U.S. patent application number 10/142857 was filed with the patent office on 2002-11-21 for novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them.
This patent application is currently assigned to Dr. Reddy's Research Foundation. Invention is credited to Dharmaraja, Sreenivasa Rao, Ebdrup, Soren, Gaddam, Om Reddy, Krishnamurthi, Vyas, Lugstein, Petra Christine, Mamillapalli, Ramabhadra Sarma, Potlapally, Rajender Kumar, Sirisilla, Raju.
Application Number | 20020173647 10/142857 |
Document ID | / |
Family ID | 56290007 |
Filed Date | 2002-11-21 |
United States Patent
Application |
20020173647 |
Kind Code |
A1 |
Gaddam, Om Reddy ; et
al. |
November 21, 2002 |
Novel polymorphic forms of an antidiabetic agent: process for their
preparation and a pharmaceutical composition containing them
Abstract
This invention relates to novel polymorphic/pseudopolymorphic
forms of arginine salt of
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropano- ic acid,
having the formula I shown below. 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 and hypolipidemic agent, than the novel
3-[4-[2-(phenoxazin-10-yl)ethoxy]phen- yl]-2-ethoxypropanoic acid.
1
Inventors: |
Gaddam, Om Reddy;
(Hyderabad, IN) ; Potlapally, Rajender Kumar;
(Hyderabad, IN) ; Sirisilla, Raju; (Hyderabad,
IN) ; Krishnamurthi, Vyas; (Hyderabad, IN) ;
Dharmaraja, Sreenivasa Rao; (Hyderabad, IN) ;
Mamillapalli, Ramabhadra Sarma; (Hyderabad, IN) ;
Ebdrup, Soren; (Copenhagen, DK) ; Lugstein, Petra
Christine; (Wien, AT) |
Correspondence
Address: |
LADAS & PARRY
26 WEST 61ST STREET
NEW YORK
NY
10023
US
|
Assignee: |
Dr. Reddy's Research
Foundation
|
Family ID: |
56290007 |
Appl. No.: |
10/142857 |
Filed: |
May 9, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10142857 |
May 9, 2002 |
|
|
|
09550862 |
Apr 17, 2000 |
|
|
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Current U.S.
Class: |
544/102 |
Current CPC
Class: |
A61K 31/538 20130101;
A61P 3/10 20180101; C07C 279/14 20130101; A61P 3/04 20180101; C07D
265/38 20130101 |
Class at
Publication: |
544/102 |
International
Class: |
C07D 265/38 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 16, 1999 |
IB |
PCT/IB99/00681 |
Claims
We claim:
1. A polymorphic Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-- yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I, 4which is characterized by the data described
hereunder: DSC: Endotherms at 181.21.degree. C. (onset at
177.70.degree. C.) X-ray powder diffraction (2.theta.): 8.18,
12.40, 16.66, 18.80, 19.44, 22.32, 22.84, 23.10, 23.50, 24.72,
29.84, Infrared absorption bands (cm.sup.-1): 3249, 3062, 1709,
1587, 1489, 1374, 1272, 1243, 1112, 1043, 919, 737, 673, 543.
2. A polymorphic Form-II of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I, 5which is characterized by the data described
hereunder: DSC: Endotherms at 131.degree. C., 166.24.degree. C. and
178.96.degree. C. Exotherm at 169.73.degree. C. X-ray powder
diffraction (2.theta.): 6.78, 11.5, 12.08, 16.44, 19.34, 22.30,
22.72, 24.40, 26.66 Infrared absorption bands (cm.sup.-1): 3055,
1711, 1589, 1510, 1491, 1376, 1274, 1111, 1039, 810, 730, 543.
3. A polymorphic Form-III of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I, 6which is characterized by the data described
hereunder: DSC: Exotherm at 168.00.degree. C. Endotherm at
182.20.degree. C. (onset at 171.degree. C.), Small endotherms at
99.66.degree. C., 164.38.degree. C. X-ray powder diffraction
(2.theta.): 6.80, 12.10, 15.84, 17.02, 19.40, 22.32, 22.68, 2438,
26.36, Infrared absorption bands (cm.sup.-1): 3061, 1710, 1588,
1510, 1491, 1379, 1273, 1110, 1040, 805, 739, and 543.
4. A polymorphic Form-IV of L-arginine salt of (2S)
3-(4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I, 7which is characterized by the data described
hereunder: DSC: Small Exotherm at 171.80.degree. C. Endotherms at
149.85.degree. C., 185.60.degree. C. (onset at 147.78.degree. C.)
Small Endotherm at 164.51.degree. C. X-ray powder diffraction
(2.theta.): 6.78, 12.66, 15.96, 16.54, 19.34, 22.78, 24.42, 26.70,
31.70, Infrared absorption bands (cm.sup.-1): 3056, 1711, 1589,
1493, 1381, 1274, 1242, 1101, 1060, 805, 743, and 543.7.
5. A polymorphic Form-V of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-- yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I, 8which is characterized by the data described
hereunder: DSC: Small exotherm at 173.82.degree. C. Endotherm at
185.95.degree. C., (onset at 178.09.degree. C.) Small endotherms at
119.81.degree. C., 164.69.degree. C., 172.44.degree. C. X-ray
powder diffraction (2.theta.): 6.76, 12.10, 15.96, 17.00, 18.50,
19.40, 22.38, 22.44, 24.44, 26.30, Infrared absorption bands
(cm.sup.-1). 3266, 3055, 1711, 1589, 1510, 1492, 1379, 1274, 1175,
1111, 1040, 918, 819, 730, 676, 544.
6. A polymorphic Form-VI of L-arginine salt of (2S)
3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I, 9which is characterized by the data described
hereunder: DSC: Exotherm at 157.98.degree. C., Endotherms at
179.11.degree. C. and 183.69.degree. C. (onset at 157.98.degree.
C.), Small endotherm at 77.80.degree. C. X-ray powder diffraction
(2.theta.): No diffraction peaks due to its amorphous nature,
Infrared absorption bands (cm.sup.-1): 3065, 1629,.1490, 1377,
1273, 1244, 1109, 1042, 805, 740, 539.
7. A polymorphic Form-VII of L-arginine salt of (2S)
3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I, 10which is characterized by the data
described hereunder: DSC: Exotherm at 132.93.degree. C., Endotherms
at 176.63.degree. C. (onset at 169.06.degree. C.) and
184.09.degree. C. X-ray powder diffraction (2.theta.): No
diffraction peaks due to its amorphous nature, Infrared absorption
bands (cm.sup.-1): 3065, 1629, 1490, 1377, 1273, 1109, 1042, 740,
541.
8. A polymorphic Form-VIII of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I, 11which is characterized by the data
described hereunder: DSC: Exotherm at 158.27.degree. C. Endotherm
at 178.12.degree. C. (onset at 167.15 C.), Small Endotherm at
152.72.degree. C. X-ray powder diffraction (2.theta.): 4.16, 11.02,
15.94, 19.50, 20.22, 22.22, 27.38, Infrared absorption bands
(cm.sup.-1): 3151, 1629, 1490, 1378, 1272, 1244, 1104, 1041, 742,
549.
9. A polymorphic Form-IX of L-arginine salt of (2S)
3-(4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I, 12which is characterized by the data
described hereunder: DSC: Endotherm at 176.67.degree. C. (onset at
173.36.degree. C.), (FIG. 21) X-ray powder diffraction (2.theta.):
8.20, 12.42, 16.66, 18.80, 19.44, 22.30, 23.08, 27.38, 28.48,
29:84, (FIG. 9) Infrared absorption bands (cm.sup.-1): 3066, 1588,
1489, 1376, 1273, 1243, 1110, 1043, 919, 805, 737, 543, (FIG.
33)
10. A polymorphic Form-X of L-arginine, salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I, 13which is characterized-by the data
described hereunder: DSC: Endotherm at 184.53.degree. C.,) Exotherm
at, 162.67.degree. C. X-ray powder diffraction (2.theta.): No
diffraction peaks due to its amorphous nature, Infrared absorption
bands (cm.sup.-1): 3413, 1630, 1511, 1491, 1377, 1273, 1244, 1176,
1108, 741.
11. A polymorphic Form-XI of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I, 14which is characterized by the data
described hereunder: DSC: Endotherm at 184.40.degree. C. (onset at
177.67.degree. C.), X-ray powder diffraction (2.theta.): 7.38,
7.56, 11.90, 12.32, 14.80, 16.40, 19.58, 20.48, 22.34, 22.90,
23.54, Infrared absorption bands (cm.sup.-1): 3383, 2925, 1629,
1510, 1490, 1377, 1273, 1243, 1090, 1041, 739, 539.
12. A mixture of polymorphic Form I and X of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, having the formula I, 15which is characterized by the
following data: DSC: Endotherms at 181.28.degree. C.,
185.31.degree. C., (onset at 173.54.degree. C.) X-ray powder
diffraction (2.theta.): 8.16, 12.40, 16.64, 18.78, 19.42, 22.34,
22.80. 23.08, 29.84, Infrared absorption bands (cm.sup.-1): 3247,
3066, 1708, 1587, 1510, 1489, 1375, 1273, 1244, 1178, 1111, 1043,
805, 737, 673, 543.
13. A pharmaceutical composition comprising any one of polymorphic
Form selected from Form I to XI or a mixture of polymorphic Form I
and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid,
having the formula I 16and a pharmaceutically acceptable carrier,
diluent, excipient or solvate.
14. A process for the preparation of the polymorphic Form-I of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the characteristics defined in claim 1, which comprises: (i)
synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropan- oic acid,
employing known methods and dissolving in an organic solvent, (ii)
adding L-arginine dissolved in water slowly with constant stirring
to the solution obtained in step (i), (iii) stirring the reaction
mixture at a temperature of 40-80.degree. C. for a period in the
range of 18-30 h to obtain a white crystalline precipitate, (iv)
filtering the white crystalline precipitate obtained in step (iii)
above and (v) drying under vacuum at a temperature of 40-45.degree.
C. for a period in the range of 4-0.16 h to yield Form-I of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
15. A process for the preparation of the polymorphic Form-I of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the characteristics defined in claim 1, which comprises: (i)
synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropan- oic acid,
employing known methods, and dissolving in an organic solvent, (ii)
adding L-arginine dissolved in water slowly with constant stirring
to the solution obtained in: step (i), (iii) stirring the reaction
mixture at room temperature for a period in the range of 90-100 h
to obtain a white crystalline precipitate, (iv) filtering the white
crystalline precipitate obtained in step (iii) above and (v) drying
under vacuum at a temperature of 40-45.degree. C. for a period in
the range of 4-16 h to yield Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-- yl)ethoxy]phenyl]-2-ethoxypropanoic
acid.
16. A process for the preparation of the polymorphic Form-II of
L-arginine salt of (2S)
3-[4-2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxyropanoic acid,
having the characteristics defined in claim 2, which comprises: (i)
synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropan- oic acid,
employing known methods and dissolving in acetone, (ii) adding
L-arginine dissolved in water slowly with constant stirring to the
solution obtained in step (i), (iii) stirring the reaction mixture
at room temperature for a period in the range of 18-30 h to obtain
a-white crystalline precipitate (iv) filtering the white
crystalline precipitate obtained in step (iii) above and (v) drying
under vacuum at a temperature of 40-45.degree. C. for a period in
the range of 4-16 h to yield Form-II of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-eth- oxypropanoic
acid.
17. A process for the preparation of the polymorphic Form-II of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the characteristics defined in claim 3, which comprises: (i)
synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropan- oic acid,
employing known methods and dissolving in 1,4-dioxane, (ii) adding
L-arginine dissolved in Water slowly with constant stirring to the
solution obtained in step (i), (iii) stirring the reaction mixture
at room temperature for a period in the range of 18-30 h to obtain
a white crystalline precipitate (iv) filtering the white
crystalline precipitate obtained in step (iii) above and (v) drying
wider vacuum at a temperature of-40-45.degree. C. for a period in
the range of 4-16 h to yield Form-III of L-arginine salt of (2S)
3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-etho- xypropanoic
acid.
18. A process for the preparation of the polymorphic Form-IV of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the characteristics defined in claim 4, which comprises: (i)
synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropan- oic acid,
employing known methods and dissolving in dimnethyl sulfoxide, (ii)
adding L-arginine dissolved in water slowly with constant stirring
to the solution obtained in step (i), (iii) stirring the reaction
mixture at room temperature for a period in the range of 18-30 h to
obtain a white crystalline precipitate (iv) filtering the white
crystalline precipitate obtained in step (iii) above and (v.)
drying under vacuum at a temperature of 40-45.degree. C. for a
period in the range of 4-16 h to yield Form-IV of L-arginine salt
of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy-
]phenyl]-2-ethoxypropanoic acid.
19. A process for the preparation of the polymorphic Form-V of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the characteristics defined in claim 5, which compnses: (i)
synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropan- oic acid,
employing known methods and dissolving in dimethyl formamide,
(ii)-adding L-arginine dissolved in water slowly with constant
stifling in the solution obtained in step (i), (iii) stirring the
reaction mixture at room temperature for a period in the range of
18-30 h to obtain a white crystalline precipitate, (iv) filtering
the white crystalline precipitate obtained in step (iii) above and
(vi) drying under vacuum at a temperature of 40-45.degree. C. for a
period in the range of 4-16 h to yield Form-V of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]- phenyl]-2-ethoxypropanoic
acid.
20. A process for the preparation of the polymorphic Form-VI of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the characteristics defined in claim 6, which comprises: (i)
dissolving any of the polymorphic Forms I-V of L-arginine salt of
(2S) 3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, in water and (ii) freeze drying the resulting solution to
yield an amorphous white powder of Form-VI of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)et- hoxy]phenyl]-2-ethoxypropanoic
acid.
21. A process for the preparation of the polymorphic Form-VII of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid,
having the characteristics defined in claim 7, which comprises: (i)
dissolving any of -the polymorphic Forms I-V of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, in methanol and (ii) evaporating the resulting solution under
vacuum to obtain an amorphous white powder of Form-VII of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid.
22. A process for the preparation of the polymorphic Form-VIII of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid,
having the characteristics defined in claim 8, which comprises: (i)
synthesizing (2S) 3-[4-[2phenoxazin-10-yl)ethoxy]phenyl]-2-
-ethoxypropanoic acid, employing known methods and dissolving in an
organic solvent, (ii) adding L-arginine dissolved in water slowly
with constant stirring in the solution obtained in step (i), (iii)
stirring the reaction mixture at a temperature of 40-80.degree. C.
for a period in the range of 18-30 h to obtain a white crystalline
precipitate, (iv) filtering the white crystalline precipitate
obtained in step (iii) above and (v) drying under vacuum at a
temperature of 40-45.degree. C. for a period in the range of 4-16 h
to yield Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
(vi) refluxing the Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl- )ethoxy]phenyl]-2-ethoxypropanoic acid,
obtained above in step (v) in 1,4-dioxane for a period in the range
of 8-16 h and (vii) filtering and drying under vacuum at a
temperature of 40-45.degree. C. for a period in the range of 4-16 h
to yield Form-VIII of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid.
23. A process for the preparation of the polymorphic Form-IX of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid;
having the characteristics defined in claim 9, which comprises (i)
synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropan- oic acid,
employing known methods and dissolving in an organic solvent, (ii)
adding L-arginine dissolved in water slowly with constant stirring
in the solution in I; is obtained in step (i), (iii) stirring the
reaction mixture at a temperature of 40-80.degree. C. for a period
in the range of 18-30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step
(iii) above and (v) drying under vacuum at a temperature of
40-45.degree. C. for a period in the range of 4-16 h to yield
Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
(vi) refluxing the Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl- )ethoxy]phenyl]-2-ethoxypropanoic acid,
obtained above in step (v) in 1,4-dioxane for a period in the range
of 8-16 h, (vii) filtering and drying under vacuum at a temperature
of 40-45.degree. C. for a period in the range of 4-16 h to yield
Form-VIII of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
(viii) refluxing the Form-VIII of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-11-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
obtained in step (vii) above in isopropyl alcohol for a period in
the range of 8-16 h and (viii) filtering and drying under vacuum at
a temperature of 40-45.degree. C. for a period in the range of 4-16
h to yield Form-IX of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic
acid.
24. A process for the preparation of the polymorphic Form-X of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the characteristics defined in claim 10, which comprises:
(i) synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypr- opanoic acid,
employing known methods and dissolving in an organic solvent, (ii)
adding L-arginine dissolved in water slowly with constant stirring
to the solution obtained in step (i), (iii) stirring the reaction
mixture at a temperature of 40-80.degree. C. for a period in the
range of 18-30 h to obtain a white crystalline precipitate, (iv)
filtering the white crystalline precipitate obtained in step (iii)
above and (v) drying under vacuum at a temperature of 40-45.degree.
C. for a period in the range of 4-16 h to yield Form-I of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and
(vi) heating the polymorphic Form-I obtained in step (v) at
185.degree. C. and cooling it to room temperature to yeild Form-X
of L-arginine salt of (2S)
3-[4-[2-(phenoxazn-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
25. A process for the preparation of the polymorphic. Form-XI of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phcnyl]-2-ethoxy- propanoic acid,
having the characteristics defined in claim 1 1, which comprises:
(i) synthesizing (29) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-
-2-ethoxypropanoic acid, employing known methods and dissolving in
an organic solvent, (ii) adding L-arginine dissolved in water
slowly with constant stirring to the solution obtained in step (i),
(iii) stirring the reaction mixture at a temperature of
40-80.degree. C. for a period in the range of 18-30 h to obtain a
white crystalline precipitate, (iv) filtering the white crystalline
precipitate obtained in step (iii) above and (v) drying under
vacuum at a temperature of 40-45.degree. C. for a period in the
range of 4-16 h to yield Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
(vi) heating the polymorphic Form-I obtained in step (v) to
185.degree. C. and cooling it to room temperature to yeild Form-X
of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and
(vii) heating the polymorphic Form-X obtained in step (vi) to
175.degree. C. and cooling it to room temperature to yield Form-XI
of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)etloxylphenyl]-2-ethoxypropanoic
acid.
26. A process for the preparation of the mixture of polymorphic
Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-e- thoxypropanoic acid,
having the characteristics defined in claim 11, which comprises:
(i) synthesizing (2S) 3-[4-[-(phenoxazin-10-yl)ethoxy]phenyl]--
2-ethoxypropanoic acid, employing known methods and dissolving in
an organic solvent (ii) adding L-arginine dissolved in water slowly
with constant stirring in the solution obtained in step (i), (iii)
stirring the reaction mixture at room temperature for a period in
the range of 18-30 h to separate white crystalline powder, (iv)
filtering the white crystalline powder obtained in step (iii) and
(v) drying under vacuum at a temperature of 4045.degree. C. for a
period in the range of 4-16 h to yield mixture of polymorphic Form
I and X of L-arginine salt of (2S)
3-(4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid.
27. A process for the preparation of polymorphic Form I of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the characteristics defined in claim 1, which comprises: (i)
suspending any of the polymorphic Form II to XI or the mixture of
polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in
isopropyl alcohol and stirring in dark conditions at room
temperature for a period of 35-50 h, (ii) filtering and washing
with isoporpyl alcohol and (iii) drying under vacuum at a
temperature of 40-45.degree. C. for a period in the range of 4-16 h
to yield polymorphic Form of I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic
acid.
28. A pharmaceutical composition comprising a mixture of any of
polymorphic Forms I to XI of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of
the formula (I) aid a pharmaceutically acceptable carrier, diluent,
excipient or solvate.
29. A process as claimed in claims 14 and 22 to 26, wherein the
organic solvents arc selected from acetonitrile, ethanol, methanol,
1,4-dioxane, and isopropanol.
30. A pharmaceutical composition as claimed in claim 13, in the
form of a tablot, capsule, powder, syrup, solution or
suspension.
31. 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 XI or a mixture of polymorphic Form I and X of L-arginine
salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]-
phenyl]-2-ethoxypropanoic acid, having the formula I as defined in
claims 1-12 or a pharmaceutical composition as claimed in claims
13, 28 and 30 to a patient in need thereof.
32. A method according to claim 31, 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, glomexulosclerosis, 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.
33. A method according to claim 31 for the treatment and I or
prophylaxis. of disorders related to Syndrome X, which comprises
administering an agonist of PPAR.alpha. and/or PPAR.gamma. of
formula (I).
34. 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
XI or a mixture of polymorphic Form I and X of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]- phenyl]-2-ethoxypropanoic
acid, having the formula I as defined in claims 1-12 or a
pharmaceutical composition as claimed in claims 13 and 30.
35. A method of preventing or treating hyperlipemia,
hypercholesteremia, hyperglycemnia, 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 XI or a mixture of polymorphic Form I and X of L-arginine
salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]-
phenyl]-2-ethoxypropanoic acid, having the formula I as defined in
claims 1-12 or a pharmaceutical composition as claimed in claims
13, 28 and 30 in combination/concomittant with HMG CoA reductase
inhibitors or fibrates or nicotinic acid or cholestyrarine 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.
36. A method according to claim 35, 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.
37. A method according to claim 35 for the treatment and/or
prophylaxis of disorders related to Syndrome X, which comprises
administering a polymorphic Form selected from Form I to XI or a
mixture of polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]- phenyl]-2-ethoxypropanoic acid,
having the formula I as defined in claims 1-12 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.
38. 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
XI or a mixture of polymorphic Form I and X of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2 ethoxypropanoic
acid, having the formula I as defined in claims 1-12 or a
pharmaceutical composition as claimed in claims 13, 28 and 30 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.
39. A method according to claim 35 for the treatment and/or
prophylaxis of disorders related to Syndrome X, which comprises
administering to a patient in need thereof an agonist of
PPAR.alpha. and/or PPAR.gamma. of formula (I) as claimed in claims
1-12 or a pharmaceutical composition according to claim 13 or 30
and HMG CoA reductase inhibitors, fibrates, nicotinic acid,
cholestyra mine, colestipot or probucol or their combination within
such a period as to act synergistically.
40. Use of a polymorphic Form selected from Form I to XI or a
mixture of polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I as defined in claims 1-12 or a pharmaceutical
composition as claimed in claims 13, 28 and 30 for preventing or
treating hyperlipidemia, hypercholesteremia, hyperglycomia,
osteoporosis, obesity, glucose intolerance, leptin resistance,
insulin resistance, or diseases in which insulin resistance is the
underlying pathophysiological mechanism.
41. Use of a polymorphic Form according to claim 40, 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 uephrosclerosis, retinopathy,
nepbropathy, 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.
42. Use of a polymorphic Form selected from Form I to XI or a
mixture of polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I as defined in claims 1-12 or a pharmaceutical
composition as claimed in claims 13, 28 and 30 for reducing plasma
glucose, triglycrides, total cholesterol, LDL, VLDL and free fatty
acids in the plasma.
43. Use of a polymorphic Form selected from Form I to XI or a
mixture of polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I as defined in claims 1-12 or a pharmaceutical
composition as claimed in claims 13, 28 and 30 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, hypercholesterernia, 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.
44. Use of a polymorphic Form according to claim 43, 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.
45. Use of a polymnorphic Form selected from Form I to M or a
mixture of polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I as defined in claims 1-12 or a pharmaceutical
composition as claimed in claims 13, 28 and 30 in
combination/conconittant 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.
46. Use of a polymorphic Form selected from Form I to M or a
mixture of polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I as defined in claims 1-12 or a pharmaceutical
composition as claimed in claims 13, 28 and 30 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.
47. Use of a polymorphic form according to claim 37, wherein the
disease is type II diabetes, impaired glucose tolerance,
dyslipidaemia, disorders related to Syrndrome 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.
48. Use of a polymorphic Form selected from Form I to XI or a
mixture of polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I as defined in claims 1-12 or a pharmaceutical
composition as claimed in claims 13, 28 and 30 for preparing a
medicament for reducing plasma glucose, triglycerides, total
cholesterol, LDL, VLDL and free fatty acids in the plasma.
49. Use of a polymorphic Form selected from Form I to XI or a
mixture of polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I as defined in claims 1-12 or a pharmaceutical
composition as claimed in claims 13, 28 and 30 for preparing a
medicament in combination/concomittant with UMG CoA reductase
inhibitors, fibrates, nicotinic acid, cholestyramife, colestipol or
probucol for preventing or treating hyperlipemia,
hypercholesteremria, hyperglycemia, osteoporosis, obesity, glucose
intolerance, leptin resistance, insulin resistance, or diseases in
which insulin resistance is the underlying pathophysiolggical
mechanism.
50. Use of a polymorphic form according to claim 49, 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 (COS), 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.
51. Use of a polymorphic Form selected from Form I to XI or a
mixture of polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(henoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I as defined in claims 1-12 or a pharmaceutical
composition as claimed in claims 13, 28 and 30 for preparing a
medicament in. combination/concomittant with HMG CoA reductase
inhibitors, fibrates, nicotini acid, cholestyramine, colestipol or
probucol for reducing plasma glucose:, triglycerides, total
cholesterol, LDL, VLDL or free fatty acids in the plasma.
52. 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 XI or a mixture of
polymorphic Form I and X of L-arginine salt of
(2S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic
acid, having the formula I as defined in claims 1-12 or a
pharmaceutical composition as claimed in claims 13, 28 and 30.
53. A medicine according to claim 52, 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.
54. 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 XI or a mixture of polymorphic Form I and X -of
L-argnine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I as defined in claims 1-12 or a pharmaceutical
composition as claimed in claims 13, 28 and 30.
55. 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 XI
or a mixture of polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I as defined in claims 1-12 or a pharmaceutical
composition as claimed in claims 13, 28 and 30 and HMG CoA
reductase inhibitors, fibrates, nicotinic acid, cholestyramine,
colestipol or probucol.
56. A medicine according to claim 55, 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, myotoriic
dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.
57. 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 XI or a
mixture of polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I as defined in claims 1-12 or a pharmaceutical
composition as claimed in claims 13, 28 and 30 and HMG CoA
reductase inhibitors, fibrates, nicotinic acid, cholestyranine,
colestipol or probucol.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to novel
polymorphic/pseudopolymorphic forms of arginine salt of
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxyprop- anoic acid,
preferably, L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)-
ethoxy]phenyl]-2-ethokypropanoic acid, having the formula I shown
below. 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 and
hypolipidemic agent, than the novel
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
2
[0002] The present invention also relates to a process for the
preparation of novel polymorphic/pseudopolymorphic Forms of
arginine salt of
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula (I).
[0003] The polymorphic Forms of argine salt of
3-[4-[2-(phenoxazin-10-yl)e- thoxy]phenyl]-2-ethoxyproptoic acid,
of formula (I) defined above of the present invention lower total
cholesterol (TC); increase high density lipoprotein (HDL) and
decrease low density lipoprotein (LDL), which have a beneficial
effect on coronary heart disease and atherosclerosis.
[0004] The novel polymorphic Forms of arginine salt of
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-etoxypropanoic acid, of
formula (I) defined above of the present 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. These novel polymorphic Forms compounds are useful for
the treatment of familial hypercholesterolemia,
hypertriglyceridemia, lowering of atherogewic lipoproteins, VLDL
(very low density lipoprotein) and LDL. The novel polymorphic Forms
of arginine salt of
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2ethoxypropanoic acid, of
formula (I) of the present invention can be used for the treatment
of certain renal diseases including glomerulouephritis,
glomerulosclerosis, nephrotic syndrome, hypertensive
nephrosclerosis and nephropathy. The novel polymorphic Forms of
arginine salt of 3-[4-[2-(phenoxazin-10-yl)eth-
oxy]phenyl]-2-ethoxypropanoic acid, 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 arginine
salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]ph-
enyl]-2-ethoxypropanoic acid, 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
polymorpbic. Forms of arginine salt of
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of
formula (V) of the present invention are useful in the treatment
and/or prophylaxis of the above said diseases in
combination/conwcomittant with one or more HMG CoA reductase
inhibitors, hypolipidemic, hypolipoproteinemic agents such as
fibric acid derivatives, nicotinic acid, cholestyramine,
colestipol, probucol.
BACKGROUND OF THE INVENTION
[0005] Atherosclerosis and other peripheral vascular diseases are
the major causes effecting the quality of life of millions of
people. Therefore, considerable attention has been directed towards
understanding the etiology of hypercholesterolemia and
hyperlipidemia and development of effective therapeutic
strategies.
[0006] Hypercholesteroleria has been defined as plasma cholesterol
level that exceeds arbitrarily defined value called "normal" level.
Recently, it has been accepted that "ideal" plasma levels of
cholesterol are much below the "normal" level of cholesterol in the
general population and the risk of coronary artery disease (CAD)
increases as cholesterol level rises above the "optimum" (or
"ideal") value. There is clearly a definite cause and
effect-relationship between hypercholesterolemia and CAD,
particularly for individuals with multiple risk factors. Most of
the cholesterol is present in the esterified forms with various
lipoproteins such as Low density lipoprotein (LDL), intermediate
density lipoprotein (IDL), High density lipoprotein (HDL) and
partially as Very low density lipoprotein (CLDL). Studies clearly
indicate that there is an inverse correlationship between CAD and
atherosclerosis with serum HDL-cholesterol concentrations.
(Stampfer et al., N. Engl. J. Med., 325 (1991), 373-381) and the
risk of CAD increases with increasing levels of LDL and VLDL.
[0007] In CAD, generally "fatty streaks" in carotid, coronary and
cerebral arteries, are found which are primarily free and
esterified cholesterol. Miller et al., (Br Med. J., 282 (1981),
1741-1744) have shown that increase in HDL-particles may decrease
the number of sites of stenosis in coronary arteries of human, and
high level of HDL-cholesterol may protect against the progression
of atherosclerosis. Picardo et al., (Arteriosclerosis 6 (1986)
434-441) have shown by in vitro experiment that HDL is capable of
removing cholesterol from cells. They suggest that RDL may deplete
tissues of excess free cholesterol and transfer it to liver
(Macikinnon et, al., J. Biol. chem. 261 (1986), 2548-2552).
Therefore, agents that increase HDL cholesterol would have
therapeutic significance for the treatment of hypercholesterolemia
and coronary heart diseases (CHD).
[0008] Obesity is a disease highly prevalent in affluent societies
and in the developing world and is a major cause of morbidity and
mortality. It is a state of excess body fat accumulation. The
causes of obesity are unclear. It is believed to be of genetic
origin or promoted by an interaction between the genotype and
environment. Irrespective of the cause, the result is fat
deposition due to imbalance between the energy intake versus energy
expenditure. Dieting, exercise and appetite suppression have been a
part of obesity treatment. There is a need for efficient therapy to
fight this disease since it may lead to coronary heart disease,
diabetes, stroke, hyperlipidemia, gout, osteoathritis, reduced
fertility and many other psychological and social problems.
[0009] Diabetes and insulin resistance is yet another disease which
severely effects the. quality of a large population in the world.
Insulin resistance is the diminished ability of insulin to exert
its biological action across a broad range of concentrations. In
insulin resistance, the body secretes abnormally high amounts of
insulin to compensate for this defect; failing which, the plasma
glucose concentration inevitably rises and develops into diabetes.
Among the developed countries, diabetes mellitus is a common
problem and is associated with a variety of abnormalities including
obesity, hypertension, hyper-lipidemia (J. Clin. Invest., (1985) 75
: 809-817; N. Engl. J. Med. (1987) 317: 350-357; J. Clin.
Endocrinol. Metab., (1988) 66 : 580-583; J. Clin. Invest., (1975)
68-957-969) and other renal, complications (See Patent Application
No. WO 95/21608). It is now increasingly being recognized that
insulin resistance and relative hyperinsulinemia have a
contributory role in obesity, hypertension, atherosclerosis and
type 2 diabetes mellitus. The association of insulin resistance
with obesity, hypertension and angina has been described as a
syndrome having insulin resistance as the central pathogenic
link-Syndrome-X.
[0010] Hyperlipidemia is the primary cause for cardiovascular (CVD)
and other penrpheral vascular diseases. High risk of CVD is related
to the higher LDL (Low Density Lipoprotein) and VLDL (Very Low
Density Lipoprotein) seen in hyperlipidemia. Patients having
glucose intolerance/insulin resistance in addition to
hyperlipidemia have higher risk of CVD. Numerous, studies in the
past have shown that lowering of plasma triglycerides and total
cholesterol, in particular LDL and VLDL and increasing HDL
cholesterol help in preventing cardiovascular diseases.
[0011] Peroxisome proliferator activated receptors (SPAR) are
members of the nuclear receptor super family. The gamma (.gamma.).
isoform of PPAR (PPAR.gamma.) has been implicated in regulating
differentiation of adipocytes (Endocrinology, (1994) 135: 798-800)
and energy horneostasis (Cell, (1995) 83: 803-812), whereas the
alpha (.alpha.) isoform of PPAR (PPAR.alpha.) mediates fatty acid
oxidation (Trend. Endocfin. Metab., (1993) 4: 291-296) thereby
resulting in reduction of circulating fee fatty acid in plasma
(Current Biol. (1995) 5: 618-621). PPAR.alpha. agonists have been
found useful for the treatment of obesity (WO 97/36579). It has
been recently disclosed that there exists synergism for the
molecules, which are agonists for both PPAR.alpha. and PPAR.gamma.
and suggested to be useful for the treatment of syndrome X (WO
97/25042). Similar synergism between the insulin sensitizer
(PPAR.gamma. agonist) and HMG CoA reductase inhibitor has been
observed which may be useful for the treatment of atherosclerosis
and xanthoma (EP 0 753 298).
[0012] It is known that PPAR.gamma. plays an important role in
adipocyte differentiation (Cell, (1996)87, 377-389). Ligand
activation of PPAR is sufficient to cause complete terminal
differentiation (Cell, (1994) 79, 1147-1156) including cell cycle
withdrawal. PPAR.gamma. is consistently expressed in certain cells
and activation of this nuclear receptor with PPAR.gamma. agonists
would stimulate the terminal differentiation of adipocyte
precursors and cause is morphological and molecular changes
characteristics of a more differentiated, less malignant state
(Molecular Cell, (1998), 4.65470; Carcinogenesis, (1998), 1949-53;
Proc. Natl. Acad. Sci., (1997) 94, 237-241) and inhibition of
expression of prostate cancer tissue (Cancer Research (1998)
58:3344-3352). This -would be useful in the treatment of certain
types of cancer, which express PPAR.gamma. and could lead to a
quite nontoxic chemotherapy.
[0013] Leptin resistance is a condition wherein the target cells
are unable to respond to leptin. signal. This may give rise to
obesity due to excess food itake and reduced energy expenditure and
cause impaired glucose tolerance, type 2 diabetes, cardiovascular
diseases and such o'ther interrelated complications. Kallen et al
(Proc. Natl. Acad. Sci. (1996) 93, 5793-5796) have reported that
insulin sensitizers which perhaps due to the PPAR agonist
expression and therefore lower plasma leptin concentrations.
However, it has been recently disclosed that compounds having
insulin sensitizing property also possess leptin sensitization
activity. They lower the circulating plasma leptin concentrations
by improving the target cell response to leptin (WO/98/02159). 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/noncrystalline
(amorphous) forms. This has especially become very interesting
after observing that many antibiotics, antibacterials,
tranquilizers etc. exhibit polymorphism and some/one of the
polymorphic forms of a given drug exhibit superior bio-availability
and consequently show much higher activity compared to other
polymorphs. Sertraline, Frentizole, Ranitidine, Sulfathiazole,
Iudomethacine etc. are some of the important examples of
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. Pat. No. 5,700,820
discloses six polymorphic forms of Troglitazone, U.S. Pat. No.
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 subject of
polymprphism in drugs.
SUMMARY OF THE INVENTION
[0014] With an objective to develop novel polymorphic forms for
lowering cholesterol and reducing body weight with beneficial
effects in the treatment and/or prophylaxis of diseases related to
increased levels of lipids, atherosclerosis, coronary artery
diseases, Syndrome-X, impaired glucose tolerance, insulin
resistance, insuin 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 focussed 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).
[0015] Another objective of the present invention is to provide
polymorphic forms of arginine salt of
3-[4-[2-phenoxazin-10-yl)ethoxy]phe- nyl]-2-ethoxypropanoic acid,
their stereoisomers, their pharmaceutically acceptable solvates and
pharmaceutical compositions containing them or their mixtures which
may have agonist activity against PPAR.alpha. and/or PPAR.gamma.,
and optionally inhibit HMG CoA reductase, in addition to having
agonist activity against PPAR.alpha. and/or PPAR.gamma..
[0016] Another objective of the present invention is to provide
novel polymorphic forms of arginine salt of
3-[4-[2-phenoxazin-10-yl)ethoxy]phe- nyl]-2-etoxypropaxoic acid,
their stereoisomers, pharmaceutically acceptable solvates and
pharmaceutical compositions containing them or their mixtures
having enhanced activities, without toxic effect or with reduced
toxic effect.
[0017] Yet another objective of the present invention to provide a
process for the preparation of novel polymorphic forms of arginine
salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, their stereoisomers, pharmaceutically acceptable
solvates.
[0018] Still another objective of the present invention is to
provide pharmaceutical compositions containing novel polymorphic
forms of arginine salt of
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropano- ic acid,
their stereoisomers, solvates or their mixtures in combination with
suitable carriers, solvents, diluents and other media normally
employed in preparing such compositions.
[0019] In our PCT publication No. WO 99/19313 we have described
novel .beta.-aryl .alpha.-oxy substituted alkylcarboxylic acids of
the general formula (a), 3
[0020] their pharmaceutically salts, their pharmaceutically
solvated and their pharmaceutically acceptable compositions
containing them. The pharmaceutical salts of the compounds of the
general formula (a) includes salts of the organic bases such as
guanine, arginine, guanidine, diethylamine, choline, and the like.
Particularly the compounds disclosed include
3-[4-[2-(henoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid. The
current interest in the field of polymorphism in drugs prompted us
to take up the investigation as to the possibility of polymorphism
in such compounds particularly the arginine salt of
3-[4-[2-(phenoxazin-10-yl)eth- oxy]phenyl]-2-ethoxypropanoic acid.
Our observations and results form the subject matter of the present
invention.
[0021] We have, due to our sustained research directed towards
finding out effective antidiabetic drugs, observed that arginine
salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, exists in different polymorphic forms possessing enhanced
anti diabetic activity. Accordingly we have, in the course of
research, prepared and studied at least eleven polymorphic forms of
arginine salt of
3-[4-[2-(pheuuxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
These polymorphs have been designated, by us, as Forms I, II, III,
IV, V, VI, VII, VII, IX, X and the mixture.
DETAILED DESCRIPTION OF THE INVENTION
[0022] The present invention relates to an observation that
arginine salt of
3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid
exhibits polymorphism, which has not been reported till date. The
polymorphic Forms. I, II, III, IV and V are obtained from different
solvents like isopropyl alcohol, acetone, 1,4-dioxane,
dimethylsulphoxide, and dimnethyliformamide respectively. Form VI
is obtained by dissolving any form (Form I-V) in water and freeze
drying. Similarly Form VII is obtained by dissolving any form (Form
I-V) in methanol and quick evaporation of the solvent under reduced
pressure at 40-60.degree. C. Form VII is obtained by refluxing
Form-I in 1,4-dioxane. Form-IX is obtained by refluxing Form-VIII
in isopropyl alcohol. Form X is prepared by heating Form I to
185.degree. C. and cooling it to room temperature. Form XI is
prepared by heating Form X to 175.degree. C. and cooling it to room
temperature.
[0023] From powder X-ray difraction studies Forms I, II, II, IV, V,
VIII, IX and XI are found to be crystalline in nature. Forms VI,
VII and X did not give any peaks in X-ray diffraction due to
amorphous nature.
[0024] DSC of the polymorphic Form I shows melting endotherm at
181.degree. C. In the mixture of polymorphic Forms I and X there is
an indication to one of the endotherm at 185.degree. C. and
181.degree. C. Form II displays endotherms at 131.degree. C.,
166.degree. C., 178.degree. C., 214.degree. C. and 276.degree. C.
and exotherms at 169.degree. C. Form III exhibits melting endotherm
182.degree. C. in addition to an exotherm at 168.degree. C. Form IV
exhibits endotherms at 149.degree. C., 164.degree. C. and
185.degree. C. and an exotherm at 171.degree. C. Form V exhibits
endotherms at 119.degree. C., 164.degree. C., 172.degree. C. and
185.degree. C. in addition to a melting exotherm at 173.degree. C.
Form VI exhibits exotherm at 157.degree. C. and endotherms at
179.degree. C. and 183.degree. C. Form VII exhibits exotherm at
132.degree. C. and endotherms at 176.degree. C. and 184.degree. C.
Form III there was a similar exotherm of Form VI at 158.degree. C.
and the melting endotherm at 178.degree. C., whereas in Form IX
there was only one sharp melting endotherm at 176.degree. C. Form X
displays an exotherm at 163.degree. C. and melting endotherm at
184.degree. C. Form XI exhibits a melting endotherm at 184.degree.
C.
[0025] All these polymorphic forms were proved to be identical in
solution as evident from Nuclear Magnetic Resonance (NMR), Ultra
Violet (UV) & Mass spectral data. On the other hand, solid
state techniques like Differential Scanning Calorimetry (DSC),
Powder, X-Ray Diffactometry (XR) and Infra Red spectroscopy (IR)
revealed the difference among these forms.
BRIEF DESCRIPTION OF THE FIGURES
[0026] X-ray powder diffraction pattern has been obtained on a
Rigaku D/Max 2200 model diffractometer equiped with horizontal
gonimometer in .THETA./2 .THETA. geometry. The copper K
.alpha.(.lambda.=1.5418A) radiation was used and the sample was
scanned between 3-45 degrees
[0027] FIG. 1 is a characteristic X-ray powder diffraction pattern
of Form I.
[0028] FIG. 2 is a characteristic X-ray powder diffraction pattern
of Form II.
[0029] FIG. 3 is a characteristic X-ray powder diffraction pattern
of Form III.
[0030] FIG. 4 is a characteristic X-ray powder diffraction pattern
of Form IV.
[0031] FIG. 6 is a characteristic X-ray powder diffraction pattern
of Form V.
[0032] FIG. 6 is a characteristic X-ray powder diffraction pattern
of Form VI.
[0033] FIG. 7 is a characteristic X-ray powder diffraction pattern
of Form VII.
[0034] FIG. 8 is a characteristic: x-ray powder diffraction pattern
of Form VIII.
[0035] FIG. 9 is a characteristic X-ray powder diffraction pattern
of Form IX.
[0036] FIG. 10 is a characteristic X-ray powder diffraction pattern
of Form X.
[0037] FIG. 11 is a characteristic X-ray powder diffraction pattern
of Form XI.
[0038] FIG. 12 is a characteristic X-ray powder diffraction pattern
of polymorphic form mixture.
[0039] 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.degree. C. at a heating rate of 5.degree. 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 of
30 ml/min.
[0040] FIG. 13 is a characteristic differential scanning
calorimetric thermogram of Form I.
[0041] FIG. 14 is a characteristic differential scanning
calorimetric thermogram of II.
[0042] FIG. 15 is a characteristic differential scanning
calorimetric thermogram of Form III.
[0043] FIG. 16 is a characteristic differential scanning
calorimetric thermogram of Form IV.
[0044] FIG. 17 is a characteristic differential scanning
calorimetric thermogram of Form V.
[0045] FIG. 18 is a characteristic differential scanning
calorimetric thermogram of Form VI.
[0046] FIG. 19 is a characteristic differential scanning
calorimetric thermogram of Form, VII.
[0047] FIG. 20 is a characteristic differential scanning
calorimetric thermogram of Form VIII.
[0048] FIG. 21 is a characteristic differential scanning
calorimetric thermogram of Form IX.
[0049] FIG. 22 is a characteristic differential scanning
calorimetric thermogram of Form X.
[0050] FIG. 23 is a characteristic differential scanning
calorimetric thermogram of Form XI.
[0051] FIG. 24 is a characteristic differential scanning
calorimetric thermogram of polymorphic form mixture.
[0052] FT-IR Spectrum was recorded in solid state as KBr dispersion
using Perkin-Elner 1650 -FT-TR SpectrophQtometer.
[0053] FIG. 25 is a characteristic infrared Absorption spectrum of
Form I in KBr.
[0054] FIG. 26.is a characteristic infrared absorption spectrum of
Form II in KBr.
[0055] FIG. 27 is a characteristic infrared absorption spectrum of
Form III in KBr.
[0056] FIG. 28 is a characteristic infrared absorption spectrum of
Form IV in KBr.
[0057] FIG. 29 is a characteristic infrared absorption spectrum of
Form V in KBr.
[0058] FIG. 30 is a characteristic infrared absorption spectrum of
Form VI in KBr.
[0059] FIG. 31 is a characteristic infrared absorption spectrum of
Form VII in KBr.
[0060] FIG. 32 is a characteristic infrared absorption spectrum of
Form VIII in KBr.
[0061] FIG. 33 is a characteristic infrared absorption spectrum of
Form IX in KBr.
[0062] FIG. 34 is a characteristic infrared absorption spectrum of
Form X in KBr.
[0063] FIG. 35 is a characteristic infrared absorption spectrum of
Form XI in Kr.
[0064] FIG. 36 is a characteristic infrared absorption spectrum of
polymorphic form mixture in KBr.
[0065] According to a feature of the present invention, there is
provided a novel polymorphic Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I which is characterized by the following
data
[0066] DSC: Endotherms at 181.21.degree. C. (onset at
177.70.degree. C.) (FIG. 13)
[0067] X-ray powder diffraction (2.theta.): 8.18, 12,40, 16.66,
18.80, 19.44, 22.32, 22.84, 23.10, 23.50; 24.72, 29.84, (FIG.
1)
[0068] Infrared absorption bands (cm.sup.-1): 3249, 3062, 1709,
.1587, 1489, 1374, 1272, 1243, 1112, 1043, 919, 737, 673, 543,
(FIG. 25)
[0069] According, to another feature of the present invention,
there is provided a novel polymorphic Form-II of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, having the formula I which is characterized by the following
data:
[0070] DSC Endotherms at 131.degree. C., 166.24.degree. C. and
178.96.degree. C. (FIG. 14)
[0071] Exotherm at 169.73.degree. C.
[0072] X-ray powder diffraction (2.theta.): 6.78, 11.5, 12.08,
16.44, 19.34, 22.30, 22.72, 24.40, 26.66 (FIG. 2)
[0073] Infrared absorption bands (cm.sup.-1): 3055, 1711, 1589,
1510, 1491, 1376, 1274, 1111, 1039, 810, 730, 543, (FIG. 26)
[0074] According to yet another feature of the present invention,
there is provided a novel polymorphic Form-III of L-arginine salt
of (2S) 3-[4-[2-(phenoxazin-10 yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, having the formula I which is characterized by the following
data:
[0075] DSC: Endotherm at 182.20.degree. C. (onset at 171.degree.
C.) (FIG. 15)
[0076] Small endotherms at 99.66.degree. C., 164.38.degree. C.
[0077] Exotherm at 168.00.degree. C.
[0078] X-ray powder diffraction (2.theta.): 6.80, 12.10, 15.84,
17.02, 19.40, 22.32, 22.68, 24.38, 26.36 (FIG. 3), 5
[0079] Infrared absorption bands (cm.sup.-1) 3061, 1710, 1588,
1510, 1491, 1379, 1273, 1 10, 1040, 805, 739, and 543, (FIG.
27)
[0080] According to yet another feature of the present invention,
there is provided a novel polymorphic, Form-IV of L-arginine salt
of (2S) 3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropoanoic
acid, having the formula I which is characterized by the following
data:
[0081] DSC: Endotherms at 149.85.degree. C., 185.60.degree. C.
(onset at 147.78.degree. C.) (FIG. 16)
[0082] Small Endotherm at 164.51.degree. C.
[0083] Small Exotherm at 171.80.degree. C.
[0084] X-ray powder diffraction (2.theta.): 6.78, 12.66, 15.96,
16.54, 19.34, 22.78, 24.42, 26.70, 31.70, (FIG. 4)
[0085] Infrared absorption bands (cm.sup.-1): 3056, 1711, 1589,
1493, 1381, 1274, 1242, 1101, 1060, 805; 743, and 543.7, (FIG.
28)
[0086] According to yet another feature of the present invention,
there is provided a novel polymorphic Form-V of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, having the formula I which is characterized by the following
data:
[0087] DSC: Endotherm at 185.95.degree. C., (onset at
178.09.degree. C.) (FIG. 17)
[0088] Small endotherms at 119.81.degree. C., 164.69.degree. C.,
172.44.degree. C.
[0089] Small exotherm at 173.82.degree. C.
[0090] X-ray powder diffraction (2.theta.): 6.76, 12.10, 15.96,
17.00, 18.50, 19.40, 22.38. 22.44, 24.44, 26.30, (FIG. 5)
[0091] Infrared absorption bands (cm.sup.-1): 3266, 3055, 1711,
1589, 1510, 1492, 1379, 1274, 1175, 1111, 1040, 918, 919, 730, 676,
544, (FIG. 29)
[0092] According to yet another feature of the present invention,
there is provided a novel polymorphic Form-VI of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, having the formula I which is characterized by the following
data:
[0093] DSC: Endotherms at 179.11.degree. C. and 183.69.degree. C.
(onset at 157.98.degree. C.), (FIG. 18)
[0094] Small endotherm at 77.80.degree. C.
[0095] Exotherm-at 157.98.degree. C.,
[0096] X-ray powder diffraction (2.theta.): No diffraction peaks
due to its amorphous nature, (FIG. 6)
[0097] Infrared absorption bands (cm.sup.-1): 3065, 1629, 1490,
1377, 1273, 1244, 1109, 1042, 805,740, 539, (FIG. 30)
[0098] According to yet another feature of the present invention,
there is provided a novel polymorphic Form-VII of L-arginine salt
of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, having the formula I which is characterized by the following
data:
[0099] DSC: Endotherms at 176.63.degree. C. (onset at
169.06.degree. C.) and 184.09.degree. C. (FIG. 19)
[0100] Exotherm at 132.93.degree. C.,
[0101] X-ray powder diffraction (2.theta.): No diffraction peaks
due to its amorphous nature, FIG. 7)
[0102] Infrared absorption bands (cm.sup.-1): 3065, 1629, 1490,
1377, 1273, 1109, 1042, 740, 541, (FIG. 31)
[0103] According to yet another feature of the present invention,
there is provided a novel polymorphic Form-VIII of L-arginine salt
of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, having the formula I which is characterized by the following
data:
[0104] DSC: Endotherm at 178.12.degree. C. (onset at 167.15.degree.
C.), (FIG. 20)
[0105] Small Endorthem at -152.72.degree. C.
[0106] Exotherm at 158.27.degree. C.
[0107] X-ray powder diffraction (2.theta.) 4.16, 11.02, 15.94,
19.50, 20.22, 22.22, 27.38, (FIG. 8)
[0108] Infrared absorption bands (cm.sup.-1): 3151, 1629, 1490,
1378, 1272, 1244, 1104, 1041, 742, 549, (FIG. 32)
[0109] According to yet another feature of the present invention,
there is provided a novel polymorphic Form-IX of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-etoxypropanoic
acid, having the formula I which is characterized by the following
data:
[0110] DSC: Endotherm at 176.67.degree. C. (onset at 173.36.degree.
C.), (FIG. 21)
[0111] X-ray powder diffraction (2.theta.): 8.20, 12.42, 16.66,
18.80, 19.44, 22.30, 23.08, 27.38, 28.48, 29.84, (FIG. 9)
[0112] Infrared absorption bands (cm.sup.-1): 3066, 1588, 1489,
1376, 1273, 1243, 1110, 1043, 919, 805, 737, 543, (FIG. 33)
[0113] According to still another feature of the present invention,
there is provided a novel polymorphic Form-X of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, having the formula I which is characterized by the following
data:
[0114] DSC: Endotherm at 184.53.degree. C., (FIG. 22)
[0115] Exotherm at, 162.67.degree. C.
[0116] X-ray powder diffraction (2.theta.): No diffraction peaks
due to its amorphous nature, (FIG. 10)
[0117] Infrared absorption bands (cm.sup.-1): 3413, 1630, 1511,
1491, 1377, 1273, 1244, 1176, 1108, 741, (FIG. 34)
[0118] According to yet another feature of the present invention,
there is provided a novel polymorphic Form-XI of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, having the formula I which is characterized by the following
data:
[0119] DSC: Endotherm at 184.40.degree. C. (onset at 177.67.degree.
C.), (FIG. 23)
[0120] X-ray powder diffraction (2.theta.): 7.38, 7.56, 11.90,
12.32, 14.80, 16.40, 19.58, 20.48, 22.34, 22.90, 23.54, (FIG.
11)
[0121] Infrared-absorption bands (cm.sup.-1): 3383, 2925, 1629,
1510, 1490, 1377, 1273, 1243, 1090, 1041, 739, 539, (FIG. 35)
[0122] According to yet another feature of the present invention,
there is provided a novel mixture of polymorphic Forms I and X of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
having the formula I which is characterized by the following
data:
[0123] DSC: Endotherms at 181.28.degree. C., 185.31.degree. C.,
(onset at 173.54.degree. C.) (FIG. 24)
[0124] X-ray powder diffraction (2.theta.): 8.16, 12.40, 16.64,
18.78, 19.42, 22.34, 22.80, 23.08, 29.84, (FIG. 12)
[0125] Infrared absorption bands (cm.sup.-1): 3247, 3066, 1708,
1587, 1510, 1489, 1375, 1273,1244, 1178,1111, 1043, 805, 737, 673,
543, (FIG. 36)
[0126] According to another feature of the present invention, there
is provided a process for the preparation of novel polymorphic
Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxylphenyl]-2-ethoxy- propanoic acid,
of the formula I, having the characteristics described earlier,
which comprises
[0127] (i) synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid,
employing known methods and dissolving in an organic solvent,
[0128] (ii) adding L-arginine dissolved in water slowly with
constant stirring to the solution obtained in step (i),
[0129] (iii) stirring the reaction mixture at a temperature of
40-80.degree. C. for a period in the range of 1-30 h to obtain a
white crystalline precipitate,
[0130] (iv) filtering the white crystalline precipitate obtained in
step (iii) above and
[0131] (v) drying under vacuum at a temperature of 40-45.degree. C.
for a period in the range of 4-16 h to yield, Form-I of L-arginine
salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid
[0132] The temperature employed in the stirring step (iii) may be
preferably 40-50.degree. C.
[0133] According to another feature of the present invention, there
is provided an alternate process for the preparation of novel
polymorphic Form-I of L-arginine salt of (2S)
3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]- -2-ethoxypropanoic acid,
of the formula I, having the characteristics described earlier,
which comprises:
[0134] (i) synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid,
employing known methods and dissolving in an organic solvent,
[0135] (ii) adding L-arginine dissolved in water slowly with
constant stirring to the solution obtained in step (i),
[0136] (iii) stirring the reaction mixture at room temperature for
a period in the range of 90-100 h to obtain a white crystalline
precipitate,
[0137] (iv) filtering the white crystalline precipitate obtained in
step (iii) above and
[0138] (v) drying under vacuum at a temperature of 40-45.degree. C.
for a period in the range of 4-16 h to yield Form-I of L-arginine
salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid.
[0139] According to another feature of the present invention, there
is provided a process for the preparation of novel polymorphic
Form-II of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid,
of the formula I, having the characteristics described earlier,
which comprises:
[0140] (i) synthesizing (2S)
3-[4-2-phenoxazin-10-yl)ethoxy]phenyl]-2-etho- xypropanoic acid,
employing known methods and dissolving in acetone,
[0141] (ii) adding L-arginine dissolved in water slowly with
constant stirring to the solution obtained in step (i),
[0142] (iii) stirring the reaction mixture at room temperature for
a period in the range of 18-30 h to obtain a white crystalline
precipitate
[0143] (iv) filtering the white crystalline precipitate obtained in
step (iii) above and
[0144] (v) drying under vacuum at a temperature of 40-45.degree. C.
for a period in the range of 4 16 h. to yield Form-II of L-arginine
salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid.
[0145] According to yet another feature of the present invention,
there is provided a process for the preparation of novel
polymorphic Form-III of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid
of the formula I, having the characteristics described earlier,
which comprises:
[0146] (i) synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid,
employing known methods and dissolving in 1,4-dioxane,
[0147] (ii) adding L-arginine dissolved in water slowly with
constant stirring to the solution obtained in step (i),
[0148] (iii) stirring the reaction mixture at room temperature for
a period in the range of 18-30 h to obtain a white crystalline
precipitate
[0149] (iv) filtering the white crystalline precipitate obtained in
step (iii) above and
[0150] (v) drying under vacuum at a temperature of 40-45.degree. C.
for a period in the range of 4-16 h to yield Form-III of L-arginine
salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxylphenyl]-2-ethoxypropanoic
acid.
[0151] According to yet another feature of the present invention,
there is provided a process for the preparation of novel
polymorphic Form-IV of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10yl)ethoxy]phenyl]-2-ethoxyp- ropanoic acid of
the formula I, having the characteristics described earlier, which
comprises:
[0152] (i) synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid,
employing known methods and dissolving in dimethyl sulfoxide,
[0153] (ii) adding L-arginine dissolved in water slowly with
constant stirring to the solution obtained in step (i),
[0154] (iii) stirring the reaction mixture at room temperature for
a period in the range of 18-30 h to obtain a white crystalline
precipitate
[0155] (iv) filtering the white crystalline precipitate obtained in
step (iii) above and
[0156] (v) dying under vacuum at a temperature of 40-45.degree. C.
for a period in the range of 4-16 h to yield. Form-IV of L-arginine
salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid
[0157] According to another feature of the present invention, there
is provided a process for the preparation of novel polymorphic
Form-V of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-y-l)ethoxy]phenyl]-2-ethox- ypropanoic acid
of the formula I, having the characteristics described earlier,
which comprises:
[0158] (i) synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid,
employing known-methods and dissolving in dimethyl formamide,
[0159] (ii) adding L-arginine dissolved in water slowly with
constant stirring in the solution obtained in step (i),
[0160] (iii) stirring the reaction mixture at room temperature for
a period in the range of 18-30 h to obtain a white crystalline
precipitate,
[0161] (iv) filtering the white crystalline precipitate obtained in
step (iii) above and
[0162] (v) drying-under vacuum at a temperature of 40-45.degree. C.
for a period in the range of 4-16 h to yield Form-V of L-arginine
salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-etoxypropanoic acid.
[0163] According to another feature-of the present invention, there
is provided a process for the preparation of novel polymorphic
Form-VI of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid
of the formula I, having the characteristics described earlier,
which comprises:
[0164] (i) dissolving any of the polymorphic Forms I-V of
L-arginine salt of (2S)
3-[4-[2(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in
water and
[0165] (ii) freeze drying the resulting solution to yield an
amorphous white powder of Form-VI of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid.
[0166] According to another feature of the present invention, there
is provided a process for the preparation of novel polymorphic
Form-VII of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid
of the formula I, having the characteristics described earlier,
which comprises:
[0167] (i) dissolving any of the polymorphic Forms I-V of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in
methanol and
[0168] (ii) evaporating the resulting solution under vacuum to
obtain an amorphous white powder of Form-VII of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid.
[0169] According to another feature of the present invention, there
is provided a process for the preparation of novel polymorphic
Form-VIII of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid,
of the formula I, having the characteristics described, earlier,
which comprises:
[0170] (i) synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid,
employing known methods and dissolving in an organic solvent,
[0171] (ii) adding L-arginine dissolved in water slowly with
constant stirring in the solution obtained in step (i),
[0172] (iii) stirring the reaction mixture at a temperature of
40-80.degree. C. for a period in the range of 18-30 h to obtain a
white crystalline precipitate
[0173] (iv) filtering the white crystalline precipitate obtained in
step (iii) above and
[0174] (v) drying under vacuum at a temperature of 40-45.degree. C.
for a period in the range of 4-16 h. to yield Form-I of L-arginine
salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid,
[0175] (vi) refluxing the Form-I of L-arginine salt of (2S)
3-[4-2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
obtained above in step (v) 1,4-dioxane for a period in the range of
8-16 h and
[0176] (vii) filtering and drying under vacuum at a temperature of
40-45.degree. C. for a period in the range of 4-16 b to yield
Form-VIII of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-eth- oxypropanoic
acid.
[0177] According to another feature of the present invention, there
is provided a process for the preparation of novel polymorphic
Form-IX of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid,
of the formula I, having the characteristics described earlier,
which comprises:
[0178] (i) synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid,
employing known methods and dissolving in an organic solvent,
[0179] (ii) adding L-arginine dissolved in water slowly with
constant stirring in the solution obtained in step (i),
[0180] (iii) stirring the reaction mixture at a temperature of
40-80.degree. C. for a period in the range of 18-30 h to obtain a
white crystalline precipitate,
[0181] (iv) filtering the white crystalline precipitate obtained in
step (iii) above and
[0182] (v) drying under vacuum at a temperature of 40-45.degree. C.
for a period in the range of 4-16 h to yield Form-I of L-arginine
salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid,
[0183] (vi) refluxing the Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
obtained above in step (v) in 1,4-dioxane for a period in the range
of 8-16 h,
[0184] (vii) filtering, and drying under vacuum at a temperature of
40-45.degree. C. for a period in the range of 4-16 h to yield
Form-VIII of L-arginine salt of(2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-etho- xypropaiioic
acid,
[0185] (viii) refluxing the Form-VIII of L-arginine salt of (2S)
3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
obtained in step (vii) above in isopropyl alcohol for a period in
the range of 8-16 hand
[0186] (ix) filtering and drying under vacuum at a temperature of
40-45.degree. C. for a period in the range of 4-16 h to yield
Form-IX of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic
acid.
[0187] According to another feature of the present invention, there
is provided a process for the preparation of novel polymorphic
Form-X of L-arginine salt of: (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethox- ypropanoic acid,
of the formula I, having the characteristics described earlier;
which comprises
[0188] (i) synthesizing (2S)
3-[4-[-2-(phenoxazin-10-yl)ethoxy]phenyl]-2-e- thoxypropanoic acid,
employing known methods and dissolving in an organic solvent,
[0189] (ii) adding L-arginine dissolved in water slowly with
constant stirring to the solution obtained in step (i),
[0190] (iii) stirring the reaction mixture at a temperature of
40-80.degree. C. for a period in the range of 18-30 h to obtain a
white crystalline precipitate,
[0191] (iv) filtering the white crystalline precipitate obtained in
step (iii) above and
[0192] (v) drying under vacuum at a temperature of 40-45.degree. C.
for a period in the range of 4-16 h to yield Form-I of L-arginine
salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid
and
[0193] (vi) heating the polymorphic Form-I obtained in step (v) to
185.degree. C. and cooling it to room temperature to yeild Form-X
of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic
acid.
[0194] According to another feature of the present invention, there
is provided a process for the preparation of novel polymorphic
Form-XI of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid,
of the formula I, having the characteristics described earlier,
which comprises:
[0195] (i) synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid,
employing known methods and dissolving in an organic solvent,
[0196] (ii) adding L-arginine dissolved in water slowly with
constant stirring to the solution obtained in step (i),
[0197] (iii) stirring the reaction mixture at a temperature of
40-80.degree. C. for a period in the range of 18-30 h to obtain a
white crystalline precipitate,
[0198] (iv) filtering the white crystalline precipitate obtained in
step (iii) above and
[0199] (v) drying under vacuum at a temperature of 40-45.degree. C.
for a period in the range of 4-16 h to yield Form-I of L-arginine
salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoy]phenyl]-2-ethoxypropanoic acid,
[0200] (vi) heating the polymorphic Form-I obtained in step (v) to
185.degree. C. and cooling it to room temperature to yeild Form-X
of L-arginine salt of (2S)
3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-pthoxyp- ropanoic acid
and
[0201] (vii) heating the polymorphic Form-X obtained in step (vi)
to 175.degree. C. and cooling it to room temperature to yield
Form-XI of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic
acid.
[0202] According to another feature of the present invention, there
is provided a process for the preparation of novel -mixture of
polymorphic Form of I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)etho- xy]phenyl]-2-ethoxypropanoic acid,
of the formula I, described earlier, which comprises:
[0203] (i) synthesizing (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid,
employing known methods and dissolving in an organic solvent,
[0204] (ii) adding L-arginine dissolved in water slowly with
constant stirring in the solution obtained in step (i),
[0205] (iii) stirring the reaction mixture at room temperature for
a period in the range of 18-30 h to separate white crystalline
powder,
[0206] (iv) filtering the white crystalline powder obtained in step
(iii) and
[0207] (v) drying under vacuum at a temperature of 40-45.degree. C.
for a period in the range of 4-16 h to yield mixture of polymorphic
Form of I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]- -2-ethoxypropanoic
acid.
[0208] According to another feature of the present invention, there
is provided an alternate process for the preparation of novel
polymorphic Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl- ]-2-ethoxypropanoic acid,
of the formula I, having the characteristics described earlier,
which comprises
[0209] (i) suspending any of the polymorphic Form II to XI or the
mixture of polymorphic Form I and X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in
isopropyl alcohol and stirring in dark conditions at room
temperature for a period of 35-50 h,
[0210] (ii) filtering and washing with isopropyl alcohol and
[0211] (iii) drying under vacuum at a temperature of 40-45.degree.
C. for a period in the range of 4-16 h to yield polymorphic Form of
I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenayl]-2-ethox- ypropanoic
acid,
[0212] The organic solvents are selected from acetonitrile,
ethanol, methanol and, isopropanol.
[0213] The present invention also envisages a pharmaceutical
composition comprising a polymorphic Forms I to XI of L-arginine
salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of
the formula (I) or the mixture of polymorphic Form of I and X and a
pharmaceutically acceptable carrier.
[0214] The present invention also envisages a pharmaceutical
composition comprising a mixture of any of polymorphic Forms I to
XI of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]pheny]-2-ethoxypropanoic acid, of
the formula (I) and a pharmaceutically acceptable carrier
[0215] 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.
[0216] 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, intanasal,
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 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.
[0217] Suitable pharmaceutically acceptable carriers 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 polymorphic form can be combined with a
suitable solid or liquid carrier 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 his
manner can then be administered intravenously, intraperitoneally,
subcutaneously, or intramuscularly, with intramuscular
administration being preferred in humans.
[0218] 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 carrier, 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.
[0219] Tablets, dragees or capsules having talc and/or a
carbohydrate carried 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.
[0220] A typical tablet production method is exemplified below:
[0221] Tablet Production Example:
1 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
[0222] 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.
2 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
[0223] 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.
EXAMPLES.
[0224] Synthesis of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid,
is described in our WO publication No. WO 99/19313 and copending
PCT application No. PCT/IB99/00683.
[0225] 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.
[0226] Examples 1-4 illustrates the process for the preparation of
the polymorphic Form-1 of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)e- thoxy]phenyl]-2-ethoxypropanoic
acid,
Example-1
[0227] To a solution of (2S)
3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl)-2-eth- oxypropanoic acid (1
g) in ethanol (25 ml).was added L-arginie dissolved in water (1.2
ml) slowly with constant stirring. The reaction mixture was stirred
at 40-50.degree. C. for 24 h. The white crystalline precipitate
formed was separated and dried under vacuum at 40-45.degree. C. for
4 h to yield Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)etho- xy]phenyl]-2-ethoxypropanoic acid
(1.15 g) which has the characteristics given earlier.
Example 2
[0228] To a solution of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxypheryl]-2-eth- oxypropaioic acid (1
g) in isopropyl alcohol (25 ml) was added L-arginine dissolved in
water (1.2 ml) slowly with constant stirring. The reaction mixture
was stirred at 40-50.degree. C. for 24 h. The white crystalline
precipitate formed was separated and dried under vacuum at
40-45.degree. C. for 4 h to yield Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid
(1.27 g) which has the characteristics given earlier.
Example 3
[0229] To a solution of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid
(1 g) in acetonitrile (25 ml) was added L-arginine dissolved in
water (1.2 ml) slowly with constant stirring, The reaction mixture
was stirred at 40-50.degree. C. for 24h. The white crystalline
precipitate formed was separated and dried under vacuum at
40-45.degree. C. for 4 h to yield Form-I L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid
(1.24 g) which has the characteristics given earlier.
Example 4
[0230] To a solution of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid
(1 g) in methanol (15 ml) was added L-arginine dissolved in water
(1.2 ml) slowly with constant stirring. The reaction mixture was
stirred at 40-50.degree. C. for 24 h. The white crystalline
precipitate formed was separated and dried under vacuum at
40-45.degree. C. for 4 h to yield Form-I L-arginine salt of (2S)
3-(4-(2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid
(1.05 g) which has the characteristics given earlier.
Example 5
[0231] To a solution of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid
(1 g) in isopropyl alcohol (25 ml) was added L-arginine dissolved
in water (1.2 ml) slowly with constant stirring. The reaction
mixture was stirred at room temperature for 90-100 h. The white
crystalline precipitate formed was separated and dried under vacuum
at 40-45.degree. C. for 4 h to yield Form-I L-arginine salt of (2S)
3-[4-[2-(henoxazin-10-yl)ethoxylphenyl]-2-ethoxypropanoic acid
(1.05 g) which has the characterstics given earlier.
Example 6
Process for the Preparation of the Polymorphic Form-II of
L-arginine Salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic Acid
[0232] To a solution of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxyphenyl]-2-eth- oxypropanoic acid (1
g) in acetone (25 ml) was added L-arginine dissolved in water (1.2
ml) slowly with constant stirring. The reaction mixture was stirred
at room temperature for 24 h. The white crystalline precipitate
formed was separated and dried under vacuum at 40-45.degree. C. for
4h to yield Form-II of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy- ]phenyl]-2-ethoxypropanoic acid
(1.29 g) which has the characteristics given earlier.
Example 7
Process for the Preparation of the Polymorphic Form-III of
L-arginine Salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]penyl]-2-ethoxypropanoic Acid
[0233] To a solution of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic Acid
(1 g) in 1,4-dioxane (25 ml) was added L-arginine dissolved in
water (1.2 ml) slowly with constant stirring. The reaction mixture
was stirred at room temperature for 24 h. The white crystalline
precipitate formed was separated and dried under vacuum at
40-45.degree. C. for 4 h. to yield Form-III of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid (1.25 g) which has the characteristics given earlier.
Example 8
Process for the Preparation of the Polymorphic Form-IV of
L-arginine Salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic Acid
[0234] To a solution of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid
(1 g) in DMSO (20 ml) was added L-arginine dissolved in water (1.2
ml) slowly with constant stirring. The reaction mixture was stirred
at room temperature for 24 h. The white crystalline precipitate
formed was separated and dried under vacuum at 40-45.degree. C. for
4 h. to yield Form-III of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)et- hoxy]phenyl]-2-ethoxypropanoic acid
(1.3 g) which has the characteristics given earlier.
Example 9
Process for the Preparation of the Polymorphic Form-V of L-arginine
Salt of (2S)
3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic Acid
[0235] To a solution of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid
(1 g) in DMF (25 ml) was added L-arginine dissolved in water (1.2
ml) slowly with constant stirring The reaction mixture was stirred
at room temperature for 24 h. The white crystalline precipitate
formed was separated and dried under vacuum at 40-45.degree. C. for
4 h to yield Form-V of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)etho- xy]phenyl]-2-ethoxypropanoic acid
(1.17 g) which has the characteristics given earlier.
Example 10
Process for the Preparation of the Polymorphic Form-VI of
L-arginine Salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic Acid
[0236] Polymorphic Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1
g), obtained by the process described in Example-2 above was
dissolved in water (10 ml) and freeze dried to yield Form-VI of
L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, as
an amorphous white powder (0.95 g) which has the characteristics
given earlier.
Example 11
Process for the Preparation of the Polymorphic Form-VII of
L-arginine Salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic Acid
[0237] Polymorphic, Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1
g), obtained by the process described in Example-3 above: was
dissolved in methanol (25 ml) and evaporated under vacuum to yield
Form-VII of L-arginine salt of (2S)
3-[4-[2-[phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid,
as an amorphous white powder (0.9 g) which has the characteristics
given earlier.
Example 12
Process for the Preparation of the Polymorphic form-VII of
L-arginine Salt of (2S)
3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic Acid
[0238] Polymorphic Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropaaoic acid (1
g), obtained by the process described in Example-2 above was
refluxed in 1,4-dioxane (10 ml), filtered and dried under vacuum to
yield Form-VIII of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-eth- oxypropanoic acid
which has the characteristics given earlier.
Example 13
Process for the Preparation of the Polymorphic Form-IX of
L-arginine Salt of (2S) 3-[4-[2
(phenoxazin-10-yl)ethoxy]phenyl]-2ethoxypropauoic Acid
[0239] Polymorphic Form-VII L-arginine salt of (2S)
3-[4-[2-phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1
g), obtained by the process described in Example-12 was refluxed in
isopropanol (10 ml), filtered and dried under vacuum to yield
Form-IX of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy- propanoic acid
which has the characteristics given earlier.
Example 14
Process for the Preparation of the Polymorphic Form-X of L-arginine
Salt of (2 S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic Acid
[0240] Polymorphic Form-I of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid
obtained by any of the process described in Examples-1-5 was heated
to 185.degree. C. and cooled it to room temperature to yield Form-X
of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid
which has the characteristics given earlier.
Example 15
Process for the Preparation of the Polymorphic Form-XI of
L-arginine Salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic Acid
[0241] Polymorphic Form-X of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid
obtained by the process described in Example 14 was heated to
175.degree. C. and cooled it to room temperature to yield Form-XI
of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid
which has the charactenstics given earlier.
Example 16
Process for the Preparation of Mixture of Polymorphic Forms I and X
of L-arginine Salt of (2S)
3-4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2is Ethoxypropanoic
Acid
[0242] To a solution of (2S) 3-[4-[2
(phenoxazin-10-yl)ethoxy]phenyl]-2-et- hoxypropanoic acid (1 g) in
isopropyl alcohol (25 ml) was added L-arginine dissolved in water
(1.2 ml) slowly with constant stirring. The reaction mixture was
stirred at room temperature for 24 h. The white crystalline powder
formed was separated and dried under vacuum at 40-45.degree. C. for
4 h to yield a mixture of polymorphic Forms I and X of L-arginine
salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxylphenyl]-2-ethoxypropanoic acid
(1.05 g).
Example 17
Process for the Preparation of Polymorphic Form I of L-arginine
Salt of (2S)
3-[4-[2-(phenoxazin-10yl)ethoxy]phenyl]-2-ethoxypropanoic Acid
[0243] A mixture of polymorphic Forms I and X of L-arginine salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid (1.0 g) is suspended in isopropyl alcohol (10 ml) the reaction
flask was covered with carbon paper and stirred at room temperature
for a period of 35-50 h. The reaction mixture was filtered, washed
with little isopropyl alcohol and dried under vacuum at
40-45.degree. C. for 4 h to yield polyymorphic Form I of L-arginine
salt of (2S) 3-[4-[2-(phenoxazin-10-yl)-
ethoxy]phenyl]-2-ethoxypropanoic acid (0.97 g).
[0244] Advantages of the Invention:
[0245] The polymorphic Forms of L-arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
are more active/bio-available and are therefore very useful for the
treatment or prophylaxis.
[0246] Ease in formulation containing these forms resulting in
higher activity/bioavailability, in terms of lowering plasma blood
sugar and plasma triglycerides.
* * * * *