Title of Invention

A PROCESS FOR THE PREPARATION OF THIAZOLIDINEDIONE DERIVATIVE

Abstract A process for the preparation of Thiazolidinedione derivative of the general formula I, as well as the pharmaceutically acceptable salts and tautomeric forms thereof characterized in that a pyrimidine derivative of the general formula (III) is reacted with a amino-ethoxy-benzyl-thiazolidene-2,4-dione derivative of the formula (II): wherein R1 R2, R3 and R4 are as previously defined and X is a leaving group such as a halogen, especially C1or Br, in a inert medium such as herein described at a temperature ranging from 10 to 120° C. Dated this 13th day of May, 2002. RITUSHKA NEGI OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS
Full Text ORIGINAL
IN/PCT/2002/00607/MUMNP
FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
COMPLETE SPECIFICATION
[See Section 10, Rule 13]
A PROCESS FOR THE PREPARATION OF THIAZOLIDINEDIONE DERIVATES"
LABORATORIES VITA, S.A., a Spanish firm, domiciled at Av. De Barcelona, 69, 08970 Sant Joan Despi, Barcelona, Spain,
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:-
GRANTED
28/3/2005

The present invention relates to a process for preparation of Compound of Formula I which
display a high hypoglycemic activity and, therefore, they
are potentially useful in. the treatment and/or prevention
of diabetes and/or -other alterations or complications
characteristic of diabetes, such as hyperglycemia or
hyperlipidemia.
Background of the invention
Diabetes mellitus encompasses a group of syndromes whose main characteristic feature is the high blood-glucose levels, or hyperglycemia. This ,gives rise to a long-term series of vascular-type complications such as nephropathy, retinopathy, and neuropathy.
Two diabetes types are distinguished. The one known
as type-I diabetes (IDDM),caused by the deficiency in the
secretion of insulin, the regulating hormone of glucose in
blood, and the type-II diabetes (NIDDM) that is
characterized mainly by a resistance to the regulating
effect of insulin, this latter type being so much or even
more important than the first one. • —
The current treatments against type II diabetes, with sulfonylureas and biguanides, are far from being ideal. Sulfonylureas can induce hypoglycemia and biguanides can cause lactic acidosis.
In the last years, thiazolidinedione derivatives wi'th . hypoglycemic activity have • been described and, therefore, with application in the treatment of diabetes, mainly of the so-called "type II diabetes". The general structure of these compounds is:



wherein R is. a radical generally of aromatic or heteroaromatic type, and it can be linked or not to a N-type heteroatom.
A good review of this subject matter has been published by B. Hulin et al. (Current Pharmaceutical Design (1996), 2, 85-102)
As initial reference of this kind of structures the article of T. Sohda et al. (Chem. Pharm. Bull., 30- (10)., 3580-36.00 (1982)) may be taken into consideration. In this paper, the authors describe the synthesis of thiazolidine-dione structures and, concretely, that of Ciglitazone, true starting point in the research of thiazolidinediones as hypoglycemic agents, also well-known as glitazones.
Ciglitazone

Several modifications have been made around the structure of these glitazones.



Modifications have been introduced in the lipo-phyllic moiety of the Ciglitazone structure, which has lead to the synthesis of new such compounds as Troglitazone (EP139421), Rosiglitazone (EP306228), Piogli-tazoen (EP193256)
Furthermore, modifications on ' the ether function have been disclosed (D. A. Clark et al. , J. Med. Chem. , 1991, 34, 319-325; R. L. Dow et.al. , J. Med. Chem., 1991, 34, 1538-1544; B. Hulin et al.' J. Med. Chem. 1992, 35, 1853-1864), in which this function is built-in in a cycle fused with the aromatic ring, such as it happens in Englitazone (EP207605B):

Englitazone
On the other hand, XP002901546 by Cantello et al. refers to "[[ ώ- (Heterocyclylamino) alkoxy]benzyl] -2, 4-
thiazolidlnediones as Potent Antihyperglycemic Agents" in J. Med. Chem., 1.994, 37, (3977-3985). The more potent antihyperglycemic analoges were the series of [ [Hete'rocyclylamino) alkoxy] -benzyl] -2, 4-thiazolidinedio-nes. However, the heterocicles with better biological
activity were those having a pyridyl group in front of the pyrimidinyl group linked at its 2-position to the amino alkoxy chain.
Further, XP002901547 by Hulin et al. which refers to "The Glitazone Family of Antidiabetic Agents" in

Current Pharmaceutical Design, 1996, 2, 85-102 describes substituted thiazolidinedione derivatives wherein heterocyclyl group can be a pyridinyl or pyrimidinyl group. However, in said document the better biological activity is achieved with a pyridinyl group. Said document teaches away from the use of the pyridinyl group in the 4-position to the ;.amino alko'xy chain due to the fact that said change makes the compounds significantly less active. Furthermore, US-A-5.002.953 by- Hindley, 1989, describes substituted thiazolidinedione derivatives wherein the heterocyclyl group can be a pyridyl or 2-pyrimidinyl group.
None of said documents describes or suggests that a change of position of the pyrimidinyl group can result in an increase of the biological activity of the compounds.
Surprisingly, the authors of the present invention have found new thiazolidindiones. that show . very.' good hypoglycemic properties.
Description of the invention
The present invention refers to compounds of the general formula (I):





to their possible pharmaceutically acceptable salts and tautomeric forms. The present invention also refers to a process for their production and to their use as antidiabetic and hypoglycemic agents, alone or in combination with other antidiabetic agents, such as sulfonilureas or biguanides, as well as for the treatment of complications associated to the resistance . to the insulin, such as hypertension, hyperuricemia or other cardiovascular, metabolic and endocrine conditions, etc.

The preferred compounds of the present invention are
those in which:
R-: CH3;
R 0R&, NRSR6; R3: H, halogen (F, CI, Br, I), OR;,;





wherein X is a leaving group, such as a halogen group, specially Cl or Br.
The reaction is carried out in an inert medium at a temperature ranging from 10 to 120oC. -As inert medium, toluene, DMF, etc. are preferably used. METHOD B.-
This method consists in following the procedure described in the schema (II) below:




wherein the pyrimidine (III) is reacted with N-alkylamino-ethanol (R1 = C1-C2 alkyl) or with ethanolamine (R2 = H), in the presence or the absence of a solvent, to a temperature between 10oC and 120oC, to yield a compound of the formula (IV).
Compounds of the general formula (IV) are reacted with p-fluorobenzaldehyde in an inert solvent and in the presence of an eguivalent of sodium borohydride. The reaction is carried out at temperatures between 0oC and 120oC. In this way, compounds of the general formula V are obtained, which are reacted with 2,4-thiazolidinedione in toluene, heating to reflux, using piperidine acetate in catalytic amounts, while separating the water that is formed in the reaction with a Dean-Stark apparatus. In this way, compdunds of the general formula (VI) are obtained.
The compounds- of the general formula (VI) are subjected to a reduction process to obtain compounds of the general formula (I). This reduction reaction may be carried out with sodium borohydride, with metals in the presence or not of a proton donor, by enzymatic reduction or by catalytic hydrogenation.
Preferably, the reduction is carried out by means of a catalytic hydrogenatidn or by using a solution of sodium borohydride in water alkalinized with sodium hydroxide, and adding this solution onto a solution of the compound of the general formula (VI) in THF-DMF in the presence of catalytic amounts of cobalt chloride and dimethylglyoxime.
METHOD C-
This method consists in reacting a compound of the general formula (I), to obtain a compound of the general





EXPERIMENTAL PART
METHOD A.
Example No. 1
5-(4-{2-[(6-chloro-2,5-diphenylpyrimidin-4-yl)-methyl-
amino]-ethoxy}-thiazolidine-2,4-dione.

0.57 g 1.89 mmol) 4,6-dichloro-2, 5-diphenylpyrimi-dine and 0.53 g (1:89 mmol) 5- (4- (2-methylamino-ethoxy}-benzyl]-thiazolidine-2,4-dione in 30 ml DMF are heated at 80°C for 1 h.
Once the reaction completed, (CCF 90/10/1 CHC1.7 EtOH/NH4OH) , the mixture is poured onto 300 ml water and then extracted with 3 x 300 ml ethyl acetate.
The organic phase is dried and concentrated. The residue is chromatographed on silica gel. Eluting with 95/5 CK — Cl2/EtOH 0.4 g of a white solid is obtained (Yield40%)
H-NMR (DMSO-d6) :12.00 (br. s, 1H, NH) ; 8.36-8.32 (m, 2H) ;
7.60-7.30 (m, 8H); 7.12 (d, 2H); 6.82 (d, 2H); 4.82-4.76 (m, 1H); 4.17 (t, 2H)/ 3.83 (t, 2H); 3.24 (dd, 1H) ; 3.00 (dd, 1H) ; 2.74 (s, 3H, NCH3)
Following the same procedure the following compounds lave been obtained:

Example No. 2
5- (4-{2- [Methyl- (2-methylsulfanil-pyrimidin-4-yl) -amino]
ethoxy}-benzyl)-thiazolidine-2,4-dione



Starting from 1.15 g (8.3 mmol) 4-chloro-2-methyl-thiopyrimidine, 1.56 g of a solid is obtained (Yield 54%).
H-NMR (DMSO-d6) : 12.00 (br. s, 1H, NH) ; 3.01 (d, 1H) ;
7.08 (d, 2H);'6.86 (d, 2H); 6.42 (d, 2H) ; 4.84 (dd, 1H; ; 4.18 (t, 2H) ; 3.84 (br.s, 2H) ; 3.36.(dd, 1H) ; 3-10 (S, 3H, SCH3 ) ; 3.04 (dd, 2H); 2.00-2.38 (S, 3H, NCH;,)

Example No. 3
5- (4-,{2- [ (2-amino-6-chloropyrimidin-4-yl) -methyl-amino]
ethoxy}-benzyl)-thiazolidine-2,4-dione
v..

Gl " ■ '

Starting from 1.18g (7.2 mmol) 2-amino-4, 6-dichloro-pyrimidine, 1.8 g of a solid is obtained (Yield 62%).

H-NMR (DMSO-d6)

12.00 (br. s, 1H, NH)-; 7.19 (d, 2H); 6.86 (d, 2H); 6.48(s, 2H, NH ) ; 6.00 (s, 1H) ; 4.82 (dd, 1H) ; 4.10 (t, 2H) ; 3.84 (br. s, 2H); 3.36. (dd, 1H); 3.05 (dd, 1H) ; 3.04 ;t, 3H, NCH.) .

Example No. 4
5- (4-{2- [ (2 , 6-Dimethoxypyrimidin-4-yl) -methyl-amino] -
sthoxy}-benzyl)-thiazolidine-2,4-dione



Starting from. 0.94 g (5.3 mmol) 6-chloro-2,4-iimethoxypyrimidine, 0.84 g of a solid is obtained (Yield 38%.) .

H-NMR (DMSO-d6)

12.00 (br. s, 1H, NH); 7.18 (d, 2H); 6.84 (d, 2H) ; 5.80 (s, 1H) ; 4.84 (dd, 1H) ; 4.16 (t, 2H); 3.90 (t, 2H) ; 3.78 (s, 3H, OCH3) ; 3.76 (s, 3H, OCH:i) ; 3.36 (dd, 1H) ; 3.05 (dd, 1H) ; 3.04 (s, 3H, NCH3) .



Example No. 5 5-(4-{2-[(5-amino-6-chloropyrimidin-4-yl)-methyl-amino]-ethbxy}-benzyl)-thiazolidine-2,4-dione

Starting from 0.99 (5.3 ramol) 5-amino-4-dichloro-pyrimidine, 1.1 g cf a yellow solid is obtained. H-NMR (DMSO-d6) : 12.00 (br. s, 1H, NH) ; 7.95 (s, 1H) ;
7.18 (d, 2H);.6.84 (d, 2H) ; 5.21 (br. s,
2H, NH:) ; 4.84 (dd, 1H) ; 4.11 (t, 2H) ;
.3.64 (t, 2H); 3.30 (dd, 1H); 3.03 (dd,
1H); 2.96 (s, 3H).
Example No. 6
5- (4-{-2- [ (6-chloro-2-methylsulfanil-5-phenylpyrimidin-4-il)-methylamino]-ethoxy}-benzyl)-thiazolidine-2,4-dione


Starting from 1,5 g (5,3 mmol) of 4,6-dichloro-5-phenyl-2-methylthiopyridine 1.88 g of a solid is obtained (Yield 69V,) . •
H-NMR (DMSO-d6) : 12.00 (br. s,lH, NH) ; 7.46-7.38 (m, 3H) ;
7.30-7.26 (m, 2H) ; 7.18 (d, 2H); 6.82 (d, 2H) ; 4.82 .(dd, IB); 4.0.3 (t, 2H) ; 3.71 (t, 2H) ; 3.30 (dd, 1H) ; 3..02 (dd, 1H) ; 2.63 (s, 3H, NCH3); 2.42 (s, 3H, SCH,) .
Example No. 7
5-(4-{2-[Methyl-(7H-purin-6-yl)-amino]-ethoxy}-benzyl)-
thiazolidine-2,4-dione

Starting from 0.83 g (5.3 mmol) 6-chloropurine, 0.6 g of a yellow solid is obtained (Yield 29%).
H-NMR (DMSO-de) : 13.04 (br; s, 1H, NH) ; 12.00 (br. s, NH) ;
8.22 (s, 1H) ; 8.15 (s, 1H) ; 7.17 (d, 2K); 6.90 (d, 2H); 4.82 (dd, 1H); 4.40 (br. s, 2H) ; 4.14 (br. s, 2H) ; 3:44 (br.- s, 3H) ; 3.30 (dd, 1H);.3.03 (dd, 1H).
Example No. 8
5-(4-{2-[(6-chloro-5-nitropyrimidin-4-yl)-methyl-amino]-
ethoxy}-benzyl)-thiazolidine-2,4-dione



Starting from 1.04 g (5.3 mmol) 4,6-dicloro-5-nitro-pyridine, 0.3 g of the title compound is' obtained (Yield 13%).
H-NMR (DMSO-d6) : 12.00 (br. s, 1H, NH) ; 8.54 ,(S, 1H) ; 7.18
(d, 2H) ; 6.83 (d, 2H) ; 4.79 (dd, 1H) ; 4.23
(t, 2H); 4.08 (t, 2H); 3.30 (dd, 1H); 3.06 (s, 3H, NCH3) ; 3.04 (dd, 1H) .
Example No. 9 5- (4-{2-[ (8-amino-7H-purin-6-yl)-methylamino]-ethoxy} benzyl)-thiazolidine-2,4-dione

Starting from 1 g (9 mmol) 2-amino-6-chloropurine, 1.28 g of a yellow solid is obtained (Yield 54%).


H-NMR (DMSO-d6) : 12.10 (br. s, 1H, ' NH) ; 7.71 (s, 1H) ; 7.17
(d, 2H); 6.81 (d, 2H) ; 5.74 (br. s) 2H, NH.,) ; 4.81 (dd, 1H) ; 4.30 (br. s, 2H) ; 4.20 (br. s, 2H) ; 3 .'4 0 (br. s, 3H) ; 3.32 (dd, 1H) ; 3.05 (dd, 1H.) .
Example No. 10
5-[4-(2-Methyl-[9- (tetrahidropyran-2-yl) -9H-purin-6-yl ] -
amino} -ethoxy) -benzyl] -thiazolidine-2 ,'4-dione



Starting from 1 g (4.5 mmol) 6-chloro-9-(tetrahydro-2-pyranil) purine, 1.3 g of a solid is obtained (Yield 65%) .

NMR ((DMSO-d6)

■12.00 (br. s, 1H, NH) ; 8.41 (s, 1H) ; 8.25 (s, 1H); 7.18 (d, 2H), 6.80 (d, 2H); 5.64 (d, 1H); 4.80 dd); 4.60-4.20 (br. s, 2H); 4.24 (br. s, 2H); 4.04 (d, 1H); 3.80-3.60 (m, 1H) ; 3.60-3.40 (br. s, 3H, NCH3); 3.30 (dd, 1H) ; 3.03 (dd, 1H) ; 2.30-2.10 (m, 1H) ; 2.10-1.90 (m, 2H-) ; 1.90-1.70 (m,1H); 1.70-1.50 (m, 2H).



Example No. 11
5-[4-{2-[9-(3,4-Dihydroxy-5-hYdroxymethyl-tetrahydrofuran-2-yl)-9H-purin-6-yl]-methylamino}-ethoxy)-benzyl]-thiazo-lidine-2;4-dione



Starting from 1 g (3.5 mmol) 6-chloropurine-D-riboside, 1.2 g of a solid is obtained (Yield 65%).

NMR (DMSO-d6

12.00 (br. s, 1H, NH); 8.42 (s, 1H); 8.23
(s, 1H) ; 7.18 (d, . 2H) ; 6.80 (d, 2H) ; 5.95
(d, 1H) ; 5.46 (d, 1H, . OH) ; 5.37 (t, 1H,
OH); 5.21 (d, 1H, OH); 4.86 (dd, 1H); 4.62
(t, 2H) ; 4.25 (br. s, 2H) ; 4.21-4.17 (m,
2H) ; 3.98-3.95 (m, 1H) ; 3.75-3.25 (m,. 6H) ;
3.05 (dd, 1H).

Example No. 12
5-(4-{2-[Methyl-(9~methyl-9H-purin-6-yl)-amino]-ethoxy}
benzyl)-thiazolidine-2,4-dione



Starting from 1 g (6 mmol) 6-chloro-9-methylpurine, obtained by methylation of 6-chloropurine with methyl iodide in acetone and in the presence of potassium carbonate, 1.02 g of a yellow solid is obtained (Yield 41%) .
H-NMR(DMSO-d6) : 12.00 (br. s, 1H, NH) ; 8.24 (S, 1H) ; 8.17
(s, 1H) ; 7.16 (d, 2H) ; 6.84 (d, 2H) ; 4.82 (dd, 1H); 4.60-4.10 (br. s, 2H); 4.30-4.20 (br. s,2H); 3.75 (br. s, 3H, NCH3) ; 3.60-3.20 (br. s, 3H, NCH3) ; 3.30 (dd, 1H) ; 3.03 (dd, 1H) . Example No. 13
5- (4-{2- [Methyl- (7-methyl-7H-purin-6-yl) -amino] -ethoxy} -benzyl)-thiazolidine-2,4-dione
%€>
N==

Starting from 0.5 g (3 mmol) 6-chloro-7-methyl-purine, obtained as a byproduct in the alkylation of 6-chloropurine with methyl iodide, 0.38 g of an orange colored solid are obtained (Yield 31%) . H-NMR (DMSO-d6) :12-00 (br. s, 1H, NH) ; 8.40 (s, 1H) ; 8.35
is, ,1H); 7.12 id, 2H); 6.81 (d, 2H); 4.69 (dd, 1H) ; 4.25 (t, 2H); 3.97 (s, . 3H, NCH.}) ; 3.90 (t, 2H) ; 3.30 (dd, 1H) ; 3.20 (S, 3H, NCH2); 2.95 (dd, 1H) . Example No. 14
5- (4-{2-[ (6-chloropyrimidin-4-yl) -methyl amino] -ethoxy}-benzyl)-thiazolidine-2,4-dibhe

Starting from 1.1 g (7.4 mmol) 4,6-dichloro-pyrimidine, 2 g of a white solid is obtained (Yield 72%). H-NMR (DMSO-d6) :12:00 (br. s, 1H, NH) ; 8.19 (s, 1H) ; 7.18
(d, 2H);'6.85 (s, 1H) ; 6.83 (d, 2H) ; 4.82
(dd, 1H); 4.17 (t, 2H) ; 4.03 - 3.82 (br.
s, 2H) ; 3.30 (dd, 1H)'; 3.14 (s, 3H, NCH3) ;
3.05 (dd, 1H).
Example No. 15
5- (4-{2- [ (2-amino-6-methylpyrimidin-4-yl) -methylamino] -
ethoxy}-benzyl)-thiazolidine-2,4-dione



Starting from 0.8 g (5.3 mmo 1) 2-amino-4-chloro-6-
methylpyrimidine, 1.2 g of a white solid is obtained
(Yield 58%).
H-NMR (DMSO-d6) : 12.00 (br. s, 1H, NH) ; 7.16 (d, 2H) ; 6.87
(d, 2H); 6.08 (br. s, 2H, NH. ) ; 5.84 (s, 1H); 4.71 (dd, 1H); 4.10 (t, 2H); 3.85 (t, 2H) ; 3.31 (dd, 1H) ; 3.05 3H, NCH3) ; 2.98 (dd, 1H) ; 2.10 (s, 3H, CH3)
Example No. 16
5-(4-{2-[Methyl-(2-phenylquinazolin-4-yl)-amino]-ethoxy}-
benzyi)-thiazolidine-2,4-dione


Starting from 1.3 g (5.3 mmol) 4-chlo'ro-2-phenyl-quinazoline, 1'. 6 g of a yellow solid is obtained (Yield 62) H-NMR (DMSO-d6) :'12.00 (br. s, 1H, NH) ; 8.50-8.42 (m, 2H) ;
8.24 (d, 1H); 7.84-7.76 (m, 2H); 7.52-7.42
(m, 4H); 7.15 (d, 2H) ; 6.84 (d, 2H.) ; 4.84 (dd, 1H) ; 4.42; (t, 2H) ; 4.24 (t, 2H) ; 3.58
(s, 3H, NCH3) , 3.30 (dd, 1H.) ; 3.04 (dd,
1H) .
Example No. 17 ' .
5- (4-{2-[ (6-Methoxypyrimidin-4-yl) -methylamino] -ethoxy}-benzyl)-thiazolidine-2,4-dione

A starting mixture consisting of 2.9 g (0.02 mol) 4-chloromethoxypyrimidine and 5.6 g (0.02 mol) 5-[4-(2-methylaminoethoxy)-benzyl]-thiazolidine-2,4-dione in 60 ml DMF and in the presence of 17 g NaHCO is heated at 100oC for 24 h. Once the reaction completed, . the mixture is poured onto 600 ml water and it is extracted with 4 x 200 ml AcOEt.
r
The extracts are dried and concentrated, and the residue is chromatographed on silica gel. By elution with 95/5 CH2Cl2/EtOH 2.5g of a white solid is obtained. Yield 32%


H-NMR (DMSO-d6) : 12.00 (br. s,. 1H, NH) ; 8.22 (s, 1H) ; 7.18
(d, 2H); 6.84 (d, 2H) ; 5.92 (s, 1H) ;• 4.84 (dd.-lH); 4.10 (t, 2H) ; 3.90 (t, 2H) ; 3.82 (s, OCH.,) ; 3.32 (dd, 1H) ; 3.0'4 (s, NCH3) ; 3.02 (dd, 1H). Example No. 18

5- (4-{2-[(2-amino-6-methoxypyrimidin-4-yl)-methylamino]ethoxy}-benzyl)-thiazolidine-2,4-dione




A starting mixture consisting of 1.8 g (0.01 mmol) 2-methoxy-4,6-dichloropyrimidine, 2.7 g (0.01 mol) 5-[4-2-aminoethoxy)-benzyl]-thiazolidine-2,4-dione hydrochlo¬ride and 1.68 g (0.02 mol) sodium bicarbonate was heated to 12C in 50 ml" dimethylformamide for 2 hours. Once the reaction completed, the mixture is cooled and then poured onto 500 ml of water, whereby a solid precipitates, which is then filtered.
The filtration liquors are extracted with 3 x 100 ml AcOEt.. The extracts are dried with sodium sulfate, filtered and concentrated. The residue is pooled together with the previously filtrated solid and stirred in 50 ml methanol. The undissolved solid is then filtered to give 3.4 g (Yield: 84%). of a entirely pure product. H-NMR (DMSO-d6) :-12.00 (br. s, 1H', NH) ; 8.05 (br. s, 1H,
NH) ; 7.21 (d, 2H); 6.90 (d, 2H) ; 6.24 (s, 1H); 4.86 (dd, 1H); 4.12 (t, 2H); 3.84 (s, 3H); 3.68 (br. s, 2H); 3.38 (dd, 1H) ; 3.05 (dd, 1H).
METHOD B.-
Example No. 20
5-{4 -[2-(Methylpyrimidin-4-yl-amino)ethoxy]benzyl}-
thiazolidine-2,4-dione
Synthesis of 2-[( 6-chloropyrimidin-4-yl)-methyl-


25"
amino]-ethanol
To a solution of 14.8 g (0.1 mmol) 2,4-dichloropyrimidine in 120 ml ethanol and 20 ml water, cooled to 0OC, 11.3 g (0.15 mol) 2-(N-methylamino)ethanol is added. The resulting mixture is Stirred at room temperature for 1/2 then concentrated to dryness and finally partitioned between CH2Cl2 and a NaHCO3 saturated solution.
The organic phase is. dried, and concentrated. The residue is . stirred in 20 ml CH2Cl2, and then the precipitated white solid is filtered. 7.7 g is obtained. From the filtration liquor a further 5.8 g of pure product Ls.recovered by means of a silica gel column, eluting with L/l heptane / AcOEt. field 72% H-NMR (CDC12) : 8.30 (s,. 1H) ; 6.45 (1, 1H) ; 3.89 (t, 2H) ;
3.78. (t,, 2H); 3.10 (s, 3H, NCH3.) . . >0.2 - Synthesis of 2-(methylpyrimidin-4-yl-amino)-ethanol

'o 9.4 g (50 mmol) 2-[(6-chloropyrimidin-4-yl)-
ethylamino)ethanol in 50 ml .ethanol and 10 ml water, 1 g

of a 10s" Pd/C paste is added and the resulting mixture is subjected to hydrogenation at a pressure of 60 atmospheres and at room temperature for 8 h.
The solution is -filtered on decalite." The filtrate is concentrated to dryness and then partitioned between a saturated sodium bicarbonate solution (100 ml) and 100 ml CH2Cl2 The aqueous phase is extracted with an additional 2 x 100 ml CH2Cl2 and the extracts are pooled together with the previous ones.
The extracts are dried, then concentrated, and the residue is purified by column chromatography using silica gel as a support, and eluting with 9/1 CH2Cl2/EtOH.
4.1 g of a colorless oil is obtained (Yield 54%). 1H-NMR (CDC13) : 8:48 (s, 1H) ; 8.09 (d, 1H) ; 6.43 (d, 1H) ;
4.90 - 4:80 (br . s, lH, ' OH) ; 3,83,.(t, 2H) ; 3.74 (t, 2H); 3.10 (s, 3H, NCH3) . Synthesis of 4-[2-(methylpyrimidin-4-yl-amino)-ethoxy]-benzaldehyde

Onto 30 ml DMF 0.88 g (22 mmol) sodium hydride (60% in mineral oil) and 2.9 g (19 mmol) 2-[6-chloropyrimidin-4-yl)-methylamino]-ethanol are added. The mixture is stirred at room temperature for 1/2 h. A 2.6 g portion (21 mmol) of p-fluorobenzaldehyde is then added thereto and the resulting mixture, is heated at 50O'C for 15 minutes.
The reaction mixture is poured onto 300 ml water and then extracted with 3 x 100.ml AcOEt. The organic phase is


dried, filtered and concentrated, and the residue chromatographed on' silica gel. Eluting with '1/1 Heptane /AcOEt 2,5 g of the title compound is obtained (Yield 51%) . NMR -(CDC13) : 9.90 (s, 1H, CHO) ; . 3. 62 (s, 1H) ; 8,28-8,18
(br. s, 1H) 7.83 (d, 2H);-7.00 (d, 2H) ; 6.51 (d, lH)-;.4.30 (t, 2H) ; 4.08 (t,2H}; 3.21 (s, 3H, NCH3) . 4- Synthesis of 5-.4- [2-methylpyrimidin-4-yl-amino) -10 ethoxy]-benzylidene}-thiazolidine-2,4-dione

To 2.3 g (8 mmol) 4-[2-(methylpyrimidin-4-yl-amino)-ethoxy]-benzaldehyde in 40 ml toluene' 1.06 g (8.9 mmol) of 901 2,4-thiazolidinedione is added. Then, 0.06 ml (0.78 mmol) piperidine and 0.044 ml (0.78 mmol) acetic acid are further added thereto. The mixture is heated to reflux for 5 h while separating the water that is formed with a Dean-Stark apparatus.
The reaction mixture is allowed to cool and the solid precipitate is then filtered off. 2.5 g of product is obtained (yield 88%)
1H RMN (DMSO-d6) : 8.50 ' (s, 1H) ; 8.15 (d, 1 H) ; 7.70 (s,
1H) ; 7.51 (d,, 2H) ; 7.07 (d, 2H) ; 6.70 (d, 1H) ; 4.25 (t, 2H) ; 3.96 (t, 2H) ; 3.10 (s, 3H, NCH3) . Synthesis of 5-{4-[2-(methylpyrimidin-4-yl-amino)-ethoxy]-benzyl}-thiazolidine-2,4-dione


To a stirred solution of 7.5 mg (0.025 mmol) cobalt chloride hexahydrate and 116 mg (1 mmol) dimethylglyoxime Ln 40 ml of water, 4. drops 1N NaOH are added, followed by the addition' of 0.57 g (15 mmol) sodium borohydride.
Onto this solution, cooled to OoC, 1.8 g (5 mmol) 5- {4- [2- (methylpyriimidin-4-yl-amino) -ethoxy] -benzylidene}-thiazolidine-2,4-dione dissolved in 30 ml of DMF is added. The reaction mixture is kept at room temperature for 24 h and then poured onto 300 ml water, and the pH adjusted to 6-7 with acetic acid. The -precipitated white solid is filtered off, treated with 100 ml MeOH, and heated to reflux. ' The . MeOH solution is hot-filtered . in order to remove any residual starting compound.
From the filtration-liquor, 1.5 g end product is obtained by crystallization (Yield 84%).
H-NMR (DMSO-dc6 :12.00 (br. s, 1H, NH) ; 8.48 (s, 1H) ; 8.17
(d, 1H) ; 7.14 (d, 2H) ; 6.84 (d, 2H) ; 6.70 (d, 1H); 4.82 (dd, 1H) ; 4.12, (t, 2H) ; 3.90 (t, 2H); 3.30 (dd, 1H); 3.10 (s, 3H, NCH3) ; 3.03 (dd, 1H) .
METHOD C. -
Example No. 21
i- (4-{2- [ (6-Dimethylaminopyrimidin-4-yl) -methyl ami no] -
ithoxy) -benzyl) -thiazolidine-2 , 4-dione


To 1 g (2.5 mmol) of the compound obtained in the Example No. 14 in 30 ml DMF, 0.21 g (2.5 mmol) NaHCO3 and 1.8 ml (25 mmol) 6o% dimethylamine in water are added.
The mixture is heated at 800C for 24 h, then concentrated to dryness and the residue partitioned between 100 ml water and 100 ml CH2Cl The organic phase is dried and concentrated. The residue is chromatographed on silica gel.
Eluting with 96/4 CH2Cl2/EtOH 0.5 g of the title compound is obtained.
H-NMR (DMSO-d6) :12.00 (br. s, 1H): 8.06 (s , 1H) ; 7.18 (d,
2H); 6.86 (d, 2H); 5.50 (s, 1H); 4.84 (dd,
1H) ; 4.10 (t,.2H); 3.56 (t, 2H) ; 3.30 (dd,
1H);' 3.04 (s, 3H, NCH3) ; 3.02 (dd, 1H)
2.98 '(s, 6H) .
Example No. 22
5_- (4-{2- [ (6-Hydroxypyrimidin-4-yl> -methyl ami no] -ethoxy}-
bgnzyl)-thiazolidine-2,4-dione



To. 1.9 (5 mmol) of the compound obtained in the Example No. 17 in 40 ml acetic acid, 3.5 ml (20 mmol) of a •hydrobromic acid solution in 33% acetic acid is added.
The reaction is heated at 80°C for 4 h. Once the reaction completed, the mixture is poured onto water and the white solid which precipitates is filtered off and -then stirred for .30 minutes in 50 ml EtOH. The resulting suspension is filtered again, and 1.'2 g of a completely' pure white solid is obtained. Yield 64. H-NMR (DMSO-d6) : 12. 00 (br. s, 1H) ;. 11.62 (br. s, 1H) •;
7.90 (s, 1H) ; 7.18 (d, 2H) ; 6.84 (d, 2H) ;
5.10 (s, 1H); 4.82 (dd, 1H); 4.10 (t, 2H) ;
3.86-3.80 (br. s, 2H) ; 3.32 (dd, 1 H) ;
3.04 (dd, 1H) ; 2.97 (s, 3H, NCH3)'.
Pharmacological methods . .
The pharmacological effect of the compounds is assessed in genetically diabetic C57 BL male db/db 9-11 weeks old mice, as well as in control C57 BL db/+ animals of the same strain and age. The db/db mice show most of the metabolic alterations' that appear in the type-2 diabetes, . while the control animals do not develop the illness. In each experimental group, 8-10 animals are :used,. which are treated with different doses of the


compounds: 1 mg/kg, 5 mg/kg, 10 mg/kg or 2.5 mg/kg orally during 5 consecutive days.
In the day 0 of the experiment, blood samples are collected in . heparinized tubes by punction of the retroorbital vein. Plasma is separated and the levels of basal glucose and insulin are quantified.
After concluding the treatments, blood samples of each animal are collected again and plasmatic post-treatment glucose and insulin levels are quantified.
The determination of glucose is carried out by means of an enzymatic method that converts glucose into glucose 6-phosphate, a . reaction coupled with the reduction of nicotinamide-dinucleotide phosphate (NADP) to NADPH by the action of glucose-6-P-dehydrogenase. The NADPH reduces the iodonitrotetrazolium, which is quantified spectrophoto-metrically. The absorbancy at- 520 nm is proportional to the concentration of glucose, ref: Randox GI, 2623 (Bergmeyer H.U., Bernt E., Schmidt F.H., Stork H. In Methods of Enzymatic Analysis, Academic Press: London and New York 1974, p. 1196).
The results are expressed as the reduction percent with regard to the basal levels determined before the beginning of the treatment.
V The obtained results are shown in Table 1. As it can be seen from the Table, the compounds of the present invention attain a reduction of glucose levels higher than that achieved by the standard (troglitazone), even with doses 100-fold lower.


TABLE 1

Compound Dose
(mg/kg, p.o.) % glucose reduction
Troglitazone 100 . 33
Example 3 1 47
Example 4 1 53
Example 7 10 47
Example 11 10 30
Example 12 10 25
Example 14 1 51
Example 17 1 48
Example 2 0 5 21
Example 21 25 36
Example 22 5 22

We claim:


1. A process for the preparation of Thiazolidinedione derivative of the general formula I,
as well as the pharmaceutically acceptable salts and tautomeric forms thereof

characterized in that a pyrimidine derivative of the general formula (III) is reacted with a amino-ethoxy-benzyl-thiazolidene-2,4-dione derivative of the formula (II):

wherein R1 R2, R3 and R4 are as previously defined and X is a leaving group such as a halogen, especially C1or Br, in a inert medium such as herein described at a temperature ranging from 10 to 120° C.
Dated this 13th day of May, 2002.
RITUSHKA NEGI OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS


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Patent Number 208861
Indian Patent Application Number IN/PCT/2002/00607/MUM
PG Journal Number 35/2007
Publication Date 31-Aug-2007
Grant Date 14-Aug-2007
Date of Filing 13-May-2002
Name of Patentee LABORATORIS VITA, S.A.
Applicant Address A SPANISH FIRM, AV. DE. BARCELONA, 69, 08970 SANT JOAN DESPI, BARCELONA.
Inventors:
# Inventor's Name Inventor's Address
1 MARISABEL MOURELLE MANCINI AV. XILE, 28 08028 BARCELONA.
2 ELISABET DE RAMON AMAT POESIA 11, 08035 CARCELONA.
3 JUAN CARLOS DEL CASTILLO NIETO CASTILLEJOS 389, 08025 BARCEKIBA.
PCT International Classification Number C07D 417/12
PCT International Application Number PCT/ES00/00432
PCT International Filing date 2000-11-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 P 9902533 1999-11-18 Spain