Novel heterocyclic compounds process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases

IS 2 199 366 T3

DESCRIPTION

Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases.

Field of the invention

The present invention relates to novel antidiabetic compounds, their tautomeric forms, their derivatives, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing the same. This invention particularly relates to novel azolidinedione derivatives of general formula (I), and their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing the same.

<img file="ES2199366T3_D0001.tif" />

Y - / - N

R³

R⁴ OR

B

NH (l)

The present invention also relates to a process for the preparation of the aforementioned novel azolidinedione derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, novel intermediates and pharmaceutical compositions containing a the same.

The azolidinedione derivatives of the general formula (I) defined above of the present invention are useful for the treatment and / or prophylaxis of diseases or conditions in which insulin resistance is the underlying pathophysiological mechanism. Examples of these diseases or conditions are type II diabetes, impaired glucose tolerance, dyslipidemia, hypertension, coronary heart disease, and other cardiovascular disorders, including atherosclerosis. The azolidinedione derivatives of formula (I) are useful for the treatment of insulin resistance associated with obesity and psoriasis. The azolidinedione derivatives of formula (I) can also be used to treat diabetic complications and can be used for the treatment and / or prophylaxis of other diseases and conditions such as polycystic ovary syndrome (PCOS), certain kidney diseases, including diabetic nephropathy. , glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease and microalbuminuria, as well as certain eating disorders, such as aldose reductase inhibitors, and to improve cognitive functions in dementia.

Fundamentals of the invention

Insulin resistance is the decreased ability of insulin to exert its biological action over a wide range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect; failing this, the plasma glucose concentration inevitably rises and diabetes develops. Among developed countries, diabetes mellitus is a common problem and is associated with several abnormalities, including obesity, hypertension, hyperlipidemia (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 recognized that insulin resistance and relative hyperinsulinemia play a role in contributing to obesity, hypertension, atherosclerosis, and type 2 diabetes mellitus. The association of insulin resistance with obesity, hypertension and angina has been described as a syndrome that has insulin resistance as the central pathogenic point -Syndrome X. Furthermore, polycystic ovary syndrome (Patent Application No. WO 95/07697), psoriasis (Patent Application No. WO 95/35108), dementia (Behavioral Brain Research (1996) 75: 1-11), etc. . they may also have insulin resistance as a central pathogenic trait.

Several molecular defects have been associated with insulin resistance. These include reduced expression of insulin receptors on the plasma membranes of insulin-sensitive cells and alterations in signal transduction pathways that are activated after insulin binds to its receptor, including glucose transport and synthesis. of glycogen.

Since a defective action of insulin is thought to be more important than a lack of insulin secretion in the development of non-insulin-dependent diabetes mellitus and other related complications, this raises doubts about the intrinsic suitability of the antidiabetic treatment that relies on entirely on the stimulation of insulin release. Recently, Takeda has developed a new class of compounds that are derivatives of 5- (4-alkoxybenzyl) -2,4-thiazolidinediones of formula (II) (Ref. Chem. Pharm. Bull. 1982, 30, 3580-3600). In formula (II), V represents a substituted or unsubstituted divalent aromatic group and U represents various groups that have been published in various patent documents.

IS 2 199 366 T3

<img file="ES2199366T3_D0002.tif" />

As examples, U can represent the following groups:

(i) a group of formula (IIa), in which R¹ is hydrogen or a hydrocarbon residue or a heterocyclic residue which may each be substituted, R² is hydrogen or a lower alkyl which may be substituted with a hydroxy group, X is an oxygen or sulfur atom, Z is a hydroxylated methylene or carbonyl, m is 0 or 1, n is an integer of 1-3. These compounds have been described in European Patent Application No. 0 177 353.

<img file="ES2199366T3_D0003.tif" />

(Ha)

An example of these compounds is shown in formula (IIb)

<img file="ES2199366T3_D0004.tif" />

(ii) a group of formula (IIc), in which R¹ and R² are the same or different and each represents hydrogen or (C1-C5) alkyl, R³ represents hydrogen, an acyl group, a (C1-C6) alkoxycarbonyl group or an aralkyloxycarbonyl group, R⁴-R⁵ are the same or different and each represents hydrogen, (C1-C5) alkyl or (C1-C5) alkoxy or R⁴ and R⁵ together they represent an alkenedioxy group (C1-C4), n is 1, 2 or 3, W represents CH2, CO, a CHOR group⁶ in which R⁶represents any of the items or groups defined for R³ and can be equal to or different from R³. These compounds are described in European Patent Application No. 0 139 421.

<img file="ES2199366T3_D0005.tif" />

An example of these compounds is shown in formula (IId)

<img file="ES2199366T3_D0006.tif" />

(iii) a group of formula (IIe), in which A¹ represents a substituted or unsubstituted aromatic heterocyclic group, R¹ represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group in which the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group, n represents an integer in the range of 2 to 6. These compounds are described in European Patent No. 0 306 228.

IS 2 199 366 T3

R '|

A'-N- (CH₂) n - (Ile)

An example of this compound is shown in formula (IIf)

<img file="ES2199366T3_D0007.tif" />

(iv) a group of formula (IIg), in which Y represents N or CR⁵, R¹ , R², R³, R⁴ and R⁵ represent hydrogen, halogen, alkyl and the like and R⁶ represents hydrogen, alkyl, aryl and the like, n represents an integer from 0 to 3. These compounds are described in European Patent Application No. 0 604 983.

<img file="ES2199366T3_D0008.tif" />

An example of this compound is shown in formula (IIh)

<img file="ES2199366T3_D0009.tif" />

Yet another class of antihyperglycemic agents are the 5-substituted oxazolidine-2,4-diones and the 2-substituted 1,2,4-oxadiazolidine-3,5-diones, which can be represented by formula (IIi),

<img file="ES2199366T3_D0010.tif" />

wherein V represents a substituted or unsubstituted divalent aryl or heteroaryl group, W represents various groups that have been published in various patent documents, A represents a nitrogen atom or a CH group, and B is an oxygen atom.

As examples, W can represent the following groups:

(v) a group of formula (IIj), in which R is a (C1-C6) alkyl group, a cycloalkyl, furyl, thienyl group, a substituted or unsubstituted phenyl group, X is hydrogen, methyl, methoxy, chloro or fluorine. These compounds have been described in US Patent No. 5,037,842.

<img file="ES2199366T3_D0011.tif" />

IS 2 199 366 T3

An example of these compounds is shown in formula (IIk)

<img file="ES2199366T3_D0012.tif" />

(vi) a group of formula (II l), in which A¹ represents a substituted or unsubstituted aromatic heterocyclic group, R¹ represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group in which the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group, n represents an integer in the range of 2 to 6. These compounds are described in Patent Application No. WO 92/02520.

R '|

A'-N- (CH₂) n -O- (II l)

An example of these compounds is shown in formula (IIm)

<img file="ES2199366T3_D0013.tif" />

(vii) a group of formula (IIn) and (IIo), in which R¹ is hydrogen, (C1-C8) alkyl, (C1-C8) alkoxy, trifluoroalkoxy, halogen or a trifluoromethyl group, R² is hydrogen or methyl and X is oxygen or sulfur. These compounds have been described in US Patent No. 5,480,486.

<img file="ES2199366T3_D0014.tif" />

<img file="ES2199366T3_D0015.tif" />

(Ho)

An example of these compounds is shown in formula (IIp)

<img file="ES2199366T3_D0016.tif" />

Some of the previously referred to hitherto known antidiabetic compounds appear to have a bone marrow depressive effect, liver and cardiac toxicity and moderate potency, and consequently their regular use for the treatment and control of diabetes is becoming limited and restricted.

Summary of the invention

With the aim of developing new compounds for the treatment of type II diabetes [non-insulin dependent diabetes mellitus (NIDDM)] that could be more potent at relatively low doses and that have greater efficacy with less toxicity, we directed our research efforts in the direction of incorporating safety and having greater efficiency, which has resulted in the development of novel azolidinedione derivatives having the general formula (I) as defined above.

IS 2 199 366 T3

The main objective of the present invention is, therefore, to provide novel azolidinedione derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing the same, or mixtures thereof. themselves.

Another object of the present invention is to provide novel azolidinedione derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing the same or mixtures thereof that have improved activities, no toxic effect or reduced toxic effect.

Yet another objective of the present invention is to produce a process for the preparation of novel azolidinediones of formula (I) as defined above, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.

Yet another objective of the present invention is to provide pharmaceutical compositions containing compounds of general formula (I), their tautomers, their stereoisomers, their polymorphs, their salts, solvates, or mixtures thereof in combination with suitable excipients, solvents, diluents and other means normally employed in the preparation of such compositions.

Yet another object of the present invention is to provide a process for the preparation of the novel intermediate of formula (III)

<img file="ES2199366T3_D0017.tif" />

where G represents -CHO, -NO2, -NH2, -CH = NHOH, -CH2NHOH, -CH2N (OH) CONH2 or -CH2CH (J) COOR, where J represents a hydroxy group, such a halogen atom such as chlorine, bromine or iodine and R represents H or a lower alkyl group such as methyl, ethyl, or propyl, X, Y, Z, R¹ , R² , R³ , n and Ar are defined as in formula (I).

Detailed description of the invention

The azolidinedione derivatives of the present invention have the general formula (I)

<img file="ES2199366T3_D0018.tif" />

where one of the symbols X, Y, or Z represents C = O or C = S and one of the remaining symbols X, Y, and Z represents C = and the other of the remaining symbols X, Y, and Z represents C = C ; R¹ , R² and R³ are substituents of both X, Y or Z and of a nitrogen atom and are the same or different, and represent hydrogen, halogen, hydroxy or nitro, or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl , a heterocycle selected from aziridinyl, pyrrolidinyl, morpholinyl or piperidinyl; a heteroaryl selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, tetrazolyl, benzopyranyl or benzofuranyl; heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, thioalkyl, alkylthio, carboxylic acid, or a carboxylic acid derivative selected from CONH2, CONHMe, CONMe2, CONEPh2, or CONEt, CONEt, CONH , or sulfonic acid or a sulfonic acid derivative selected from SO2 NH2, SO2 NHMe, SO2 NMe2, or SO2 NHCF3; provided that when R¹ , R² or R³ are substituents of a nitrogen atom, do not represent hydrogen, halogen, nitro, carboxylic or sulfonic acid groups; or any two of the R substituents¹ , R² and R³ together with the adjacent atoms to which they are attached they form a substituted or unsubstituted cyclic structure of 4 to 7 atoms with one or more double bonds, which may be carbocyclic or may contain one or more heteroatoms selected from oxygen, nitrogen and sulfur; wherein, when the cyclic structure formed by any two of the R substituents¹ , R² or R³ together with the adjacent atoms to which they are attached is substituted, the substituents are selected from halogen, alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, a heterocycle selected from aziridinyl, pyrrolidinyl, morpholinyl or piperidinyl; a heteroaryl selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, tetrazolyl, benzopyranyl or benzofuranyl; heteroaralkyl, hydroxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, carboxylic acid or a carboxylic acid derivative selected from

IS 2 199 366 T3

CONH2, CONHMe, CONMe2, CONHEt, CONEt2, or CONHPh, or sulfonic acid or a sulfonic acid derivative selected from SO2NH2, SO2NHMe, SO2NMe2, or SO2NHCF3; in which, when R¹, R² or R³ are substituents of X, Y or Z and are substituted, the substituent may be the same or different and is selected from halogen, hydroxy, nitro or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, a heterocycle selected from aziridinyl, pyrrolidinyl, morpholinyl or piperidinyl; a heteroaryl selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, tetrazolyl, benzopyranyl or benzofuranyl; heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, thioalkyl, alkylthio, carboxylic acid or a carboxylic acid derivative selected from CONH2, CONHMe, CONMe2, CONHEt, CONHPEt2 or sulfonic acid or a sulfonic acid derivative selected from SO2NH2, SO2NHMe, SO2NMe2, or SO2NHCF3; in which, when R¹, R² or R³ are substituents of a nitrogen atom and are substituted, the substituent is selected from halogen, hydroxy, nitro or substituted or unsubstituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, a heteroaryl selected from pyridyl, thienyl, furyl , pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, tetrazolyl, benzopyranyl or benzofuranyl; a heterocycle selected from aziridinyl, pyrrolidinyl, morpholinyl, or piperidinyl; heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl, thioalkyl, alkylthio, carboxylic acid, or a carboxylic acid derivative selected from CONH2, CONHMe, CONMe2, CONEPh2, or CONHt , or sulfonic acid or a sulfonic acid derivative selected from SO2NH2, SO2NHMe, SO2NMe2, or SO2NHCF3; the linking group represented by - (CH2) nO- may be attached either through a nitrogen atom, or through X, Y or Z, where n is an integer in the range of 1-4; Ar represents substituted or unsubstituted phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, or benzoxazolyl, and when Ar is substituted the substituents are selected from C1-C6 alkyl ) linear or branched, (C1-C3) alkoxy, halogen, acyl, amino, acylamino, thio, or carboxylic acid or a carboxylic acid derivative selected from CONH2, CONHMe, CONMe2, CONHEt, CONEt2, or CONHPh, or sulfonic acid or a sulfonic acid derivative selected from SO2NH2, SO2NHMe, SO2NMe2, or SO2NHCF3; R⁴ represents hydrogen, halogen or an alkyl group, or forms a bond together with the adjacent group A; A represents a nitrogen atom or a CR group⁵, in which R⁵ represents hydrogen, halogen or an alkyl group, or R⁵ forms a bond together with R⁴; B represents an oxygen or sulfur atom when A is CR⁵, and B represents an oxygen atom when A is a nitrogen atom.

The following Table represents suitable combinations of X, Y and Z that form the structure of the ring containing X, Y and Z in formula (I):

<td>IN °</td><td>X</td><td>Y</td><td>Z</td>

<td> 1.</td><td>C = O or C = S</td><td>= C</td><td>C = C</td>

<td> 2.</td><td>C = O or C = S</td><td>C = C</td><td>= C</td>

<td> 3.</td><td>= C</td><td>C = O or C = S</td><td>C = C</td>

<td> 4.</td><td>= C</td><td>C = C</td><td>C = O or C = S</td>

<td> 5.</td><td>C = C</td><td>C = O or C = S</td><td>= C</td>

<td> 6.</td><td>C = C</td><td>= C</td><td>C = O or C = S</td>

It is preferred that at least one of the symbols X, Y or Z is C = C.

It is preferred that one of the symbols X or Y is C = O. Suitable ring structures containing X, Y, and Z include

<img file="ES2199366T3_D0019.tif" />

IS 2 199 366 T3

A preferred ring structure is

<img file="ES2199366T3_D0020.tif" />

When the R groups¹ , R² and R³ are attached to X, Y and Z, it is preferred that R¹ , R² and R³ are selected from hydrogen, a halogen atom such as fluorine, chlorine, bromine or iodine; hydroxy; nitro; a substituted or unsubstituted (C1-C12) alkyl group, especially a linear or branched (C1-C6) alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like; a cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; a cycloalkyloxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like; an aryl group such as phenyl or naphthyl, the aryl group may be substituted; aralkyl such as benzyl or phenethyl, the aralkyl group may be substituted; a heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroaryl group may be substituted; heterocyclic groups such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl and the like, the heterocyclic group may be substituted; aryloxy such as phenoxy, naphthyloxy, the aryloxy group may be substituted; alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl; an aryloxycarbonyl group such as optionally substituted phenoxycarbonyl; an arylamino group such as HNC6 H5; an amino group; amino (C1-C6) alkyl; hydroxyalkyl (C1-C6); (C1-C6) alkoxy; thio (C1-C6) alkyl; (C1-C6) alkylthio; an acyl group such as acetyl, propionyl or benzoyl, the acyl group may be substituted; acylamino groups such as NHCOCH3, NHCOC2H5, NHCOC3 H7, NHCOC6H5; an aralkoxycarbonylamino group such as NHCOOCH2C6 H5, an alkoxycarbonylamino group such as NHCOOCH2 H5, NHCOOCH3 and the like; a carboxylic acid or its derivatives such as amides, such as CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHPh and the like, the derivatives of the carboxylic acid may be substituted; an acyloxy group such as OCOMe, OCOEt, OCOPh, and the like, which may be optionally substituted; sulfonic acid or its derivatives such as SO2 NH2, SO2 NHMe, SO2 NMe2, or SO2 NHCF3 and the like, the derivatives of sulfonic acid may be substituted.

All preferred groups that R can represent¹ , R² and R³ they can be substituted or unsubstituted.

When R¹ , R² or R³ are attached to a nitrogen atom, it is preferred that R¹ , R² and R³ are selected from a (C1-C12) alkyl group, especially a linear or branched (C1-C6) alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl groups and the like ; a cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; an aryl group such as phenyl or naphthyl; aralkyl such as benzyl or phenethyl; a heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, tetrazolyl, and the like; heterocyclic groups such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, and the like; alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl; an aryloxycarbonyl group such as phenoxycarbonyl; amino (C1-C6) alkyl; hydroxyalkyl (C1-C6); thio (C1-C6) alkyl; or an acyl group such as acetyl, propionyl, benzoyl, and the like.

All preferred groups that R can represent¹ , R² and R³ they can be substituted or unsubstituted.

When the groups represented by R¹ , R² and R³ are substituted, the selected substituents are from the same groups as the groups representing R¹ , R² and R³ , and can be selected from halogen, hydroxy or nitro, or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocycle, heteroaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy , alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, thioalkyl groups, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.

A suitable ring structure made up of any two of the R groups¹ , R² and R³ together with the adjacent atoms to which they are attached, includes a substituted or unsubstituted 4-7 membered cyclic structure that may contain one or more double bonds, the cyclic structure may be carbocyclic or optionally contain one or more heteroatoms selected from nitrogen, oxygen and sulfur. Examples of cyclic structures are phenyl, naphthyl, thienyl, furyl, pyrrolyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl, azacyclobutenyl, isoxazolyl, azepinyl, pyridyl, pyridazyl, pyrimidinyl, dihydrofuryl, dihydrothienyl, tetrahydropyridyl, tetrahydropyridyl, and the like. The substituents of the cyclic structure can be selected from the same groups as R¹ , R² and R³ . Examples of possible substituents are halogen, alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aralkyl, heterocycle, heteroaryl, heteroaralkyl, hydroxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, arylamino, aminoalkyl, aryloxy, alkoxycarbonyl, alkylamino, alkoxyalkyl acid carboxylic acid or its derivatives, or sulfonic acid or its derivatives.

More preferred than R groups¹ , R² and R³ represent hydrogen; a halogen atom such as fluorine, chlorine, bromine or iodine; an alkyl group such as methyl, ethyl, n-propyl or n-butyl; a cycloalkyl group such as cyclopropyl; an aryl group such as phenyl; or an aralkyl group such as benzyl.

IS 2 199 366 T3

When the groups represented by R¹ , R² and R³ are substituted, it is preferred that the substituents are selected from halogen, haloalkyl, haloalkoxy, and halocycloalkoxy, where the halogen atom is preferably a fluorine atom.

The ring structure formed by any two of the R groups¹ , R² and R³, along with the adjacent atoms to which they are attached, can be substituted or unsubstituted. Preferred ring structures are phenyl, thienyl, furyl or pyridyl groups. When these ring structures are substituted, it is preferred that the substituents are selected from halogen; a lower alkyl group such as methyl or ethyl; trifuloromethyl; fluoromethyl; difluoromethyl; and alkoxy groups such as methoxy, trifluoromethoxy, fluoromethoxy, and difluoromethoxy.

The linking group - (CH2) n -O- may be attached either through a nitrogen atom, or through X, Y, or Z. The integer n may be in the range of 1 to 4, preferably n is 1 or 2. It is preferred that the linking group is attached either through nitrogen, or through Z, when Z represents = C.

It is preferred that the group represented by Ar is substituted or unsubstituted divalent phenylene, naphthylene, pyridyl, quinolinyl, benzofuryl, dihydrobenzofuryl, benzopyranyl, indolyl, indolinyl, azaindolyl, azaindolinyl, pyrazolyl, benzothiazolyl, benzoxazolyl, and the like. The substituents of the group represented by Ar can be selected from linear or branched (C1-C6) alkyl, (C1-C3) alkoxy, halogen, acyl, amino, acylamino, thio, or carboxylic or sulfonic acids or their derivatives.

It is more preferred that Ar represents substituted or unsubstituted divalent phenylene, naphthylene, benzofuryl, indolinyl, quinolinyl, azaindolyl, azaindolinyl, benzothiazolyl or benzoxazolyl.

It is still more preferred that Ar represents divalent phenylene or naphthylene, which may be optionally substituted with methyl, halomethyl, methoxy or halomethoxy groups.

R⁴ suitable include hydrogen; a lower alkyl group such as methyl, ethyl or propyl; a halogen atom such as fluorine, chlorine, bromine or iodine; or R⁴ together with A they represent a link.

A suitable group A can be nitrogen or CR⁵ , in which R⁵ can be a hydrogen atom, halogen, a lower alkyl group, or forms a bond together with R⁴ .

A suitable group B includes a heteroatom selected from O or S, provided that when A is CR⁵ , B is selected from sulfur or oxygen, and when A is nitrogen, B represents oxygen.

A suitable ring structure comprising A and B includes the groups 2,4-dioxooxazolidin-5-yl, 2,4-dioxothiazolidin-5-yl, 3,5-dioxo-1,2,4-oxadiazolidin-2-yl . Preferred ring structures that comprise A and B include the 2,4-dioxooxazolidin-5-yl and 2,4-dioxothiazolidin-5-yl groups.

It is more preferred that the ring structure comprising A and B is a 2,4-dioxothiazolidin-5-yl group.

Pharmaceutically acceptable salts forming part of this invention include salts of the azolidinedione moiety such as alkali metal salts such as Li, Na, and K salts, alkaline earth metal salts such as Ca and Mg salts, organic base salts such as lysine, arginine, guanidine, diethanolamine, choline and the like, ammonium or substituted ammonium salts, salts of a carboxy group where appropriate, such as aluminum or alkali metal salts; alkaline earth metal salts; ammonium or substituted ammonium salts. Salts can include acid addition salts which are sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzene sulfonates, ascorbates, glycerophosphates, ketophosphates and the like. The pharmaceutically acceptable solvates can be hydrates, or comprise other crystallization solvents such as alcohols.

Particularly useful compounds in accordance with the present invention include: 5- [4- [2- [2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts, 5- [4- [ 2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts, 5- [4- [2- [4 -methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts, 5- [4- [2- [2-butyl-4 -methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts, 5- [4- [2- [2-Ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts, 5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione and its salts and its polymorphs,

5- [4 - [[3-ethyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidin-2,4-dione and its salts,

IS 2 199 366 T3

5- [4- [2- [2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts,

5- [4- [2- [2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts,

5- [4- [2- [6,7-dimethoxy-2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione and its salts,

5- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] oxazolidine-2,4-dione and its salts,

5- [4- [2- [4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] oxazolidine-2,4-dione and its salts,

5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] oxazolidine-2,4-dione and its salts,

2- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] -1,2,4-oxadiazolidine-3,5-dione and its salts,

2- [4- [2- [4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] -1, 2,4-oxadiazolidine-3,5-dione and its salts,

2- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] -1,2,4-oxadiazolidine-3,5-dione and its salts, 5- [ 4- [2- [2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione and its salts, 5- [4- [2- [ 2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione and its salts, 5- [4- [2- [4-methyl- 2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione and its salts, 5- [4- [2- [2-Ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione and its salts, 5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethylene] thiazolidine-2,4-dione and its salts, 5- [4 - [[3-ethyl-4-oxo -3,4-dihydro-2-quinazolinyl] methoxy] phenylmethylene] thiazolidine-2,4-dione and its salts, 5- [4- [2- [2-methyl-4-oxo-3,4-dihydro-3 -quinazolinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione and its salts, 5- [4- [2- [2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione and its salts, 5- [4 - [[3 -methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] -3-methoxyphenylmethylene] thiazolidine-2,4-dione and its salts. More preferred compounds according to the present invention include

5- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione,

5- [4- [2- [4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione,

5- [4- [2- [2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione, sodium salt,

5- [4- [2- [2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione, sodium salt,

5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione and its polymorphs, sodium salt of 5- [4- [ [3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione and its polymorphs,

5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione, potassium salt,

5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethylene] thiazolidine-2,4-dione, sodium salt.

According to a characteristic of the present invention, a process is provided for the preparation of the novel intermediate compound of general formula (III)

<img file="ES2199366T3_D0021.tif" />

ES 2 199 366 T3 in which X, Y, Z, R¹, R², R³ and n are as defined above, the linking group - (CH2) nO- is attached to a nitrogen atom, G represents a -CHO- or -NO2 group comprising reacting a compound of general formula (IV)

<img file="ES2199366T3_D0022.tif" />

where X, Y, Z, R¹, R² and R³ are as defined above and the H atom is attached to one of the nitrogen atoms of the ring, with a compound of general formula (V)

L¹ - (CH2) n - O - Ar - G (V) where Ar and n are as defined above and L¹ it can be a halogen atom such as Cl, Br, I or a leaving group such as methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, etc., and G represents a CHO or NO2 group.

The reaction of a compound of general formula (IV) with a compound of general formula (V) to produce a compound of general formula (III) can be carried out in the presence of solvents such as DMSO, DMF, DME, THF, dioxane, ether and the like, or a combination thereof. The reaction can be carried out in an inert atmosphere that can be maintained using inert gases such as N2, Ar, He. The reaction can be carried out in the presence of a base such as alkalis, such as sodium hydroxide, potassium hydroxide; alkali metal carbonates, such as sodium carbonate, potassium carbonate; alkali metal hydrides, such as sodium hydride or potassium hydride; organometallic bases, such as n-butyllithium; alkali metal amides, such as sodamide, or mixtures thereof. The amount of base can be between 1 and 5 equivalents, based on the amount of compound of formula (IV), preferably the amount of base is between 1 and 3 equivalents. Between 1 and 3 equivalents of alkali metal halides, based on the amount of compound of formula (IV), such as lithium bromide, can be added as an additive. The reaction can be carried out at a temperature in the range of 0 ° C to 150 ° C, preferably at a temperature in the range of 15 ° C to 100 ° C. The duration of the reaction can be between 0.25 and 24 hours, preferably between 0.25 and 6 hours.

In another embodiment of the invention, the novel intermediate compound of general formula (III) defined and obtained above, in which G is a CHO or NO2 group, can be prepared by reacting the compound of general formula (VI)

<img file="ES2199366T3_D0023.tif" />

<img file="ES2199366T3_D0024.tif" />

(^CH2) n-OH

<img file="ES2199366T3_D0025.tif" />

(VI) in which X, Y, Z, R¹, R², R³ and n are as defined above, with a compound of general formula (VII)

L² - Ar - G (VII) in which L² is a halogen atom, G is a CHO or NO2 group and Ar is as defined above.

The reaction of a compound of formula (VI) with a compound of formula (VII) to produce a compound of formula (III) can be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like. The inert atmosphere can be maintained using inert gases such as N2, Ar or He. The reaction can be carried out in the presence of a base such as K2CO3, Na2CO3, NaH. The reaction temperature may be between 20 ° C and 150 ° C, preferably at a temperature in the range of 30 ° C to 100 ° C. The duration of the reaction can be between 1 and 24 hours, preferably between 2 and 6 hours.

In another embodiment of the present invention, the novel intermediate compound of general formula (III), in which G is a CHO or NO2 group, can also be prepared by reaction of the compound of general formula (VIII)

IS 2 199 366 T3

<img file="ES2199366T3_D0026.tif" />

(CHjk-1?

(HIV) in which X, Y, Z, R¹, R², R³, n and L¹ are as defined above, with a compound of general formula (IX)

HO-Ar -G (IX) where G is a CHO or NO2 group and Ar is as defined above.

The reaction of a compound of formula (VIII) with a compound of formula (IX) to produce a compound of formula (III) can be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like, or mixtures thereof . The reaction can be carried out in an inert atmosphere that can be maintained using inert gases such as N2, Ar or He. The reaction can be carried out in the presence of a base such as K2CO3, Na2CO3 or NaH or their mixtures. The reaction temperature can be between 20 ° C and 120 ° C, preferably at a temperature in the range of 30 ° C to 100 ° C. The duration of the reaction can be between 1 and 12 hours, preferably between 2 and 6 hours.

The present invention provides a process for the preparation of novel azolidinedione derivatives of general formula (I), their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, wherein R¹, R², R³, X, Y, Z, n and Ar are as defined above and A represents CR⁵ in which R⁵ along with R⁴ represent a bond and B represents a sulfur or oxygen atom, and also a compound of formula (I) in which R⁴ and R⁵ represent hydrogen and all symbols are as defined above, comprising:

reacting the novel intermediate compound of general formula (III) obtained above, in which G represents a CHO group, with 2,4-thiazolidinedione or 2,4-oxazolidinedione, and removing the water formed during the reaction by conventional methods to provide a compound of general formula (X)

<img file="ES2199366T3_D0027.tif" />

in which R¹, R², R³, X, Y, Z, n and Ar are as defined above and B represents sulfur or oxygen.

The reaction between the compound of general formula (III), in which G represents a CHO group, with 2,4-thiazolidinedione or 2,4-oxazolidinedione to provide the compound of general formula (X) in which B represents an atom sulfur or oxygen, respectively, can be carried out alone in the presence of sodium acetate or in the presence of a solvent such as benzene, toluene, methoxyethanol or their mixtures. The reaction temperature can be between 80 ° C and 140 ° C depending on the solvents used, and in the range of 80 ° C to 180 ° C when the reaction is carried out only in the presence of sodium acetate. A suitable catalyst such as piperidinium acetate or benzoate, sodium acetate or mixtures of catalysts can also be used. Sodium acetate can be used in the presence of a solvent, but it is preferred that sodium acetate is used alone. The water produced in the reaction can be removed, for example, using a Dean Stark water trap or using water-absorbing agents such as molecular sieves. Oxazolidine-2-oxo-4-thione can be used instead of 2,4-oxazolidinedione. However, it is necessary to convert the thio group to oxo group by oxidation using agents such as hydrogen peroxide or peroxyacids like mCPBA.

The compound of the general formula (X) obtained in the manner described above is reduced by a known method to obtain the compound of the general formula (XI)

IS 2 199 366 T3

<img file="ES2199366T3_D0028.tif" />

in which R¹, R², R³, X, Y, Z, n and Ar are as defined above and B represents a sulfur atom or an oxygen atom. The compound of general formula (XI) represents the compound of general formula (I), in which R⁴ is hydrogen, A is CR⁵ in which R⁵ is hydrogen, and other symbols are as defined above.

The reduction of the compound of formula (X) to provide the compound of general formula (XI) can be carried out in the presence of hydrogen gas and a catalyst such as Pd / C, Rh / C, Pt / C, and the like. Catalyst mixtures can be used. The reaction can also be carried out in the presence of solvents such as dioxane, acetic acid, ethyl acetate, and the like. A pressure between atmospheric pressure and 5.6 kg / cm can be used.² (80 psi). The catalyst can be 5-10% Pd / C and the amount of catalyst used can be between 50-300% w / w. The reaction can also be carried out using metal reduction in solvents such as magnesium in methanol or sodium amalgam in methanol.

The compound of general formula (XI) obtained above is converted into its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates by conventional methods.

In another embodiment of the present invention, the compound of general formula (I) can also be prepared by reacting the compound of general formula (VIII) defined above with a compound of general formula (XII)

<img file="ES2199366T3_D0029.tif" />

in which R⁴, A, B and Ar are as defined above and R⁶ It is hydrogen or a nitrogen protecting group that is removed after the reaction.

The reaction of the compound of formula (VIII) with the compound of formula (XII) to produce a compound of formula (I) can be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like, or mixtures thereof. The reaction can be carried out in an inert atmosphere which is maintained using inert gases such as N2, Ar or He. The reaction can be carried out in the presence of a base such as K2CO3, Na2CO3 or NaH or their mixtures. The reaction temperature can be between 20 ° C and 120 ° C, preferably at a temperature in the range of 30 ° C to 80 ° C. The duration of the reaction can be between 1 and 12 hours, preferably between 2 and 6 hours.

In yet another embodiment of the present invention, the compound of general formula (I), in which the linking group - (CH2) nO- is attached to a nitrogen atom, can be prepared by reacting the compound of general formula (IV) defined above with a compound of general formula (XIII)

<img file="ES2199366T3_D0030.tif" />

in which L¹, n, Ar, A, B, R⁴ and R⁶ are as defined before, and removing the protecting group when R⁶ it is a nitrogen protecting group.

IS 2 199 366 T3

The reaction of the compound of general formula (IV) with a compound of general formula (XIII) to produce a compound of formula (I) can be carried out in the presence of solvents such as THF, DMF, DMSO, DME and the like, or their mixtures. The reaction can be carried out in an inert atmosphere which is maintained using inert gases such as N2, Ar or He. The reaction can be carried out in the presence of a base such as alkalis, such as sodium hydroxide, or potassium hydroxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; alkali metal hydrides, such as sodium hydride; organometallic bases, such as n-butyllithium; alkali metal amides, such as sodamide, or mixtures thereof. Multiple solvents and bases can be used. The amount of base can be between 1 and 5 equivalents, preferably between 1 and 3 equivalents. Between 1 and 3 equivalents of alkali metal halides such as lithium bromide can be added as an additive. The reaction temperature may be in the range of 0 ° C to 120 ° C, preferably at a temperature in the range of 20 ° C to 100 ° C. The duration of the reaction can be between 0.5 and 24 hours, preferably between 0.5 and 6 hours.

In yet another embodiment of the present invention, the compound of general formula (I), wherein R¹, R², R³, X, Y, Z, n and Ar are as defined above, R⁴ represents hydrogen and A is CH and B represents S or O can be prepared by reacting the compound of general formula (XIV)

<img file="ES2199366T3_D0031.tif" />

in which R¹, R², R³, X, Y, Z, n and Ar are as defined above, J is a halogen atom such as chlorine, bromine or iodine or a hydroxy group and R is a lower alkyl group, with urea when J is an OH group and with thiourea when J is a halogen atom, followed by treatment with an acid.

The reaction of the compound of the general formula (XIV) with urea or thiourea is normally carried out in the presence of an alcoholic solvent such as methanol, ethanol, propanol, isobutanol, 2-methoxybutanol, etc., or DMSO or sulfonate. The reaction can be carried out at a temperature in the range of 20 ° C to the reflux temperature of the solvent used. Bases such as NaOAc, KOAc, NaOMe, NaOEt, etc. can be used. Following the reaction, a treatment with a mineral acid such as hydrochloric acid is normally carried out at a temperature between 20 ° C and 100 ° C.

The compound of general formula (XIV) in which J is a hydroxy group is prepared by hydrolysis of the compound of general formula (XIV) in which J is a halogen atom, using aqueous alkali at a temperature between 20 ° C and 100 ° C, followed by reesterification of the hydrolyzed acid group by conventional methods.

The compound of general formula (XIV) in which J is a hydroxy group can also be prepared from the compound of formula (XIV) in which J is a halogen atom by reacting it with formamide in the presence of water. The amount of formamide used in the reaction is between 0.5 and 1.5 mL, and the water used is between 20 μL and 0.1 mL, for 1 mmol of the halo compound (XIV). The reaction is carried out at a temperature between 80 ° C and 180 ° C, preferably between 120 ° C and 150 ° C, for a period of time between 1 and 8 hours.

The compound of the general formula (XIV) in which J is a halogen atom can be prepared by diazotizing the amino compound of the general formula (XV)

<img file="ES2199366T3_D0032.tif" />

wherein all symbols are as defined above, using alkali metal nitrites, followed by treatment with acrylic acid esters in the presence of hydrohalic acids and a catalytic amount of copper oxide or copper halide.

The compound of general formula (XV) can in turn be prepared by conventional reduction of the novel intermediate compound (III) in which G is a group NO2 and other symbols are as defined above.

In another embodiment of the present invention, the compound of general formula (I), wherein R¹, R², R³, X, Y, Z, n and Ar are as defined above and A is a nitrogen atom and B is an oxygen atom, it can be prepared by a process comprising: the reaction of the novel intermediate of formula (III) in where all symbols are as defined above, and G represents a CHO group, with NH2OH.HCl to provide a compound of general formula (III) wherein G represents a CH = NOH group and all symbols are as shown

ES 2 199 366 T3 defined above, followed by reduction with a metal borohydride to provide the compound of general formula (XVI)

Rk hk&gt;?

V -f (CHz) nO-Ar — CH₂—NHOH (XVI) in which all symbols are as defined above.

The reaction of the compound of general formula (III), in which G is a CHO group and other symbols are as defined above, with hydroxylamine hydrochloride is carried out in solvents such as ethanol, methanol, THF, dioxane and the like. , followed by the conventional method for preparing oximes. Between 1 and 10 equivalents of NH2 OH.HCl can be used, preferably between 2 and 5 equivalents. Bases such as alkali metal acetates or ammonium acetate can be used. The reaction can be carried out in the presence of water. A temperature in the range of 0 ° C to the reflux temperature of the solvent can be used. The oxime obtained in the manner described above is reduced using reducing agents such as alkali metal borohydrides, such as sodium borohydride or sodium cyanoborohydride, or borane reagents, using conventional conditions to provide the compound of general formula (XVI).

The compound of general formula (XVI) in turn is reacted with a halocarbonyl isocyanate or an alkoxycarbonyl isocyanate to provide a compound of general formula (I), or with KOCN to provide a compound of general formula (III) in the that G is CH2N (OH) CONH2, followed by treatment with carbonylating agents such as an alkyl haloformate to produce the compound of general formula (I) in which R¹, R², R³, X, Y, Z, n, Ar are as defined above, A represents a nitrogen atom and B is an oxygen atom.

The reaction of the compound of general formula (XVI) with a halocarbonyl isocyanate such as chlorocarbonyl isocyanate, or an alkoxycarbonyl isocyanate such as ethoxycarbonyl isocyanate, can be carried out in inert solvents such as THF, dioxane, etc., at a temperature in the range of -15 ° C to 50 ° C. The reaction can be carried out for 0.5 to 12 hours, depending on the substrates used in the reaction.

Alternatively, the compound of general formula (XVI) can be treated with an excess of KOCN in organic acids such as acetic acid. Water can be used in the reaction. The reaction can be carried out at a temperature in the range of 20 ° C to 120 ° C. The product isolated in the reaction is further treated with an alkyl haloformate such as ethyl chloroformate in the presence of 1 to 10 equivalents of alkali such as sodium hydroxide, potassium hydroxide and the like, to obtain the compound of general formula (I) wherein all symbols are as defined above and A represents a nitrogen atom and B represents an oxygen atom.

In yet another embodiment of the invention, the compound of general formula (I), in which the linking group - (CH2) nO- is attached through Z, in which Z represents = C, and all other symbols are as defined above, it can be prepared by reacting the compound of general formula (XVII)

<img file="ES2199366T3_D0033.tif" />

in which R¹, R² and R³ are as defined above, X represents C = O or C = S and Y represents C = C; or when R² and R³together with Y they form a cyclic structure as defined above, X represents C = O or C = S, Y represents C = C and R¹ is as defined before, with a compound of general formula (XVIII)

D— (CH ^ nO-Ar

<img file="ES2199366T3_D0034.tif" />

(XVIII) in which Ar, R⁴, A, B and n are as defined above, D may be -CN; -C (OR⁷) 3 in which R⁷ is a (C1-C4) alkyl; -C (= O) -R⁸ in which R⁸ can be selected from -OH, Cl, Br, I, -NH2, -NHR, OR where R is a lower alkyl group such as methyl, ethyl, propyl and the like, or R⁸ can be O- (C = O) - R⁹ in which R⁹ It can be a

ES 2 199 366 T3 linear or branched (C1-C5) alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like, 2,4-dichlorophenyl and 2,4,6-trichlorophenyl groups. The reaction proceeds through the intermediate formation of a compound of general formula (XIX)

<img file="ES2199366T3_D0035.tif" />

in which all R symbols¹, R², R³, R⁴, X, Y, A, B, Ar, and n are as defined above.

The X-NHR group¹ in formula (XIX) can also be generated by conventional methods such as the amidation of an ester group (XOR) or the partial hydrolysis of a CN group (in a compound in which a CN group is present instead of X-NHR¹).

The reaction of the compound of the general formula (XVII) with a compound of the general formula (XVIII) to produce a compound of the general formula (I) can be carried out alone or in the presence of solvents such as xylene, toluene, THF, dioxane, acid acetic acid, DMF, DMSO and the like, or their mixtures. The reaction can be carried out in an inert atmosphere that can be maintained using gases such as N2, Ar or He. The reaction can be carried out at a temperature in the range of 50 ° C to 200 ° C, preferably at a temperature in the range of 60 ° C to 180 ° C. The reaction can be carried out in the presence or in the absence of a base or an acid. The nature of the base or acid is not critical. Examples of such bases include organic bases such as pyridine, lutidine, triethylamine, diisopropylethylamine and the like, metal carbonates such as K2CO3, Na2CO3. Examples of acids include organic acids such as AcOH, C2H5COOH, butyric acid, p-toluenesulfonic acid, benzenesulfonic acid and the like, mineral acids such as HCl, HBr, etc. The duration of the reaction can be between 0.25 and 48 hours, preferably between 0.50 and 18 hours.

Alternatively, the novel intermediate of formula (XIX) can be isolated and then cyclized to provide a compound of formula (I).

The reaction of the compound of formula (XVII) with a compound of formula (XVIII) to provide a compound of formula (XIX) can be carried out alone or in the presence of a solvent such as xylene, toluene, dioxane, DMF, DMSO, hydrocarbons halogenates such as CH2Cl2, CHCl3, ClCH2CH2Cl and the like, or mixtures thereof. The reaction can be carried out in the presence or in the absence of a base or an acid. The nature of the base or acid is not critical. Examples of such bases include organic bases such as pyridine, lutidine, triethylamine, diisopropylethylamine, and the like. Examples of acids used for this reaction include CH3COOH, C2H5COOH, butyric acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. The reaction can be carried out in an inert atmosphere that can be maintained using inert gases such as N2, Ar or He. The reaction can be carried out at a temperature in the range of 25 ° C to 180 ° C, preferably at a temperature in the range of 25 ° C to 100 ° C. The reaction is generally instantaneous and the duration of the reaction can be between 0.25 and 24 hours, preferably between 0.25 and 2 hours.

The cyclization of the compound of formula (XIX) to provide a compound of formula (I) can be carried out alone or in the presence of solvents such as THF, toluene, xylene, 1,4-dioxane and the like, or mixtures thereof. The reaction temperature can be between 60 ° C and 150 ° C, depending on the solvent used and in the range of 100 ° C to 200 ° C when the reaction is carried out alone. The reaction can be carried out in the presence or in the absence of acids. Commonly used acids include acetic acid, propionic acid, butyric acid, pTsOH, and the like. The amount of acid can be between 0.1 and 100 equivalents, preferably between 0.1 and 10 equivalents. The reaction can also be carried out in acid alone. The reaction is preferably carried out in solvents such as THF, toluene, xylene, 1,4-dioxane or their mixtures, in the presence of an acid such as acetic acid, propionic acid, pTsOH and the like. The duration of the reaction can be between 3 and 48 hours, preferably between 4 and 18 hours.

The procedure described in the previous embodiment is novel and unique, since the heterocycle has been constructed in the final step of the procedure. No by-products are observed in the present procedure. The yields are high and no purification of any intermediates involved is required. The procedure described in the above embodiment does not involve any stringent conditions. This procedure works well for both small-scale and large-scale reactions. The procedure described in the previous embodiment is preferably used for compounds of formula (I) in which R² and R³ together they form a cyclic structure as defined above with Y, where Y represents C = C.

IS 2 199 366 T3

The compound of general formula (XVIII) in which D represents -COOH and all other symbols are as defined above is prepared from the compound of general formula (XVIII) in which D represents -COOR, in which R is a lower alkyl group such as CH3, C2H5, C3H7, and all other symbols are as defined above, by conventional hydrolysis procedures.

The hydrolysis of the compound of general formula (XVIII) in which D represents a COOR group to provide a compound of formula (XVIII) in which D represents a COOH group, can be carried out in the presence of solvents such as methanol, ethanol, dioxane, ether, THF, water, and the like, or mixtures thereof. The reaction can be carried out in the presence of a base such as an alkali such as NaOH, KOH, or alkali metal carbonates such as sodium carbonate, potassium carbonate, and the like. The amount of base can be between 1 and 5 equivalents. The reaction can be carried out at a temperature in the range of 0 ° C to 120 ° C, preferably at a temperature in the range of 15 ° C to 100 ° C. The duration of the reaction can be between 0.25 and 24 hours, preferably between 0.5 and 5 hours.

The compound of general formula (XVIII) in which D represents COCl or COBr and other symbols are as defined above, can be prepared by reacting the compound of general formula (XVIII) in which D represents COOH and other symbols are as defined above, with reagents such as SOCl2, PCl3, PCl5, PBr3, and the like. The reaction can be carried out alone or in the presence of solvents such as benzene, xylene, etc. The reaction can be carried out in the range of 0 ° C to 140 ° C, preferably in the range of 25 ° C to 100 ° C. The duration of the reaction can be between 0.25 and 24 hours, preferably between 0.5 and 5 hours.

The compound of general formula (XVIII) in which all symbols are as defined above and D represents -C (= O) -O- (C =) - R⁹, in which R⁹ represents a linear or branched (C1-C5) alkyl group, dichlorophenyl, a trichlorophenyl and similar group, can be prepared by reaction of the compound of general formula (XVIII) in which D represents COOH and other symbols are as defined above, with acid halides organic such as acetyl chloride, acetyl bromide, propanoyl chloride, butanoyl chloride, pivaloyl chloride, trichlorobenzoylchloride and the like in the presence of a base such as pyridine, N, N-dimethylaminopyridine, triethylamine, diisopropylethylamine, lutidine, and the like or a mixture thereof. The reaction can be carried out in solvents such as CH2Cl2, CHCl3, ClCH2CH2Cl, 1,4-dioxane, xylene, and the like. The reaction can be carried out at a temperature in the range of 0 ° C to 120 ° C, preferably in the range of 0 ° C to 50 ° C. The duration of the reaction can be between 0.25 and 12 hours, preferably between 0.5 and 5 hours.

The particularly useful compound of general formula (I) in which X represents C = O, Y represents C = C, Z represents = C, n represents the integer 1, R¹ represents a methyl group, B represents a sulfur atom, R² and R³together with Y they form a phenyl ring, represented by formula (XX), it can be prepared according to the procedure described in the previous embodiment, which comprises:

<img file="ES2199366T3_D0036.tif" />

a) Reduce a compound of formula (XXI) which is described in JP 2558473.

<img file="ES2199366T3_D0037.tif" />

in which R¹⁰ is a lower alkyl group such as methyl, ethyl, and the like, using conventional reducing conditions to provide a compound of formula (XXII)

IS 2 199 366 T3

<img file="ES2199366T3_D0038.tif" />

in which R¹⁰ it is as defined above.

The reduction of the compound of formula (XXI) to provide a compound of formula (XXII) can be carried out in the presence of hydrogen gas and a catalyst such as Pd / C or Raney nickel. Catalyst mixtures can be used. Solvents such as dioxane, acetic acid, ethyl acetate, and the like can be used. A pressure between atmospheric pressure and 5.6 kg / cm can be used.² (80 psi). The catalyst can be 5-10% Pd / C and the amount of catalyst used can be between 50-300% w / w. The reaction can also be carried out using metal reduction in solvents such as magnesium in methanol or sodium amalgam in methanol.

b) Hydrolysis of the compound of formula (XXII) using conventional conditions to provide a compound of formula (XXIII)

<img file="ES2199366T3_D0039.tif" />

The hydrolysis of the compound of formula (XXII) to provide a compound of formula (XXIII) can be carried out in the presence of solvents such as methanol, ethanol, dioxane, ether, THF, water and the like, or mixtures thereof. The reaction can be carried out in the presence of a base such as alkali such as NaOH, KOH, alkali metal carbonates such as sodium carbonate and potassium carbonate. The amount of base can be between 1 and 5 equivalents, based on the amount of compound of formula (XXII). The reaction can be carried out at a temperature in the range of 0 ° C to 120 ° C, preferably at a temperature in the range of 15 ° C to 100 ° C. The duration of the reaction can be between 0.25 and 24 hours, preferably between 0.5 and 5 hours.

c) Reacting a compound of formula (XXIII) with an acid halide or halogenating agent to obtain a compound of formula (XXIV)

<img file="ES2199366T3_D0040.tif" />

where D represents COCl or COBr or -C (= O) -O- (C = O) -R⁹, in which R⁹ represents a methyl or t-butyl group.

The reaction of the compound of formula (XXIII) with a halogenating agent such as SOCl2, PCl5, PBr3 can be carried out alone or in the presence of a solvent such as benzene, xylene, etc. The reaction can be carried out between 0 ° C and 140 ° C, preferably between 25 ° C and 100 ° C. The duration of the reaction can be between 0.25 and 24 hours, preferably between 0.5 and 5 hours. The reaction of the compound of formula (XXIII) with an acid halide to provide a mixed anhydride can be carried out with acid halides such as acetyl chloride or pivaloyl chloride in the presence of a base such as pyridine, triethylamine, N, N-dimethylaminopyridine , or their mixtures. The amount of base can be between 1 and 5 equivalents, based on the amount of compound of formula (XXIII). The reaction can be carried out in solvents such as dichloromethane, chloroform, dichloroethane, 1,4-dioxane, xylene, and the like. The reaction can be carried out at a temperature in the range of 0 ° C to 120 ° C, preferably at a temperature in the range of 15 ° C to 50 ° C. The duration of the reaction can be between 0.25 and 12 hours, preferably between 0.5 and 5 hours.

d) Reaction of the compound of formula (XXIV) with a compound of formula (XXV)

IS 2 199 366 T3

<img file="ES2199366T3_D0041.tif" />

to provide a compound of formula (XX) defined above. The reaction proceeds through the intermediate formation of the compound of formula (XXVI)

<img file="ES2199366T3_D0042.tif" />

The reaction of the compound of formula (XXIV) with a compound of formula (XXV) to produce a compound of general formula (XX) can be carried out alone or in the presence of solvents such as xylene, toluene, THF, dioxane, acetic acid, DMF, DMSO and the like, or their mixtures. The reaction can be carried out in an inert atmosphere that can be maintained using inert gases such as N2, Ar or He. The reaction can be carried out at a temperature in the range of 50 ° C to 200 ° C, preferably at a temperature in the range of 80 ° C to 180 ° C. The reaction can be carried out in the presence of an acid. The nature of the acid is not critical. Examples of acids include organic acids such as AcOH, C2H5COOH, p-toluenesulfonic acid and the like, mineral acids such as HCl, HBr, etc. The duration of the reaction can be between 0.25 and 48 hours, preferably between 0.50 and 18 hours, based on the solvent, temperature and acid used.

Alternatively, the novel intermediate of formula (XXVI) can be isolated and then cyclized to provide a compound of formula (XX).

The reaction of the compound of formula (XXIV) with a compound of formula (XXV) to provide a compound of formula (XXVI) can be carried out alone or in the presence of a solvent such as xylene, toluene, dioxane, DMF, DMSO, hydrocarbons halogenates such as CH2Cl2, CHCl3, ClCH2CH2Cl and the like, or mixtures thereof. The reaction can be carried out in the presence of an acid. The nature of the acid is not critical. Examples of acids used for this reaction include CH3COOH, C2H5COOH, butyric acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. The reaction can be carried out in an inert atmosphere that can be maintained using inert gases such as N₂, Ar or He. The reaction can be carried out at a temperature in the range of 25 ° C to 180 ° C, preferably in the range of 25 ° C to 60 ° C. The reaction is generally instantaneous and the duration of the reaction can be between 0.25 and 12 hours, preferably between 0.25 and 2 hours.

The cyclization of the compound of formula (XXVI) to provide a compound of formula (XX) can be carried out alone or in the presence of solvents such as THF, toluene, xylene, 1,4-dioxane and the like, or mixtures thereof. The reaction temperature can be between 60 ° C and 150 ° C depending on the solvent used and in the range of 100 ° C to 200 ° C when the reaction is carried out alone. The reaction can be carried out in the presence of acids. Commonly used acids include acetic acid, propionic acid, and pTsOH. The amount of acid used can be between 0.1 and 100 equivalents, preferably between 0.1 and 10 equivalents. The reaction can also be carried out in acid alone. The reaction is preferably carried out in solvents such as THF, toluene, xylene, 1,4-dioxane or their mixtures, in the presence of an acid such as acetic acid, propionic acid, pTsOH and the like. The duration of the reaction can be between 3 and 48 hours, preferably between 4 and 18 hours, based on the solvent, the temperature and the acid used.

The term "alone" as used herein means that the reaction is carried out without using a solvent.

Pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with between 1 and 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, hydroxide of magnesium and the like, in solvents such as ether, THF, methanol, tbutanol, dioxane, isopropanol, ethanol, etc. A mixture of solvents can be used. Organic bases such as lysine, arginine, diethanolamine, choline, guanidine and their derivatives, etc. can also be used. Alternatively, acid addition salts are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid. , hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like, in solvents such as ethyl acetate, ether, alcohols, acetone, THF, dioxane, etc. Mixtures of solvents can also be used.

IS 2 199 366 T3

The stereoisomers of the compounds that are part of this invention can be prepared using reagents in their unique enantiomeric form in the process when possible, or by conducting the reaction in the presence of reagents or catalysts in their unique enantiomeric forms, or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include the use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like, or chiral bases such as rucin, quinine alkaloids and their derivatives. and the like.

Various polymorphs of the compound of general formula (I) that form part of this invention can be prepared by crystallization of the compound of formula (I) under different conditions. For example, using different commonly used solvents or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs can also be obtained by heating or melting the compound, followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectroscopy, ir spectroscopy, differential scanning colorimetry, X-ray powder diffractogram, or other techniques such as these.

The present invention also provides a pharmaceutical composition, which contains the compounds of general formula (I), as defined above, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, in combination with the excipients, diluents and the like, normally used pharmaceutically useful for the treatment and / or prophylaxis of diseases in which insulin resistance is the underlying pathophysiological mechanism such as type II diabetes, impaired glucose tolerance, dyslipidemia, hypertension, coronary heart disease and other cardiovascular disorders, including atherosclerosis; insulin resistance associated with obesity and psoriasis, to treat diabetic complications and other diseases such as polycystic ovary syndrome (PCOS), certain kidney diseases, including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, kidney diseases in terminal phase and microalbuminuria, as well as certain eating disorders, such as aldose reductase inhibitors, and to improve cognitive functions in dementia.

The pharmaceutical composition can be in the forms normally used, such as tablets, capsules, powders, syrups, solutions, suspensions, and the like, they can contain flavoring agents, sweeteners, etc. in suitable solid or liquid excipients or diluents, or in suitable sterile media to form injectable solutions or suspensions. Such compositions typically contain between 1 and 20%, preferably between 1 and 10% by weight of active compound, the remainder of the composition being pharmaceutically acceptable excipients, diluents or solvents.

A typical tablet production is exemplified below:

Tablets production example

a) 1) Active ingredient 10 g

2) Lactose 110 g

3) Corn starch 35 g

4) Carboxymethylcellulose 44 g

5) Magnesium stearate 1 g

200 g for 1000 tablets

Ingredients 1-3 are evenly mixed with water and made into granules after drying under reduced pressure. Ingredients 4 and 5 are mixed well with the granules and compressed by a tablet machine to prepare 1000 tablets, each containing 10 mg of active ingredient.

b) 1) Active ingredient 10 g

2) Calcium phosphate 90 g

3) Lactose 50 g

4) Corn starch 45 g

5) Polyvinylpyrrolidone 3.5 g

6) Magnesium stearate 1.5 g

200 g for 1000 tablets

Ingredients 1 to 4 are uniformly moistened with an aqueous solution of ingredient 5 and become granules after drying under reduced pressure. Ingredient 6 is added and the granules are compressed by a tablet machine to prepare 1000 tablets containing 10 mg of active ingredient 1.

The compounds of formula (I) as defined above are administered clinically to mammals, including man, both by oral and parenteral routes. Oral administration is preferred, being more convenient and avoiding the possible damage and irritation of the injection. However, in circumstances where the patient cannot

EN 2 199 366 T3 swallowing the medication, or the absorption following oral administration is impaired, by disease or other abnormality, it is essential that the drug is administered parenterally. For either route, the dosage is in the range of about 0.10 to about 200 mg / kg of subject body weight per day, or preferably about 0.10 to about 30 mg / kg of body weight per day, administered singly or as divided doses. However, the optimal dosage for the individual subject being treated will be determined by the person responsible for the treatment, generally administering smaller doses initially and making increments thereafter to determine the most suitable dosage.

Suitable pharmaceutically acceptable excipients include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage in the range described above. Thus, for oral administration, the compounds can be combined with a suitable solid or liquid excipient or diluent to form capsules, tablets, powders, syrups, solutions or suspensions and the like. The pharmaceutical compositions may contain, if desired, additional components such as flavoring agents, sweeteners, excipients, and the like. For parenteral administration, the compounds 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, as well as aqueous solutions of pharmaceutically acceptable water soluble acid addition salts or base salts of the compounds can be used. Injectable solutions prepared in this way can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.

The invention is explained in detail in the examples below, which are provided for illustrative purposes and should not therefore be construed as limiting the scope of the invention.

Preparation 1

4- [2- [4-Methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0043.tif" />

To a stirred suspension of NaH (570 mg, 22.57 mmol, 95%) in dry DMF (35 mL) at 25 ° C was added a solution of 4-methyl-2-propyl-1,6-dihydro-6- pyrimidone (2.64 g, 17.36 mmol) in dry DMF. After effervescence ceased, anhydrous LiBr (3.51 g, 40.0 mmol) was added, followed by 4- [2-bromoethoxy] benzaldehyde (4.37 g, 19.08 mmol) in dry DMF at the same temperature. The reaction mixture was immersed in a preheated 70 ° C oil bath and stirred for 2 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The combined EtOAc phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The crude compound was subjected to silica gel chromatography using 3: 7 EtOAc / petroleum ether as eluent to obtain the title compound (1.61 g, 31%).

¹H NMR (CDCl₃): δ 9.80 (s, 1H), 7.82 (d, J = 8.72 Hz, 2H), 6.95 (d, J = 8.72 Hz, 2H), 6.20 (s, 1H), 4.45 (t, J = 5.30Hz, 2H), 4.35 (t, J = 5.30Hz, 2H), 2.92 (t, J = 7.50Hz, 2H), 2, 25 (s, 3H), 1.92-1.70 (m, 2H), 1.20 (t, J = 7.50Hz, 3H).

Preparation 2

4- [2- [2,4-Dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde

OR

<img file="ES2199366T3_D0044.tif" />

The title compound (0.8 g, 30%) was prepared from 2,4-dimethyl-1,6-dihydro-6-pyrimidone (1.3 g, 10.48 mmol) and 4- [2- bromoethoxy] benzaldehyde (2.4 g, 10.48 mmol) in the presence of the base K2CO3 (2.89 g, 20.96 mmol) by a procedure similar to that described in preparation 1.

¹H NMR (CDCl3): δ 9.90 (s, 1H), 7.80 (d, J = 8.70 Hz, 2H), 7.02 (d, J = 8.70 Hz, 2H), 6, 20 (s, 1H), 4.50-4.30 (m, 4H), 2.70 (s, 3H), 2.20 (s, 3H).

IS 2 199 366 T3

Preparation 3

4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0045.tif" />

The title compound (1.7 g, 42%) was prepared from 2-ethyl-4-methyl-1,6-dihydro-6-pyrimidone (2.0 g, 14.49 mmol), 4- [ 2-bromoethoxy] benzaldehyde (3.32 g, 14.49 mmol), LiBr (2.9 g, 33.33 mmol) and NaH (0.45 g, 18.84 mmol) as the base, by a procedure similar to that of described in preparation 1.

¹H NMR (CDCl3): δ 9.90 (s, 1H), 7.80 (d, J = 8.70 Hz, 2H), 6.98 (d, J = 8.70 Hz, 2H), 6, 20 (s, 1H), 4.52-4.25 (m, 4H), 3.02 (q, J = 7.40 Hz, 2H), 2.30 (s, 3H), 1.40 (t , J = 7.40 Hz, 3H).

Preparation 4

4- [2- [2-Butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0046.tif" />

The title compound (1.1 g, 25%) was prepared from 2-butyl-4-methyl-1,6-dihydro-6-pyrimidone (2.3 g, 13.85 mmol), 4- [ 2-bromoethoxy] benzaldehyde (3.17 g, 13.85 mmol) in the presence of K2CO3 (3.82 g, 27.7 mmol) as base, by a procedure similar to that described in preparation 1.

¹H NMR (CDCl3): δ 9.90 (s, 1H), 7.84 (d, J = 8.72 Hz, 2H), 6.98 (d, J = 8.72 Hz, 2H), 6, 20 (s, 1H), 4.52-4.30 (m, 4H), 2.96 (t, J = 7.47 Hz, 2H), 2.26 (s, 3H), 1.90-1 , 70 (m, 2H), 1.70-1.50 (m, 2H), 1.01 (t, J = 7.47 Hz, 3H). Preparation 5

4- [2- [2-Benzyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0047.tif" />

The title compound (2.0 g, 20.6%) was prepared from 2-benzyl-4-methyl-1,6-dihydro-6-pyrimidone (5.6 g, 28.0 mmol), 4 - [2-bromoethoxy] benzaldehyde (17.05 g, 30.1 mmol) in the presence of 95% NaH (873 mg, 35.0 mmol) as a base, by a procedure similar to that described in preparation 1.

¹H NMR (CDCl3): δ 9.89 (s, 1H), 7.83 (d, J = 8.72 Hz, 2H), 7.45-7.15 (m, 5H), 6.98 (d , J = 8.72 Hz, 2H), 6.44 (s, 1H), 4.70 (t, J = 4.71 Hz, 2H), 4.30 (t, J = 4.71 Hz, 2H ), 4.14 (s, 2H), 2.42 (s, 3H).

Preparation 6

4- [2- [2,5-Diethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0048.tif" />

IS 2 199 366 T3

The title compound (1.42g, 28%) was prepared from 2,5-diethyl-4-methyl-1,6-dihydro-6-pyrimidone (2.70 g, 16.26 mmol) and 4- [2-bromoethoxy] benzaldehyde (4.09 g, 17.86 mmol) in the presence of 95% NaH (508 mg, 20 mmol) as a base, by a procedure similar to that described in preparation 1.

¹H NMR (CDCl3): δ 9.88 (s, 1H), 7.82 (d, J = 8.62 Hz, 2H), 6.97 (d, J = 8.62 Hz, 2H), 4, 50-4.20 (m, 4H), 2.95 (q, J = 7.47Hz, 2H), 2.52 (q, J = 7.47Hz, 2H), 2.28 (s, 3H), 1.34 (t, J = 7.47Hz, 3H), 1.09 (t, J = 7.47Hz, 3H). Preparation 7

4- [2- [2-Ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0049.tif" />

The title compound (2.0 g, 44%) was prepared from 2-ethyl-4-phenyl-1,6-dihydro-6-pyrimidone (2.6 g, 13.0 mmol), 4- [ 2-bromoethoxy] benzaldehyde (2.97g, 13.0mmol) and LiBr (2.59g, 29.9mmol) in the presence of NaH as base (0.4g, 16.9mmol), by a similar procedure to that described in preparation 1.

¹H NMR (CDCl3): δ 9.89 (s, 1H), 8.10-7.95 (m, 2H), 7.83 (d, J = 8.72Hz, 2H), 7.55-7, 45 (m, 3H), 6.98 (d, J = 8.72Hz, 2H), 6.78 (s, 1H), 4.60-4.40 (m, 4H), 3.08 (q , J = 7.30 Hz, 2H), 1.48 (t, J = 7.30 Hz, 3H).

Preparation 8

4- [2- [4-N-Acetylamino-2-oxo-1,2-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0050.tif" />

The title compound (1.8 g, 66%) was prepared from 4-acetylamino-1,2-dihydro-2-pyrimidone (1.8 g, 11.9 mmol) and 4- [2-bromoethoxy] benzaldehyde (2.72 g, 11.9 mmol) in the presence of K2CO3 (3.28g, 23.8 mmol) as base, by a similar procedure to that described in preparation 1.

¹H NMR (CDCl₃): δ 9.90 (s, 1H), 8.70 (bs, 1H, exchangeable D2O), 7.85 (d, J = 8.70 Hz, 2H), 7.75 (d, J = 7, 80 Hz, 1H), 7.42 (d, J = 7.80 Hz, 1H), 6.95 (d, J = 8.70 Hz, 2H), 4.40-4.20 (m, 4H) , 2.30 (s, 3H).

Preparation 9

4- [2- [4-Oxo-3,4-dihydro-3-quinazolinyl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0051.tif" />

The title compound (1.5 g, 73%) was prepared from 4-oxo-3,4-dihydroquinazoline (1.03 g, 7.05 mmol) and 4- [2-bromoethoxy] benzaldehyde (1, 77 g, 7.7 mmol) in the presence of K2CO3 (2.0 g, 14.5 mmol) as base, by a procedure similar to that described in preparation 1.

¹H NMR (CDCl₃): δ 9.88 (s, 1H), 8.32 (d, J = 7.88 Hz, 1H), 8.21 (s, 1H), 7.88-7.70 (m, 2H), 7.82 (d, J = 8.72 Hz,

2H), 7.60-7.42 (m, 1H), 7.00 (d, J = 8.72Hz, 2H), 4.55-4.25 (m, 4H).

IS 2 199 366 T3

Preparation 10

4- [2- [2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0052.tif" />

The title compound (0.6 g, 39%) was prepared from 2-methyl-4-oxo-3,4-dihydroquinazoline (0.8 g, 5 mmol) and 4- [2-bromoethoxy] benzaldehyde ( 1.37 g, 6 mmol) in the presence of K2CO3 (1.38 g, 10.0 mmol) as base, by a similar procedure to that described in preparation 1.

¹H NMR (CDCl3): δ 9.85 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.84-7.72 (m, 3H), 7.59-7 , 41 (m, 2H), 7.10 (d, J = 7.0Hz, 2H), 4.50-4.40 (m, 2H), 4.40-4.30 (m, 2H), 2.76 (s, 3H).

Preparation 11

4- [2- [2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0053.tif" />

The title compound (5.0 g, 27%) was prepared from 2-ethyl-4-oxo-3,4-dihydroquinazoline (9.2 g, 57.5 mmol) and 4- (2-bromoethoxy) benzaldehyde (14.5 g, 69.0 mmol) in the presence of K2CO3 (14.6 g, 115.0 mmol) as base, by a similar procedure to that described in preparation 1.

¹H NMR (CDCl3): δ 9.86 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.87-7.76 (m, 3H), 7.65-4 , 45 (m, 2H), 7.13 (d, J = 8.0 Hz, 2H), 4.60-4.50 (m, 2H), 4.50-4.40 (m, 2H), 3.07 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).

Preparation 12

4- [2- [8-Aza-2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0054.tif" />

The title compound (0.26 g, 41%) was prepared from 8-aza-2-methyl-4-oxo-3,4-dihydroquinazoline (0.33 g, 2.0 mmol), 4- [ 2-bromoethoxy] benzaldehyde (0.52 g, 2.25 mmol) in the presence of K2CO3 (0.57 g, 4.1 mmol) as base, by a similar procedure to that described in preparation 1.

¹H NMR (CDCl3): δ 9.87 (s, 1H), 9.02-8.90 (m, 1H), 8.58 (d, J = 7.30 Hz, 1H), 7.82 (d , J = 8.72 Hz, 2H), 7.487.35 (m, 1H), 6.97 (d, J = 8.72 Hz, 2H), 4.58 (t, J = 4.72 Hz, 2H ), 4.43 (t, J = 4.72 Hz, 2H), 2.91 (s, 3H).

IS 2 199 366 T3

Preparation 13

4 - [[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] benzaldehyde

<img file="ES2199366T3_D0055.tif" />

A mixture of 4-hydroxybenzaldehyde (3.21 g, 26.3 mmol) and K2CO3 (3.64 g, 26.3 mmol) in dry DMF (50 mL) was stirred for 15 min at 30 ° C. A solution of 2-chloromethyl-3-methyl-4-oxo-3,4-dihydroquinazoline (5.0 g, 24.0 mmol) was added to the above stirred mixture and stirred for a further 90 min at the same temperature. The reaction mixture was diluted with EtOAc (200 mL), washed with an aqueous Na2CO3 solution (3 x 50 mL), then brine, dried over anhydrous Na2SO4, and concentrated to provide the title compound (5.08 g, 72%).

¹H NMR (CDCl3): δ 9.89 (s, 1H), 8.29 (d, J = 7.89 Hz, 1H), 7.85 (d, J = 8.71 Hz, 2H), 7, 80-7.62 (m, 2H), 7.52 (t, J = 7.81 Hz, 1H), 7.19 (d, J = 8.71 Hz, 2H), 5.27 (s, 2H ), 3.74 (s, 3H).

Preparation 14

4 - [[3-Ethyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] benzaldehyde

<img file="ES2199366T3_D0056.tif" />

The title compound (4.24 g, 88%) was prepared from 2-chloromethyl-3-ethyl-4-oxo-3,4-dihydroquinazoline (3.5 g, 15.7 mmol) and 4-hydroxybenzaldehyde (2.10 g, 17.21 mmol) in the presence of K2CO3 (2.38 g, 17.26 mmol) as base, by a similar procedure to that described in preparation 13.

¹H NMR (CDCl3): δ 9.91 (s, 1H), 8.31 (d, J = 7.89 Hz, 1H), 7.88 (d, J = 8.72 Hz, 2H), 7, 82-7.68 (m, 2H), 7.657.45 (m, 1H), 7.22 (d, J = 8.72 Hz, 2H), 5.28 (s, 2H), 4.28 (q , J = 7.06 Hz, 2H), 1.41 (t, J = 7.06 Hz, 3H).

Preparation 15

4 - [[1-Methyl-4-oxo-1,4-dihydro-2-quinazolinyl] methoxy] benzaldehyde

<img file="ES2199366T3_D0057.tif" />

The title compound (364 mg, 65%) was prepared from 2-chloromethyl-1-methyl-4-oxo-1,4-dihydroquinazoline (416 mg, 2.0 mmol) and 4-hydroxybenzaldehyde (244 mg, 2.0 mmol) in the presence of K₂CO₃ (276 mg, 2.0 mmol) as a base, by a similar procedure to that described in preparation 13.

¹H NMR (CDCl3): δ 9.88 (s, 1H), 8.34 (d, J = 7.89 Hz, 1H), 7.83 (d, J = 8.71 Hz, 2H), 7, 80-7.70 (m, 1H), 7.607.40 (m, 2H), 7.22 (d, J = 8.71 Hz, 2H), 5.34 (s, 2H), 3.91 (s , 3H).

IS 2 199 366 T3

Preparation 16

3-Methoxy-4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] benzaldehyde

<img file="ES2199366T3_D0058.tif" />

The title compound (250 mg, 77%) was obtained from 2-chloromethyl-3-methyl-4-oxo-3,4-dihydroquinazoline (209 mg, 1.0 mmol) and vanillin (167 mg, 1, 1 mmol) in the presence of K2CO3 (276 mg, 2.0 mmol) as a base, by a procedure similar to that described in preparation 13.

¹H NMR (CDCl3): δ 9.88 (s, 1H), 8.29 (d, J = 8.30 Hz, 1H), 7.80-7.62 (m, 2H), 7.58-7 , 39 (m, 2H), 7.26 (d, J = 8.30 Hz, 2H), 5.30 (s, 2H), 3.90 (s, 3H), 3.78 (s, 3H) .

Preparation 17

4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde oxime

<img file="ES2199366T3_D0059.tif" />

To a stirred solution of hydroxylamine hydrochloride (10.0 g, 143 mmol) in sodium acetate trihydrate (20.0 g, 146.9 mmol) in water (100 mL) at 30 ° C was added a hot solution of 4 - [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde (5.72 g, 20.0 mmol) (obtained in Preparation 3) in ethanol (100 mL). The reaction mixture was immersed in a preheated oil bath (95 ° C) and refluxed for 3 h. The reaction mixture was then cooled to room temperature and concentrated to a volume where the oxime crystals were beginning to separate and was set aside for 30 min at 1 h at 25 ° C. The resulting crystals were filtered and washed with water and dried to obtain the title compound (5.42 g, 90%).

¹H NMR (CDCl3 + DMSO-d6): δ 10.56 (s, 1H, OH, D2O exchangeable), 8.08 (s, 1H), 7.55 (d, J = 8.56 Hz, 2H), 6 , 88 (d, J = 8.56 Hz, 2H), 6.20 (s, 1H), 4.51-4.40 (m, 2H), 4.40-4.28 (m, 2H), 3.05 (q, J = 7.06Hz, 2H), 2.30 (s, 3H), 1.40 (t, J = 7.06Hz, 3H).

Preparation 18

4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzylhydroxylamine

<img file="ES2199366T3_D0060.tif" />

To a stirred solution of 4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde oxime (301 mg, 1.0 mmol) (obtained in Preparation 17) in a mixture of methanol (7 mL) and THF (3 mL) was added 4N HCl (2 mL) in dioxane at 30 ° C and stirred for 10 min at the same temperature. The reaction mixture was basified to pH 9 with 1N NaOH and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4, and concentrated to provide the title compound (272 mg, 90%).

¹H NMR (CDCl3): δ 7.23 (d, J = 8.72 Hz, 2H), 6.80 (d, J = 8.72 Hz, 2H), 6.18 (s, 1H), 4, 45-4.35 (m, 2H), 4.354.20 (m, 2H), 3.98 (s, 2H), 3.01 (q, J = 7.56 Hz, 2H), 2.22 (s , 3H), 1.32 (t, J = 7.56 Hz, 3H).

IS 2 199 366 T3

Preparation 19

N- [4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzyl] N-hydroxyurea

<img file="ES2199366T3_D0061.tif" />

To a stirred solution of 4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] ben-cylhydroxylamine (303 mg, 1.0 mmol) (obtained in Preparation 18) in a mixture of water (2 mL) and acetic acid (0.5 mL), a solution of KOCN (343 mg, 3.0 mmol) in water (1 mL) was added and stirred for 1 hr. ° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated to provide the compound (295 mg, 85%).

¹H NMR (CDCl3): δ 7.18 (d, J = 8.65 Hz, 2H), 6.90 (d, J = 8.65 Hz, 2H), 6.60 (bs, 1H, exchangeable D2O) , 6.15 (s, 1H), 5.85 (bs, 1H, exchangeable D2O), 4.70 (s, 2H), 4.50 (bs, 1H, exchangeable D2O), 4.40-4.30 (m, 2H), 4.224.10 (m, 2H), 2.92 (q, J = 7.56 Hz, 2H), 2.20 (s, 3H), 1.20 (t, J = 7, 56 Hz, 3H).

Preparation 20

4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] nitrobenzene

<img file="ES2199366T3_D0062.tif" />

The title compound (5.2 g, 25%) was prepared from 2-ethyl-4-methyl-1,6-dihydro-6-pyrimidone (7.65 g, 55.43 mmol), 4- [ 2-bromoethoxy] nitrobenzene (15.0 g, 60.97 mmol), LiBr (11.09 g, 127.49 mmol) and 60% NaH (2.76 g, 72.06 mmol) as base, for a procedure similar to that described in preparation 1.

¹H NMR (CDCl3): δ 8.20 (d, J = 8.81 Hz, 2H), 6.94 (d, J = 8.81 Hz, 2H), 6.22 (s, 1H), 4, 55-4.42 (m, 2H), 4.424.34 (m, 2H), 2.99 (q, J = 7.4 Hz, 2H), 2.27 (s, 3H), 1.38 (t , J = 7.4 Hz, 3H).

Preparation 21

4- [2- [2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] nitrobenzene

<img file="ES2199366T3_D0063.tif" />

The title compound (1.246 g, 64%) was prepared from 2-ethyl-4-oxo-3,4-dihydroquinazoline (1.0 g, 5.7 mmol) and 4- [2-bromoethoxy] nitrobenzene (1.696 g, 6.8 mmol) and K2CO3 (1.58 g, 11.49 mmol) as base, by a similar procedure to that described in preparation 1.

¹H NMR (CDCl3): δ 8.24 (d, J = 7.93 Hz, 1H), 8.18 (d, J = 9.20 Hz, 2H), 7.82-7.61 (m, 2H ), 7.46 (t, J = 7.93 Hz, 1H), 6.94 (d, J = 9.20 Hz, 2H), 4.58 (t, J = 4.82 Hz, 2H), 4.44 (t, J = 4.82 Hz, 2H), 3.09 (q, J = 7.38 Hz, 2H), 1.46 (t, J = 7.38 Hz, 3H).

IS 2 199 366 T3

Preparation 22

4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] aniline

<img file="ES2199366T3_D0064.tif" />

A solution of 4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] nitrobenzene (1.0 g, 3.3 mmol) (obtained in the preparation 20) in 1,4-dioxane (20 mL) was subjected to hydrogen reduction in the presence of 10% palladium on carbon (100 mg) at 2.1 kg / cm² (30 psi) for 16 h. The reaction mixture was filtered through a pad of celite and washed with dioxane and evaporated to dryness under reduced pressure to provide the title compound (625 mg, 70%).

¹H NMR (CDCl3): δ 6.78-6.52 (m, 4H), 6.18 (s, 1H), 4.38 (t, J = 4.98 Hz, 2H), 4.19 (t , J = 4.98 Hz, 2H), 2.99 (q, J = 7.47 Hz, 2H), 2.24 (s, 3H), 1.33 (t, J = 7.47 Hz, 3H ).

Preparation 23

4- [2- [2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] aniline

<img file="ES2199366T3_D0065.tif" />

The title compound (1.107 g, 98%) was prepared from 4- [2- [2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] nitrobenzene (1.246 g, 3.67 mmol) (obtained in preparation 21), by a similar procedure to that described in preparation 22.

¹H NMR (CDCl3): δ 8.24 (d, J = 7.93 Hz, 1H), 7.80-7.60 (m, 2H), 7.43 (t, J = 7.93 Hz, 1H ), 6.80-6.50 (m, 4H), 4.51 (t, J = 5.19 Hz, 2H), 4.24 (t, J = 5.19 Hz, 2H), 3.10 (q, J = 7.34 Hz, 2H), 1.42 (t, J = 7.34 Hz, 3H).

Preparation 24

Ethyl 2-Bromo-3- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenyl] propanoate

<img file="ES2199366T3_D0066.tif" />

To a stirred solution of 4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] aniline (2.80 g, 10.26 mmol) (obtained in Preparation 22) in acetone (10 mL) was added aqueous HBr (47%, 1 mL) and stirred for 10 min at 0 ° C. A solution of NaNO2 (850 mg, 12.30 mmol) in water (1.7 mL) was slowly added dropwise to the above reaction mixture at 0 ° C, and stirring was continued for a further 30 min thereto temperature. To this reaction mixture, ethyl acetate (6.77 mL, 62.0 mmol) was added and allowed to warm to 30 ° C. A catalytic amount of copper (I) iodide (20 mg) was added in one portion, and the reaction mixture was stirred for a further 1 hr at 30 ° C. Acetone was removed under reduced pressure and the resulting residue was extracted with EtOAc (3 x 10 mL). The combined EtOAc phases were washed with dilute NH3 solution, water, followed by brine; dried over anhydrous Na2SO4 and concentrated to the crude compound which was purified by flash chromatography using 40% EtOAc / petroleum ether as eluent to provide the title compound (2.47 g, 55%).

¹H NMR (CDCl3): δ 7.11 (d, J = 8.63 Hz, 2H), 6.78 (d, J = 8.63 Hz, 2H), 6.19 (s, 1H), 4, 50-4.32 (m, 2H), 4.304.02 (m, 5H), 3.38 (dd, J = 13.72, 8.31 Hz, 1H), 3.17 (dd, J = 13, 72, 7.06 Hz, 1H), 3.10-2.90 (m, 2H), 2.25 (s, 3H),

1.35 (t, J = 7.47Hz, 3H), 1.24 (t, J = 7.05Hz, 3H).

IS 2 199 366 T3

Preparation 25

Ethyl 2-Bromo-3- [4- [2- [2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenyl] propanoate

<img file="ES2199366T3_D0067.tif" />

The title compound (671 mg, 55%) was prepared from 4- [2- [2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] aniline (800 mg, 2.58 mmol) (obtained in preparation 23), NaNO2 (214 mg, 3.1 mmol) and ethyl acrylate (1.7 mL, 1.574 g, 15.74 mmol), by a similar procedure to that described in preparation 24.

¹H NMR (CDCl3): δ 8.23 ​​(d, J = 7.88 Hz, 1H), 7.80-7.55 (m, 2H), 7.52-7.30 (m, 1H), 7 , 15-7.01 (m, 2H), 6.77 (d, J = 8.71 Hz, 2H), 4.52 (t, J = 5.03 Hz, 2H), 4.45-4, 30 (m, 1H), 4.30 (t, J = 5.03 Hz, 2H), 4.20-4.00 (m, 2H), 3.35 (dd, J = 14.12.8, 71 Hz, 1H), 3.20-3.00 (m, 3H), 1.43 (t, J = 7.34 Hz, 3H), 1.20 (t, J = 7.34 Hz, 3H) .

Preparation 26

5- [4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] -2-iminothiazolidin-4-one hydrochloride

<img file="ES2199366T3_D0068.tif" />

A mixture of ethyl 2-bromo-3- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenyl] propanoate (1.70 g , 3.89 mmol) (obtained in preparation 24), molten sodium acetate (637 mg, 7.78 mmol) and thiourea (592 mg, 7.78 mmol) in ethanol (10 mL) was heated under reflux for 12 h. The reaction mixture was cooled to room temperature and the resulting solid was filtered and dried to give the title compound (1.35 g, 89%).

¹H NMR (CDCl3): δ 7.12 (d, J = 8.59 Hz, 2H), 6.76 (d, J = 8.59 Hz, 2H), 6.12 (s, 1H), 4, 50-4.30 (m, 3H), 4.304.15 (m, 2H), 3.40 (dd, J = 14.11, 3.74 Hz, 1H), 2.98 (q, J = 7, 47 Hz, 2H), 2.85 (dd, J = 14.11, 9.43 Hz, 1H), 2.23 (s, 3H), 1.32 (t, J = 7.47 Hz, 3H) .

Preparation 27

5- [4- [2- [2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] -2-iminothiazolidin-4-one hydrochloride

<img file="ES2199366T3_D0069.tif" />

The title compound (329 mg, 78%) was prepared from 2-bromo-3- [4- [2- [2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenyl ] Ethyl propanoate (473 mg, 1.0 mmol) (obtained in Preparation 25), sodium acetate (164 mg, 2.0 mmol) and thiourea (152 mg, 2.0 mmol), by a procedure similar to that of described in preparation 26.

¹H NMR (CDCl3): δ 8.12 (d, J = 7.88 Hz, 1H), 7.80 (t, J = 7.03 Hz, 1H), 7.62 (d, J = 7.88 Hz, 1H), 7.49 (t, J = 7.03 Hz, 1H), 7.12 (d, J = 7.58 Hz, 2H), 6.84 (d, J = 7.58 Hz, 2H), 4.50 (dd, J = 9.43, 3.72 Hz, 1H), 4.46 (t, J = 5.31 Hz, 2H), 4.25 (d, J = 5.31 Hz, 2H), 3.25 (dd, J = 14.11, 3.72 Hz, 1H), 3.04 (q, J = 7.17 Hz, 2H), 2.81 (dd, J = 14 , 11, 9.43 Hz, 1H), 1.31 (t, J = 7.19 Hz, 3H).

IS 2 199 366 T3

Preparation 28

3- [4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenyl] -2-hydroxy-propanoic acid

<img file="ES2199366T3_D0070.tif" />

A mixture of ethyl 2-bromo-3- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenyl] propanoate (438 mg, 1 , 0 mmol) (obtained in preparation 24), sodium hydroxide (44 mg, 1.1 mmol) and calcium carbonate (100 mg, 1.0 mmol) in 1,4-dioxane (2 mL) and water (3 mL) was heated under reflux for 10 h. The reaction mixture was cooled to room temperature and acidified to pH 4 with 2N HCl and extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give the title compound (92 mg, 27%).

¹H NMR (CDCl3 + DMSO-O6): δ 7.12 (d, J = 8.61 Hz, 2H), 6.78 (d, J = 8.61 Hz, 2H), 6.19 (s, 1H ), 4.50-4.32 (m, 2H), 4.30-4.05 (m, 3H), 3.10-2.60 (m, 4H), 2.25 (s, 3H), 1.30 (t, J = 7.20 Hz, 3H).

Preparation 29

Ethyl 3- [4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenyl] -2-hydroxypropanoate

<img file="ES2199366T3_D0071.tif" />

Method a

A solution of 3- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenyl] -2-hydroxypropanoic acid (346 mg, 1.0 mmol) (obtained in preparation 28) in ethanol (3 mL) containing concentrated hydrochloric acid (0.1 mL) was heated under reflux for 10 h. The solution was cooled to room temperature, diluted with water, and extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated to provide the title compound (97 mg, 26%).

Method b

A mixture of ethyl 2-bromo-3- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenyl] propanoate (1.0 g , 2.28 mmol) (obtained in preparation 24), formamide (225 µL) and water (45 µL, 45 mg, 2.5 mmol) were heated at 160 ° C for 3 h. Water (45 µL) was added once more and stirred for 2 h at 175 ° C. The reaction mixture was cooled to room temperature, diluted with EtOAc (10 mL), washed with brine, dried over anhydrous Na2SO4, and concentrated to provide the crude compound which was purified by flash chromatography to give the compound from titer (306 mg, 36%).

¹H NMR (CDCl3): δ7.11 (d, J = 8.62Hz, 2H), 6.77 (d, J = 8.62Hz, 2H), 6.18 (s, 1H), 4.50-4 , 31 (m, 2H), 4.304.05 (m, 5H), 3.10-2.80 (m, 4H), 2.25 (s, 3H), 1.40-1.15 (m, 6H ).

Preparation 30

5- [4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] -2-thio-1,3-oxazolidin-4-one

<img file="ES2199366T3_D0072.tif" />

IS 2 199 366 T3

An intimate mixture of 4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde (286 mg, 1.0 mmol) (obtained in Preparation 3 ), 2-thio-1,3-oxazolidin-4-one (175 mg, 1.5 mmol) and anhydrous sodium acetate (246 mg, 3.0 mmol) was heated to 120 ° C under reduced pressure (266.644 Pa (2.0 torr)) for 90 min. After cooling, the reaction mixture was poured into ethyl acetate (80 mL) and water (20 mL) and stirred for 30 min, the aqueous phase was separated and acidified to pH 4 with 2N HCl. The separated solid was filtered and dried to provide the title compound (207mg, 54%).

¹H NMR (CDCl₃): δ 7.76 (d, J = 8.62 Hz, 2H), 6.93 (d, J = 8.62 Hz, 2H), 6.59 (s, 1H), 6.17 (s, 1H), 4.50-4.30 (m, 4H), 2.98 (q, J = 7.47 Hz, 2H), 2.27 (s, 3H), 1.35 (t, J = 7 , 47 Hz, 3H).

Preparation 31

4- [2- [2,5,6-Trimethyl-4-oxo-3,4-dihydro-thieno- [2,3-d] -pyrimidin-3-yl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0073.tif" />

The title compound (5.04 g, 27%) was prepared from 2,5,6-trimethyl-4-oxo-thienopyrimidine (10.59 g, 54.6 mmol), 4- [2-bromoethoxy] benzaldehyde (12.82 g, 56 mmol) and K2CO3 (15.04 g, 109 mmol) as base, by a similar procedure to that described in preparation 1.

¹H NMR (CDCl3): δ 9.88 (s, 1H), 7.82 (d, J = 8.72 Hz, 2H), 6.98 (d, J = 8.72 Hz, 2H), 4, 60-4.30 (m, 4H), 2.78 (s, 3H), 2.46 (s, 3H), 2.37 (s, 3H).

Preparation 32

4- [2- [2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] nitrobenzene

<img file="ES2199366T3_D0074.tif" />

The title compound (1.2 g, 60%) was prepared from 2-methyl-4-oxo-3,4-dihydroquinazoline (1.0 g, 6.25 mmol) and 4- [2-bromoethoxy] nitrobenzene (1 , 69 g, 6.9 mmol) and K2CO3 (1.73 g, 12.5 mmol) as base, by a similar procedure to that described in preparation 1.

¹H NMR (CDCl₃): δ 8.24 (d, J = 7.5 Hz, 1H), 8.18 (d, J = 9.22 Hz, 2H), 7.75 (t, J = 7.50 Hz, 1H) , 7.63 (d, J = 7.50Hz, 1H), 7.46 (t, J = 7.50.1H), 6.94 (d, J = 9.22Hz, 2H), 4.58 (t, J = 4.98Hz, 2H), 4.46 (t, J = 4.98Hz, 2H), 2.82 (s, 3H).

Preparation 33

4- [2- [2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] aniline

<img file="ES2199366T3_D0075.tif" />

The title compound (9.07 mg, 99%) was prepared from 4- [2- [2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] nitrobenzene (1.0 g , 3.1 mmol) (obtained in preparation 32), by a similar procedure to that described in preparation 22.

IS 2 199 366 T3 ¹H NMR (CDCl3): δ 8.24 (d, J = 7.50 Hz, 1H), 7.69 (t, J = 4.13 Hz, 1H), 7.62 (d, J = 7.50 Hz, 1H), 7.43 (t, J = 7.50 Hz, 1H), 6.64 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.80 Hz, 2H), 4.49 (t, J = 4.98Hz, 2H), 4.26 (t, J = 4.98Hz, 2H), 2.81 (s, 3H).

Preparation 34

Ethyl 2-Bromo-3- [4- [2- [2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenyl] propanoate

<img file="ES2199366T3_D0076.tif" />

The title compound (3.4 g, 58%) was prepared from 4- [2- [2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] aniline (3.75 g , 12.7 mmol) (obtained in preparation 33), NaNO2 (955 mg, 13.8 mmol) and ethyl acrylate (8.2 mL, 7.62 g, 76.2 mmol), by a procedure similar to that of described in preparation 24.

¹H NMR (CDCl3): δ 8.23 ​​(d, J = 7.50 Hz, 1H), 7.80-7.60 (m, 2H), 7.43 (t, J = 7.50 Hz, 1H ), 7.31 (d, J = 7.50 Hz, 1H), 7.10 (d, J = 7.50 Hz, 1H), 6.85-6.70 (m, 2H), 4.53 (t, J = 4.98 Hz, 2H), 4.33 (t, J = 4.98 Hz, 2H), 4.31 (dd, J = 8.71, 3.83 Hz, 1H), 4 , 12 (q, J = 5.80 Hz, 2H), 3.35 (dd, J = 14.12, 8.71 Hz, 1H), 3.13 (dd, J = 14.12, 3.83 Hz, 1H), 2.80 (s, 3H), 1.22 (t, J = 5.8 Hz, 3H).

Preparation 35

5- [4- [2- [2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] -2-iminothiazolidin-4-one hydrochloride

<img file="ES2199366T3_D0077.tif" />

The title compound (1.8 g, 60%) was obtained from 2-bromo-3- [4- [2- [2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy ] phenyl] ethyl propanoate (3.4 g, 7.4 mmol) (obtained in Preparation 34), sodium acetate (2.0 g, 14.8 mmol) and thiourea (1.13 g, 14.8 mmol), by a procedure similar to that described in preparation 26.

¹H NMR (CDCl3): δ 8.79 (bs, 1H, exchangeable D2O), 8.11 (d, J = 7.50 Hz, 1H), 7.80 (t, J = 7.50 Hz, 1H) , 7.59 (d, J = 7.50 Hz, 1H), 7.48 (t, J = 7.50 Hz, 1H), 7.12 (d, J = 8.48 Hz, 2H), 6 , 86 (d, J = 8.48 Hz, 2H), 4.51 (dd, J = 9.54, 3.91 Hz, 1H), 4.44 (t, J = 4.98 Hz, 2H) , 4.26 (t, J = 4.98 Hz, 2H), 3.22 (dd, J = 14.11, 3.91 Hz, 1H), 2.82 (dd, J = 14.11.9 , 54 Hz, 1H), 2.71 (s, 3H).

Preparation 36

4- [2- [2-Ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde

<img file="ES2199366T3_D0078.tif" />

The title compound (138 mg, 40%) was prepared from 2-ethyl-4-trifluoromethyl-1,6-dihydro-6-pyrimidone (200 mg, 1.04 mmol) and 4- [2-bromoethoxy] Benzaldehyde (238.5 mg, 1.04 mmol) in the presence of K2CO3 (287.5 mg, 2.08 mmol) as base, by a similar procedure to that described in preparation 1.

¹H NMR (CDCl3): δ 9.89 (s, 1H), 7.83 (d, J = 8.67 Hz, 2H), 6.95 (d, J = 8.67 Hz, 2H), 6, 70 (s, 1H), 4.50 (t, J = 4.66 Hz, 2H), 4.39 (t, J = 4.66 Hz, 2H), 3.1 (q, J = 7.4 Hz, 2H), 1.4 (t, J = 7.4 Hz, 3H).

IS 2 199 366 T3

Preparation 37

Ethyl [4 - [[2,4-Dioxo-1,3-thiazolidin-5-yl] methyl] phenoxy] acetate

<img file="ES2199366T3_D0079.tif" />

Method a

A solution of ethyl [4 - [[2,4-dioxo-1,3-thiazolidin-5-yl] methylene] phenoxy] acetate (10 g) in 1,4-dioxane (200 mL) was subjected to reduction with hydrogen in the presence of 5% palladium on carbon (15 g) at a pressure of 2.8 kg / cm²(40 psi) for 24 h. The mixture was filtered through a pad of celite. The filtrate was evaporated to dryness under reduced pressure to give the title compound (9.5 g, 95%).

Method b

A solution of ethyl [4 - [[2,4-dioxo-1,3-thiazolidin-5-yl] methylene] phenoxy] acetate (5 g, 16.3 mmol) in methanol (50 mL) was added to chips magnesium (6.6 g, 0.277 mol) in methanol (150 mL) and stirred for 12 h, keeping the temperature below 50 ° C once the reaction started, as evidenced by the evolution of hydrogen and the generation of heat. The reaction mixture was poured into ice water (150 mL), neutralized with 10% aqueous hydrochloric acid, and the solution was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water (150 mL), brine (100 mL), and dried (MgSO4), and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel in 2% methanol in dichloromethane to give the title compound (2.3 g, 46%), mp 107 ° C.

¹H NMR (CDCl3): δ 8.5 (bs, 1H, exchangeable D2O), 7.20 (d, J = 8.50 Hz, 2H), 7.06 (d, J = 8.50 Hz, 2H) , 4.65 (s, 2H), 4.53 (dd, J = 9.39, 3.74Hz, 1H), 4.32 (q, J = 7.20Hz, 2H), 3.50 (dd, J = 14.12, 3.74Hz, 1H), 3.14 (dd, J = 14.12.9.39Hz, 1H), 1.34 (t, J = 7.17Hz, 3H).

Preparation 38

[4 - [[2,4-dioxo-1,3-thiazolidin-5-yl] methyl] phenoxy] acetic acid

<img file="ES2199366T3_D0080.tif" />

To a stirred solution of ethyl [4 - [[2,4-dioxo-1,3-thiazolidin-5-yl] methyl] phenoxy] acetate (110 g, 0.36 mol) in methanol (0.65 L) A solution of Na2CO3 (200 g, 1.88 mol) in water (0.65 L) was added and it was stirred for 5 h at a temperature between 25 ° C and 30 ° C. After completion of the reaction, the methanol was removed under reduced pressure, water was added to the residue and acidified with hydrochloric acid. The precipitated white solid was filtered and dried to provide the title compound (80 g, 80%), mp 181-183 ° C.

¹H NMR (DMSO-d6): δ 12.40 (bs, 1H, D2O exchangeable), 8.60 (bs, 1H, D2O exchangeable), 7.16 (d, J = 8.40 Hz, 2H), 6 , 50 (d, J = 8.40Hz, 2H), 4.87 (dd, J = 9.14.4.20Hz, 1H), 4.65 (s, 2H), 3.32 (dd, J = 14.12, 4.20Hz, 1H), 3.05 (dd, J = 14.12.9.14Hz, 1H).

Preparation 39

5 - [[4- [N- [Methylbenzamid-2-yl] aminocarbonyl] methoxy] phenylmethyl] thiazolidin-2,4-dione

<img file="ES2199366T3_D0081.tif" />

IS 2 199 366 T3

Method a

A stirred solution of [4 - [[2,4-dioxo-1,3-thiazolidin-5-yl] methyl] phenoxy] acetic acid (1.9 g, 6.75 mmol) in dichloromethane (15 mL) was Triethylamine (1.86 mL, 1.36 g, 13.48 mmol) was added, followed by pivaloyl chloride (0.913 mL, 899 mg, 5.46 mmol) at 0 ° C and stirred for an additional 1 h at 0 ° C. The reaction mixture was added to a solution of 2 amino-N-methylbenzamide (920 mg, 6.13 mmol) in acetic acid (10 mL) and xylene (10 mL), and the reaction mixture was stirred for 30 min to 25 ° C. The solvents were removed under reduced pressure and the product was purified to provide the title compound (2.51 g, 91%), mp 201-203 ° C.

Method b

A stirred solution of [4 - [[2,4-dioxo-1,3-thiazolidin-5-yl] methyl] phenoxy] acetic acid (1.9 g, 6.75 mmol) in xylene (15 mL) was Thionyl chloride (2.46 mL, 4.02 g, 33.75 mmol) was added and refluxed for 1 hr. The reaction mixture was cooled to room temperature and excess thionyl chloride was removed under reduced pressure. The residue was added to a solution of 2-amino-N-methylbenzamide (920 mg, 6.13 mmol) in acetic acid (10 mL) and xylene (10 mL) and stirred for 1 h at 25 ° C. The solvents were removed under reduced pressure and the product was purified to provide the title compound (2.4 g, 86%).

¹H NMR (CDCl3, 200 MHz): δ 12.21 (s, 1H, exchangeable D2O), 11.17 (bs, 1H, exchangeable D2O), 8.63 (d, J = 8.30 Hz, 1H), 7.96 (bs, 1H, exchangeable D2O), 7.65 (d, J = 7.80 Hz, 1H), 7.47 (t, J = 7.80 Hz, 1H), 7.30-6, 96 (m, 5H), 4.60 (s, 2H), 4.48 (dd, J = 9.6, 3.70 Hz, 1H), 3.45 (dd, J = 13.70, 3, 70 Hz, 1H), 3.05 (dd, J = 13.70, 9.60 Hz, 1H),

2.94 (d, J = 3.74Hz, 3H).

Example 1

5- [4- [2- [4-Methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0082.tif" />

A mixture of 4- [2- [4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde (10 g, 24.5 mmol) (obtained in Preparation 1) , thiazolidine-2,4-dione (3.5 g, 30 mmol), benzoic acid (388 mg, 3.18 mmol) and piperidine (352 μL, 303 mg, 3.68 mmol) in toluene (50 mL) are heated under reflux for 1 hr with continuous removal of water. The reaction mixture was cooled to room temperature and the resulting crystalline compound was filtered and washed with water and dried to give the title compound (12.3 g, 99%), mp 240-242 ° C.

¹H NMR (DMSO-d6): δ 12.40 (bs, 1H, exchangeable D2O), 7.75 (s, 1H), 7.54 (d, J = 8.72 Hz, 2H), 7.02 ( d, J = 8.72 Hz, 2H), 6.15 (s, 1H), 4.45-4.15 (m, 4H), 2.91 (t, J = 7.65 Hz, 2H), 2.20 (s, 3H), 1.90-1.65 (m, 2H), 1.06 (t, J = 7.65Hz, 3H).

Example 2

5- [4- [2- [2,4-Dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0083.tif" />

The title compound (0.98 g, 95%) was obtained from 4- [2- [2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde (0, 8 g, 2.8 mmol) (obtained in preparation 2) and thiazolidine-2,4-dione (0.344 g, 2.8 mmol), by a procedure similar to that described in example 1, mp 235 ° C.

¹H NMR (CDCl3): δ 8.50 (bs, 1H, exchangeable D2O), 7.80 (s, 1H), 7.48 (d, J = 8.40 Hz, 2H), 6.98 (d, J = 8.40 Hz, 2H), 6.21 (s, 1H), 4.52-4.30 (m, 4H), 2.70 (s, 3H), 2.25 (s, 3H).

IS 2 199 366 T3

Example 3

5- [4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0084.tif" />

The title compound (2.13 g, 92%) was obtained from 4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde ( 1.7 g, 5.94 mmol) (obtained in preparation 3) and thiazolidine-2,4-dione (0.695 g, 5.94 mmol), by a procedure similar to that described in example 1, mp 248-250 ° C.

¹H NMR (CDCl3 + DMSO-d6): δ 12.25 (bs, 1H, exchangeable D2O), 7.78 (s, 1H), 7.40 (d, J = 7.40 Hz, 2H), 7, 0 (d, J = 7.40 Hz, 2H), 6.20 (s, 1H), 4.48-4.24 (m, 4H), 3.0 (q, J = 6.4 Hz, 2H ), 2.20 (s, 3H), 1.28 (t, J = 6.4 Hz, 3H). Example 4

5- [4- [2- [2-Butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0085.tif" />

The title compound (1.2 g, 83%) was obtained from 4- [2- [2-butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde ( 1.1 g, 3.5 mmol) (obtained in preparation 4) and thiazolidine-2,4-dione (410 mg, 3.5 mmol), by a procedure similar to that described in example 1, mp 209 ° C .

¹H NMR (CDCl3): δ 7.80 (s, 1H), 7.40 (d, J = 8.63 Hz, 2H), 6.95 (d, J = 8.63 Hz, 2H), 6, 21 (s, 1H), 4.55-4.22 (m, 4H), 2.95 (t, J = 7.47 Hz, 2H), 2.25 (s, 3H), 1.85-1 , 60 (m, 2H), 1.60-1.40 (m, 2H), 0.99 (t, J = 7.10 Hz, 3H).

Example 5

5- [4- [2- [2-Benzyl-4-methyl-6-oxo-1,6-dihydro-1- pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0086.tif" />

The title compound (1.70 g, 66%) was obtained from 4- [2- [2-benzyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde ( 2.0 g, 5.74 mmol) (obtained in preparation 5) and thiazolidine-2,4-dione (0.74 g, 6.4 mmol), by a procedure similar to that described in example 1, mp 223 ° C.

¹H NMR (CDCl3 + DMSO-d6): δ 7.74 (s, 1H), 7.44 (d, J = 8.71 Hz, 2H), 7.40-7.10 (m, 5H), 6 , 95 (d, J = 8.71 Hz, 2H), 6.26 (s, 1H), 4.38 (s, 2H), 4.35-4.10 (m, 4H), 2.32 ( s, 3H).

IS 2 199 366 T3

Example 6

5- [4- [2- [2,5-Diethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0087.tif" />

The title compound (881 mg, 92%) was obtained from 4- [2- [2,5-diethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde ( 730 mg, 2.32 mmol) (obtained in preparation 6) and thiazolidine-2,4-dione (451 mg, 2.55 mmol), by a procedure similar to that described in example 1, mp 252-254 ° C .

¹H NMR (CDCl3 + DMSO-d6): δ 12.08 (bs, 1H, exchangeable D2O), 7.69 (s, 1H), 7.44 (d, J = 8.58 Hz, 2H), 6, 97 (d, J = 8.58 Hz, 2H), 4.50-4.20 (m, 4H), 2.93 (q, J = 7.43 Hz, 2H), 2.50 (q, J = 7.43 Hz, 2H), 2.26 (s, 3H), 1.33 (t, J = 7.43 Hz, 3H), 1.07 (t, J = 7.43 Hz, 3H).

Example 7

5- [4- [2- [2-Ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0088.tif" />

The title compound (2.2 g, 88%) was obtained from 4- [2- [2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde ( 2.09 g, 6.0 mmol) (obtained in preparation 7) and thiazolidine-2,4-dione (0.702 g, 6.0 mmol), by a procedure similar to that described in example 1, mp 234 ° C .

¹H NMR (DMSO-d6): δ 12.58 (bs, 1H, exchangeable D2O), 8.22-8.05 (m, 2H), 7.74 (s, 1H), 7.66-7.38 (m, 5H), 7.11 (d, J = 8.30 Hz, 2H), 6.92 (s, 1H), 4.48-4.20 (m, 4H), 3.06 (q, J = 7.06 Hz, 2H), 1.35 (t, J = 7.06 Hz, 3H). Example 8

5- [4- [2- [4-Oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethylene] thiazolidin-2,4-dione

<img file="ES2199366T3_D0089.tif" />

The title compound (1.91 g, 84%) was obtained from 4- [2- [4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] benzaldehyde (1.7 g, 5.78 mmol) (obtained in preparation 9) and thiazolidine-2,4-dione (678 mg, 5.79 mmol), by a similar procedure to that described in example 1, mp 242-244 ° C.

¹H NMR (CDCl3 + DMSO-d6): δ 12.56 (bs, 1H, exchangeable D2O), 8.42 (s, 1H), 8.18 (d, J = 7.89 Hz, 1H), 7, 84 (t, J = 7.47 Hz, 1H), 7.72 (s, 1H), 7.72-7.50 (m, 2H), 7.54 (d, J = 8.72 Hz, 2H ), 7.11 (d, J = 8.72 Hz, 2H), 4.40 (s, 4H).

IS 2 199 366 T3

Example 9

5- [4- [2- [2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0090.tif" />

The title compound (4.28 g, 93%) was obtained from 4- [2- [2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] benzaldehyde (3.4 g , 11.04 mmol) (obtained in preparation 10) and thiazolidine-2,4-dione (1.6 g, 13.8 mmol), by a procedure similar to that described in example 1, mp 278 ° C.

¹H NMR (DMSO-d6): δ 12.58 (bs, 1H, exchangeable D2O), 8.19 (d, J = 8.0 Hz, 1H), 7.89-7.44 (m, 6H), 7.03 (d, J = 8.7Hz, 2H), 4.58-4.42 (m, 2H), 4.42-4.25 (m, 2H), 2.81 (s, 3H) .

Example 10

5- [4- [2- [2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0091.tif" />

The title compound (0.42 g, 92%) was obtained from 4- [2- [2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] benzaldehyde (0.35 g , 1.08 mmol) (obtained in preparation 11) and thiazolidine-2,4-dione (0.16 g, 1.4 mmol), by a procedure similar to that described in example 1, mp 257 ° C.

¹H NMR (DMSO-d6): δ 12.58 (bs, 1H, exchangeable D2O), 8.15 (d, J = 8.0 Hz, 1H), 7.82-7.44 (m, 6H), 7.08 (d, J = 8.0 Hz, 2H), 4.47-4.40 (m, 2H), 4.40-4.30 (m, 2H), 3.08 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H).

Example 11

5- [4- [2- [8-Aza-2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0092.tif" />

The title compound (0.25 g, 68%) was obtained from 4- [2- [8-aza-2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] benzaldehyde ( 0.28 g, 0.9 mmol) (obtained in preparation 12) and thiazolidine-2,4-dione (0.106 g, 0.9 mmol), by a procedure similar to that described in example 1, mp 276 ° C .

¹H NMR (CDCl3 + DMSO-d6): δ 9.00-8.90 (m, 1H), 8.51 (d, J = 7.30 Hz, 1H), 7.72 (s, 1H), 7 , 51 (d, J = 8.72 Hz, 2H), 7.55-7.45 (m, 1H), 7.05 (d, J = 8.72 Hz, 2H), 4.60-4, 50 (m, 2H), 4.50-4.38 (m, 2H), 2.85 (s, 3H).

IS 2 199 366 T3

Example 12

5- [4 - [[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0093.tif" />

The title compound (11.10g, 96%) was obtained from 4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] benzaldehyde (9.0 g, 30.61 mmol) (obtained in preparation 13) and thiazolidine-2,4-dione (3.6 g, 30.61 mmol), by a similar procedure to that described in example 1, mp 280 ° C.

¹H NMR (CDCl3 + DMSO-d6): δ12.38 (bs, 1H, exchangeable D2O), 8.19 (d, J = 7.47 Hz, 1H), 7.82-7.60 (m, 2H) , 7.72 (s, 1H), 7.53 (d, J = 8.7Hz, 2H), 7.60-7.48 (m, 1H), 7.23 (d, J = 8.72 Hz, 2H), 5.35 (s, 2H), 3.68 (s, 3H). Example 13

5- [4 - [[3-Ethyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0094.tif" />

The title compound (3.3 g, 83%) was obtained from 4 - [[3-ethyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] benzaldehyde (3.0 g, 9 , 74mmol) (obtained in preparation14) and thiazolidine-2,4-dione (1.14g, 9.74mmol), by a similar procedure to that described in Example 1, mp 260-261 ° C.

¹H NMR (CDCl3 + DMSO-d6): δ12.58 (bs, 1H, exchangeable D2O), 8.18 (d, J = 7.88 Hz, 1H), 7.92-7.74 (m, 1H) , 7.78 (s, 1H), 7.74-7.54 (m, 2H), 7.61 (d, J = 8.72Hz, 2H), 7.29 (d, J = 8.72Hz, 2H), 5.40 (s, 2H), 4.14 (q, J = 6.84Hz, 2H), 1.34 (t, J = 6.84Hz, 3H).

Example 14

5- [4 - [[1-Methyl-4-oxo-1,4-dihydro-2-quinazolinyl] methoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0095.tif" />

The title compound (3 10 mg, 79%) was obtained from 4 - [[1-methyl-4-oxo-1,4-dihydro-2-quinazolinyl] methoxy] benzaldehyde (294 mg, 1.0 mmol ) (obtained in preparation 15) and thiazolidine-2,4-dione (117 mg, 1.0 mmol), by a procedure similar to that described in example 1.

¹H NMR (DMSO-dg): δ 8.09 (d, J = 7.88 Hz, 1H), 8.00-7.04 (m, 4H), 7.58 (d, J = 8.72 Hz , 2H), 7.24 (d, J = 8.72Hz, 2H), 5.41 (s, 2H), 3.86 (s, 3H).

IS 2 199 366 T3

Example 15

5- [3-Methoxy-4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0096.tif" />

The title compound (235mg, 90%) was obtained from 3-methoxy-4 - [[3-methyl-4-oxo-3,4-dihydro-quinazolinyl] methoxy] benzaldehyde (200 mg, 0.62 mmol) (obtained in Preparation 16) and thiazolidine-2,4-dione (79 mg, 0.68 mmol), by a procedure similar to that described in Example 1, mp 244-246 ° C.

¹H NMR (DMSO-d₆ + CDCl₃): δ 12.25 (bs, 1H, D₂O interchangeable) 8.02 (d, J = 7.20 Hz, 1H), 7.82-7.60 (m, 2H), 7.66 (s, 1H), 7.51 (t, J = 7 , 20 Hz, 1H), 7.38-7.03 (m, 3H), 5.52 (s, 2H), 3.91 (s, 3H), 3.68 (s, 3H).

Example 16

5- [4- [2- [4-Acetylamino-2-oxo-1,2-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0097.tif" />

The title compound (1.8 g, 81%) was obtained from 4- [2- [4-acetylamino-2-oxo-1,2-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde (1.7 g , 5.65 mmol) (obtained in preparation 8) and thiazolidine-2,4-dione (0.661 g, 5.65 mmol), by a procedure similar to that described in example 1, mp 274 ° C.

¹H NMR (CDCl3 + DMSO-d6): δ 12.56 (bs, 1H, exchangeable D2O), 10.85 (s, 1H, exchangeable D2O), 8.11 (d, J = 7.2Hz, 1H), 7.74 (s, 1H), 7.55 (d, J = 8.30Hz, 2H), 7.17 (d, J = 7.20Hz, 1H), 7.11 (d, J = 8.30Hz , 2H), 4.40-4.05 (m, 4H), 2.08 (s, 3H).

Example 17

5- [4- [2- [4-Methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione

<img file="ES2199366T3_D0098.tif" />

A solution of 5- [4- [2- [4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione (5.0 g , 12.46 mmol), obtained in example 1, in 1,4-dioxane (75 mL) was subjected to reduction with hydrogen in the presence of palladium on carbon at 10% (12.0 g) at a pressure of 4, 2 kg / cm^{1 2} (60 psi) for 40 h. The mixture was filtered through a pad of celite. The filtrate was evaporated to dryness under reduced pressure, purified by column chromatography (2: 1 EtOAc / petroleum ether as eluent) followed by crystallization (CH2Cl2) to give the title compound (4.6 g, 92% ), mp 144-146 ° C.

¹H NMR (CDCl3): δ 8.25 (bs, 1H, exchangeable D2O), 7.12 (d, J = 8.48 Hz, 2H), 6.79 (d, J = 7.48 Hz, 2H) , 6.21 (s, 1H), 4.47 (dd, J = 9.36, 4.06 Hz, 1H), 4.41 (t, J = 4.47 Hz, 2H), 4.26 ( t, J = 4.47 Hz, 2H), 3.41 (dd, J = 14,11,4.06 Hz, 1H), 3.10 (dd, J = 14.11, 9.36 Hz, 1H ), 2.92 (t, J = 7.63 Hz, 2H), 2.24 (s, 3H), 1.90-1.60 (m, 2H), 1.05 (t, J = 7, 65Hz, 3H).

IS 2 199 366 T3

Example 18

5- [4- [2- [2,4-Dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione

<img file="ES2199366T3_D0099.tif" />

The title compound (850 mg, 85%) was obtained from 5- [4- [2- [2,4-dimethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine -2,4-dione (1.0 g) (obtained in example 2), by a similar procedure to that described in example 17, mp 170 ° C.

¹H NMR (CDCl₃): δ 8.15 (bs, 1H, D₂O interchangeable), 7.14 (d, J = 8.30 Hz, 2H), 6.80 (d, J = 8.30, 2H), 6.21 (s, 1H), 4.50 (dd, J = 9.13.3.73Hz, 1H), 4.48-4.20 (m, 4H), 3.41 (dd, J = 14.12.3.73Hz, 1H), 3.13 (dd , J = 14,12,9,13 Hz, 1H), 2.70 (s, 3H), 2.25 (s, 3H).

Example 19

5- [4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione

<img file="ES2199366T3_D0100.tif" />

Method a

The title compound (820 mg, 82%) was obtained from 5- [4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene ] thiazolidine-2,4-dione (1.0 g, 2.6 mmol) (obtained in example 3), by a similar procedure to that described in example 17.

Method b

To a stirred solution of 5- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] -2-iminothiazolidin-4-one (1 , 93 g, 5.0 mmol) (obtained in preparation 26) in ethanol (15 mL) was added 2N HCl (10 mL) and heated under reflux for 12 h. The reaction mixture was cooled to room temperature and ethanol was removed under reduced pressure. The aqueous phase was neutralized with an aqueous NaHCO3 solution and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated to provide the title compound (1.63 g, 84%) which was crystallized from CH₂Cl₂/ petroleum ether, mp 148 ° C. The title compound provided another polymorph, upon crystallization from MeOH, mp 155 ° C.

¹H NMR (CDCl3): δ 8.65 (bs, 1H, exchangeable D2O), 7.12 (d, J = 8.51 Hz, 2H), 6.79 (d, J = 8.51 Hz, 2H) , 6.21 (s, 1H), 4.48 (dd, J = 9.27.3.83Hz, 1H), 4.42 (t, J = 4.57Hz, 2H), 4.26 (t, J = 4.57Hz, 2H), 3.41 (dd, J = 14.11.3.83 Hz, 1H), 3.11 (dd, J = 14.11.9.27Hz, 1H), 2, 99 (q, J = 7.47Hz, 2H), 2.25 (s, 3H), 1.34 (t, J = 7.47Hz, 3H).

Example 20

5- [4- [2- [2-Butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione

<img file="ES2199366T3_D0101.tif" />

IS 2 199 366 T3

The title compound (780 mg, 78%) was obtained from 5- [4- [2- [2-butyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene ] thiazolidine-2,4-dione (1.0 g) (obtained in example 4), by a similar procedure to that described in example 17, mp 150-152 ° C.

¹H NMR (CDCl3): δ 9.53 (bs, 1H, exchangeable D2O), 7.13 (d, J = 8.40 Hz, 2H), 6.79 (d, J = 8.40 Hz, 2H) , 6.22 (s, 1H), 4.45 (dd, J = 9.22, 3.83 Hz, 1H), 4.42 (t, J = 4.57 Hz, 2H), 4.26 ( t, J = 4.57 Hz, 2H), 3.42 (dd, J = 14.12 Hz, 3.83 Hz, 1H), 3.09 (dd, J = 14.12, 9.22 Hz, 1H), 2.95 (t, J = 7.47 Hz, 2H), 2.24 (s, 3H), 1.85-1.65 (m, 2H), 1.58-1.32 (m , 2H), 0.98 (t, J = 7.38 Hz, 3H).

Example 21

5- [4- [2- [2-Ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione

<img file="ES2199366T3_D0102.tif" />

The title compound (300 mg, 50%) was obtained from 5- [4- [2- [2-ethyl-4-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene ] thiazolidine-2,4-dione (600 mg, 1.38 mmol) (obtained in example 7), by a similar procedure to that described in example 17, mp 178 ° C.

¹H NMR (CDCl3): δ 8.20-7.95 (m, 2H), 7.55-7.35 (m, 3H), 7.12 (d, J = 8.30 Hz, 2H), 6 , 80 (d, J = 8.30 Hz, 2H), 6.80 (s, 1H), 4.60-4.40 (m, 3H), 4.40-4.20 (m, 2H), 3.41 (dd, J = 14.1, 3.65 Hz, 1H), 3.09 (dd and q overlap, 3H), 1.46 (t, J = 7.30 Hz, 3H).

Example 22

5- [4 - [[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione

<img file="ES2199366T3_D0103.tif" />

Method a

The title compound (750 mg, 75%) was obtained from 5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethylene] thiazolidin-2,4 -dione (1.0 g) (obtained in example 12), by a similar procedure to that described in example 17.

Method b

To a stirred solution of [4 - [[2,4-dioxo-1,3-thiazolidin-5-yl] methyl] phenoxy] acetic acid (1.9 g, 6.75 mmol) (obtained in Preparation 38) In dichloromethane (15 mL), triethylamine (1.876 mL, 1.36 g, 13.48 mmol) was added, followed by pivaloyl chloride (0.913 mL, 899 mg, 5.46 mmol) at 0 ° C, and the stirring for 1 hr at 0 ° C. The above reaction mixture was added to a solution of 2-amino-N-methylbenzamide (920 mg, 6.13 mmol) in acetic acid (20 mL) and heated under reflux for 24 h. The reaction mixture was cooled to room temperature and acetic acid was removed under reduced pressure. Water (50 mL) was added to the residue and it was extracted with CHCl3 (3 x 25 mL). The combined CHCl3 extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to provide the title compound (2.16 g, 81%), mp 190 ° C.

Method c

To a stirred solution of [4 - [[2,4-dioxo-1,3-thiazolidin-5-yl] methyl] phenoxy] acetic acid (33 g, 0.117 mol) in dichloromethane (300 mL) was added triethylamine (35 , 4 mL, 0.254 mol), followed by pivaloyl chloride (17.3 mL, 0.127 mol) at 0 ° C, and stirred for 1 h at 0 ° C. The reaction mixture was added to a solution of 2-amino-N-methylbenzamide (16 g, 0.106 mol) in a mixture of acetic acid (300 mL) and xylene (300 mL) and heated under reflux for 18 h. The

ES 2 199 366 T3 reaction mixture was cooled to room temperature and solvents were removed under reduced pressure. The product was purified to provide the title compound (35.5g, 85%).

Method D

A stirred solution of [4 - [[2,4-dioxo-1,3-thiazolidin-5-yl] methyl] phenoxy] acetic acid (1.9 g, 6.75 mmol) in dichloromethane (15 mL) was added triethylamine (1.876 mL, 1.36 g, 13.48 mmol), followed by pivaloyl chloride (0.913 mL, 899 mg, 5.46 mmol) at 0 ° C, and stirring was continued for 1 h at 0 ° C . The above reaction mixture was added to a solution of 2-amino-N-methylbenzamide (920 mg, 6.13 mmol) in xylene (20 mL) containing pTsOH.H2O (646 mg, 3.4 mmol) and heated at reflux for 24 h. The reaction mixture was cooled to room temperature and the xylene was removed under reduced pressure. Water (50 mL) was added to the residue and it was extracted with CHCl3 (3 x 25 mL). The combined CHCl3 extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to provide the title compound (1.79 g, 58%).

Method E

A stirred solution of [4 - [[2,4-dioxo-1,3-thiazolidin-5-yl] methyl] phenoxy] acetic acid (1.0 g, 3.56 mmol) in xylene (10 mL) was Thionyl chloride (1.6 mL, 2.12 g, 17.8 mmol) was added and refluxed for 1 hr. The reaction mixture was cooled to 25 ° C and excess thionyl chloride was removed and then added to a solution of 2 amino-N-methylbenzamide (534 mg, 3.56 mmol) in a mixture of acetic acid (10 mL ) and xylene (5 mL) and refluxed for 20 h. The reaction mixture was cooled to room temperature and the solvents were removed under reduced pressure. Water was added to the residue (20 mL) and extracted with CHCl3 (3 x 25 mL). The combined CHCl3 extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to provide the title compound (750 mg, 54%).

Method F

5 - [[4- [N- [Methylbenzamid-2-yl] aminocarbonyl] methoxy] phenylmethyl] thiazolidin-2,4-dione (1.0 g) (obtained in preparation 39) was heated at 180 ° C for 8 h. The reaction mixture was cooled to room temperature and diluted with water and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated.

Method G

The title compound (345 mg, 34%) was prepared from 5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethylene] thiazolidine-2,4 -dione (1.0 g) (obtained in Example 12), by a similar procedure to that described in Preparation 37, Method B.

Polymorphs

Polymorph I

5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione (10 g), obtained by any of the above methods, is dissolved in dioxane (200 mL) heating to 60 ° C. The solution was concentrated to 30-50 mL to which methanol was added and stirred for 15-30 min. The white solid precipitated and was filtered and dried to give polymorph I, which has the endotherm according to DSC (Differential Scanning Calorimetry) analysis at 198 ° C.

Polymorph II

5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione (10 g), obtained by any of the above methods, is dissolved in acetone (300 mL). The solution was concentrated to 30-50 mL and methanol was added. After stirring for 15-30 min, the precipitated white solid was filtered and dried to provide polymorph II, which has the endotherm according to DSC analysis at 180 ° C.

¹H NMR (CDCl3): δ 8.70 (bs, 1H, exchangeable D2O), 8.31 (d, J = 7.89 Hz, 1H), 7.88-7.68 (m, 2H), 7, 60-7.45 (m, 1H), 7.19 (d, J = 8.46 Hz, 2H), 7.02 (d, J = 8.46 Hz, 2H), 5.18 (s, 2H ), 4.50 (dd, J = 9.22, 3.90 Hz, 1H), 3.75 (s, 3H), 3.45 (dd, J = 14.11.3.90Hz, 1H), 3.13 (dd, J = 14.11.9.22Hz, 1H).

IS 2 199 366 T3

Example 23

5- [4 - [[3-Ethyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione

<img file="ES2199366T3_D0104.tif" />

Method a

The title compound (1.186 g, 58%) was obtained from 5- [4 - [[3-ethyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethylene] thiazolidin-2,4 -dione (2.035 g, 5.0 mmol) (obtained in example 13), by a similar procedure to that described in example 17.

Method b

The title compound (278 mg, 68%) was obtained from [4 - [[2,4-dioxo-1,3-thiazolidin-5-yl] methyl] phenoxy] acetic acid (281 mg, 1.0 mmol) (obtained in preparation 38) and 2-amino-N-methylbenzamide (164 mg, 1.0 mmol), by a similar procedure to that described in Example 22 in Method B, mp 218 ° C.

¹H NMR (CDCl3): δ 9.20 (bs, 1H, exchangeable D2O), 8.30 (d, J = 7.84 Hz, 1H), 7.84-7.64 (m, 2H), 7, 60-7.48 (m, 1H), 7.19 (d, J = 8.46 Hz, 2H), 7.02 (d, J = 8.46 Hz, 2H), 5.25 (s, 2H ), 4.51 (dd, J = 9.30, 3.95 Hz, 1H), 3.94 (q, J = 6.92 Hz, 2H), 3.42 (dd, J = 14.12, 3.95 Hz, 1H), 3.11 (dd, J = 14.2, 9.30 Hz, 1H), 1.35 (t, J = 6.92 Hz, 3H).

Example 24

5- [4- [2- [2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione

<img file="ES2199366T3_D0105.tif" />

The title compound (173 mg, 82%) was obtained from 5- [4- [2- [2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] -2- Iminothiazolidin-4-one (211 mg, 0.5 mmol) (obtained in Preparation 27), by a similar procedure to that described in Example 19 (Method B), mp 178-180 ° C.

¹H NMR (CDCl3): δ 8.24 (d, J = 7.88 Hz, 1H), 7.80-7.60 (m, 2H), 7.43 (t, J = 7.56 Hz, 1H ), 7.10 (d, J = 8.63 Hz, 2H), 6.80 (d, J = 8.63 Hz, 2H), 4.54 (t, J = 5.03 Hz, 2H), 4.46 (dd, J = 9.22, 3.83 Hz, 1H), 4.32 (t, J = 5.03 Hz, 2H), 3.40 (dd, J = 14.35, 3, 83Hz, 1H), 3.20-2.90 (m, 3H), 1.43 (t, J = 7.48Hz, 3H).

Example 25

2- [4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] -1,2,4-oxadiazolidine-3,5-dione

<img file="ES2199366T3_D0106.tif" />

IS 2 199 366 T3

Method a

To a stirred solution of N- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzyl] N-hydroxyurea (346 mg, 1.0 mmol) (obtained in preparation 19) in water (2 mL) 1 N NaOH (3 mL) was added followed by ethyl chloroformate (191 μL, 217 mg, 2.0 mmol) and stirred for 1 h at 30 ° C . The reaction mixture was diluted with water, acidified to H3.0, and extracted with EtOAc (3x10mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated to provide the title compound (283 mg, 76%).

Method b

To a cold solution (-5 ° C) of 4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzylhydroxylamine (304 mg, 1.0 mmol ) (obtained in preparation 18) in anhydrous THF (4.0 mL) N- (chlorocarbonyl) isocyanate (88 µL, 116 mg, 1.1 mmol) was added dropwise. The mixture was stirred for 30 min and poured into 2N HCl, then extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to provide the title compound (264 mg, 71%).

¹H NMR (CDCl₃ + DMSO-dg): δ 12.40 (bs, 1H, D₂O interchangeable), 7.25 (d, J = 8.72 Hz, 2H), 6.90 (d, J = 8.72 Hz, 2H), 6.15 (s, 1H), 4.70 (s , 2H), 4.40-4.25 (m, 2H), 4.25-4.12 (m, 2H), 2.91 (q, J = 7.56Hz, 2H), 2.12 (s , 3H), 1.20 (t, J = 7.56 Hz, 3H).

Example 26

5- [4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] oxazolidine-2,4-dione

<img file="ES2199366T3_D0107.tif" />

To a stirred solution of 5- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] -2-thio-1,3oxazolidin-4 -one (100 mg, 0.259 mmol) (obtained in preparation 30) in dry DMF (2 mL) 3-chloroperbenzoic acid (179 mg, 0.68 mmol, 65%) was added at 0 ° C and stirred for 30 min at a temperature between 0 ° C and 10 ° C and then at 30 ° C for 5 h. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (5 mL) and then brine (5 mL), dried over anhydrous Na2SO4, and concentrated. The crude product was purified by flash chromatography to provide the title compound (72 mg, 75%).

¹H NMR (CDCl3 + DMSO-d6): δ7.68 (d, J = 8.72Hz, 2H), 6.91 (d, J = 8.72Hz, 2H), 6.61 (s, 1H), 6 , 16 (s, 1H), 4.50-4.38 (m, 2H), 4.38-4.00 (m, 2H), 3.12 (q, J = 7.47Hz, 2H), 2 , 24 (s, 3H), 1.35 (t, J = 7.47Hz, 3H).

Example 27

5- [4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] oxazolidine-2,4-dione

<img file="ES2199366T3_D0108.tif" />

Method a

A solution of 5- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] oxazolidine-2,4-dione (100 mg) ( obtained in Example 26) in 1,4-dioxane (10 mL) was subjected to reduction with hydrogen in the presence of 10% palladium on carbon (20 mg) at 3.5 kg / cm² (50 psi) for 24 h. The mixture was filtered through a pad of celite. The filtrate was evaporated to dryness under reduced pressure, purified by column chromatography (2: 1 EtOAc / petroleum ether as eluent) to give the title compound (90 mg, 90%).

IS 2 199 366 T3

Method b

A solution of ethyl 3- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenyl] -2-hydroxypropanoate (93 mg, 0, 25 mmol) (obtained in preparation 29), urea (30 mg, 0.5 mmol) and sodium methoxide (22 mg, 0.4 mmol) in a mixture of methanol (0.5 mL) and ethanol (2, 0 mL) was stirred for 2 h at 30 ° C, then reflux for 2 h. The reaction mixture was cooled to room temperature and acidified with 2N HCl to pH 4 and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4, and concentrated to provide the title compound (35 mg, 38%).

¹H NMR (CDCl3 + DMSO-d6): δ 7.14 (d, J = 8.51 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 6.17 (s, 1H ), 4.95 (t, J = 4.82 Hz, 1H), 4.42 (t, J = 4.94 Hz, 2H), 4.24 (t, J = 4.94 Hz, 2H), 3.38-3.00 (m, 2H), 3.00 (q, J = 7.42 Hz, 2H), 2.25 (s, 3H), 1.34 (t, J = 7.42 Hz , 3H).

Example 28

5- [4 - [[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione, sodium salt

<img file="ES2199366T3_D0109.tif" />

To a stirred suspension of 5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione (21, og, 53.2 mmol ) (obtained in example 22) in methanol (200 mL) a solution of sodium methoxide (11.45 g, 212 mmol) in methanol (25 mL) was added dropwise at 30 ° C. During this period the suspension slowly dissolved completely and a white solid precipitated which was stirred for a further 1 h. The solid was filtered and washed with methanol (20 mL) and dried to give the title compound (20.6 g, 93%), mp 235 ° C.

¹H NMR (DMSO-d6): δ 8.16 (d, J = 7.47 Hz, 1H), 7.84 (t, J = 7.47 Hz, 1H), 7.69 (d, J = 7 , 47 Hz, 1H), 7.56 (t, J = 7.47 Hz, 1H), 7.15 (d, J = 8.72 Hz, 2H), 7.00 (d, J = 8.72 Hz, 2H), 5.25 (s, 2H), 4.09 (dd, J = 10.34, 3.36 Hz, 1H), 3.61 (s, 3H), 3.30 (dd, J = 13.82, 3.36 Hz, 1H), 2.62 (dd, J = 13.82, 10.34 Hz, 1H).

Polymorphs

The reactions were carried out in various solvents, using different equivalents of base and different amounts of solvents.

Different polymorphs were observed depending on the conditions used, which are shown in the following table:

<td rowspan="2">M. N °</td><td rowspan="2">Polymorphs</td><td colspan="3">Terms</td><td rowspan="2">endotherm DSC</td>

<td>Free Acid</td><td>Solvent-mL</td><td>eq. by NaOMe</td>

<td> 1.</td><td>Formal</td><td>1 g</td><td>Isopropanol - 10 mL</td><td>1.5 eq</td><td>280 ° C</td>

<td> 2.</td><td>Form II</td><td>1 g</td><td>Methanol - 15 mL</td><td>2.0 eq</td><td>276 ° C</td>

<td> 3.</td><td>Form III</td><td>1 g</td><td>Methanol - 10 mL</td><td>2.0 eq</td><td>272 ° C</td>

<td> 4.</td><td>Form IV</td><td>1 g</td><td>Ether - 5 mL</td><td>1.5 eq</td><td>263 ° C</td>

<td> 5.</td><td>Form V</td><td>1 g</td><td>Ethanol - 10 mL</td><td>1.1 eq</td><td>185 ° C</td>

IS 2 199 366 T3

Example 29

5- [4- [2- [2,5,6-Trimethyl-4-oxo-3,4-dihydro-thieno- [2,3-d] -pyrimidin-3-yl] ethoxy] phenylmethylene] thiazolidin-2 , 4-dione

<img file="ES2199366T3_D0110.tif" />

The title compound (550 mg, 85%) was obtained from 4- [2- [2,5,6-trimethyl-4-oxo-thieno-3-pyrimidinyl] ethoxy] benzaldehyde (500 mg, 1.46 mmol) (obtained in preparation 31) and thiazolidine-2,4-dione (257 mg, 2.2 mmol), by a similar procedure to that described in example 1, mp 280 ° C.

¹H NMR (DMSO-d₆): δ 12.52 (bs, 1H, D₂O interchangeable), 7.71 (s, 1H), 7.52 (d, J = 8.39 Hz, 2H), 7.10 (d, J = 8.39 Hz, 2H), 4.50-4 , 20 (m, 4H), 2.66 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H).

Example 30

5- [4- [2- [2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione, sodium salt

<img file="ES2199366T3_D0111.tif" />

The title compound (385 mg, 90%) was obtained from 5- [4- [2- [2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethylene] thiazolidin-2 , 4-dione (obtained in example 9) (407 mg, 1.0 mmol), by a similar procedure to that described in example 28, mp 280 ° C (decomposes).

¹H NMR (DMSO-d6 + CDCL): δ 8.12 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0Hz, 1H), 7.45 (d, J = 8.7Hz, 2H), 7.25 (s, 1H), 6, 98 (d, J = 8.7Hz, 2H), 4.55-4.40 (m, 2H), 4.40-4.25 (m, 2H), 2.75 (s, 3H).

Example 31

5- [4- [2- [2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione, sodium salt

<img file="ES2199366T3_D0112.tif" />

The title compound (405 mg, 91%) was obtained from 5- [4- [2- [2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethylene] thiazolidin-2 , 4-dione (obtained in example 10) (421 mg, 1.0 mmol), by a similar procedure to that described in example 28, mp 250 ° C (decomposes).

¹H NMR (DMSO-d₆ + CDCl₃): δ 8.15 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.60-7, 45 (m, 4H), 7.10 (d, J = 8.7Hz, 2H), 4.60-4.45 (m, 2H), 4.45-4.32 (m, 2H), 3 , 10 (q, J = 7.5 Hz, 2H), 1.35 (t, J = 7.5 Hz, 3H).

IS 2 199 366 T3

Example 32

5- [4- [2- [4-Methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione, sodium salt

<img file="ES2199366T3_D0113.tif" />

The title compound (460 mg, 88.5%) was obtained from 5- [4- [2- [4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy ] phenylmethyl] thiazolidine-2,4-dione (obtained in example 17) (560 mg, 1.21 mmol), by a similar procedure to that described in example 28, mp 230 ° C.

¹H NMR (DMSO-d6): δ 7.09 (d, J = 8.53 Hz, 2H), 6.78 (d, J = 8.53 Hz, 2H), 6.15 (s, 1H), 4.38-4.25 (m, 2H), 4.254.10 (m, 2H), 4.06 (dd, J = 10.47, 3.42 Hz, 1H), 3.28 (dd, J = 13.69, 10.47 Hz, 1H), 2.85 (t, J = 7.4 Hz, 2H), 2.62 (dd, J = 13.69, 3.42 Hz, 1H), 2, 15 (s, 3H), 1.71 (q, J = 7.47 Hz, 2H), 0.96 (t, J = 7.47 Hz, 3H).

Example 33

5- [4- [2- [2-Ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione, sodium salt

<img file="ES2199366T3_D0114.tif" />

The title compound (0.6 g, 94.6%) was obtained from 5- [4- [2- [2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione (0.6 g, 1.55 mmol) (obtained in example 19), by a similar procedure to that described in example 28, mp 258-260 ° C.

¹H NMR (DMSO-d6): δ 7.10 (d, J = 7.53 Hz, 2H), 6.80 (d, J = 7.53 Hz, 2H), 6.16 (s, 1H), 4.32 (t, J = 5.26 Hz, 2H), 4.16 (t, J = 5.26 Hz, 2H), 4.10 (dd, J = 9.6, 3.4 Hz, 1H ), 3.4-3.25 (dd, J = 13.6, 9.62 Hz, 1H), 2.91 (q, J = 7.3 Hz, 2H), 2.59 (dd, J = 13.6, 3.4 Hz, 1H), 2.66 (s, 3H), 1.25 (t, J = 7.3 Hz, 3H).

Example 34

5- [4- [2- [2-Ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene] thiazolidine-2,4-dione

<img file="ES2199366T3_D0115.tif" />

The title compound (550 mg) was obtained from 4- [2- [2-ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] benzaldehyde (700 mg, 2, 05 mmol) (obtained in preparation 36) and thiazolidine-2,4-dione (240 mg, 2.05 mmol), by a similar procedure to that described in example 1, mp&gt; 250 ° C.

¹H NMR (CDCl3 + DMSO-d6): δ 7.70 (s, 1H), 7.45 (d, J = 8.3 Hz, 2H), 6.95 (d, J = 8.3 Hz, 2H ), 6.69 (s, 1H), 4.50 (t, J = 4.5 Hz, 2H), 4.35 (t, J = 4.5 Hz, 2H), 3.11 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).

IS 2 199 366 T3

Example 35

5- [4- [2- [2-Ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione

<img file="ES2199366T3_D0116.tif" />

The title compound (0.3 g, 66%) was obtained from 5- [4- [2- [2-ethyl-4-trifluoromethyl-6-oxo-1,6-dihydro-1-pyrimidinyl] ethoxy] phenylmethylene ] thiazolidine-2,4-dione (0.45 g, 1.025 mmol) (obtained in example 34), by a procedure similar to that described in example 17, mp 135 ° C.

¹H NMR (DMSO-d₆): δ 7.11 (d, J = 8.53 Hz, 2H), 6.77 (d, J = 8.53 Hz, 2H), 6.70 (s, 1H), 4.52-4, 38 (m, 1H), 4.46 (t, J = 4.68 Hz, 2H), 4.28 (t, J = 4.68 Hz, 2H), 3.4 (dd, J = 14.21 , 3.83 Hz, 1H), 3.20-2.98 (m, 3H), 1.38 (t, J = 7.33 Hz, 3H).

Example 36

5- [4- [2- [2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione

<img file="ES2199366T3_D0117.tif" />

The title compound (1.6 g, 89%) was obtained from 5- [4- [2- [2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] - 2-iminothiazolidin-4-one (1.8 g, 4.4 mmol) (obtained in preparation 35), by a similar procedure to that described in example 19 (Method B), mp 242-244 ° C.

¹H NMR (DMSO-d6): δ11.98 (bs, 1H, D2O exchangeable), 8.11 (d, J = 7.50Hz, 1H), 7.80 (t, J = 7.50Hz, 1H), 7 , 59 (d, J = 7.50Hz, 1H), 7.48 (t, J = 7.50Hz, 1H), 7.14 (d, J = 8.35Hz, 2H), 6.89 (d, J = 8.35Hz, 2H), 4.85 (dd, J = 9.03, 4.20 Hz, 1H), 4.45 (t, J = 5.14Hz, 2H), 4.27 (t, J = 5.14Hz, 2H), 3.28 (dd, J = 14.12.4.20Hz, 1H), 3.04 (dd, J = 14.12.9.03Hz, 1H), 2.71 (s, 3H).

Example 37

5- [4- [2- [2-Methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione, sodium salt

<img file="ES2199366T3_D0118.tif" />

The title compound (348 mg, 81%) was obtained from 5- [4- [2- [2-methyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] thiazolidin-2 , 4-dione (409 mg, 1 mmol) (obtained in example 36), by a similar procedure to that described in example 28, mp 317 ° C.

¹H NMR (DMSO-d6): δ 8.11 (d, J = 7.88 Hz, 1H), 7.79 (t, J = 7.05 Hz, 1H), 7.59 (d, J = 7 , 88Hz, 1H), 7.48 (t, J = 7.05Hz, 1H), 7.08 (d, J = 8.40Hz, 2H), 6.83 (d, J = 8.40Hz, 2H ), 4.44 (t, J = 5.40Hz, 2H), 4.26 (t, J = 5.40Hz, 2H), 4.06 (dd, J = 10.43, 3.42Hz, 1H) , 3.28 (dd, J = 13.8, 3.42Hz, 1H), 2.62 (dd, J = 13.8, 10.43Hz, 1H), 2.71 (s, 3H).

IS 2 199 366 T3

Example 38

5- [4- [2- [2-Ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] thiazolidine-2,4-dione, sodium salt

<img file="ES2199366T3_D0119.tif" />

The title compound (700 mg, 68%) was obtained from 5- [4- [2- [2-ethyl-4-oxo-3,4-dihydro-3-quinazolinyl] ethoxy] phenylmethyl] thiazolidin-2 , 4-dione (978 mg, 2.3 mmol) (obtained in example 24), by a similar procedure to that described in example 28, mp 280 ° C.

¹H NMR (DMSO-d6): δ 8.15 (d, J = 7.89 Hz, 1H), 7.82 (t, J = 7.89 Hz, 1H), 7.65 (d, J = 7 , 89 Hz, 1H), 7.51 (t, J = 7.89 Hz, 1H), 7.11 (d, J = 8.40 Hz, 2H), 6.83 (d, J = 8.40 Hz, 2H), 4.48 (t, J = 5.4 Hz, 2H), 4.27 (t, J = 5.40 Hz, 2H), 4.08 (dd, J = 10.39, 3 , 12 Hz, 1H), 3.25 (dd, J = 10.39, 3.12 Hz, 1H), 3.06 (q, J = 7.15 Hz, 2H), 2.64 (dd, J = 13.82, 10.39 Hz, 1H), 1.34 (t, J = 7.15 Hz, 3H).

Example 39

5- [4 - [[6,7-Dimethoxy-3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione

<img file="ES2199366T3_D0120.tif" />

The title compound (1.0 g, 44%) was obtained from 4 - [[2,4-dioxo-1,3-thiazolidin-5-yl] methyl] phenoxy] acetic acid (1.05 g, 5.0 mmol), 2-amino-N-methylbenzamide (1.5 g, 5.34 mmol), by a procedure similar to that described in Example 22, Method B, mp 252 ° C.

¹H NMR (CDCl3): δ 7.61 (s, 1H), 7.46 (s, 1H), 7.14 (d, J = 8.72 Hz, 2H), 6.98 (d, J = 8 , 72 Hz, 2H), 5.15 (s, 2H), 4.5 (dd, J = 10.20, 3.30 Hz, 1H), 4.0 (s, 6H), 3.74 (s , 3H), 3.45 (dd, J = 14.3, 3.30 Hz, 1H), 3.16 (dd, J = 14.3, 10.20 Hz, 1H).

Example 40

5- [4 - [[6,7-Dimethoxy-3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione, sodium salt

<img file="ES2199366T3_D0121.tif" />

The title compound (140 mg, 64%) was obtained from 5- [4 - [[6,7-dimethoxy-3-methyl-4-oxo-3,4-dihydro-2quinazolinyl] methoxy] phenylmethyl] thiazolidine -2,4-dione (210 mg, 0.46 mmol) (obtained in example 39), by a similar procedure to that described in example 28, mp 275 ° C.

¹H NMR (DMSO-d6): δ 7.46 (s, 1H), 7.16 (s, 1H), 7.14 (d, J = 7.50 Hz, 2H), 6.98 (d, J = 7.50 Hz, 2H), 5.19 (s, 2H), 4.20 (dd, J = 10.50, 3.50 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.60 (s, 3H), 3.32 (dd, J = 13.70 Hz, 3.50 Hz, 1H), 2.67 (dd, J = 13.7, 10, 0 Hz, 1H).

IS 2 199 366 T3

Example 41

5- [4 - [[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione, potassium salt:

<img file="ES2199366T3_D0122.tif" />

To a stirred solution of 5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione (10.0 g, 25.3 mmol) (obtained in example 22) in methanol (100 mL) a solution of tBuOK (3.40 g, 30.3 mmol) in methanol (50 mL) was added dropwise at 30 ° C. During this period the suspension slowly dissolved completely and a white solid precipitated which was stirred for a further 1 h. The solid was filtered and washed with methanol (20 mL) and dried to give the title compound (9.8 g, 90%), mp 302 ° C.

¹H NMR (DMSO-d_g): δ 8.17 (d, J = 7.89 Hz, 1H), 7.85 (t, J = 7.52 Hz, 1H), 7.7 (d, J = 7.89 Hz, 1H) , 7.58 (t, J = 7.52Hz, 1H), 7.16 (d, J = 8.63Hz, 2H), 7.01 (d, J = 8.63Hz, 2H), 5.25 (s, 2H), 4.12 (dd, J = 10.47, 3.56 Hz, 1H), 3.62 (s, 3H), 3.32 (dd, J = 13.70, 3.56 Hz, 1H), 2.65 (dd, J = 13.70, 10.47 Hz, 1H).

Example 42

5- [4 - [[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione, calcium salt

<img file="ES2199366T3_D0123.tif" />

A mixture of 5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione (1.0 g, 2.53 mmol) (obtained in Example 22) and Ca (OH) 2 (94 mg, 1.27 mmol) in methanol (40 mL) was immersed in a preheated 100 ° C oil bath and heated under reflux for 4 h. The reaction mixture was cooled to room temperature and methanol was completely removed under reduced pressure at 40-50 ° C. The resulting foamy solid was triturated with ether. The obtained white crystalline compound was filtered and washed with ether (5-10 mL) and dried to give the title compound (1.025g, 94%), mp 225 ° C.

¹H NMR (DMSO-d_g): δ 8.15 (d, J = 7.89 Hz, 1H), 7.83 (t, J = 7.89 Hz, 1H), 7.68 (d, J = 7.89 Hz, 1H) , 7.56 (t, J = 7.89Hz, 1H), 7.16 (d, J = 8.35Hz, 2H), 7.01 (d, J = 8.35Hz, 2H), 5.24 ( s, 2H), 4.23 (dd, J = 10.38, 3.23 Hz, 1H), 3.61 (s, 3H), 3.33 (dd, J = 13.70, 3.23 Hz , 1H), 2.70 (dd, J = 13.7, 10.38 Hz, 1H).

Example 43

5- [4 - [[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethylene] thiazolidine-2,4-dione, sodium salt

<img file="ES2199366T3_D0124.tif" />

The title compound (1.89 g, 90%) was obtained from 5- [4 - [[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethylene] thiazolidin-2 , 4-dione (2.0 g, 5.09 mmol) (obtained in example 12), by a similar procedure to that described in example 28, mp 299 ° C.

IS 2 199 366 T3 ¹H NMR (DMSO-d6): δ 8.18 (d, J = 7.89 Hz, 1H), 7.86 (t, J = 7.89 Hz, 1H), 7.69 (d, J = 7 , 89 Hz, 1H), 7.59 (t, J = 7.89Hz, 1H), 7.52 (d, J = 8.72Hz, 2H), 7.28 (s, 1H), 7.21 ( d, J = 8.72Hz, 2H), 5.35 (s, 2H), 3.64 (s, 3H).

Mutation in colonies of laboratory animals and different sensitivities to dietary regimens have made possible the development of animal models of non-insulin-dependent diabetes associated with obesity and insulin resistance. Genetic models such as db / db and ob / ob (see Diabetes (1982) 31 (1): 1-6) have been developed in mice and fa / fa and Zucker rats by various laboratories to understand the pathophysiology of the disease. and testing the efficacy of new antidiabetic compounds (Diabetes (1983) 32: 830-838; Annu. Rep. Sankyo Res. Lab. (1994) 46: 1-57). Homozygous animals, C57 BL / KsJ-db / db mice developed by Jackson Laboratory, USA, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest. (1990) 85: 962-967), while heterozygous they are thin and normoglycemic. In the db / db model, the mouse progressively develops insulinopenia with age, a trait commonly seen in late stages of human type II diabetes, when blood sugar levels are not sufficiently controlled. The state of the pancreas and its evolution varies according to the models. Since this model resembles type II diabetes mellitus, the compounds of the present invention were tested for blood sugar and triglyceride lowering activities.

The compounds of the present invention exhibited blood sugar and triglyceride lowering activities through improved insulin resistance. This was demonstrated by the following in vivo experiments.

Male C57BL / KsJ-db / db mice between 8 and 14 weeks old, with body weights in the range of 35 to 60 grams, obtained from Jackson Laboratory, USA, were used in this experiment. A standard diet (National Institute of Nutrition, Hyderabad, India) and acidified water were provided to the mice ad libitum. Animals with more than 300 mg / dl blood sugar were used for the test. The number of animals in each group was 4.

Random blood sugar and triglyceride levels were measured by collecting blood (100 μL) through the orbital sinus, using heparinized capillaries in tubes containing EDTA, which were centrifuged to obtain plasma. Plasma glucose and triglyceride levels were measured spectrophotometrically, using the enzyme glucose oxidase and glycerol-3-PO4 oxidase / peroxidase methods (Dr. Reddy's Lab. Diagnostic Kits Division, Hyderabad, India), respectively. On the sixth day, blood samples were collected one hour after administration of the compounds / vehicles to be tested, to test for biological activity.

The compounds to be tested were resuspended in 0.25% carboxymethylcellulose and administered to the test group in a dose between 10 mg and 100 mg / kg by oral gavage daily for 6 days. The control group received the vehicle (dose 10 mL / kg). Troglitazone (100 mg / kg, daily dose) was used as the standard drug, which showed a 28% reduction in random blood sugar level on the sixth day.

The blood sugar and triglyceride lowering activities of the test compound were calculated according to the formula:

Blood sugar / triglyceride lowering activity (%) = 1 DT / DC

TC / ZC

X 100

ZC = value of the control group on day zero CD = value of the treated group on day zero TC = value of the control group on the day of the trial DT = value of the treated group on the day of the trial

No adverse effects were observed with any of the mentioned compounds of the invention in the above test.

The compounds of the present invention also showed cholesterol lowering activity in the experimental animals used.

<td>Compound</td><td>Dose mg / kg / day</td><td>Days treated</td><td>Maximum reduction in blood glucose level (%)</td><td>Triglyceride reduction (%)</td>

<td>Example 3</td><td> 100</td><td> 6</td><td> 67</td><td> 12</td>

<td>Example 6</td><td> 100</td><td> 6</td><td> 41</td><td> 31</td>

<td>Example 7</td><td> 100</td><td> 6</td><td> 66</td><td> 35</td>

ES 2 199 366 T3 (continued)

<td>Compound</td><td>Dose mg / kg / day</td><td>Days treated</td><td>Maximum reduction in blood glucose level (%)</td><td>Triglyceride reduction (%)</td>

<td>Example 9</td><td> 30</td><td> 6</td><td> 46</td><td> 35</td>

<td>Example 12</td><td> 100</td><td> 6</td><td> 71</td><td> 57</td>

<td>Example 13</td><td> 100</td><td> 6</td><td> 52</td><td> 57</td>

<td>Example 17</td><td> 30</td><td> 6</td><td> 65</td><td> 45</td>

<td>Example 19</td><td> 30</td><td> 6</td><td> 73</td><td> 70</td>

<td>Example 21</td><td> 30</td><td> 6</td><td> 64</td><td> 76</td>

<td>Example 22</td><td> 30</td><td> 6</td><td> 55</td><td> 41</td>

<td>Example 24</td><td> 10</td><td> 6</td><td> 63</td><td> 17</td>

<td>Example 11</td><td> 30</td><td> 6</td><td> 32</td><td> 42</td>

<td>Example 28</td><td> 10</td><td> 6</td><td> 63</td><td> 57</td>

The experimental results of the db / db mice suggest that the novel compounds of the present invention also possess therapeutic utility as prophylactic or regular treatment of obesity, cardiovascular disorders such as hypertension, hyperlipidemia and other diseases, since it is known from the bibliography that such diseases are interrelated with each other.