Note: Descriptions are shown in the official language in which they were submitted.
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TARTRATE SALTS OF THIAZOLIDINEDIONE DERTVATIVE
This invention relates to a novel pharmaceutical, to a process for the
preparation
of the pharmaceutical and to the use of the pharmaceutical in medicine.
European Patent Application, Publication Number 0,306,228 relates to certain
thiazolidinedione derivatives disclosed as having hypoglycaemic and
hypolipidaemic
activity. The compound of example 30 of EP 0,306,228 is 5-[4-[2-(N-methyl-N-(2-
pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter also referred
to as
"Compound (I)").
International Patent Application, Publication Number W094/05659 discloses
certain salts of the compounds of EP 0,306,228 one of which is the tartrate
salt. The
preferred salt of W094/05659 is the malefic acid salt.
It has now been discovered that Compound (I) forms. a novel tartrate salt
(hereinafter also referred to as the "Meso-Tartrate") .
The novel Meso-Tartrate is a stable, high melting crystalline material hence
is
suitable for bulk preparation and handling. The Meso-Tartrate is amenable to
Large scale
pharmaceutical processing, especially in manufacturing processes which require
or
generate heat, for example milling, fluid bed drying, spray drying, hot melt
processing
and sterilisation by autoclaving. The Meso-Tartrate can also be prepared by an
efficient,
economic and reproducible process particularly suited to large-scale
preparation.
The novel Meso-Tartrate also has useful pharmaceutical properties and in
particular it is indicated to be useful for the treatment and/or prophylaxis
of diabetes
mellitus, conditions associated with diabetes mellitus and certain
complications thereof.
Accordingly, the present invention provides 5-[4-[2-(N-methyl-N-(2-
pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, meso-tartrate salt or a
solvate
thereof.
Suitably, the Meso-Tartrate is a mono-tartrate salt.
Mono tartrate salts also optionally comprise another monovalent salting ion
such
as an alkali metal or ammonium cation.
In one favoured aspect, the Meso-Tartrate provides an infrared spectrum
substantially in accordance with Figure 1.
In one favoured aspect, the Meso-Tartrate provides a Raman spectrzun
substantially in accordance with Figure 2.
In one favoured aspect, the Meso-Tartrate provides an X-Ray powder diffraction
pattern (XRPD) substantially in accordance with Table 1 or Figure 3.
In one favoured aspect, the Meso-Tartrate provides a Solid State 13C NMR
spectrum substantially in accordance with Figure 4.
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In one favoured aspect, the Meso-Tartrate provides a melting point in the
range of
from 147 to 157oC, such as 148 to 155 oC, for example 148 oC, 153 oC and 155
oC.
In a preferred aspect, the invention provides 5-[4-[2-(N-methyl-N-(2-
pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, meso-tartrate salt,
characterised in
that it provides:
(i) an infrared spectrum substantially in accordance with Figure 1; and
(ii) a Raman spectrum substantially in accordance with Figure 2;and
(iii) an X-Ray powder diffraction pattern (~RPD) substantially in accordance
with Table
1 or Figure 3; and
(iv) a Solid State 13C NMR spectrum.substantially in accordance with Figure 4.
The present invention encompasses the Meso-Tartrate or solvate thereof
isolated
in pure form or when admixed with other materials. Thus in one aspect there is
provided
the Meso-Tartrate or solvate thereof in isolated form.
In a further aspect there is provided the Meso-Tartrate or solvate thereof in
a
purified form.
In yet a further aspect there is provided the Meso-Tartrate or solvate thereof
in
crystalline form.
Also, the invention provides the Meso-Tartrate or solvate thereof in a solid
pharmaceutically acceptable form, such as a solid dosage form, especially when
adapted
for oral administration.
Moreover, the invention also provides the Meso-Tartrate or solvate thereof in
a
pharmaceutically acceptable form, especially in bulk form, such form being
particularly
capable of pharmaceutical processing, especially in manufacturing processes
which
require or generate heat, for example milling; for example heat-drying
especially fluid-
bed drying or a spray drying; for example hot melt processing; for example
heat-
sterilisation such as autoclaving.
Furthermore, the invention provides the Meso-Tartrate or solvate thereof in a
pharmaceutically acceptable form, especially in bulk form.and especially in
form having
been processed in a manufacturing process requiring or generating heat, for
example in
a milled form; for example in heat-dried form, especially a fluid-bed dried
form or a
spray dried form; for example in a form having being hot melt processed; for
example in
a form having being heat-sterilised by such as autoclaving.
A suitable solvate is a hydrate.
The invention also provides a process for preparing the Meso-Tartrate or a
solvate
thereof, characterised in that 5-[4-[2-(N-methyl-N-(2-
pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) or a salt
thereof,
preferably dispersed or dissolved in a suitable solvent, is reacted with a
source of meso-
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tartrate ion and thereafter, if required, a solvate of the resulting Meso-
Tartrate is
prepared; and the Meso-Tartrate or a solvate thereof is recovered.
A suitable reaction solvent is a ketone for example acetone, or an ether for
example tetrahydrofuran , an alkanol, such as propan-2-ol, a hydrocarbon, such
as
toluene, an ester, such as ethyl acetate, a nitrite such as acetonitrile, or a
halogenated
hydrocarbon such as dichloromethane or water, or an organic acid such as
acetic acid; or
a mixture thereof.
Conveniently, the source of meso-tartrate ion is meso-tartaric acid. The meso-
tartaric acid is preferably added as a solid or in solution, for example in
water or a lower
alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents.
An alternative
source of meso-tartrate ion is provided by a suitably soluble base salt of
meso-tartaric
acid for example ammonium meso-tartrate, or the meso-tartaric acid salt of an
amine, for
example ethylamine or diethylamine.
The concentration of Compound (I) is preferably in the range 2 to 25%
weightlvolume, more preferably in the range 5 to 20%. The concentration of the
tartaric
acid solutions are preferably in the range of 5 to 125% weight/volume.
The reaction is usually carried out at ambient temperature or at an elevated
temperature, for example at the reflux temperature of the solvent, although
any
convenient temperature that provides the requixed product may be employed.
Solvates, such as hydrates, of the Meso-Tartrate are prepared according to
conventional procedures.
Recovery of the required compound generally comprises crystallisation from an
appropriate solvent or mixture of solvents, conveniently the reaction solvent,
usually
assisted by cooling. For example, the Meso-Tartrate may be crystallised from a
ketone
such as acetone, or an ether such as tetrahydrofuran or water or a mixture
thereof.. An
improved yield of the salt may be obtained by evaporation of some or all of
the solvent
or by crystallisation at elevated temperature followed by controlled cooling,
optionally in
stages. Caxeful control of precipitation temperature may be used to improve
the
reproducability of the product form.
Crystallisation can also be initiated by seeding with crystals of the Meso-
Tartrate
or a solvate thereof but this is not essential.
When the mono tartrate salt comprise another monovalent salting ion such as an
alkali metal or ammonium cation.the said ion is conveniently formed by
reacting the
mono tartrate salt with a solution of the chosen monovalent salting ion for
example a
metal ox ammonium ion. Alternatively Compound (I) may be treated with a mono
tartrate
salt of the said monovalent salting ion.
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Compound (I) is prepared according to known procedures, such as those
disclosed
in EP 0,306,228 and W094105659. The disclosures of EP 0,306,228 and W094/05659
are incorporated herein by reference.
Meso-tartaric acid is a commercially available compound.
When used herein the term "Tonset" is generally determined by Differential
Scanning Calorimetry and has a meaning generally understood in the art, as for
example expressed in Pharmaceutical Thermal Analysis, Techniques and
Applications", Ford and Tirmnins, 1989 as "The temperature corresponding to
the
intersection of the pre-transition baseline with the extrapolated leading edge
of the
transition" .
When used herein in respect of certain compounds the term "good flow
properties" is suitably characterised by the said compound having a Hausner
ratio of less
than or equal to 1.5, especially of less than or equal to 1.25. .
"Hausner ratio" is an art accepted term.
When used herein the term 'prophylaxis of conditions associated with diabetes
mellitus' includes the treatment of conditions such as insulin resistance,
impaired glucose
tolerance, hyperinsulinaemia and gestational diabetes.
Diabetes mellitus preferably means Type II diabetes mellitus.
Conditions associated with diabetes include hyperglycaemia and insulin
resistance
and obesity. Further conditions associated with diabetes include hypertension,
cardiovascular disease, especially atherosclerosis, certain eating disorders,
in particular
the regulation of appetite and food intake in subjects suffering from
disorders associated
with under-eating, such as anorexia nervosa, and disorders associated with
over-eating,
such as obesity and anorexia bulimia. Additional conditions associated with
diabetes
include polycystic ovarian syndrome and steroid induced insulin resistance.
The complications of conditions associated with diabetes mellitus encompassed
herein includes renal disease, especially renal disease associated with the
development of
Type II diabetes including diabetic nephropathy, glomerulonephritis,
glomerular
sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage
renal disease.
As mentioned above the compound of the invention has useful therapeutic
properties: The present invention accordingly provides the Meso-Tartrate or a
solvate
thereof for use as an active therapeutic substance.
More particularly, the present invention provides the Meso-Tartrate or a
solvate
thereof for use in the treatment and/or prophylaxis of diabetes mellitus,
conditions
associated with diabetes mellitus and certain complications thereof.
The Meso-Tartrate or a solvate thereof may be administered her se or,
preferably,
as a pharmaceutical composition also comprising a pharmaceutically acceptable
carrier.
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Suitable methods for formulating the Meso-Tartrate or a solvate thereof are
generally
those disclosed for Compound (I) in the above mentioned publications.
Accordingly, the present invention also provides a pharmaceutical composition
comprising the Meso-Tartrate or a solvate thereof and a pharmaceutically
acceptable
carrier therefor.
The Meso-Tartrate or a solvate thereof is normally administered in unit dosage
form.
The active compound may be administered by any suitable route but usually by
the oral or parenteral routes. For such use, the compound will normally be
employed in
the form of a pharmaceutical composition in association with a pharmaceutical
carrier,
diluent andlor excipient, although the exact form of the composition will
naturally depend
on the mode of administration.
Compositions are prepared by admixture and are suitably adapted for oral,
parenteral or topical administration, and as such may be in the form of
tablets, capsules,
oral liquid preparations, powders, granules, lozenges, pastilles,
reconstitutable powders,
injectable and infusable solutions or suspensions, suppositories and
transdermal devices.
Orally administrable compositions are preferred, in particular shaped oral
compositions,
since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit
dose,
and contain conventional excipients such as binding agents, fillers, diluents,
tabletting
agents, lubricants, disintegrants, colourants, flavourings, and wetting
agents. The tablets
may be coated according to well known methods in the art.
Suitable fillers for use include cellulose, mannitol, lactose and other
similar
agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch
derivatives
such as sodium starch glycollate. Suitable lubricants include, for example,
magnesium
stearate. Suitable pharmaceutically acceptable wetting agents include sodium
lauryl
sulphate.
Solid oral compositions may be prepared by conventional methods of blending,
filling, tabletting or the like. Repeated blending operations may be used to
distribute the
active agent throughout those compositions employing large quantities of
fillers. Such
operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily
suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as
a dry product
for reconstitution with water or other suitable vehicle before use. Such
liquid
preparations may contain conventional additives such as suspending agents, for
example
sorbitol, syrup, nnethyl cellulose, gelatin, hydroxyethylcellulose,
carboxymethyl cellulose,
aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for
example
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lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may
include edible
oils), for example, almond oil, fractionated coconut oil, oily esters such as
esters of
glycerine, propylene glycol, or ethyl alcohol; preservatives, for example
methyl or propyl
p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or
colouring
agents.
For parenteral administration, fluid unit dose forms are prepared containing a
compound of the present invention and a sterile vehicle. The compound,
depending on
the vehicle and the concentration, can be either suspended or dissolved.
Parenteral
solutions are normally prepared by dissolving the active compound in a vehicle
and filter
sterilising before filling into a suitable vial or ampoule and sealing.
Advantageously,
adjuvants such as a local anaesthetic, preservatives and buffering agents are
also
dissolved in the vehicle. To enhance the stability, the composition can be
frozen after
filling into the vial and the water removed under vacuum. .
Parenteral suspensions are prepared in substantially the same manner except
that
the active compound is suspended in the vehicle instead of being dissolved and
sterilised
by exposure to ethylene oxide before suspending in the sterile vehicle.
Advantageously,
a surfactant or wetting agent is included in the composition to facilitate
uniform
distribution of the active compound.
As is common practice, the compositions will usually be accompanied by written
or printed directions for use in the medical treatment concerned.
As used herein the term'pharmaceutically acceptable' embraces compounds,
compositions and ingredients for both human and veterinary use: for example
the term
'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.
The present invention further provides a method for the treatment andlor
prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus
and certain
complications thereof, in a human or non-human mammal which comprises
administering
an effective, non-toxic, amount of Meso-Tartrate or a solvate thereof to a
human or
non-human mammal in need thereof.
Conveniently, the active ingredient may be administered as a pharmaceutical
composition hereinbefore defined, and this forms a particular aspect of the
present
invention.
In a further aspect the present invention provides the use of Meso-Tartrate or
a
solvate thereof for the manufacture of a medicament for the treatment and/or
prophylaxis
of diabetes mellitus, conditions associated with diabetes mellitus and certain
complications thereof.
In the treatment and/or prophylaxis of diabetes mellitus, conditions
associated
with diabetes mellitus and certain complications thereof the Meso-Tartrate or
a solvate
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thereof may be taken in amounts so as to provide Compound (I) in suitable
doses, such as
those disclosed in EP 0,306,228, W094/05659 or W098/55122.
No adverse toxicological effects are indicated in the above mentioned
treatments
for the compounds of the invention.
The following examples illustrate the invention but do not limit it in any
way.
Example 1 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-
dione
meso-tartrate
A mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine -
2,4-
dione (8.0 g) and tetrahydrofuran (160 ml) was stirred and heated to
50°C. A solution of
meso-tartaric acid (3.84 g) in water (20 ml) was added and the mixture stirred
at 50°C for 15
minutes, filtered and the clear filtrate cooled to 21 °C. The solvent
was evaporated under
reduced pressure at 40°C, acetone (40 ml) was added and the mixture
stirred at 21 °C to give a
white suspension. The product was collected by filtration, washed with acetone
and dried under
vacuum to give 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-
2,4-dione
meso-tartrate (10.6 g) as a white, crystalline solid.
Example 2 5-(4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazoIidine-2,4-
dione meso-tartrate
A mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]
thiazolidine-2,4-dione (3.0 g, 8.4 mmol), acetone (40 ml) and tetrahydrofuran
(5 ml) was
heated at reflux for 2.5 hours with stirring. To this was added a solution of
meso-tartaric
acid monohydrate (1.41 g, 8.4 mmol) in water (2 ml). The reaction mixture was
heated at
reflux with stirring for 2.5 hours, then cooled to 21 °C and stirred
for 16 hours at 21 °C.
The white solid was collected by filtration, washed with acetone (40 ml) then
dried under
reduced pressure for 2.5 hours at 21°C to afford 5-[4-[2-(N-methyl-N-(2-
pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione meso-tartrate (3.25 g) as a
white
crystalline solid.
Example 3 5-(4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-
dione meso-Tartrate
A mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]
thiazolidine-2,4-dione (10.0 g, 28 mmol), acetone (120 ml) and tetrahydrofuran
(15 ml)
was heated at reflux for 50 minutes with stirring. To this was added a
solution of meso-
tartaric acid monohydrate (4.7 g, 28 mmol) in water (6.0 ml). The reaction
mixture was
heated at reflux with stirring for 1 hour, then cooled to 21°C and
stirred for 16 hours at
21 °C. The white solid was collected by filtration, washed with acetone
(50 ml) then dried
under reduced pressure for 3 hours at 21 °C to afford 5-[4-[2-(N-methyl-
N-(2-
pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione meso-tartrate (11.7 g) as a
white
crystalline solid.
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Characterising data recorded for the product of Example 1
The infrared absorption spectrum of a mineral oil dispersion of the product
was
obtained using a Nicolet 710 FT-IR spectrometer at 2 cm-1 resolution (Figure
1). Data
were digitised at 1 cm-1 intervals. Bands were observed at: 3405, 1738, 1694,
1629,
1556, 1537, 1505, 1459, 1436, 1418, 1330, 1268, 1249, 1223, 1182, 1167, 1143,
1104, 1074, 1057, 1033, 1000, 949, 916, 887, 853, 818, 771, 717, 668, 619,
568,
528, 515 cm-1.
The infrared spectrum of the solid product was recorded using Perkin-Elmer
Spectrum One FT-IR spectrometer fitted with a universal ATR accessory. Bands
were
observed at: 3407, 2937, 2750, 1739, 1693, 1628, 1555, 1535, 1504, 1476, 1459,
1412, 1388, 1358, 1330, 1261, 1248, 1222, 1182, 1167, 1143, 1101, 1074, 1056,
1033, 999, 948, 916, 887, 853, 818, 771, 744, 717, 667 cm-1.
The Raman spectrum of the product (Figure 2) was recorded with the sample in
an NMR tube using a Nicolet 960 E.S.P. FT-Raman spectrometer, at 4 cm-1
resolution
with excitation from a Nd:V04 laser (1064 nm) with a power output of 400mW.
Bands
were obserbed at: 3101, 3059, 2952, 2922, 2877, 1739, 1604, 1544, 1458, 1438,
1394, 1331, 1270, 1222, 1203, 979, 887, 827, 739, 668, 638, 605, 472, 344 cm-1
The X-Ray Powder Diffractogram pattern of the product (Figure 3) was recorded
using
the following acquisition conditions: Tube anode: Cu, Generator tension: 40
kV, Generator
current: 40 mA, Start angle: 2.0 °20, End angle: 35.0 °2~, Step
size: 0.02 °2B , Time per step:
2.5 seconds.Characteristic XRPD angles and relative intensities are recorded
in Table 1.
Table 1.
Angle Rel.lntensity
2-Theta
4.9 11.4
9.3 12.4
9.9 3.1
12.2 1.9
14.3 3.3
14.9 7
15.2 19
15.9 23.8
16.2 13.9
17.0 8.6
17.3 17.5
18.1 25.9
18.5 31.3
19.1 10.7
_ 18.4
19.9
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20.4 100
21.6 26
22.2 23.7
22.7 6.1
23.6 23.1
24.5 5.7
25.2 23
25.8 9.2
26.2 17.8
26.8 11.5
27.4 14.7
28.1 6.8
28.4 8.7
29.7 5.7
30.2 9.7
30.6 9.3
31.1 23.6
31.4 13.4
32.2 14
32.6 19.7
32.9 15.2
33.6 11.4
33.8 12.4
34.4 8.7
34.7 - ~ 9
The solid-state NMR spectrum of the product (Figure 4) was recorded on a
Broker AMX360
instrument operating at 90.55 MHz: The solid was packed into a 4 mm zirconia
MAS rotor
fitted with a Kel-F cap and rotor spun at ca.10 kHz. The 13C MAS spectrum was
acquired
by cross-polarisation from Hartmann-Hahn matched protons (CP contact time 3ms,
repetition
time 15 s) and protons were decoupled during acquisition using a two-pulse
phase modulated
(TPPM) composite sequence. Chemical shifts were externally referenced to the
carboxylate
signal of glycine at 176.4 ppm relative to TMS and were observed at:
183.0, 177.2, 175.4, 173.0, 160.0, 159.0, 151.8, 144.2, 138.9, 134.3, 130.8,
128.2,
123.6, 113.7, I I2.8, 77.4, 76.7, 74.5, 55.5, 53.5, 50.0, 42.4, 36.6, 33.8
ppm.
Properties of the Meso-Tartrate
Solid State Stability of the Meso-Tartrate, recorded for the product of
Example 1
The solid state stability of the drug substance was determined by storing
approximately
1.0 g of the material in a glass bottle at i) 40oC / 75 % Relative Humidity
(RH), open
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exposure, for 1 month and b) at SOoC, closed, for 1 month. The material was
assayed
by HPLC for final content and degradation products in both cases.
a) 40oC / 75 % RH: No significant degradation observed (HPLC assay 97
initial).
b) 50°C: No significant degradation observed (HPLC assay 98% initial).
Melting Point of the Meso-Tartrate
The melting point of the Meso-Tartrate was determined according to the method
described in
the U.S. Pharmacopoeia, USP 23, 1995, <741 > "Melting range or temperature,
Procedure
for Class Ia", using a Buchi 545 melting point instrument.
Product of example 1, Melting Point: 149oC
Product of example 2, Melting Point: 153oC
Product of example 3, Melting Point: 155oC
Tonset of the Meso-Tartrate
The To~et of the drug substance was determined by Differential Scanning
Calorimetry
using a Perkin-Elmer DSC apparatus.
Product of example 1, Tonset (10°C/minute, closed pan): 146oCProduct of
example 2,
Tonset (lOoC/minute, open pan): 153oC
Product of example 3, To~et (10°C/minute, open pan): 154°C
