NOVEL POLYMORPHIC FORMS OF 5-[4-[2-[N-METHYL-N-(2-PYRIDYL)AMINO]ETHOXY]BENZYL] THIAZOLIDINE-2,4-DIONE MALEATE AND PROCESS FOR THEIR PREPARATION

NOUVELLES FORMES POLYMORPHES DE 5-[4-[2-[N-METHYL-N-(2-PYRIDYL)AMINO]ETHOXY]BENZYL] THIAZOLIDINE-2,4-DIONE MALEATE ET PROCEDE DE PREPARATION ASSOCIE

English Abstract

This invention relates to novel polymorphic/pseudopolymorphic forms of 5-[4-
[2[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate
having formula (I). The invention also relates to a pharmaceutical composition
comprising the novel polymorphic form or their mixture and a pharmaceutically
acceptable carrier. The polymorphic forms of the present invention are more
active, as antidiabetic agent, than the hitherto known 5-[4-[2-[N-(2-methyl-N-
(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate.

French Abstract

L'invention concerne des nouvelles formes polymorphes/pseudo-polymorphes de 5-[4-[2[N-méthyl-N-(2-pyridyl)amino]éthoxy]benzyl] thiazolidine-2,4-dione maléate de formule (I). L'invention concerne également une composition pharmaceutique renfermant les nouvelles formes polymorphes ou un mélange de celles-ci et un adjuvant acceptable sur le plan pharmaceutique. Les formes polymorphes selon l'invention sont plus actives, comme agent anti-diabétique, que le 5-[4-[2-[N-(2-méthyl-N-(2-pyridyl)amino]éthoxy]benzyl] thiazolidine-2,4-dione maléate connu jusqu'à présent.

Claims

-13-
CLAIMS
1. A novel polymorphic Form-I of 5-[4-[2-[N-methyl-N-(2-pyridyl) amino]
ethoxy]benzyl]thiazolidine-2,4-dione maleate, and its stereoisomers having the
formula I
<IMG>
which is characterized by the following data:
DSC endotherm at 100.53°C (on set at 88.65°C),
X Ray powder diffraction (2.THETA.) : 10.90, 14.54, 15.96, 18.46, 18.60,
19.76, 20.72,
21.84, 22.36, 22,46, 23.90, 24.04, 24.72, 25.30, 25.98, 27.44, 29.70,
IR (cm-1) : 3435 (m), 2997 (w), 2773 (m), 1750 (m), 1701 (s), 1620 (m), 1510
(m), 1362 (m), 1332 (m), 1237 (s), 1165 (m), 864 (s), 764 (s), 717 (m), 654
(m), 540 (w).
2. A novel polymorphic Form-II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]
ethoxy]benzyl]thiazolidine-2,4-dione maleate, and its stereoisomers having the
formula I
<IMG>
which is characterized by the following data:
DSC : Endotherm at 127.67°C (on set at 123.17°C),
XRD (2.THETA.): 8.90, 15.40, 18.06, 19.20, 22.30, 23.40, 23.62, 24.80, 25.10,
25.84,
26.72, 27.18, 29.30, 29.54, 29.84, 33.26,
IR : 3424 (w), 3040 (w), 2947 (m), 2720 (m), 1751 (m), 1702 (s), 1641 (m),
1618
(m), 1574 (w), 1541 (w), 1412 (w), 1382 (w), 1359 (m), 1326 (m), 1265 (w),
1242 (s),
1213 (w), 1162 (s), 1067 (w), 1031 (w), 865 (s), 773 (s), 713 (s), 667 (m),
576 (w), 539
(m).
3. A novel polymorphic Form-III of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]
ethoxy]benzyl]thiazolidine-2,4-dione maleate and its stereoisomers having the
formula I

-14-
<IMG>
which is characterized by the following data:
DSC : Endotherm at 126.41°C (on set at 122.06°C),
XRD (2.THETA.): 4.60, 8.46, 9.24, 14.98, 15.86, 17.02, 18.60, 21.92, 23.50,
25.00,
25.44, 26.00, 26.38, 28.34, 33.90,
IR : 3429 (m), 2949 (m), 2738 (m), 1747 (w), 1704 (s), 1641 (m), 1617 (m),
1513
(s), 1464 (m), 1352 (m), 1244 (s), 1178 (s), 1069 (m), 862 (w), 777 (s), 717
(m), 657 (m),
589 (w).
4. A novel polymorphic Form-IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]
ethoxy]benzyl]thiazolidine-2,4-dione maleate, and its stereoisomers having the
formula I
<IMG>
which is characterized by the following data:
DSC : Endotherm at 125.39°C (on set at 121.03°C),
XRD (2.THETA.): 7.4, 8.8, 9.54, 14.98, 15.32, 15.82, 16.90, 17.70, 18.40,
18.54, 19.08,
19.72, 20.22, 20.48, 21.36, 21,66, 22.18, 22.58, 23.32, 23.96, 24.52, 25.38,
26.48, 27.00,
27.58, 27.94, 28.34, 28.54, 28.84, 29.10, 29.86, 30.02, 30.40, 30.52, 30.84,
31.40, 31.94,
IR : 3433 (m), 2930 (m), 1753 (w), 1705 (s), 1642 (w), 1617 (m), 1512 (s),
1467
(w), 1351 (m), 1244 (m), 1162 (m), 1061 (w), 864 (s), 765 (s), 714 (w), 658
(m), 526 (w).
5. A process for the preparation of novel polymorphic Form I of 5-[4-[2-[N-
methyl-
N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, which
comprises
(i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine- 2,4-dione maleate, employing known methods and dissolving in
ethanol,
(ii) heating the solution in a steam bath till the solid completely dissolved,
(iii) filtering the clean solution and cooling to room temperature over a
period
of 18 h and

-15-
(iv) isolating the Form I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate formed.
6. A process for the preparation of novel polymorphic Form II of 5-[4-[2-[N-
methyl-
N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, which
comprises:
(i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine-2,4-dione maleate, employing known methods and dissolving in
acetone,
(ii) heating the solution in a steam bath till the solid completely dissolved,
(iii) filtering the clean solution and cooling to room temperature over a
period
of 18 h and
(iv) isolating the Form II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate formed.
7. A process for the preparation of novel polymorphic Form III of 5-[4-[2-[N-
methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, which
comprises:
(i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine-2,4-dione maleate, employing known methods and dissolving in
methanol,
(ii) heating the solution in a steam bath till the solid completely dissolved,
(iii) filtering the clean solution and cooling to room temperature over a
period
of 18 h and
(iv) isolating the Form III of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate formed.
8. A process for the preparation of novel polymorphic Form IV of 5-[4-[2-[N-
methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, which
comprises:
(i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine-2,4-dione maleate, employing known methods and dissolving in 1,4-
dioxane,
(ii) heating the solution in a steam bath till the solid completely dissolved,
(iii) filtering the clean solution and cooling to room temperature over a
period
of 18 h and
(iv) isolating the Form IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate formed.
9. A pharmaceutical composition comprising a mixture of any of polymorphic
Forms

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I to IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-
2,4-dione
maleate, of the formula (I) and a pharmaceutically acceptable carrier,
diluent, excipient or
solvate.
10. A pharmaceutical composition as claimed in claim 9, in the form of a
tablet,
capsule, powder, syrup, solution or suspension.
11. A method of preventing or treating hyperlipemia, hypercholesteremia,
hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance,
insulin
resistance, or diseases in which insulin resistance is the underlying
pathophysiological
mechanism comprising administering a polymorphic Form selected from Form I to
IV of
5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione
maleate,
having the formula I as defined in claims 1-4 or a pharmaceutical composition
as claimed
in claims 9 and 10 to a patient in need thereof.
12. A method according to claim 11, wherein the disease is type II diabetes,
impaired
glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as
hypertension,
obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other
cardiovascular
disorders, certain renal diseases including glomerulonephritis,
glomerulosclerosis,
nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy,
disorders
related to endothelial cell activation, psoriasis, polycystic ovarian syndrome
(PCOS),
useful as aldose reductase inhibitors, for improving cognitive functions in
dementia and
treating diabetic complications, osteoporosis, inflammatory bowel diseases,
myotonic
dystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.
13. A method of reducing plasma glucose, triglycerides, total cholesterol,
LDL,
VLDL and free fatty acids in the plasma comprising administering a polymorphic
Form
selected from Form I to IV of 5-[4-[2-[N-methyl-N-(2-
pyridyl)amino]ethoxy]benzyl]
thiazolidine-2,4-dione maleate, having the formula I as defined in claims 1-4
or a
pharmaceutical composition as claimed in claims 9 and 10.
14. A method of preventing or treating hyperlipemia, hypercholesteremia,
hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance,
insulin
resistance, or diseases in which insulin resistance is the underlying
pathophysiological
mechanism comprising administering a polymorphic Form selected from Form I to
IV of
5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione
maleate,
having the formula I as defined in claims 1-4 or a pharmaceutical composition
as claimed

-17-
in claims 9 and 10 in combination / concomittant with HMG CoA reductase
inhibitors or
fibrates or nicotinic acid or cholestyramine or colestipol or probucol which
may be
administered together or within such a period as to act synergistically
together to a patient
in need thereof.
15. A method according to claim 14, wherein the disease is type II diabetes,
impaired
glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as
hypertension,
obesity, atherosclerosis, hyperlipidemia, coronary artery disease and other
cardiovascular
disorders, certain renal diseases including glomerulonephritis,
glomerulosclerosis,
nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, nephropathy,
disorders
related to endothelial cell activation, psoriasis, polycystic ovarian syndrome
(PCOS),
useful as aldose reductase inhibitors, for improving cognitive functions in
dementia and
treating diabetic complications, osteoporosis, inflammatory bowel diseases,
myotonic
dystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.
16. A method according to claim 14 for the treatment and / or prophylaxis of
disorders
related to Syndrome X, which comprises administering a polymorphic Form
selected
from Form I to IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine-
2,4-dione maleate, having the formula I as defined in claims 1-4 in
combination with
HMG CoA reductase inhibitors or fibrates or nicotinic acid or cholestyramine
or
colestipol or probucol which may be administered together or within such a
period as to
act synergistically together.
17. A method of reducing plasma glucose, triglycerides, total cholesterol,
LDL,
VLDL and free fatty acids in the plasma, which comprises administering a
polymorphic
Form selected from Form I to IV of 5-[4-[2-[N-methyl-N-(2-
pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in
claims 1-4 or a
pharmaceutical composition as claimed in claims 9 and 10 in combination /
concomittant
with HMG CoA reductase inhibitors or fibrates or nicotinic acid or
cholestyramine or
colestipol or probucol which may be administered together or within such a
period as to
act synergistically together to a patient in need thereof.
18. Use of a polymorphic Form selected from Form I to IV of 5-[4-[2-[N-methyl-
N-
(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the
formula I as
defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9
and 10 for
preventing or treating hyperlipidemia, hypercholesteremia, hyperglycemia,
osteoporosis,

-18-
obesity, glucose intolerance, leptin resistance, insulin resistance, or
diseases in which
insulin resistance is the underlying pathophysiological mechanism.
19. Use of a polymorphic Form according to claim 18, wherein the disease is
type II
diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to
Syndrome X
such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary
artery disease
and other cardiovascular disorders, certain renal diseases including
glomerulonephritis,
glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,
retinopathy,
nephropathy, disorders related to endothelial cell activation, psoriasis,
polycystic ovarian
syndrome (PCOS), useful as aldose reductase inhibitors, for improving
cognitive
functions in dementia and treating diabetic complications, osteoporosis,
inflammatory
bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma
or cancer.
20. Use of a polymorphic Form selected from Form I to IV of 5-[4-[2-[N-methyl-
N-
(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the
formula I as
defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9
and 10 for
reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and free
fatty acids
in the plasma.
21. Use of a polymorphic Form selected from Form I to IV of 5-[4-[2-[N-methyl-
N-
(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the
formula I as
defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9
and 10 in
combination/ concomittant with HMG CoA reductase inhibitors, fibrates,
nicotinic acid,
cholestyramine, colestipol or probucol which may be administered together or
within
such a period as to act synergistically together for preventing or treating
hyperlipidemia,
hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance,
leptin
resistance, insulin resistance, or diseases in which insulin resistance is the
underlying
pathophysiological mechanism to a patient in need thereof.
22. Use of a polymorphic Form according to claim 21, wherein the disease is
type II
diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to
Syndrome X
such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary
artery disease
and other cardiovascular disorders, certain renal diseases including
glomerulonephritis,
glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,
retinopathy,
nephropathy, disorders related to endothelial cell activation, psoriasis,
polycystic ovarian
syndrome (PCOS), useful as aldose reductase inhibitors, for improving
cognitive

-19-
functions in dementia and treating diabetic complications, osteoporosis,
inflammatory
bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma
or cancer.
23. Use of a polymorphic Form selected from Form I to IV of 5-[4-[2-[N-methyl-
N-
(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the
formula I as
defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9
and 10 in
combination/concomittant with HMG CoA reductase inhibitors, fibrates,
nicotinic acid,
cholestyramine, colestipol or probucol for reducing plasma glucose,
triglycerides, total
cholesterol, LDL, VLDL or free fatty acids in the plasma.
24. Use of a polymorphic Form selected from Form I to IV of 5-[4-[2-[N-methyl-
N-(2-
pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the formula
I as
defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9
and 10 for
preparing a medicament for preventing or treating hyperlipidemia,
hypercholesteremia,
hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance,
insulin
resistance, or diseases in which insulin resistance is the underlying
pathophysiological
mechanism.
25. Use of a polymorphic form according to claim 24, wherein the disease is
type II
diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to
Syndrome X
such as hyper-tension, obesity, atherosclerosis, hyperlipidemia, coronary
artery disease
and other cardiovascular disorders, certain renal diseases including
glomerulonephritis,
glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,
retinopathy,
nephropathy, disorders related to endothelial cell activation, psoriasis,
polycystic ovarian
syndrome (PCOS), useful as aldose reductase inhibitors, for improving
cognitive
functions in dementia and treating diabetic complications, osteoporosis,
inflammatory
bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma
or cancer.
26. Use of a polymorphic Form selected from Form I to IV of 5-[4-[2-[N-methyl-
N-
(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the
formula I as
defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9
and 10 for
preparing a medicament for reducing plasma glucose, triglycerides, total
cholesterol,
LDL, VLDL and free fatty acids in the plasma.
27. Use of a polymorphic Form selected from Form I to IV of 5-[4-j2-[N-methyl-
N-
(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the
formula I as
defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9
and 10 for

-20-
preparing a medicament in combination/concomittant with HMG CoA reductase
inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol
for preventing
or treating hyperlipemia, hypercholesteremia, hyperglycemia, osteoporosis,
obesity,
glucose intolerance, leptin resistance, insulin resistance, or diseases in
which insulin
resistance is the underlying pathophysiological mechanism.
28. Use of a polymorphic form according to claim 27, wherein the disease is
type II
diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to
Syndrome X
such as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary
artery disease
and other cardiovascular disorders, certain renal diseases including
glomerulonephritis,
glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,
retinopathy,
nephropathy, disorders related to endothelial cell activation, psoriasis,
polycystic ovarian
syndrome (PCOS), useful as aldose reductase inhibitors, for improving
cognitive
functions in dementia and treating diabetic complications, osteoporosis,
inflammatory
bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma
or cancer.
29. Use of a polymorphic Form selected from Form I to IV of 5-[4-[2-[N-methyl-
N-
(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, having the
formula I as
defined in claims 1-4 or a pharmaceutical composition as claimed in claims 9
and 10 for
preparing a medicament in combination/concomittant with HMG CoA reductase
inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol
for reducing
plasma glucose, triglycerides, total cholesterol, LDL, VLDL or free fatty
acids in the
plasma.
30. A medicine for preventing or treating hyperlipidemia, hypercholesteremia,
hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance,
insulin
resistance, or diseases in which insulin resistance is the underlying
pathophysiological
mechanism comprising administering an effective amount of a polymorphic Form
selected from Form I to IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate, having the formula I as defined in
claims 1-4 or a
pharmaceutical composition as claimed in claims 9 and 10.
31. A medicine according to claim 30, wherein the disease is type II diabetes,
impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X
such as
hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery
disease and other
cardiovascular disorders, certain renal diseases including glomerulonephritis,
glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,
retinopathy,

-21-
nephropathy, disorders related to endothelial cell activation, psoriasis,
polycystic ovarian
syndrome (PCOS), useful as aldose reductase inhibitors, for improving
cognitive
functions in dementia and treating diabetic complications, osteoporosis,
inflammatory
bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma
or cancer.
32. A medicine for reducing plasma glucose, triglycerides, total cholesterol,
LDL,
VLDL and free fatty acids in the plasma comprising an effective amount of a
polymorphic Form selected from Form I to IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)
amino]ethoxy] benzyl] thiazolidine-2,4-dione maleate, having the formula I as
defined in
claims 1-4 or a pharmaceutical composition as claimed in claims 9 and 10.
33. A medicine for preventing or treating hyperlipidemia, hypercholesteremia,
hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance,
insulin
resistance, or diseases in which insulin resistance is the underlying
pathophysiological
mechanism comprising a polymorphic Form selected from Form I to IV of 5-[4-[2-
[N-
methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate,
having the
formula I as defined in claims 1-4 or a pharmaceutical composition as claimed
in claims 9
and 10 and HMG CoA reductase inhibitors, fibrates, nicotinic acid,
cholestyramine,
colestipol or probucol.
34. A medicine according to claim 33, wherein the disease is type II diabetes,
impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X
such as
hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery
disease and other
cardiovascular disorders, certain renal diseases including glomerulonephritis,
glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,
retinopathy,
nephropathy, disorders related to endothelial cell activation, psoriasis,
polycystic ovarian
syndrome (PCOS), useful as aldose reductase inhibitors, for improving
cognitive
functions in dementia and treating diabetic complications, osteoporosis,
inflammatory
bowel diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma
or cancer.
35. A medicine for reducing plasma glucose, triglycerides, total cholesterol,
LDL,
VLDL and free fatty acids in the plasma, which comprises a polymorphic Form
selected
from Form I to IV of 5-[4-[2-[N-methyl-N-(2-
pyridyl)amino]ethoxy]benzyl]thiazolidine-
2,4-dione maleate, having the formula I as defined in claims 1-4 or a
pharmaceutical
composition as claimed in claims 9 and 10 and HMG CoA reductase inhibitors,
fibrates,
nicotinic acid, cholestyramine, colestipol or probucol.

Description

CA 02426117 2003-03-25
WO 02/26737 PCT/USO1/29896
-1
NOVEL POLYMORPHIC FORMS OF 5-[4-[2-[N-METHYL-N-(2
PYRmYL)AMINO]ETHOXY]BENZYL] THIAZOLIDINE-2,4-DIONE MALEATE
AND PROCESS FOR THEIR PREPARATION
Field of the Invention
This invention relates to novel polymorphiclpseudopolymorphic forms of 5-[4-[2-
[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate and
its
stereo- isomers having formula (I). The invention also relates to a
pharmaceutical
composition comprising the novel polymorphic form or their mixture and a
pharmaceutically acceptable carrier. The polymorphic forms of the present
invention are
more active, as antidiabetic agent, than the hitherto known 5-[4-[2-[N-methyl-
N-(2-
pyridyl)amino]ethoxy] benzyl] thiazolidine-2,4-dione maleate.
I\ O
N~N~O \ g~ COOH
CH I / NH
3
COOH
O
The present invention also relates to a process for the preparation of various
polymorphic/pseudopolymorphic 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate, having the formula (I) shown below. The
polymorphic forms prepared by the process of the present invention are more
active, as an
antidiabetic agent.
The polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine-2,4-dione maleate, of formula (I) defined above of the present
invention
reduce blood glucose and has beneficial effect on coronary heart disease and
atherosclerosis.
Out of the many drugs available for the treatment of diabetic ailments, the
thiazolidine dione derivatives are very prominent and are considered as much
superior
effective constituents compared to the sulphonyl areas. S-[4-[2-[N-methyl-N-(2-
pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, one such
thiazolidinedione
which exhibited euglycemic effect, was reported in the year 1988 by Beecham
group
England (EP 0306228A1) and created interest in the field, ever since.
The novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate, of formula (I) defined above of the
present

CA 02426117 2003-03-25
WO 02/26737 PCT/USO1/29896
_2_
invention are useful in reducing body weight and for the treatment and/or
prophylaxis of
diseases such as hypertension, coronary heart disease, atherosclerosis,
stroke, peripheral
vascular diseases and related disorders. The novel polymorphic forms of 5-[4-
[2-[N-
methyl-N-(2-pyridyl) amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of
formula (I)
of the present invention can be used for the treatment of certain renal
diseases including
glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive
nephrosclerosis and nephropathy. The novel polymorphic Forms of 5-[4-[2-[N-
methyl-
N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, of formula
(I) are
also useful for the treatment and/or prophylaxis of insulin resistance (type
II diabetes),
leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related
to syndrome
X such as hypertension, obesity, insulin resistance, coronary heart disease
and other
cardiovascular disorders. These novel polymorphic forms of 5-[4-[2-[N-methyl-N-
(2-
pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of formula (I) may
also be
useful as aldose reductase inhibitors, for improving cognitive functions in
dementia,
treating diabetic complications, disorders related to endothelial cell
activation, psoriasis,
polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis,
myotonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma,
inflammation
and for the treatment of cancer. The novel polymorphic forms of 5-[4-[2-[N-
methyl-N-
(2-pyridyl)amino]ethoxy] benzyl]thiazolidine-2,4-dione maleate, of formula (I)
of the
present invention are useful in the treatment and/or prophylaxis of the above
said diseases
in combination/con-comittant with one or more HMG CoA reductase inhibitors,
hypolipidemic/hypolipoproteinernic agents such as fabric acid derivatives,
nicotinic acid,
cholestyramine, colestipol, probucol.
Background of the invention
The latest trend that has, of late, crept into the pharmaceutical industry is
the
studies on polymorphism in drugs and the difference in the activity of
different
polymorphic forms of a given drug. By the term polymorphism we mean to include
different physical forms, crystal forms, crystalline / liquid crystalline l
non-crystalline
(amorphous) forms. This has especially become very interesting after observing
that
many antibiotics, antibacterials, tranquilizers etc., exhibit polymorphism and
someone of
the polyrnorphic forms of a given drug exhibit superior bio-availability and
consequently
show much higher activity compared to other polymorphs. Sertraline,
Frentizole,
Ranitidine, Sulfathiazole, Indomethacine etc. are some of the important
examples of

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pharmaceuticals which exhibit polymorphism. Polymorphism in drugs is a topic
of
current interest and is evident from the host of patents being granted. To
cite a few, U.S.
5,700,820 discloses six polymorphic forms of Troglitazone, U.S. 5,248,699
discusses
about five polymorphic forms of Sertraline hydrochloride while EP 014590
describes four
polymorphic forms of Frentizole. EP 490648 and EP 022527 also deal with the
subj ect of
polymorphism in drugs.
European Patent No.0306338, International publication No. WO 94125026 and
U.S. Patent Application No. 5,646,169 describe that the relative
configurations of the
diastereomers have been determined by x-ray crystallographic analysis and that
the
crystal and molecular structure of the 5-[4-[2-[N-methyl-N-(2-
pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate is under preparation. The report does
not touch
upon the possibility/observation that 5-[4-[2-[N-methyl-N-(2-
pyridyl)amino]thoxy]enzyl]
thiazolidine-2,4-dione maleate exists in different polymorphic forms. There is
no
published literature regarding such an observation till date. Polymorphism in
drugs is a
topic of current interest and is evident from the host of patents being
granted to cite a few
U.S. 5,248,699 discusses about five polymorphic forms of Sertraline
hydrochloride while
EP 014590, describes four polymorphic forms of Frentizole EP 490648 and EP
022527,
six polymorphic forms of Troglitazone WO 97/27191 also deal with the subject
of
polymorphism in drugs. The fact that polymorphism in 5-[4-[2-[N-methyl-N-(2-
pyridyl)
amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate has not been studied
earlier coupled
with the current interest in the field of polymorphism in drugs prompted us to
take-up this
investigation our observations and results from the subject matter of the
present
invention.
With a view to prevent/cure the chronic complications of diabetes, research is
being conducted round the world in recent times. 5-[4-[2-[N-methyl-N-(2-
pyridyl)amino]
ethoxy]benzyl]thiazolidine-2,4-dione maleate is being considered today as one
of the
most effective anti-diabetic drugs which as a multi-purpose activity not only
acting on
diabetes itself but also on the reduction of the triglycerides and also on the
accompanying
complications mentioned above. Indeed the said 5-[4-[2-[N-methyl-N-(2-
pyridyl)amino]
ethoxy]benzyl]thiazolidine-2,4-dione maleate is emerging as the second drug
candidate of
euglycemic class of antidiabetic agents.
With an objective to develop novel polymorpluc forms for lowering cholesterol
and reducing body weight with beneficial effects in the treatment andlor
prophylaxis of

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diseases related to increased levels of lipids, atherosclerosis, coronary
artery diseases,
Syndrome-X, impaired glucose tolerance, insulin resistance, insulin resistance
leading to
type 2 diabetes and diabetes complications thereof, for the treatment of
diseases wherein
insulin resistance is the pathophysiological mechanism and for the treatment
of
hypertension, with better efficacy, potency and lower toxicity, we focused our
research to
develop new polymorphic forms effective in the treatment of the above
mentioned
diseases. Effort in this direction has led to polymorphic forms having the
formula (I).
Another objective of the present invention is to provide polymorphic forms of
S-
[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione
maleate, their
stereoisomers, their pharmaceutically acceptable solvates and pharmaceutical
compositions containing them or their mixtures which may have agonist activity
against
PPARa and/or PPARy, and optionally inhibit HMG CoA reductase, in addition to
having
agonist activity against PPARa and/or PPARy.
Another objective of the present invention is to provide novel polymorphic
forms
of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethbxy]benzyl]thiazolidine-2,4-dione
maleate,
their stereoisomers, pharmaceutically acceptable solvates and pharmaceutical
compositions containing them or their mixtures having enhanced activities,
without toxic
effect or with reduced toxic effect.
Yet another objective of the present invention to provide a process for the
preparation of novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-
pyridyl)amino]
ethoxy]benzyl]thiazolidine-2,4-dione maleate, their stereoisomers,
pharmaceutically
acceptable solvates.
Still another objective of the present invention is to provide pharmaceutical
compositions containing novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-
pyridyl)
amino]ethoxy]benzyl]thia.zolidine-2,4-dione maleate, solvates or their
mixtures in
combination with suitable carriers, solvents, diluents and other media
normally employed
in preparing such compositions.
Summary of the Invention
The present invention relates to an observation that 5-[4-[2-[N-methyl-N-(2-
pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate exhibits
polymorphism,
which has not been reported till date. The polymorphic Forms I, II, III and IV
are
obtained from different solvents like ethanol, acetone, methanol and 1,4-
dioxane
respectively.

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From powder X-ray diffraction studies Forms I, II, III and IV are found to be
crystalline in nature.
DSC of the polymorphic Form I shows melting endotherm at 100.53°C.
Form II
dislays endotherm at 127.67°C. Form III exhibits melting endotherm at
126.41°C and
Form IV exhibits endotherm at 125.39°C.
All these polymorphic forms were proved to be identical in solution as evident
from Nuclear Magnetic Resonance (hTMR), Ultra Violet (UV) & Mass spectral
data. On
the other hand, solid state techniques like Differential Scanning Calorimetry
(DSC),
Powder X-Ray Diffractometry (XRD) and Infra Red spectroscopy (IR) revealed the
difference among these forms.
Brief Description of the Figures
X-ray powder diffraction pattern has been obtained on a Rigaku D/Max 2200
model diffractometer equiped with horizontal gonimometer in O/2 O geometry.
The
copper K a(~,=1.5418A) radiation was used and the sample was scanned between 3-
45
degrees 2U.
Differential scanning calorimeter was performed on a Shimadzu DSC-50
equipped with a controller. The data was collected on to a Pentium PC using a
Shimadzu
TA-50 software. The samples weighed in aluminum cells were heated from room
temperature to 220°C at a heating rate of 5°C /min. The empty
aluminum cell was used
as a reference. Dry nitrogen gas was purged through DSC cell continuously
throughout
the analysis at a flow rate of 30 ml/min.
Fig 1 is a characteristic differential scanning calorimetric thermogram of
Form I
Fig 2 is a characteristic differential scanning calorimetric thermogram of
Form II
Fig 3 is a characteristic differential scanning calorimetric thermogram of
Form III
Fig 4 is a characteristic differential scanning calorimetric thermogram of
Form IV
Fig 5 is a characteristic X-ray diffraction pattern of Form I
Fig 6 is a characteristic X-ray diffraction pattern of Form II
Fig 7 is a characteristic X-ray diffraction pattern of Form III
Fig 8 is a characteristic X-ray diffraction pattern of Form IV
Fig 9 is the mufti-plot of X-ray diffraction patterns of Forms I, II, III and
IV
Fig 10 is a characteristic infrared absorption spectrum of Form I in potassium
bromide.
Fig 11 is a characteristic infrared absorption spectrum of Form II in
potassium

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bromide.
Fig 12 is a characteristic infrared absorption spectrum of Form III in
potassium
bromide.
Fig 13 is a characteristic infrared absorption spectrum of Form IV in
potassium
bromide.
Detailed Description of the Invention
According to a feature of the present invention, there is provided a novel
polymorphic Form-I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine-2, 4-dione maleate, and its stereoisomers having the formula I
which is
characterized by the following data:
DSC endotherm at 100.53°C (on set at 88.65°C) (Fig. 1).
X Ray powder diffraction (20) : 10.90, 14.54, 15.96, 18.46, 18.60, 19.76,
20.72,
21.84, 22.36, 22,46, 23.90, 24.04, 24.72, 25.30, 25.98, 27.44, 29.70 (Fig. 5).
IR (cm 1) : 3435 (m), 2997 (w), 2773 (m), 1750 (m), 1701 (s), 1620 (m), 1510
(m), 1362 (m), 1332 (m), 1237 (s), 1165 (m), 864 (s), 764 (s), 717 (m), 654
(m), 540 (w),
Fig. (10).
According to another feature of the present invention, there is provided a
novel
polymorphic Form-II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine-2,4-dione maleate, and its stereoisomers having the formula I
which is
characterized by the following data:
DSC : Endotherm at 127.67°C (on set at 123.17°C) Fig. 2.
XRD (20): 8.90, 15.40, 18.06, 19.20, 22.30, 23.40, 23.62, 24.80, 25.10, 25.84,
26.72, 27.18, 29.30, 29.54, 29.84, 33.26 (Fig. 6).
IR : 3424 (w), 3040 (w), 2947 (m), 2720 (m), 1751 (m), 1702 (s), 1641 (m),
1618
(m), 1574 (w), 1541 (w), 1412 (w), 1382 (w), 1359 (m), 1326 (m), 1265 (w),
1242 (s),
1213 (w), 1162 (s), 1067 (w), 1031 (w), 865 (s), 773 (s), 713 (s), 667 (m),
576 (w), 539
(m), (Fig. 11).
According to yet another feature of the present invention, there is provided a
novel
polyrnorphic Form-III of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino] ethoxy]benzyl]
thiazolidine-2,4-dione maleate and its stereoisomers having the formula I
which is
characterized by the following data:
DSC : Endotherm at 126.41°C (on set at 122.06°C) (Fig. 3).

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XRD (2Q): 4.60, 8.46, 9.24, 14.98, 15.86, 17.02, 18.60, 21.92, 23.50, 25.00,
25.44, 26.00, 26.38, 28.34, 33.90 (Fig. 7).
IR : 3429 (m), 2949 (m), 2738 (m), 1747 (w), 1704 (s), 1641 (m), 1617 (m),
1513
(s), 1464 (m), 1352 (m), 1244 (s), 1178 (s), 1069 (m), 862 (w), 777 (s), 717
(m), 657 (m),
589 (w) (Fig. 12).
According to yet another feature of the present invention, there is provided a
novel
polymorphic Form-IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine-2,4-dione maleate, and its stereoisomers having the formula I
which is
characterized by the following data:
DSC : Endotherm at 125.39°C (on set at 121.03°C) (Fig. 4).
XRD (20): 7.4, 8.8, 9.54, 14.98, 15.32, 15.82, 16.90, 17.70, 18.40, 18.54,
19.08,
19.72, 20.22, 20.48, 21.36, 21,66, 22.18, 22.58, 23.32, 23.96, 24.52, 25.38,
26.48, 27.00,
27 ~58, 27.94, 28.34, 28.54, 28.84, 29.10, 29.86, 30.02, 30.40, 30.52, 30.84,
31.40, 31.94
(Fig. 8).
IR : 3433 (m), 2930 (m), 1753 (w), 1705 (s), 1642 (w), 1617 (m), 1512 (s),
1467
(w), 1351 (m), 1244 (m), 1162 (m), 1061 (w), 864 (s), 765 (s), 714 (w), 658
(m), 526 (w)
(Fig. 13).
According to another feature of the present invention, there is provided a
process
for the preparation of novel polymorphic Form-I of 5-[4-[2-[N-methyl-N-(2-
pyridyl)
amino]ethoxy]benzyl]thiazolidine-2,4-dione maleate, of the formula I, having
the
characteristics described earlier, which comprises:
(i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine-2,4-dione maleate, employing known methods and dissolving in
ethanol,
(ii) heating the solution in a steam bath till the solid completely dissolved,
(iii) filtering the clear solution and cooling to room temperature over a
period
ofl8h,
(iv) isolating the Form I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate formed.
According to another feature of the present invention, there is provided a
process
for the preparation of novel polymorphic Form-II of 5-[4-[2-[N-methyl-N-(2-
pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate, of the formula I,
having the
characteristics described earlier, which comprises:

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_$_
(i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine-2,4-dione maleate, employing known methods and dissolving in
acetone,
(ii) heating the solution in a steam bath till the solid completely dissolved,
(iii) filtering the clear solution and cooling to room temperature over a
period
ofl8h,
(iv) isolating the Form II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate formed.
According to another feature of the present invention, there is provided a
process
for the preparation of novel polymorphic Form-III of 5-[4-[2-[N-methyl-N-(2-
pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate, of the formula I,
having the
characteristics described earlier, which comprises:
(i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine- 2,4-dione maleate, employing known methods and dissolving in
methanol,
(ii) heating the solution in a steam bath till the solid completely dissolved,
(iii) filtering the clear solution and cooling to room temperature over a
period
ofl8h,
(iv) isolating the Form III of 5-~4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate formed.
According to yet another feature of the present invention, there is provided a
process for the preparation of novel polymorphic Form-IV of 5-[4-[2-[N-methyl-
N-(2-
~pyridyl)amino] ethoxy]benzyl]thiazolidine-2,4-dione maleate of the formula I,
having the
characteristics described earlier, which comprises:
(i) synthesizing 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]
thiazolidine-2,4-dione maleate, employing known methods and dissolving in 1,4-
dioxane,
(ii) heating the solution in a steam bath till the solid completely dissolved,
(iii) filtering the clean solution and cooling to room temperature over a
period
ofl8h,
(iv) isolating the Form IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]
benzyl]thiazolidine-2,4-dione maleate formed.
The stereoisomers of the compounds forming part of this invention may be
prepared by using reactants in their single enantiomeric form in the process
wherever
possible or by conducting the reaction in the presence of reagents or
catalysts in their

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single enantiomer form or by resolving the mixture of stereoisomers by
conventional
methods. Some of the preferred methods include use of microbial resolution,
resolving
the diastereomeric salts formed with chiral acids such as mandelic acid,
camphorsulfonic
acid, tartaric acid, lactic acid, and the like wherever applicable or chiral
bases such as
brucine, cinchona alkaloids and their derivatives and the like. Commonly used
methods
are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley
Interscience, 1981. Conventional reaction conditions may be employed to
convert acid
into an amide; the diastereomers may be separated either by fractional
crystallization or
chromatography and the stereoisomers of compound of formula (I) may be
prepared by
hydrolyzing the pure diastereomeric amide.
The present invention also envisages a pharmaceutical composition comprising
any of the polymorphic Forms I to IV of 5-[4-[2-[N-methyl-N-(2-
pyridyl)amino]ethoxy]
benzyl] thiazolidine-2,4-dione maleate, of the formula (I) and a
pharmaceutically
acceptable carrier .
The present invention also envisages a pharmaceutical composition comprising a
mixture of any of polymorphic Forms I to IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)
amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate, of the formula (1~ and a
pharmaceutically acceptable carrier .
The pharmaceutical composition may be in the forms normally employed, such as
tablets, capsules, powders, syrups, solutions, suspensions and the like, may
contain
flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents,
or in suitable
sterile media to form injectable solutions or suspensions. Such compositions
typically
contain from 1 to 25%, preferably 1 to 15% by weight of active ingredient, the
remainder
of the composition being pharmaceutically acceptable carriers, diluents or
solvents.
The polymorphic forms of the formula (I) as defined above are clinically
administered to mammals, including man, via either oral, nasal, pulmonary,
transdermal
or parenteral, rectal, depot, subcutaneous, intravenous, intraurethral,
intramuscular,
intranasal, ophthalmic solution or an ointment. Administration by the oral
route is
preferred, being more convenient and avoiding the possible pain and irritation
of
injection. However, in circumstances where the patient cannot swallow the
medication,
or absorption following oral administration is impaired, as by disease or
other
abnormality, it is essential that the drug be administered parenterally. By
either route, the
dosage is in the range of about 0.01 to about 100 mg/kg body weight of the
subject per

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day or preferably about 0.01 to about 30 mg/kg body weight per day
administered singly
or as a divided dose. However, the optimum dosage for the individual subject
being
treated will be determined by the person responsible for treatment, generally
smaller
doses being administered initially and thereafter increments made to determine
the most
suitable dosage.
Suitable pharmaceutically acceptable Garners include solid fillers or diluents
and
sterile aqueous or organic solutions. The active ingredient will be present in
such
pharmaceutical compositions in the amounts sufficient to provide the desired
dosage in
the range as described above. Thus, for oral administration, the polyrnorphic
form can be
combined with a suitable solid or liquid Garner or diluent to form capsules,
tablets,
powders, syrups, solutions, suspensions and the like. The pharmaceutical
compositions,
may, if desired, contain additional components such as flavourants,
sweeteners, excipients
and the like. For parenteral administration, the polymorphic form can be
combined with
sterile aqueous or organic media to form injectable solutions or suspensions.
For
example, solutions in sesame or peanut oil, aqueous propylene glycol and the
like can be
used, as well as aqueous solutions of water-soluble pharmaceutically-
acceptable acid
addition salts or salts with base of the compounds. Aqueous solutions with the
active
ingredient dissolved in polyhydroxylated castor oil may also be used for
injectable
solutions. The injectable solutions prepared in this manner can then be
administered
intravenously, intraperitoneally, subcutaneously, or intramuscularly, with
intramuscular
administration being preferred in humans.
For nasal administration, the preparation may contain the polymorphic forms of
the present invention dissolved or suspended in a liquid carrier, in
particular an aqueous
Garner, for aerosol application. The carrier may contain additives such as
solubilizing
agents, such as propylene glycol, surfactants, absorption enhancers such as
lecithin
(phosphatidylcholine) or cyclodextrin or preservatives such as parabenes.
Tablets, dragees or capsules having talc and/or a carbohydrate carned binder
or
the like are particularly suitable for any oral application. Preferably,
carriers for tablets,
dragees or capsules include lactose, corn starch and/or potato starch. A syrup
or elixir
can be used in cases where a sweetened vehicle can be employed.

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A typical tablet production method is exemplified below:
Tablet Production Example:
a) 1) Active ingredient 30
g
2) Lactose 95
g
3) Corn starch 30
g
4) Carboxymethyl cellulose 44
g
5) Magnesium stearate 1 g
200 g for 1000 tablets
The ingredients 1 to 3 are uniformly blended with water and granulated after
drying under reduced pressure. The ingredient 4 and 5 are mixed well with the
granules
and compressed by a tabletting machine to prepare 1000 tablets each containing
30 mg of
active ingredient.
b) 1) Active ingredient 30 g
2) Calcium phosphate 90 g
3) Lactose 40 g
4) Corn starch 35 g
5) Polyvinyl pyrrolidone 3.5
g
6) Magnesium stearate 1.5
g
200 g for 1000 tablets
The ingredients 1-4 are uniformly moistened with an aqueous solution of 5 and
granulated after drying under reduced pressure. Ingredient 6 is added and
granules are
compressed by a tabletting machine to prepare 1000 tablets containing 30 mg of
ingredient 1.
The present invention is described in detail in the examples given below which
are
provided by way of illustration only and therefore should not be construed to
limit the
scope of the invention.
EXAMPLES
Example-1
A mixture of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-
2,4-dione (69 g, 0.19 M) and malefic acid (22.~ g, 0.19 M) was heated under
reflux while
stirring in iso-propanol (1.0 L) until a clear solution was obtained (1-2 h).
The reaction

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mass was allowed to cool to RT while stirring for 15-20 h. The white to off
white
crystalline compound was filtered, washed with iso-propanol (3 x 100 ml) and
pet. ether
(2 x 100 ml) dried to furnish white to off white product (84.5 g; Yield :
92%).
Exam lt~ a - 2
1 g of the 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-
dione maleate obtained by the process as described in Example-1 was taken in
10 ml
EtOH and heated on a steam bath till the solid completely dissolved. The clear
solution
was allowed to cool to RT over a period of 18 h to yield 80% of >99% pure
polymorphic
Form I of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-
dione
maleate.
Example - 3
1 g of the 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-
dione maleate obtained by the process as described in Example-1 was taken in
50 ml
acetone and heated on a steam bath till the solid completely dissolved. The
solution was
allowed to cool to RT over a period of 18 h to yield 60% of > 99% pure
polymorphic
Form II of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-
dione
maleate.
Example - 4
1 g of the 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-
dione maleate obtained by the process as described in Example-1 was dissolved
in 10 ml
of methanol and heated on a steam bath till the solid completely dissolved.
The clear
solution was filtered and allowed to cool to RT over a period of 18 h to yield
75% of >
99% pure polymorphic Form III of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]
benzyl] thiazolidine-2,4-dione maleate.
Example - 5
1 g of the 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-
dione maleate obtained by the process as described in Example-1 was taken in
10 ml 1,4-
dioxane and heated on a steam bath till the solid completely dissolved. The
clear solution
was allowed to cool to RT over a period of 18 h to yield 70% of > 99% pure
polymorphic
Form IV of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-
dione
maleate.

Representative Drawing