salt
formation. The compounds may also be resolved by covalent linkage
to a chiral auxiliary, followed by chromatographic separation
and/or crystallographic separation, and removal of the chiral
auxiliary. Alternatively, the compounds may be resolved using
chiral chromatography. Unless otherwise noted, the scope of the
present invention is intended to cover all such isomers or
stereoisomers per se, as well as mixtures of cis and trans isomers,
mixtures of diastereomers and racemic mixtures of enantiomers
(optical isomers) as well.
[0333] The therapeutic effect of the glucose reabsorption inhibitor
administered in combination with a PPAR modulator in treating
diabetes, Syndrome X, or associated symptoms or complications can
be shown by methods known in the art. The following examples of
combination treatment with SGLT inhibitors and PPAR gamma agonists
are intended to illustrate the invention but not to limit it.
EXAMPLE 1
[0334] Effects on Plasma Glucose, Plasma Insulin, Plasma
Triglycerides, Liver Weight, Heart Weight, and Body Weight
[0335] To examine the effect of T-1095 in combination with a
PPAR.gamma. agonist, female db/db mice (6-7 weeks of age/Jackson
Labs, ME) were treated daily for 11 days with vehicle (0.5%
methylcellulose), rosiglitazone (0.1 mpk-10 mpk, Avandia), T-1095
(100 mpk), or rosiglitazone plus T-1095 (100 mpk). Mice (n=8
animals/group) received the test compounds or vehicle by oral
gavage in a volume of 10 ml/kg of body weight. Body weight was
recorded on day 1, prior to dosing, and days 4, 8 and 11. Eighteen
hours after the final dose, mice were weighed and anesthetized with
CO.sub.2/O.sub.2 (70:30). Mice were then bled by retro-orbital
sinus puncture into 2 mL heparinized polypropylene tubes on
ice.
[0336] Plasma samples were then assayed for glucose, insulin, and
triglycerides using Trinder reagent (Sigma Diagnostics), Elisa
(Alpco) and GPO-Trinder (Sigma Diagnostics), respectively. Results
are shown in Table 2 and FIGS. 1-3 (See values in table 2 for
statistical significance).
2TABLE 2 11 day oral dosing of rosiglitazone +/- T-1095 in 6-7 week
old female db/db mice (Takedown: 18 hours after the last dose) TG
Glucose Insulin Treatment mg/dL mg/dL ng/ml Vehicle mean 277.00
610.25 76.63 se 21.06 61.35 10.22 0.1 mpk mean ***188.38 ***388.13
65.75 Rosi se 10.81 35.96 10.22 1 mpk mean ***199.43 ***246.71
***25.43 Rosi se 14.49 15.50 2.34 10 mpk mean ***136.25 ***321.63
***31.63 Rosi se 10.07 25.12 7.67 T-1095 mean 248.88 ***405.13
93.88 100 mpk se 12.68 40.74 2.13 0.1 mpk mean **219.63 ***361.00
69.50 Rosi + T se 15.5 54.48 10.36 1 mpk mean ***172.13 ***192.88
***28.25 Rosi + T se 9.84 32.01 10.08 10 mpk mean ***132.13
***164.63 ***, .sup.#12.13 .sup. Rosi + T se 5.06 15.92 2.12 T:
T-1095; Rosi: rosiglitazone; se: standard error; mpk: mg/kg ***p
< 0.001, **p < 0.01 versus vehicle, #p < 0.05 compared to
rosiglitazone alone.
[0337] Livers were excised, weighed and frozen. Results are shown
in Table 3 and FIG. 4 (*p<0.01 versus 1 mg/kg rosiglitazone
alone, **p<0.05 versus 10 mg/kg rosiglitazone alone). Heart
weight can be measured in an analogous manner.
3 TABLE 3 Liver Weight (g) -T1095 +T1095 (100 mpk) Treatment mean
se mean se Vehicle 1.86 0.13 1.88 0.11 Rosi 0.1 mpk 2.31 0.13 2.20
0.14 1 mpk 2.32 0.30 *1.47 0.09 10 mpk 2.36 0.13 **1.65 0.12 T:
T-1095; Rosi: rosiglitazone; se standard error; mpk: mg/kg *p <
0.01 versus 1 mg/kg rosiglitazone alone. **p < 0.05 versus 10
mg/kg rosiglitazone alone.
[0338] Body weight change (gram) results are shown in Table 4 and
FIG. 5 (*p<0.001 versus 10 mg/kg vehicle, **p<0.01 versus 1
mg/kg rosiglitazone alone, ***p<0.001 versus 10 mg/kg
rosiglitazone alone).
4 TABLE 4 Body Weight Change (g) -T1095 +T1095 (100 mpk) Treatment
mean se mean se Vehicle 3.86 0.42 3.96 0.38 Rosi 0.1 mpk 4.34 0.49
1.93 0.70 1 mpk 2.60 0.73 *,**-0.46 0.68 10 mpk 4.76 0.46 *,***0.21
0.87 T: T-1095; Rosi: rosiglitazone; se: standard error; mpk: mg/kg
*p < 0.001 versus vehicle, **p < 0.01 versus 1 mg/kg
rosiglitazone alone, ***p < 0.001 versus 10 mg/kg rosiglitazone
alone.
[0339] The SGLT inhibitors and PPAR.gamma. agonists have distinct
mechanisms of action. Improved glycemic control, measured as a
decrease in plasma glucose, plasma insulin, or plasma
triglycerides, or a combination thereof, can be observed at lower
concentrations of rosiglitazone when given in combination with
T-1095. Therefore, a leftward shift in the dose-response curve for
effect of rosiglitazone on the above parameters can become
apparent. In addition, the weight gain observed following treatment
with PPAR.gamma. agonists is less pronounced when given with the
SGLT inhibitor, since SGLT inhibitors' promotion of the urinary
excretion of glucose and loss of calories from the body is
demonstrated by reduction in weight or weight gain. Also, since
SGLT inhibitors promote a mild diuresis, the edema (and the
edematous weight gain) commonly observed after treatment with
PPAR.gamma. agonists can be less pronounced or absent. This can be
demonstrated by a reduction in the PPAR.gamma. agonist-induced
increase in heart weight. A reduction in the amount of
rosiglitazone necessary to achieve efficacy in turn improves the
side-effect profile. The decreased side effects can include such
conditions as increased liver weight, fatty liver, body weight
gain, heart weight gain, edema, cardiac hypertrophy,
hepatohypertrophy, hypoglycemia, and hepatotoxicity, or any
combination thereof.
EXAMPLE 2
[0340] Effects on Plasma Glucose, Plasma Insulin, Plasma
Triglycerides, Liver Weight, Heart Weight, and Body Weight
[0341] To examine the effect of T-1095 in combination with a
PPAR.gamma. agonist, female db/db mice (6-7 weeks of age/Jackson
Labs, ME) were treated daily for 11 days with vehicle (0.5%
methylcellulose), a PPAR.gamma. agonist such as rosiglitazone (10
mpk, Avandia), T-1095 (3, 10, 30, or 100 mpk), or rosiglitazone
plus T-1095. Mice (n=8 animals/group) received the test compounds
or vehicle by oral gavage in a volume of 10 ml/kg of body weight.
Body weight was recorded on day 1, prior to dosing, and days 4, 8
and 11. Eighteen hours after the final dose, mice were weighed and
anesthetized with CO.sub.2/O.sub.2 (70:30). Mice were then bled by
retro-orbital sinus puncture into 2 mL heparinized polypropylene
tubes on ice. Plasma samples were then assayed for glucose,
insulin, and triglycerides using Trinder reagent (Sigma
Diagnostics), Elisa (Alpco) and GPO-Trinder (Sigma Diagnostics),
respectively. Livers and hearts were excised, weighed and frozen.
Results are shown in Table 5.
5TABLE 5 11 day oral dosing of T-1095 +/- rosiglitazone in 6-7 week
old female db/db mice (Takedown: 18 hours after the last dose). TG
Glucose Insulin Treatment mg/dL mg/dL ng/ml Vehicle mean 306 406
49.2 se 19 64 11.0 3 mpk mean 263 286 **22.5 T-1095 se 13 53 2.1 10
mpk mean 256 **263 30.1 T-1095 se 6 37 6.6 30 mpk 315 370 23.9
T-1095 22 37 2.3 100 mpk mean **243 **242 49.1 T-1095 se 11 37 13.1
Rosi Mean *192 **244 *7.4 10 mpk Se 10 7 2.7 3 mpk Mean *176 *198
*5.5 T + Rosi Se 10 20 0.7 10 mpk Mean *142 *140 *3.3 T + Rosi Se 9
11 0.6 30 mpk *164 *159 *3.6 T + Rosi 9 10 0.4 100 mpk mean **142
*177 *3.9 T + Rosi se 17 13 1.0 T: T-1095; Rosi: rosiglitazone; se:
standard error; mpk: mg/kg. *p < 0.01 versus vehicle, **p <
0.05 versus vehicle.
[0342] Livers were excised, weighed and frozen. Results are shown
in Table 6 and FIG. 6 (*p<0.001 versus rosiglitazone alone,
**p<0.05 versus rosiglitazone alone). Heart weight can be
measured in an analogous manner.
6 TABLE 6 Liver Weight (g) -Rosi +Rosi (10 mpk) Treatment mean se
mean se Vehicle 1.71 0.08 2.15 0.17 T1095 3 mpk 1.63 0.12 1.89 0.07
10 mpk 1.87 0.13 *1.41 0.07 30 mpk 1.75 0.09 **1.66 0.14 100 mpk
1.73 0.14 *1.46 0.08 Rosi: rosiglitazone; se: standard error; mpk:
mg/kg *p < 0.001 versus rosiglitazone alone, **p < 0.05
versus rosiglitazone alone.
[0343] Body weight change (gram) results are shown in Table 7 and
FIG. 7 (*p<0.05 versus vehicle, ** p<0.05 versus
rosiglitazone alone, ***p<0.001 versus rosiglitazone alone).
7 TABLE 7 Body Weight Change (g) -Rosi +Rosi (10 mpk) Treatment
Mean se mean se Vehicle 2.1 0.5 3.9 1.0 T-1095 3 mpk 3.0 0.4 2.9
0.8 10 mpk 4.3 0.9 ***-0.8 0.9 30 mpk 2.4 0.6 **0.6 0.8 100 mpk 2.3
1.0 *,***-1.1 0.7 Rosi: rosiglitazone; se: standard error; mpk:
mg/kg * p < 0.05 versus vehicle, **p < 0.05 versus
rosiglitazone alone, **p < 0.001 versus rosiglitazone alone.
[0344] The SGLT inhibitors and PPAR.gamma. agonists have distinct
mechanisms of action. Improved glycemic control, measured as a
decrease in plasma glucose, plasma insulin, or plasma
triglycerides, or a combination thereof, can be observed at lower
concentrations of T-1095 when given in combination with
rosiglitazone. Therefore, a leftward shift in the dose-response
curve for the effect of T-1095 on the above parameters can become
apparent. In addition, the weight gain observed following treatment
with PPAR.gamma. agonists is less pronounced when given with the
SGLT inhibitor, since SGLT inhibitors' promotion of the urinary
excretion of glucose and loss of calories from the body is
demonstrated by reduction in weight or weight gain. Also, since
SGLT inhibitors promote a mild diuresis, the edema (and the
edematous weight gain) commonly observed after treatment with
PPAR.gamma. agonists can be less pronounced or absent. This can be
demonstrated by a reduction in the PPAR.gamma. agonist-induced
increase in heart weight. A reduction in the amount of
rosiglitazone necessary to achieve efficacy in turn improves the
side-effect profile. The decreased side effects can include such
conditions as fatty liver, increased liver weight, body weight
gain, heart weight gain, edema, cardiac hypertrophy,
hepatohypertrophy, hypoglycemia, and hepatotoxicity, or any
combination thereof.
EXAMPLE 3
[0345] Effects on Plasma Glucose, HbA1c, Hematocrit, Plasma
Insulin, Plasma Triglycerides, Plasma Drug Levels, Liver Weight,
Heart Weight, Fat Content and Body Weight
[0346] To examine the effect of T-1095 in combination with a
PPAR.gamma. agonist, male ZDF rats (8 weeks of age/GMI) are treated
daily for 28 days with vehicle (0.5% methylcellulose), a
PPAR.gamma. agonist such as rosiglitazone (0.1 mg/kg-10 mg/kg,
AVANDIA), T-1095 (3-100 mg/kg), or rosiglitazone combined with
T-1095. Rats (n=8 animals/group) receive the test compounds or
vehicle by oral gavage in a volume of 2 ml/kg of body weight. Body
weight is recorded on day 1, prior to dosing, and twice a week for
the duration of the study. On the day prior to the final dose,
animals are fasted overnight. One hour after the final dose, rats
are weighed and anesthetized with CO.sub.2/O.sub.2 (70:30). Rats
are then bled by retro-orbital sinus puncture into 2 mL heparinized
polypropylene tubes on ice. Rats then receive a glucose challenge
(2 g/kg p.o) and are placed in metabolism cages for the urine
collection (4 hours). Animals are then sacrificed and epididymal
fat pads, livers, and hearts are excised, weighed and frozen for
histological examination. Plasma samples are then assayed for
glucose, HbA1c, insulin, hematocrit, plasma drug levels, and
triglycerides. Urine volume and urinary glucose, protein,
osmolarity, electrolytes (Na, K, Cl), BUN, creatinine are
measured.
[0347] The SGLT inhibitors and PPAR.gamma. agonists have distinct
mechanisms of action. Improved glycemic control, measured as a
decrease in plasma glucose, HbA1c, plasma insulin, or plasma
triglycerides, or a combination thereof, can be observed at lower
concentrations of PPAR.gamma. agonists when given in combination
with T-1095. Therefore, a leftward shift in the dose-response curve
for effect of PPAR.gamma. agonists on the above parameters can
become apparent. In addition, the weight gain observed following
treatment with PPAR.gamma. agonists is less pronounced when given
with the SGLT inhibitor, since SGLT inhibitors' promotion of the
urinary excretion of glucose and loss of calories from the body is
demonstrated by reduction in weight or weight gain. Also, since
SGLT inhibitors promote a mild diuresis, the edema (and the
edematous weight gain) commonly observed after treatment with
PPAR.gamma. agonists can be less pronounced or absent. This can be
demonstrated by a reduction in the PPAR.gamma. agonist-induced
increase in heart weight. A reduction in the amount of PPAR.gamma.
agonists necessary to achieve efficacy in turn improves the
side-effect profile. The decreased side effects can include such
conditions as fatty liver, increased liver weight, body weight
gain, heart weight gain, edema, cardiac hypertrophy,
hepatohypertrophy, hypoglycemia, and hepatotoxicity, or any
combination thereof.
EXAMPLE 4
[0348] Effects on Plasma Glucose, HbA1c, Plasma Insulin, Plasma
Triglycerides, Plasma Drug Levels, Liver Weight, Heart Weight and
Body Weight
[0349] To examine the effect of T-1095 in combination with a
PPAR.gamma. agonist, male db/db mice (6 weeks of age/Jackson Labs,
ME) were treated daily for 28 days with vehicle (0.5%
methylcellulose), a PPAR.gamma. agonist such as MCC-555 (3 mg/kg-30
mg/kg), T-1095 (3-100 mg/kg), or MCC-555 plus T-1095. Mice (n=8
animals/group) received the test compounds or vehicle by oral
gavage in a volume of 10 ml/kg of body weight. Body weight was
recorded on day 1, prior to dosing, and twice a week for the
duration of the study. One hour after the final dose, mice were
weighed and anesthetized with CO.sub.2/O.sub.2 (70:30). Mice were
then bled by retro-orbital sinus puncture into 2 mL heparinized
polypropylene tubes on ice. Mice were then fasted overnight and
bled by tail-clip prior to receiving a glucose challenge (2 g/kg
p.o). Blood was collected at 30, 60, 120, and 180 minutes after the
challenge. Animals were then sacrificed and epididymal fat pads,
livers, and hearts were excised, weighed and frozen for
histological examination. Plasma samples were then assayed for
glucose, HbA1c, insulin, and triglycerides. Results are shown in
Table 8 and Table 9.
8TABLE 8 Effect of 32 day oral dosing of T-1095 +/- MCC-555 in 6-7
week old female db/db mice (Takedown: 18 hours after the last
dose). Effects on plasma triglycerides, plasma glucose, and
insulin. TG Glucose Insulin Treatment mg/dL mg/dL ng/dL Vehicle
Control 178.12 .+-. 28 418.9 .+-. 42 15.8 .+-. 3.3 3 mpk T-1095
210.90 .+-. 24 490.3 .+-. 36 10.7 .+-. 2.2 10 mpk T-1095 178.10
.+-. 21 413.1 .+-. 50 11.4 .+-. 3.8 30 mpk T-1095 197.20 .+-. 26
380.6 .+-. 40 17.7 .+-. 5.1 100 mpk T-1095 151.20 .+-. 17 367.2
.+-. 42 25.5 .+-. 6.2 3 mpk MCC-555 90.20 .+-. 4.5* 201.3 .+-. 24*
31.7 .+-. 4.7* 10 mpk MCC-555 73.90 .+-. 5.4* 155.1 .+-. 22* 11.9
.+-. 1.4 30 mpk MCC-555 55.30 .+-. 4.7* 111.5 .+-. 8.0* 5.40 .+-.
0.4 3 mpk T-1095 + 3 mpk MCC-555 71.90 .+-. 3.6* 192.5 .+-. 26*
10.5 .+-. 1.6** 10 mpk T-1095 + 3 mpk MCC-555 62.80 .+-. 3.7* 178.5
.+-. 14* 12.3 .+-. 2.4** 30 mpk T-1095 + 3 mpk MCC-555 70.10 .+-.
2.9* 203.2 .+-. 15* 14.6 .+-. 4.8** 100 mpkT-1095 + 3 mpk MCC-555
60.40 .+-. 5.6* 220.9 .+-. 29* 11.3 .+-. 2.2** 3 mpk T-1095 + 10
mpk MCC-555 61.60 .+-. 4.2* 222.9 .+-. 34* 5.0 .+-. 0.7 10 mpk
T-1095 + 10 mpk MCC-555 56.60 .+-. 2.5* 190.5 .+-. 11* 10.5 .+-.
2.0 30 mpk T-1095 + 10 mpk MCC-555 68.90 .+-. 4.2* 193.7 .+-. 13*
6.0 .+-. 1.1 100 mpk T-1095 + 10 mpk MCC-555 74.30 .+-. 3.8* 198.0
.+-. 12* 7.7 .+-. 2.4 3 mpk T-1095 + 30 mpk MCC-555 49.40 .+-. 6.1*
156.5 .+-. 13* 6.9 .+-. 1.4 10 mpk T-1095 + 30 mpk MCC-555 46.90
.+-. 4.7* 123.2 .+-. 10* 3.9 .+-. 0.8 30 mpk T-1095 + 30 mpk
MCC-555 55.40 .+-. 6.1* 110.5 .+-. 9.0* 3.4 .+-. 0.6 100 mpk T-1095
+ 30 mpk MCC-555 51.90 .+-. 3.8* 190.0 .+-. 19* 2.7 .+-. 0.6 *p
< 0.01 versus the vehicle control **significantly different from
3 mpk MCC-555
[0350]
9TABLE 9 Effect of 32 day oral dosing of T-1095 +/31 MCC-555 in 6-7
week old female db/db mice (Takedown: 18 hours after the last
dose). Effects on hemoglobin A1c (HbA1c). % HbA1C Treatment +/- SEM
Vehicle Control 6.00 .+-. 0.24 3 mpk T-1095 6.10 .+-. 0.16 10 mpk
T-1095 6.00 .+-. 0.29 30 mpk T-1095 5.38 .+-. 0.23 100 mpk T-1095
4.96 .+-. 0.24* 3 mpk MCC-555 4.50 .+-. 0.17** 10 mpk MCC-555 4.10
.+-. 0.15** 30 mpk MCC-555 4.11 .+-. 0.14** 3 mpk T-1095 + 3 mpk
MCC-555 4.04 .+-. 0.09** 10 mpkT-1095 + 3 mpk MCC-555 4.16 .+-.
0.18** 30 mpk T-1095 + 3 mpk MCC-555 4.28 .+-. 0.21** 100 mpk
T-1095 + 3 mpk MCC-555 4.02 .+-. 0.14** 3 mpk T-1095 + 10 mpk
MCC-555 4.03 .+-. 0.15** 10 mpk T-1095 + 10 mpk MCC-555 4.40 .+-.
0.27** 30 mpk T-1095 + 10 mpk MCC-555 4.00 .+-. 0.15** 100 mpk
T-1095 + 10 mpk MCC-555 4.01 .+-. 0.11** 3 mpk T-1095 + 30 mpk
MCC-555 4.73 .+-. 0.36** 10 mpk T-1095 + 30 mpk MCC-555 4.84 .+-.
0.31** 30 mpk T-1095 + 30 mpk MCC-555 4.62 .+-. 0.23* 100 mpk
T-1095 + 30 mpk MCC-555 4.71 .+-. 0.26** *p < 0.05 versus
vehicle control **p < 0.01 versus vehicle control
[0351] Livers and hearts were excised, weighed and frozen. Results
are shown in Table 10.
10TABLE 10 Effect of 32 day oral dosing of T-1095 +/- MCC-555 in
6-7 week old female db/db mice (Takedown: 18 hours after the last
dose). Effects on body, heart and liver weights. Body Weight Liver
Heart Change (g) Weight (g) Weight (g) Treatment .+-.SEM .+-.SEM
.+-.SEM Vehicle Control 2.61 .+-. 0.06 1.54 .+-. 0.02 0.14 .+-.
0.02 3 mpkT-1095 6.09 .+-. 1.9* 1.51 .+-. 0.1 0.16 .+-. 0.02 10 mpk
T-1095 -0.99 .+-. 1.9 1.58 .+-. 0.08 0.13 .+-. 0.01 30 mpk T-1095
-2.44 .+-. 4.3 1.57 .+-. 0.09 0.14 .+-. 0.01 100 mpk T-1095 -4.83
.+-. 2.9 1.64 .+-. 0.11 0.14 .+-. 0.01 3 mpk MCC-555 9.14 .+-. 1.5*
2.36 .+-. 0.22* 0.11 .+-. 0.0.01 10 mpk MCC-555 9.53 .+-. 0.9* 1.91
.+-. 0.17 0.13 .+-. 0.01 30 mpk MCC-555 8.0 .+-. 0.7 1.68 .+-. 0.1
0.12 .+-. 0.01 3 mpk T-1095 + 3 mpk MCC-555 6.8 .+-. 1.6 1.93 .+-.
0.21 0.12 .+-. 0.01 10 mpk T-1095 + 3 mpk MCC-555 7.06 .+-. 1.3
1.99 .+-. 0.19 0.12 .+-. 0.01 30 mpk T-1095 + 3 mpk MCC-555 -0.57
.+-. 2.0** 1.97 .+-. 0.24 0.12 .+-. 0.01 100 mpk T-1095 + 3 mpk
MCC-555 8.3 .+-. 0.9 1.98 .+-. 0.12 0.12 .+-. 0.01 3 mpk T-1095 +
10 mpk MCC-555 10.4 .+-. 1.2* 2.09 .+-. 0.17 0.12 .+-. 0.01 10 mpk
T-1095 + 10 mpk MCC-555 5.16 .+-. 1.7 1.72 .+-. 0.16 0.11 .+-. 0.01
30 mpk T-1095 + 10 mpk MCC-555 6.36 .+-. 1.4 1.93 .+-. 0.14 0.12
.+-. 0.01 100 mpk T-1095 + 10 mpk MCC-555 6.68 .+-. 1.5 1.68 .+-.
0.18 0.10 .+-. 001 3 mpk T-1095 + 30 mpk MCC-555 5.11 .+-. 2.0 1.80
.+-. 0.2 0.13 .+-. 001 10 mpk T-1095 + 30 mpk MCC-555 4.31 .+-. 1.7
1.54 .+-. 0.16 0.12 .+-. 0.01 30 mpk T-1095 + 30 mpk MCC-555 3.0
.+-. 2.4 1.60 .+-. 0.17 0.12 .+-. 0.01 100 mpk T-1095 + 30 mpk
MCC-555 5.1 .+-. 1.1 1.75 .+-. 0.09 0.13 .+-. 0.01 *p < 0.05
compared to vehicle control **p < 0.01 versus 3 mpk MCC-555
[0352]
11TABLE 11 Effect of 32 day oral dosing of T-1095 +/- MCC-555 in
6-7 week old female db/db mice. Effects on the Area Under the Curve
for plasma glucose following an oral glucose challenge. AUC glucose
% of Vehicle Treatment .+-.SEM 3 mpk T-1095 95.75 .+-. 8.45 10 mpk
T-1095 76.6 .+-. 6.85 30 mpk T-1095 73.69 .+-. 5.7* 100 mpk T-1095
49.1 .+-. 3.21** 3 mpk MCC-555 74.11 .+-. 7.38* 10 mpk MCC-555
71.05 .+-. 8.37* 30 mpk MCC-555 48.03 .+-. 4.37** 3 mpk T-1095 + 3
mpk MCC-555 127.99 .+-. 17.7 10 mpk T-1095 + 3 mpk MCC-555 97.1
.+-. 7.07 30 mpk T-1095 + 3 mpk MCC-555 107.0 .+-. 6.02 100 mpk
T-1095 + 3 mpk MCC-555 104.9 .+-. 7.28 3 mpk T-1095 + 10 mpk
MCC-555 42.16 .+-. 2.91 #, {circumflex over ( )} 10 mpk T-1095 + 10
mpk MCC-555 41.88 .+-. 2.56 #, {circumflex over ( )}{circumflex
over ( )} 30 mpk T-1095 + 10 mpk MCC-555 37.13 .+-. 2.91 ##,
{circumflex over ( )}{circumflex over ( )}{circumflex over ( )} 100
mpk T-1095 + 10 mpk MCC-555 41.75 .+-. 4.67 # 3 mpk T-1095 + 30 mpk
MCC-555 53.67 .+-. 3.72 {circumflex over ( )} 10 mpk T-1095 + 30
mpk MCC-555 57.18 .+-. 5.49 30 mpk T-1095 + 30 mpk MCC-555 47.36
.+-. 3.61 {circumflex over ( )}{circumflex over ( )}{circumflex
over ( )} 100 mpk T-1095 + 30 mpk MCC-555 51.59 .+-. 2.66 *p <
0.05 versus vehicle control, **p < 0.001 versus vehicle control,
#p < 0.05 versus 10 mpk MCC-555 alone, ##p < 0.01 versus 10
mpk MCC-555 alone, {circumflex over ( )}p < 0.01 versus 3 mpk
T-1095 alone, {circumflex over ( )}{circumflex over ( )}p < 0.01
versus 10 mpk T-1095 alone, {circumflex over ( )}p < 0.01 versus
30 mpk T-1095 alone.
[0353] The SGLT inhibitors and PPAR.gamma. agonists have distinct
mechanisms of action. Improved glycemic control, measured as a
decrease in plasma glucose, HbA1c, plasma insulin, or plasma
triglycerides, or a combination thereof, can be observed at lower
concentrations of PPAR.gamma. agonists when given in combination
with T-1095. Therefore, a leftward shift in the dose-response curve
for effect of PPAR.gamma. agonists on the above parameters can
become apparent. In addition, the weight gain observed following
treatment with PPAR.gamma. agonists is less pronounced when given
with the SGLT inhibitor, since SGLT inhibitors' promotion of the
urinary excretion of glucose and loss of calories from the body is
demonstrated by reduction in weight or weight gain. Also, since
SGLT inhibitors promote a mild diuresis, the edema (and the
edematous weight gain) commonly observed after treatment with
PPAR.gamma. agonists can be less pronounced or absent. This may
explain the increase in heart weight typically observed following
treatment with rosiglitazone. Although MCC-555 did not produce a
significant change in heart weight in this study, it is anticipated
that the SGLT inhibitor should prevent or reduce the increase in
heart weight associated with chronic PPAR.gamma. agonist therapy. A
reduction in the amount of PPAR.gamma. agonists necessary to
achieve efficacy should, in turn, improve the side-effect profile.
The unexpected improvement can be seen in side effects such as
fatty liver, increased liver weight, body weight gain, heart weight
gain, edema, cardiac hypertrophy, hepatohypertrophy, hypoglycemia,
and hepatotoxicity, or any combination thereof.
[0354] The above studies show that the oral administration of
T-1095 in combination with one or more PPAR modulators improved the
status of markers of diabetes mellitus such as blood glucose and
insulin levels. The above studies also show that the oral
administration of T-1095 in combination with one or more PPAR
modulators, particularly TZD's such as rosiglitazone, reduced body
weight or body weight gain as well as liver weight, compared to
administration of PPAR modulators alone.
[0355] Thus, for treating diabetes, particularly Type II diabetes
mellitus, or Syndrome X, a compound of Formula I, II, III, IV, or V
in combination with one or more PPAR modulators, preferably PPAR
agonists that increases insulin sensitivity, may be employed
comprising administering repeated oral doses of the compound of
Formula I in the range of about 25 to 1000 mg once or twice daily
and repeated doses of the anti-diabetic agent or agents at jointly
effective dosages. The jointly effective dosage for PPAR modulators
disclosed herein may be readily determined by those skilled in the
art based on standard dosage guidelines. In particular, such
combined administration can be effective to accomplish reduction of
body weight, body weight gain, liver weight, or liver weight gain
in the subject.
[0356] Additionally, a method comprising (a) administering to a
subject a jointly effective amount of a glucose reabsorption
inhibitor; and (b) administering to the subject a jointly effective
amount of a PPAR modulator can be used to reduce body weight, body
weight gain, or liver weight of the subject in need thereof,
wherein the co-administration can be in any order and the combined
jointly effective amounts provide the desired therapeutic
effect.
[0357] Also, a method comprising (a) administering to a subject a
jointly effective amount of a glucose reabsorption inhibitor; and
(b) administering to the subject a jointly effective amount of a
PPAR modulator can be used to control body weight, body weight
gain, liver weight, or liver weight gain of the subject having
diabetes, Syndrome X, or associated symptoms or complications,
wherein the combined administration can be in any order and
the-combined jointly effective amounts providing the desired
therapeutic effect.
[0358] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound used, the mode of administration, the strength of the
preparation and the advancement of the disease condition. In
addition, factors associated with the particular patient being
treated, including patient's sex, age, weight, diet, time of
administration and concomitant diseases, will result in the need to
adjust dosages.
[0359] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
[0360] References
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* * * * *