Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL COMPOSITIONS CONTAINING THIAZOLIDINEDIONE DERIVATIVES AND
PROCESS FOR THEIR PREPARATION
This invention relates to a novel pharmaceutical composition and to certain
novel compounds, to a process for preparing such composition and compounds and
to
the use of such a composition and compounds in medicine.
European Patent Application, Publication Number 0306228 describes certain
thiazolidinedione derivatives of formula (A):
Ra Rb c
a
AN-(CH2)~. ~CH-C-~
S~NH
(A)
or a tautomeric form thereof and/or a pharmaceutically acceptable salt
thereof, and/or
a pharmaceutically acceptable solvate thereof, wherein:
Aa represents a substituted or unsubstituted aromatic heterocyclyl group;
Ra represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl
group,
wherein the aryl moiety may be substituted or unsubstituted, or a substituted
or
unsubstituted aryl group;
Rb and Rc each represent hydrogen or Rb and Rc together represent a bond;
Ab represents a benzene ring having in total up to five substituents; and
n' represents an integer in the range of from 2 to 6.
One particular thiazolidinedione disclosed in EP 0306228 is 5-[4-[2-(N-
methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (hereinafter
'Compound (I)~. W094/05659 discloses certain salts of Compound (I) including
the
maleate salt.
Xenobiotica, 26, 6, 627-636, 1996 and J. Clin. Pharmacol, 48(3), 424-432,
1999 discloses certain metabolites of Compound (I) .
It is now indicated that these compounds show good blood-glucose lowering
activity and are therefore of potential use in the treatment of Type 2
diabetes or
conditions associated with Type 2 diabetes.
Accordingly, the invention provides a pharmaceutical composition which
composition comprises an effective non-toxic amount of a compound of formula
(I):
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A' R' R2 R3
I - O
N (CHZ)2 O ~ ~ CH ~--
i
N S NH
° (n
or a tautomeric form thereof and/or a pharmaceutically acceptable salt
thereof, and/or
a pharmaceutically acceptable solvate thereof, wherein:
Al represents OH or-OSO~OH;
Rl represents a hydrogen atom or a C,_6 alkyl group; and
R2 and R3 each represent hydrogen or R2 and R3 together represent a bond; and
a
pharmaceutically acceptable carrier therefor.
In one aspect, A 1 represents OH.
Preferably, Al represents -OSO~OH.
Preferably, Rl represents a C,_6alkyl group, especially a methyl group.
Preferably, RZ and R3 each represent hydrogen.
Preferably, the moiety Al-(CSH3N)-NRl- represents a group of formula (a):
A'
R'
N N - (a)
wherein Al and Rl are as defined in relation to formula (n.
The invention also provides a compound of formula (I), or a tautomeric form
thereof and/or a pharmaceutically acceptable salt thereof and/or a
pharmaceutically
acceptable solvate thereof, in solid form.
The invention also provides a compound of formula (I), or a tautomeric form
thereof and/or a pharmaceutically acceptable salt thereof and/or a
pharmaceutically
acceptable solvate thereof, in purified form.
The invention also provides a compound of formula (I), or a tautomeric form
thereof and/or a pharmaceutically acceptable salt thereof and/or a
pharmaceutically
acceptable solvate thereof, in crystalline form.
The invention also provides a compound of formula (I), or a tautomeric form
thereof and/or a pharmaceutically acceptable salt thereof and/or a
pharmaceutically
acceptable solvate thereof, in pharmaceutically acceptable form.
In addition, certain of the compounds of formula (I) are novel and hence the
invention also provides a compound of formula (I), or a tautomeric form
thereof
and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically
acceptable
solvate thereof; providing that formula (I) does not encompass 5-(4-{2-[(5-
hydroxy-
pyridin-2-yl)-methyl-amino]-ethoxy}-benzyl)-thiazolidine-2,4-dione and/or
providing
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formula (I) does not encompass sulfuric acid mono-[6-( { 2-[4-(2,4-dioxo-
thiazolidin-
5-ylmethyl)-phenoxy]-ethyl}-methyl-amino)-pyridin-3-yl ester.
Suitable pharmaceutically acceptable salts include salts derived from
pharmaceutically acceptable acids or bases.
Suitable pharmaceutically acceptable salts' derived from bases include metal
salts,
such as for example aluminium, alkali metal salts such as lithium, sodium or
potassium, alkaline earth metal salts such as calcium or magnesium and
ammonium or
substituted ammonium salts, for example those with lower alkylamines such as
triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine,
bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines
such as
bicyclohexylamine, or with procaine, dibenzylpiperidine,
N-benzyl-(3-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine,
glucamine, N-methylglucamine or bases of the pyridine type such as pyridine,
collidine, quinine or quinoline.
Suitable pharmaceutically acceptable acids derived from bases include acid
addition salts.
Suitable acid addition salts include pharmaceutically acceptable inorganic
salts
such as the sulphate, nitrate, phosphate, borate, hydrochloride and
hydrobromide and
pharmaceutically acceptable organic acid addition salts such as acetate,
tartrate,
maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, oc-keto
glutarate
and a-glycerophosphate.
Suitable pharmaceutically acceptable solvates include hydrates.
As indicated above a compound of formula (I) may exist in one of several
tautomeric forms, all of which are encompassed by the present invention. It
will also
be appreciated that the compounds of formula (I) can have at least one chiral
carbon
atom and hence can form two or more stereoisomers. The present invention
encompasses all isomeric forms of the compounds of formula (I), including any
stereoisomeric forms thereof, whether as individual isomers or as mixtures of
isomers.
When used herein unless otherwise stipulated, "alkyl" whether present alone or
as part of other groups such as alkoxy or aralkyl groups, are alkyl groups
having
straight or branched carbon chains, containing up to 12 carbon atoms. Suitable
alkyl
groups are C1-6 alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-
butyl, iso-
butyl or tert-butyl groups.
When used herein the term 'conditions associated with diabetes' includes those
conditions associated with the pre-diabetic state, conditions associated with
diabetes
mellitus itself and complications associated with diabetes mellitus.
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When used herein the term 'conditions associated with the pre-diabetic state'
includes conditions such as insulin resistance, impaired fasting glucose,
impaired
glucose tolerance and hyperinsulinaemia.
'Conditions associated with diabetes mellitus itself' include hyperglycaemia,
insulin resistance and obesity. Further conditions associated with diabetes
mellitus
itself include hypertension and cardiovascular disease, especially
atherosclerosis and
conditions associated with insulin resistance. Conditions associated with
insulin
resistance include polycystic ovarian syndrome and steroid induced insulin
resistance
and gestational diabetes.
'Complications associated with diabetes mellitus' includes renal disease,
especially renal disease associated with Type 2 diabetes, neuropathy and
retinopathy.
Renal diseases associated with Type 2 diabetes include nephropathy,
glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive
nephrosclerosis and end stage renal disease.
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 invention also provides a process for the preparation of the compounds of
formula (1), which process comprises reacting a compound of formula (II):
R2 R3
O
L' \ / CH
S NH
O
wherein R2 and R3 are as defined in relation to the compounds of formula (I)
and Ll
represents a leaving group, especially a halogen atom such as a fluorine atom,
with a
compound of formula (111):
q'' R,
i ~ N -{Chi2)z - OH
N
wherein R 1 is as defined in relation to formula (I) and A 1 represents A 1 as
defined in
relation to formula (I) or a protected form thereof; and thereafter, if
required, carrying
out one or more of the following optional steps:
(i) converting a compound of formula (I) into a further compound of formula
(I);
(ii) removing any necessary protecting group;
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(iii) preparing a pharmaceutically acceptable salt of the compound of formula
(I)
and/or a pharmaceutically acceptable solvate thereof.
Suitably A 1' is OH or, preferably, a protected form thereof such as a
benzylated form.
Preferably the compound of formula (III) is used in an activated form,
generally prepared in situ in the relevant reaction.
A suitable activated form of a compound of formula (III) is an anionic form
such as a salted form and especially an alkali metal salted form, for example
a
potassium salt.
The activated form of the compound of formula (BI) may be prepared by any
appropriate conventional procedure. For example, the anionic form of the
compound
of formula (111) may be prepared by treating the compound of formula (III)
with a
base, such as a metal alkoxide, for example potassium tert-butoxide.
The reaction conditions for the reaction between the compounds of formulae
(II) and (III) are generally the appropriate, conventional conditions. For
example the
reaction between the compound of formula (II) and a salted form of a compound
of
formula (III) may be carried out in an aprotic solvent, such as
dimethylformamide, at
any temperature providing a suitable rate of formation of the required
product,
conveniently at an elevated temperature for example 60°C.
The compounds of formulae (II) and (III) are known compounds or they are
prepared by methods analogous to those used to prepare known compounds, for
example those disclosed in EP0306228. Compound (II) wherein L1 represents F
and
R2 together with R3 represents a bond can also be prepared using methods
disclosed
by Steblyuk et al. (Fiziol. Akt. Veshchestva, 1 l, 97-101, 1979).
The above mentioned conversion of a compound of formula (I) into a further
compound of formula (I) includes:
(a) converting one group A 1 into another group A 1;
(b) converting a compound wherein R2 and R3 together represent a bond into a
compound wherein R2 and R3 each represent hydrogen.
The conversion of a compound of formula (I) into a further compound of
formula (I) may be carried out by using any appropriate conventional
procedure.
Suitable conversions (a) include the conversion of a compound wherein A1 is
OH into a compound wherein A1 is -OSO~OH, which conversion may be carried out
using pyridine/sulphur trioxide complex in a solvent such as pyridine, at any
convenient temperature providing a suitable rate of formation of the required
product,
for example at ambient temperature.
Suitable conversions (b) may be carried out using any appropriate
conventional reduction procedure, for example by use of catalytic reduction
using for
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example a 10% palladium-on-carbon catalyst in an alkanolic solvent such as
ethanol,
by use of a metal/solvent system such as magnesium metal/methanol as described
in
Tet. Lett. 1986, 27, 2409 or by use of a metal borohydride, such as lithium
borohydride (generally used in stoichiometric excess) in an aprotic solvent
such as
tetrahydrofuran and pyridine, typically at an elevated temperature as
described in
International Patent Application, Publication Number W098/37073.
The above mentioned conversions may as appropriate be carried out on any of
the intermediate compounds mentioned herein.
It will be appreciated that in any of the above mentioned reactions and
conversions, any reactive group in the substrate molecule may be protected,
according
to conventional chemical practice. Suitable protecting groups are those used
conventionally in the art. Thus, for example, suitable hydroxyl protecting
groups
include benzyl or trialkylsilyl groups. The methods of formation and removal
of such
protecting groups are those conventional methods appropriate to the molecule
being
protected. Thus for example a benzyloxy group may be prepared by treatment of
the
appropriate compound with a benzyl halide, such as benzyl bromide, and
thereafter, if
required, the benzyl group may be conveniently removed using mild acidic
hydrolysis
using, for example, hydrogen chloride in acetic acid.
As mentioned above the compounds of the invention are indicated as having
useful therapeutic properties: The present invention accordingly provides a
compound
of formula (I), or a tautomeric form thereof and/or a pharmaceutically
acceptable salt
thereof and/or a pharmaceutically acceptable solvate thereof, for use as an
active
therapeutic substance.
Thus the present invention provides a compound of formula (I), or a
tautomeric form thereof and/or a pharmaceutically acceptable salt thereof
and/or a
pharmaceutically acceptable solvate thereof, for use in the treatment Type 2
diabetes
or conditions associated with Type 2 diabetes.
In such use the compound of formula (I), or a tautomeric form thereof and/or a
pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable
solvate
thereof, is administered as a pharmaceutical composition of the invention also
comprising a pharmaceutically acceptable carrier.
The composition of the invention is prepared by admixing a compound of
formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable
salt
thereof and/or a pharmaceutically acceptable solvate thereof, preferably an
effective
non-toxic amount thereof, with a pharmaceutically acceptable carrier.
The composition may, if desired, be in the form of a pack accompanied by
written or printed instructions for use.
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Usually the pharmaceutical compositions of the present invention will be
adapted for oral administration, although compositions for administration by
other
routes, such as by injection and percutaneous absorption are also envisaged.
Particularly suitable compositions for oral administration are unit dosage
forms such as tablets and capsules. Other fixed unit dosage forms, such as
powders
presented in sachets, may also be used.
In accordance with conventional pharmaceutical practice the carrier may
comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant,
flavourant
or other conventional adjuvant.
Typical carriers include, for example, microcrystalline cellulose, starch,
sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone,
magnesium
stearate or sodium lauryl sulphate.
Most suitably the composition will be formulated in unit dose form. Such unit
dose will normally contain an amount of the active ingredient in the range of
from 0.1
to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.
The present invention further provides a method for the treatment of Type 2
diabetes or conditions associated with Type 2 diabetes in a human or non-human
mammal which comprises administering an effective, non-toxic, amount of a
compound of the general formula (I), or a tautomeric form thereof and/or a
pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable
solvate
thereof to a human or non-human mammal in need thereof.
In the treatment of Type 2 diabetes or conditions associated with Type 2
diabetes, the compound of formula (>7, or a tautomeric form thereof and/or a
pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable
solvate
thereof, may be taken in doses, such as those described above, one to six
times a day
in a manner such that the total daily dose for a 70 kg adult will generally be
in the
range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg.
In the treatment of non-human mammals, especially dogs, the active ingredient
may
be administered by mouth, usually once or twice a day and in an amount in the
range
of from about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg.
Similar
dosage regimens are suitable for the treatment and/or prophylaxis of
hyperlipidaemia
in non-human mammals.
In a further aspect the present invention provides the use of a compound of
formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable
salt
thereof and/or a pharmaceutically acceptable solvate thereof, for the
manufacture of a
medicament for the treatment of Type 2 diabetes or conditions associated with
Type 2
diabetes.
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No toxicological effects have been established for the compounds of formula
(I) in the above mentioned dosage ranges.
The blood glucose lowering activity of the present compounds can be
determined using standard tests such as the Oral Glucose Tolerance Test in
C57b11/6
obese (ob/ob) mice, for example using methodology disclosed in EP0306228.
The following Procedures and Example illustrate the invention but do not limit
it in any way.
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Procedure 1: 2-f (5-Bromopyridin-2-yl)-methylaminol-ethanol.
Br ~ OOH Br
HN
--~ ~ ~ ~oH
N Br N N
[236.91 ] [75.11 ]
[231.01 ]
2,5-Dibromopyridine (27.93g) and 2-(methylamino)ethanol (36.15g) were heated
under nitrogen at 150oC for 5 hours with stirring. The reaction mixture was
cooled to
room temperature and added to brine (490mL) followed by extraction with ethyl
acetate (245mL x 3). The combined organic phases were washed with brine
(245mL)
and dried over sodium sulphate.
The mixture was filtered and the solvent removed under reduced pressure.
Toluene
( 100mL x 2) was added and evaporated to remove last traces of ethyl acetate.
The
residual oil was dried under high vacuum whereupon it crystallised.
Yield 27.23g, 117.89mmol, m.p. 38 to 43°C
Infrared (nujol): Vmax 1589, 1540, 1501, 1435, 1417, 1365, 1322, 1274, 1257,
1226,
1203, 1154, 1143, 1095, 1079, 1065, 983, 954, 944, 911, 856, 811, 806, 754,
735,
~20 722, 633, 585, 538 and 514 cm-~ .
PNMR (in dimethylsulphoxide, DMSO): 8H 3.00 (3H, s. NCH3), 3.53 (4H, t, NCH2,
OCH2), 4.66 (1H, bs, OH), 6.60 (1H, d, ArH), 7.59 (2H, dd, ArH), 8.10 (1H, d,
ArH).
CNMR (DMSO): 8~ 36.9, 51.9, 58.3, 104.8, 107.7, 139.1, 147.5, 157Ø
MS (Eh 70eV), m/z: 230 (33.8) [M.+], 199 ( 100), 156 ( 15.0).
Procedure 2: (~-Bromo-pvridin-2v1)-(2-(tert-butyl-dimethvl-silanvloxv)-ethyll-
methvl-amine
Br,
Br~.~ ~~.w
'~.~ N ~ N ~~,~OH -~ Si-CI ~ ~i' \ ~. .OSi
i i .N. ,N, ,~:
[231.01 ]
[150.73] [345.21 ]
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The aminoethanol from Procedure 1 (27.238) was dissolved in tetrahydrofuran
(THF)
(326mL) with stirring under nitrogen. tert-Butyldimethylsilyl chloride
(21.408) and
imidazole (9.678) were added and the mixture stirred at room temperature for
18
hours. The solvent was removed under reduced pressure and the residue
extracted
with water (768mL) and ethyl acetate ( 192mL). The phases were separated and
the
aqueous re-extracted with ethyl acetate ( 192mL x 2). The combined organic
phases
were washed with water (384mL x 2), dried over sodium sulphate, and evaporated
under reduced pressure to a yellow oil (weight 42.048)
This crude product was separated chromatographically on silica, eluting with
ethyl
acetate:60-80oC petrol, 3:7 by volume. The product-rich fractions were
combined and
evaporated under reduced pressure to a nearly colourless oil. This was
redissolved in
toluene ( 100mL) which was evaporated. This process was repeated once. Finally
the
product was dried under high vacuum to give an oil which crystallised on
standing.
Yield 39.538, 114.51mmol, 96.8%
Infrared (nujol): vm~ 1588, 1550, 1498, 1436, 1393, 1361, 1313, 1256, 1205,
1142,
1102, 995, 922, 836, 803, 776 and 757 cm-1.
PNMR (DMSO): 8H -0.03 (6H, s, Si(CH3)2), 0.81 (9H, s, t-BuSi), 3.00 (3H, s,
NCH3), 3.59 (2H, t, NCH2), 3.72 (3H, t, OCH2), 6.60 (1H, d, ArH), 7.59 (2H,
dd,
ArH), 8.09 ( 1 H, d, ArH).
CNMR (DMSO): 8~ -5.5, 17.8, 25.7, 37.2, 51.6, 60.2, 104.9, 107.8, 139.1,
147.5,
156.9.
MS (EI, 70eV), m/z: 344 (26.0) [M.+], 331 (7.0), 287 (85.4), 213 (34.8), 199 (
100),
186 (28.0).
35
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Procedure 3. 6-~[2-(tert-butyl-dimethvl-silanvloxvl-ethvll-methyl-amino~-
nvridin-3-of
Bf \
1
nBuLi L~ \
~OSi~
I 70p N N/~/OSi
I
[345.21 ]
1 ) B(OMe)3 HO I \
I
2) H~, OH- N~N~OSi
i
[282.21
The product ex Procedure 2 (39.53g) was dissolved in tetrahydrofuran (THF,
336mL)
with magnetic stirring under nitrogen, cooled to <-70oC and a 2.7M solution of
n-
butyl lithium (52mL) added dropwise over ca. 25 minutes ensuring that the
temperature of the reaction mixture did not rise above -68oC. When the
addition was
complete, the reaction mixture was stirred at ca. -70oC for a further 20
minutes.
Trimethylborane (48.3mL) was then added to the reaction mixture over ca. 30
minutes ensuring the temperature did not rise above -65oC. Stirring at ca. -
70oC was
continued for a further 20 minutes when the reaction mixture was allowed to
warm up
to room temperature overnight (at least 15 hours) with stirring under
nitrogen.
The reaction mixture was recooled to ca. lOoC and 2M aqueous sodium hydroxide
(27mL) added as quickly as possible whilst maintaining the temperature at ca.
lOoC
(ca. 1 minute.) followed by ?7.5% w/w hydrogen peroxide (27mL) added over 2-3
minutes while keeping the temperature <25°C. On completion of the
addition, the
cooling was removed and the reaction mixture stirred at ambient temperature
for 2
hours.
The reaction mixture was poured into dilute hydrochloric acid (54m1 1M
hydrochloric acid + 1625m1 water) and extracted with ethyl acetate (670mL x
3). The
combined organic solutions were washed with water (670mL x 2) and dried over
sodium sulphate. After filtration. the solvent was removed under reduced
pressure to
leave a dark yellow oil (35.47g).
The oily product was chromato~raphed on silica, eluting with 3:7 by volume
ethyl
acetate/60-80o petrol. Product-rich fractions were combined, evaporated under
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reduced pressure and the residue dried azeotropically with toluene ( IUUmL x
2), then
under high vacuum to give a viscous yellow oil.
Yield 29.578, 104.78mmol, 91.5%
Infrared (nujol): vm~ 2954, 2928, 2884, 2856, 1620, 1570, 1506, 1472, 1463,
1439,
1416, 1388, 1360, 1318, 1256, 1205, 1135, 1102, 1071, 1018, 1006, 993, 974,
938,
926, 900, 836, 809, 777, 741, 713, 695, 662 and 650 cm-t.
PNMR (DMSO): 8H 0.03 (6H, s, Si(CH3)2), 0.83 (9H, s, t-BuSi), 2.94 (3H, s,
NCH3),
3.51 (2H, t, J 6 Hz, NCH2), 3.69 (3H, t, J 6 Hz, OCH2), 6.46 (1H, d; J 8 Hz,
ArH),
7.01 (2H, dd, J 8, 4 Hz, ArH), 7.67 ( 1 H, d, J 4 Hz, ArH), 8.67 ( 1 H, s,
OH).
CNMR (DMSO): S~-5.5, 17.8, 25.7, 37.5, 52.1, 60.5, 106, 125.5, 134.1, 144.7,
152.6.
MS (fiI, 70eV), m/z 283 ( 14) [M+], 151 ( 100%), 136 (6), 123 (5), 110 (6).
Procedure 4.2-[(5-Benzvloxy-pvridin-2-vll-methyl-aminol-ethanol
HO \ NaH PhCH20 \
\ ~OSi Ph- ~-~ \ ~\ /~OSi~
N ~ THF N I
[282.21
PhCH20 \~
TBAF ~
\ j\ ~,~OH
N N
[258.01 j
A solution of product ex procedure 3 in THF (20 mL) was added to a stirred
mixture
of sodium hydride (4.62 e) and benzyl bromide ( 12 mL) over 35 minutes. [N.B.
Sodium hydride was supplied as a 60% dispersion in oil and was washed with
petroleum ether and THF prior to use]. When the addition was complete, the
reaction
mixture was stirred at room temperature overnight.
Water (2mL) was added followed by tetrabutylammonium fluoride hydrate (40.08)
and the reaction mixture was stirred at room temperature for 5 hours.
Water (70mL) was then added and the THF removed under reduced pressure. The
residue was shaken with ethyl acetate (200mL) and water (660mL1 and the phases
separated. The aqueous phase was re-extracted with ethyl acetate (250mL x 2)
and the
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combined organic phases washed with dilute brine (432mL x 2), then dried over
sodium sulphate. After filtration, the solution was evaporated under reduced
pressure
to a dark orange oil (32.37g).
The product was chromatographed on silica, eluting initially with ethyl
acetate/60-
80o petrol, 1:1 by volume, then with ethyl acetate/60-80o petrol, 7:3 by
volume. The
product-rich fractions were combined and evaporated under reduced pressure to
give a
yellow oil. This was dried by adding toluene ( 100mL x 2) and re-evaporating,
finally
drying under high vacuum. The product crystallised as a cream-coloured solid.
Yield 18.298, 70.89mmo1, 67.7%, m.p. 61 to 63°C.
Infrared (nujol): vm~ 1614, 1566, 1508, 1405, 1366, 1319, 1277, 1236, 1202,
1151,
1133, 1087, 1051, 1009, 972, 913, 898, 860, 824, 754, 710, 694; 643 and 541 cm-
~.
PNMR (DMSO): 8H 2.96 (3H, s, NCH3), 3.50 (4H, m, NCH2, OCH2), 4.61 (1H, t,
OH), 5.03 (2H, s, OCH2Ph), 6.56 (1H, dd, ArH), 7.28 (2H, dd, ArH), 7.31 (2H,
tt,
ArH), 7.38 (2H, tt, ArH), 7.42 (2H, dd, ArH), 7.86 ( 1 H, d, ArH).
CNMR (DMSO): b~ 37.2, 52.3, 58.6, 70.5, 105.9, 126.1, 127.6, 127.7, 128.3,
134.6,
137.3, 146.2, 153.9.
MS (EI, 70eV), m/z 258 (26.8) [M.+], 227 (28.8), 167 ( 100), 91 ( 100).
Procedure 5: 5-(4-~2-[(5-Benzyloxy-pvridin-2-yl)-methyl-amino]-ethoxy~-
benzvlidene)-thiazolidine-2,4-dione
PhCH20
OH \ \~~
~N~N~ + I ~ NH
S~
F \\
O
[258.01 ] [223.2]
O
PhCH20 ~ '~ \
KOtBu ~ \ I i S~NH
DMF 60c ~ ~ ~ ~O
N N O
[461.21]
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5-[(4-Fluorophenyl) methylene-2, 4- thiazolidinedione ( 15.82g) Steblyuk et
al. (Fiziol.
Akt. Veshchestva, 11, 97-101, 1979) was added to dimthylformamide (DMF, 159mL)
with magnetic stirring under nitrogen. The product ex Procedure 4 ( 18.29g)
was then
added, followed by potassium t-butoxide ( 17.38g) added in three or four
portions. The
resulting orange solution was heated in an oil bath at 60°C for 4 hours
when TLC
showed the reaction was complete.
After cooling to ambient temperature, the reaction mixture was poured into a
mixture of 1M HCl (72mL) and water (1160mL) with stirring to give a pale
yellow
suspension. The pH was 6.5. Stirring was continued for 30 minutes before the
solid
was filtered off, washed with water ( 100mL), and sucked dry on the filter.
The paste-like damp solid was suspended in denatured ethanol ( 100mL) and
heated
to reflux with stirring. After 30 minutes at reflux temperature the reaction
mixture was
allowed to cool slowly to 30oC when cooling was applied to take the final
temperature to lOoC. The solid was filtered off and washed on the filter with
denatured ethanol (25mL, IOmL), then dried in a fan oven at 50°C
overnight.
Yield 27.46g, 59.54mmo1, 84.0%, m.p. 186-187°C.
Infrared (nujol): vm~ 1730, 1695, 1601, 1564, 1545, 1508, 1406, 1336, 1312,
1287,
1251, 1230, 1208, 1188, 1163, 1075, 1028, 973, 896, 862, 848, 823, 813, 804,
796,
741, 716, 697, 686, 651, 631, 606, 552, 542, 520 cm-1.
PNMR (DMSO): SH 3.02 (3H, s, NCH3), 3.86 (2H, t, NCH2), 4.19 (2H, t, OCH2),
5.04 (2H, s, OCH2Ph), 6.62 ( 1 H, dd, ArH), 7.07 (2H, d, ArH), 7.31 (2H, m,
ArH),
7.38 (2H, d, ArH), 7.43 (2H, t, ArH), 7.52 (2H, d, ArH), 7.67 (1H, s, ArH),
7.91 (1H,
d, ArH), 12.4 (1H, bs, NH).
CNMR (DMSO): 8~ 36.8, 48.8, 65.8, 70.5, 106.1, 115.2, 122.1, 125.9, 126.1,
127.6,
127.7, 128.4, 130.4, 131.9, 134.7, 137.2, 146.5, 153.5, 159.9, 168.9, 169.5.
MS (EI, 70eV), m/z 461 (0.7) [M.+], 370 (1.3), 311 (43.4), 150 (55.6), 91
(100).
Procedure 6: 5-(4-]2-~(5-Benzvloxv-pvridin-2-yl)-methyl-aminol-ethoxyl-benzyl)-
thiazolidine-2,4-dione
0 0
ij i;
PhCH O / \ ~~ LIBH4 PhCH O /
\ j1 I NH pyridine Z \ ;, ~ ~ NH
iI~N~N~O S ~N~N~O \
O ~ O
[461.21 ] [463.21 ]
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2M Lithium borohydride in THF solution (6lmL) was added to a stirred mixture
of
thiazolidinedione product ex Procedure 5 (26.79g) in pyridine (47mL) and THF
(43mL) under nitrogen over 25 minutes. After cooling to ambient, the reaction
mixture was poured into a mixture of concentrated hydrochloric acid (27mL) and
ice
(181g) with stirring, maintaining the temperature < 25oC. The resulting
suspension
was stirred at ambient temperature for 30 minutes and the pH checked. It was
ca. 6.5.
The solid was filtered off and washed thoroughly with until the filtrate was
colourless. The solid was azeotropically dried using toluene ( IOOmL) and
evaporating
under reduced pressure. This was repeated once. The dry residue was extracted
by
heating it with ethyl acetate (500mL) to reflux temperature and filtering the
hot
mixture. This procedure was repeated on insoluble material with more ethyl
acetate
(500mL).
The combined filtrates were evaporated to a white solid which was dried with
toluene ( 100mL x 2) as above, then under high vacuum.
Yield 24.708, 53.32mmol, 91.870, m.p. 152-155°C.
Infrared (nujol): vm~ 1740, 1696, 1613, 1586, 1561, 1509, 1406, 1328, 1310,
1290,
1268, 1247, 1208, 1180, 1163, 1110, 1075, 1037, 1014, 975, 907, 847, 832, 810,
803,
734, 717, 695, 663, 602, 573, 548, 539, and 502 cm' 1.
PNMR (DMSO): 8H 3.01 (4H, s, NCH3, ArCH2CH), 3.29 (1H, dd. ArCH2CH), 3.82
(2H, t, NCH2), 4.08 (2H, t, OCH2), 4.83 ( 1 H, dd, ArCH2CH), 5.04 (2H, s,
OCH2Ph),
6.61 (1H. d, ArH), 6.86 (2H, d, ArH), 7.13 (2H, d, ArH), 7.31 (2H, t. ArH),
7.38 (2H,
t, ArH), 7.42 (2H, d, ArH), 7.90 (1H, d. ArH), 11.80 (1H, bs, NH).
CNMR (DMSO): b~ 36.3, 37.3 , 48.9, 53.1, 65.4, 70.5, 106.1, 114.3, 126.1.
127.6,
127.7, 128.3, 128.6. 130.3, 134.7, 137.?, 146.5. 153.6, 157.5. 171.8, 175.9.
35
MS (EI, 70eV ), m/z 463 (63.5) [M.+]. 372 ( 100), ?'?7 (95.4), 107 (96.1 ), 91
(42.7).
Example 1:: >-(4-(2-f~5-Hvdroxv-nvridin-2-vl)-methyl-aminol-ethoxv)-henzvl)-
thiazolidine-2,4-dione
0 0
PhCH~O, .~-~/'~. HO. " ,,
NH c.HCi ' \. NH
S , ~ i'~_,,. 5~__
AcOH ~- ~ O
~N ~.\~~O ~ ,O ~ N N~/ ' O
[463.21 ] [ 373.09)
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The thiazolidinedione product ex Procedure 6 (24.26g) was dissolved in glacial
acetic
acid ( 183mL) to which concentrated hydrochloric acid (91 mL) was added with
stirring. The mixture was heated at 90oC for 2 hours.
After cooling to ambient temperature, the acetic acid was removed under
reduced
pressure. The residue was vigorously stirred with ethyl acetate (535mL) and
water
(535mL) and the pH adjusted from 0.81 to 6.0 with solid sodium hydrogen
carbonate.
When constant pH was achieved, the phases were separated and the aqueous phase
re-
extracted with ethyl acetate (250mL x 2, 150mL), keeping the solid that
separated at
the interface with the aqueous throughout. The combined organic phases were
dried
over sodium sulphate.
After filtration, the ethyl acetate was removed under reduced pressure on a
rotary
evapotator to leave a pale yellow foam. This was triturated with denatured
ethanol
(25mL) with scratching to convert the foam to a yellow-cream solid which was
filtered off and washed with IMS ( l OmL total.) It was dried in a fan oven at
SOoC
overnight.
Yield 13.91g, 37.28mmol, 71.2°7o, m.p. 160 to 162°C
Infrared (nujol): Vmax 3452, 1774, 1733, 1682, 1635, 1614, 1584, 1569, 1512,
1391,
1348, 1327, 1312, 1302, 1246, 1217, 1204, 1179, 1159, 1142, 1112, 1073, 1038,
1016, 976, 942, 929, 920, 892, 851, 835, 828, 808, 733, 728, 710, 668, 605,
575, 551,
537, 526 and 505 cm-1.
PNMR (DMSO): 8H 2.98 (3H, s, NCH3), 3.05 (1H, dd, ArCH2CH), 3.29 (1H, dd,
ArCH2CH), 3.79 (2H, t, NCH2), 4.07 (2H, t, OCH2), 4.85 (1H, dd, ArCH2CH), 6.53
(1H, d, ArH), 6.86 (2H, d, ArH), 7.04 (1H, dd, ArH), 7.13 (2H, d, ArH), 7.71
(1H, d,
ArH), 8.74 (1H, brs, OH), 11.97 (1H, bs, NH).
CNMR (DMSO): S~ 36.3 , 37.5, 49.0, 53.0, 65.4, 106.2, 114.3, 125.7, 128.6,
130.3,
134.1, 145.0, 152.5, 157.5, 171.6, 175.7.
MS (EI, 70eV), m/z 373 (3.6) [M+H], 223 ( 1.4), 151 ( 12.9), 137 ( 100), 107
(40.6).
Example 2: Sulfuric acid mono-[6-(~2-(4-(2,4-dioxo-thiazolidin-S-vlmethvl)-
Lhenoxvl-ethyl)-methyl-amino)-pvridin-3-yl ester
CA 02381976 2002-02-15
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o ~ i o
I J o=s=o /;
HO \ ~~~~~ ~ NH so, O \ II ~ NH
I ~ ~/O \ S ~ ~ ~/O \ S
N I O N I O
[373.09] [453.09]
The product from Example 1 (3.40g) and pyridine-sulphur trioxide complex
(4.53g)
were dissolved in pyridine (230mL) and stirred at room temperature under
nitrogen
for 26 hours. The solvent was removed under reduced pressure and toluene
(70mL)
was added to the residue and re-evaporated. This was repeated with more
toluene
(70mL). The residue was then treated with methanol ( 140mL) and heated to
reflux
with stirring until dissolved and the hot solution filtered. On cooling at
room
temperature over 16 hours, a precipitate formed. The mixture was further
cooled in a
refrigerator (4 - 5°C) for a further 26 hours before the solid was
collected by filtration
and washed with methanol (20mL) to give crude product.
Yield 3.148, 6.93mmo1, 76.1 °1o
The crude product (3.14g) was suspended in a mixture of water (250mL) and
methanol (50mL) and heated to reflux with stirring. The resulting yellow
solution was
heated for at least 30 minutes until all the solid had dissolved when it was
filtered hot.
The filtrate was allowed to cool to room temperature and stand for at least 20
hours.
The resulting cream coloured solid was filtered off, washed with water (30mL x
2),
and dried at the pump.
Yield 2.74g, 6.05mmo1, 87.370 (recryst. recovery), m.p. 198 to
201°C
Infrared (nujol): Vrt,ax 3185, 3142, 307-1. 3046, 1759, 1701, 1659, 1613,
1552, 1513,
1409, 1362, 1345, 1331, 1306, 1279, 1228, 1214, 1186. 1143, 1083, 1050, 1013,
1003, 974, 970, 927, 848, 816. 789, 738, 708. 686, 636, 618, 606, 573 cm-[.
PNMR (DMSO): 8H 3.23 (3H. s, NCH3), 3.06 (1H, dd, ArCH2CH), 3.26 (1H, dd,
ArCH2CH), 3.99 (2H, t, NCH2). 4.21 (2H, t. OCH2), 4.84 (1H, dd. ArCH~CH). 6.84
(2H, d, ArH), 7.14 (~H, d, ArH), 7.32 (1H, dd. ArH), 7.81 (1H, d. ArH), 7.91
(1H, dd.
ArH), 11.95 ( 1 H, bs, NH).
CNMR (DMSO): 8~ 36.2 . 38Ø 50.5. 52.9, 64.9, 112.5, I 14.3, 127.8, 129Ø
130.4,
138.9, 140.9, 150.0, 157.0, 171.6. 175.6.
MS (EI, 70eV), m/z 452 (56.3) [M-H), 372 (37.6), 229 (14.0). 222 (50.5), 116
(100).
