CS264281B2 - Process for preparing derivatives of purine - Google Patents

Description

The invention relates to a process for the preparation of novel purine derivatives. Also described herein are pharmaceutical compositions comprising the compounds and methods of using the novel purine compounds. Purine derivatives of the invention are useful in the treatment of autoimmune diseases.

8- aminoguanine is a compound known since the turn of the century. R. Parks et al. [Biochem. Pharm., 31 (2), 163 (1982)] found PNP activity (purine nucleoside phosphorylase enzyme assay).

9- (2-furfuryl) guanine is also a known compound described in J. Am. Chem. Soc., 81, 3046 (1959), with no indication of its utility.

The present invention relates to novel purine derivatives which were not apparent to those skilled in the art that, in particular as 9-heteroarylguanines, could have PNP inhibitory activity.

8-Amino-9-benzylguanine was described at the 16th Annual Meeting of Graduate Medical Chemistry Students, University of Michigan, Ann Arbor, Michigan (USA). However, the compounds of the invention cannot, of course, be derived from either the synthesis or the biochemical action of 8-amino-9-benzylguanine.

Regarding various processes for the preparation of the novel compounds of the invention, Ji-Wang Chem et al. published the article "A convenient Synthesis of 2-N-Methoxycarbonylaminooxazolo [5,4-d] pyrimidines" in J. Het. Chem. 21, 1245-6 (1984). A similar synthesis procedure is described by S. Rama et al., In Heterocycles, Vol. 22, 8, 1789-1902 (1984) in "A Synthesis of Carbamic Acid-Fluidazo-Heteroaromatic-Methyl Ester Derivatives Using Methoxycarbonyl Isothiocyanate", wherein said methoxycarbonyl isothiocyanate is used as a one-time ring closure reagent to form the methoximino pyrimidine carbonyl The functional group of these two syntheses is discussed by Ji-Wang Chern et al. in The Novel Ring Opening of an Oazolo [5,4-d] Pyrimidine and Subsequent Rearrangement to Form an Imidazo [4,5-d] Pyrimidine, in Heterocycles, Vol. 22, 11, 2439-2441 (1984).

However, none of these publications contain information about the reaction conditions or the substituent Ar as a heteroaryl substituent or a substituted heteroaryl substituent, which will be defined below for compounds of formula I which are prepared by the method of the invention. In other words, the above-mentioned publications do not list the corresponding Ar substituents which will be listed below for the compound of formula I.

The present invention relates to a process for the preparation of purine derivatives of formula (I)

where

R1 represents a sulfur atom, a hydroxy group or a group of formula SH,

R2 represents a hydrogen atom or a group of the formula NHR in which R represents a hydrogen atom of the formula COR6 in which Re represents a C1-C4 alkyl group, an aryl group selected from unsubstituted phenyl or phenyl substituted by fluorine, chlorine, bromine or iodine or a (C 1 -C 4) alkyl, hydroxy, (C 1 -C 4) alkoxy or trifluoromethyl or erylalkyl group, wherein the aryl group is as defined above, and the alkyl chain contains 1 to 4 'carbon atoms,

R1 represents a hydrogen atom, a hydroxy group, a mercapto group, a bromine atom or a group of the formula NHR in which R represents a hydrogen atom or a group of formula COR6 in which R6 is as defined above, n represents 0- or 1, m represents 0, 1, 2 or 3, with the proviso that m or n is at least 1,

R 1 and R 5 independently represent hydrogen, C 1 -C 4 alkyl, aryl selected from unsubstituted phenyl or phenyl substituted by fluorine, chlorine, bromine or iodine, or C 1 -C 4 alkyl , hydroxy, C1 -C4 alkoxy or trifluoromethyl or erylalkyl, wherein the aryl group is as defined above and the C1 -C4 alkyl chain is present, or C3 -C6 cycloalkyl, hydroxyalkyl. (C 1 -C 4) group; and

Ar is 2- or 3-furanyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl or 2-, 4 or 5-thiazazolyl, which groups are optionally substituted with C1-C4 alkyl , or a pharmaceutically acceptable acid addition salt or base salt thereof, with the exception of compounds wherein R 1 is hydroxy, R 2 is amino, R 3 is hydrogen, n is zero, m is one, and Ar is

2-furanyl.

The process according to the invention consists in the compound of the formula III

where

R 4, R 5, R b, n, m and Ar are as defined above, reacted at room temperature with a base such as potassium carbonate in an alcoholic solvent such as methanol to form a compound of formula I- wherein R 1 is hydroxy and R 3 is NHGORb wherein R 6 is C 1 -C 4 alkyl, aryl as defined above, or arylalkyl skeleton as defined above, optionally then converting a compound of formula I wherein R 1 is hydroxy to a compound wherein R 1 is represents a group of formula S or SH, and the other symbols have the meanings given above, and then, to a pharmaceutically acceptable acid addition salt or a basic salt.

A process for the manufacture of a pharmaceutical composition comprising an effective amount of a compound of formula (I) comprises treating it with a pharmaceutically acceptable carrier. These pharmaceutical compositions are useful in the treatment of autoimmune diseases such as arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, juvenile diabetes, as well as 1. transplantation, viral infections and tumors, wherein the organism suffering from said disease, an effective amount of a compound of formula (I) is administered in unit dosage form. That is, this amount is understood to be an amount effective to cure such autoimmune diseases.

It will be appreciated by those skilled in the art that dosages less than those representing an effective amount in the treatment of disease could be initiated, with the desired effect being achieved by increasing the dose, taking care to provide the organism suffering from the disease with a dose less than amount toxic.

Both the above pharmaceutical composition and the method of treatment preferably use 9- (2-furfuryl) guaine as the active ingredient.

The products obtained by the process of the invention may be isolated by conventional methods such as extraction, distillation, chromatographic separation and the like.

The salts of the compounds of formula I above are prepared by reacting a suitable base with a stoichiometric equivalent amount of an acid of formula I to give a pharmaceutically acceptable salt of the compounds.

The compounds of the present invention may also exist in hydrazated or solvated forms.

The compounds of formula (I) of the invention exist in tautomeric forms such as purines or guanines, as illustrated below. Both forms form part of the invention

Ri h ₂ n

ru.

And r - ^ C

m.

X |

Rif ^R p

Ar - (C tx

O.

Guanin (IJ

The term "C 1 -C 4 alkyl" refers to a straight or branched hydrocarbon chain containing up to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobuityl, secondary butyl or tertiary butyl group. The term "C 1 -C 4 hydroxyalkyl" refers to the same alkyl group as mentioned above with a terminal hydroxy group.

The term "aryl" includes an unsubstituted or substituted aromatic ring, such as a phenyl group or a phenyl group substituted with a halogen atom such as fluorine, chlorine, bromine or iodine, as well as a C 1 -C 4 alkyl group such as a methyl group or ethyl, furthermore hydroxy, C1-C4alkoxy, such as methoxy or ethoxy, or trifluoromethyl.

The term "arylalkyl" refers to an aromatic ring that is attached to an alkyl chain of 1 to 4 carbon atoms, such as an unsubstituted or substituted phenylethyl or benzyl group, wherein the substituents on the aromatic ring may be as described above. above.

The term "heteroaryl group" refers to a 5- or 6-membered aromatic ring containing at least one heteroPurine (IJ atom such as nitrogen, oxygen, sr · ^1. Preferred groups are 2-furanyl or 3-furanyl, thienyl or 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, or 2-thiazolyl, 4-thiazolyl or n-5-thiazolyl.

Pharmaceutically acceptable acid addition salts are addition salts derived from inorganic acids such as hydrochloric acid, sulfuric acid and the like, as well as organic acids such as methanesulfonic acid, toluenesulfonic acid, tartaric acid and the like. These salts can also be prepared by conventional methods known in the art.

Pharmaceutically acceptable salts and bases are those derived from inorganic bases such as sodium hydroxide, potassium hydroxide or ammonium hydroxide, or from organic bases such as arginine, N-methylglucamine, lysine and the like. These salts can also be prepared by standard methods known in the art.

In a preferred embodiment of the invention, the compounds of formula I are those in which:

R1 is OH or SH,

R1 represents a hydrogen atom or an amino group,

R3 represents a hydrogen atom, a hydroxyl group of 264281 pin, a mercapto group, a bromine atom or an amino group, n denotes zero or 1, m denotes zero or 1, wherein n or m must be one,

R4 and Rs each independently represent a hydrogen ^treatment: ku, alkyl having 1 to 4 carbon atoms or hydroxyalkyl having 1 to 4 carbon atoms, and

Ar is 2-furanyl or 3-furanyl, 2-thienyl or n-3-thienyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl, or 2-furanyl or 3-furanyl, 2- thienyl or 3-thienyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl or 2-thiazolyl, 4-thiazolyl or 5-thiazolyl substituted with C 1 -C 4 alkyl, alkoxy C 1 -C 4 carbon atoms, with a bond of "C = C" C = C "[WSd · ''^;>'Attached to adjacent carbon atoms to form benzoskuplny, or halogen, or pharmaceutically acceptable salts -adiční acid or base salts thereof.

According to another preferred embodiment of the present invention, they are compounds of formula I wherein:

R 1 is hydroxy,

R3 is hydrogen, hydroxy, mercapto, bromo or amino, n is 1, m is 1 and

Ar is 2-furanyl or

3-furanyl, 2-thienyl or 3-thienyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl, or furthermore 2-furanyl or 3-furanyl is 2-thienyl or 3-thienyl , 2-pyridinyl, 3-pyridinyl or

A 4-pyridinyl group, a 2-thiazolyl group, a 4-thiazolyl group, or a 5-thiazolyl group, which groups are substituted by a methyl or ethyl group or by a —C = C — C = C “bond attached to adjacent carbon atoms to form or a benzo group, or a pharmaceutically acceptable acid addition salt or a basic salt.

Preferred compounds of the invention are:

9 - [(3-pyridyl) methyl] guanine,

9- (2-thienyl jguanie),

9 - [(2-pyridyl) methyl] guanine,

9 - [(5-ethyl-2-thienyl) methyl] guanine,

8-bromo-9- (2-thienylniethyl) guanine,

8-bromo-9- (5-ethyl-2-thenyl) guanine,

8-thunder-9- (2-furfuryljguanine),

8-bnom-9 - [(3-pyridyl) methyl] guanine,

8-pmino-9- (5-ethyl-2-thenyl) guanine,

8-amino-9- (2-thienylmethyl) guanine a

8-Amino-o- [9- (3-pyridyl) methyl] guanine.

The most preferred compound is 8-α-m-9- (2-thienylmethyl) guanine.

The 8-thunder compounds are useful not only pharmacologically, but can also be used as intermediates for the preparation of other certain compounds of the invention.

The compounds of formula (I) of the present invention can be prepared by the procedure illustrated in the following scheme.

Reaction scheme

'4r

· X 3

Na ₂ S 2

HCOOH

Na <>^s;>%HCOOH; HCONH boiling _from 100-140 ° .For CO Ψ 1 hour "JyNHCO

ΑΛ,

NH

Ar

7CHg>

m.

* 5 tt

aqueous NH ₄ OH aqueous H2NNH2

100% 2 HCI h ₂ n nh

IVb

Ar- ( ^cH 2kr <,

R * * 5 (X

2B4281 (short service life) of DMF • For OOCNCS ₆ (R _ol == CH ₃ or Et).

- p

^ NHC-NHCOQRt

ΗχΝ N

II

Ar—

ÍS

P (not necessary to insulate) ·

DCC

DMF

O — NHCOORé

H _Z N

N '

NH

1U

Ar - (C >

(no need to insulate)

OH / 1H Cl. 18 hours

where

Et means ethyl,

Ac means acetyl,

DCC means N, N‘-dicyclohexylcarbodiimide a

DMF means dimethylformamide; the other substituents are as defined above.

In general, the process of the invention, illustrated by the above scheme, proceeds as follows:

The 2-amino-6-chloro-4-pyrimidinol, which may be in the monohydrate form, is suspended in methoxyethanol in the presence of an excess of an amine or an organic base such as triethylamine. Then, the compound of formula XXX, wherein n, m, R4, R5 and Ar are as defined above, is added to the suspension optionally heated to a temperature at which the suspension is refluxed. Refluxing is continued until the reaction product, i.e. the compound of formula XX, wherein n, m, Ra, Rs and Ar are as defined above, is quantified by thin layer chromatography, e.g. with 20% methanol in methylene chloride. .

The reaction mixture containing the compound of formula (XX) is diluted with water and treated with sodium nitrite in the presence of acetic acid. Treatment with nitrite yields a nitroso compound of formula X wherein n, m, R4, R5 and Ar are evident from the color change of the precipitate. The treatment temperature corresponds to about room temperature.

In a further embodiment, the thus prepared mixture comprising the nitroso compound of formula X is contacted with sodium thionite in a solvent mixture such as formamide and formic acid at a temperature in the range of from 60 to 90 ° C, preferably in the range of from 70 to 80 ° C. The temperature of the reaction mixture is then increased to n and the boiling point of the solvent mixture, about 130 to 140 ° C, and this heating lasts up to about one hour, preferably at least 20 minutes, or until the color of the mixture containing said nitroso compound changes. The product of the above treatment is a compound of formula IV wherein n, m, R 1, R 5 and Ar are as defined above.

In the next step, the compound of formula IV is dried and then suspended in an anhydrous solvent such as methanol, ethanol and the like. The suspension is then treated with an anhydrous acid such as hydrochloric acid to give an acid salt of formula IVa wherein n, s, R4, R5 and Ar are as defined above, or a salt corresponding to the acid used in the treatment is obtained.

The salt of formula IVa is then basified with a concentrated mixture of ammonium hydroxide and 97% hydrazine to give bases of a compound of formula IVb wherein n, m, R4, R5 and Ar are as defined above. This base is unstable, but is dried, for example, in vacuo with phosphorus pentoxide.

The dried free base of formula (IVb) is added to a solution of a compound of formula (R50) OOCNCS, wherein R6 is as defined above. This solution can be prepared by suspending potassium thiocyanate in a solvent such as acetonitrile and treating with a slightly less than equivalent amount of a compound of formula CICOORe wherein R 6 is as defined above at reflux for about one hour, then the mixture is cooled and then stirred to allow all of the alkyl chloroformate to react before the base of formula IVb is added. The reaction of the dry free basic compound of formula IVb with a compound of formula ReOOCNCS, wherein R6 is as defined above, is monitored by thin layer chromatography, using silica in 20% methanol in methylene chloride, as appropriate.

A mixture of a compound of formula II and n, m, R e, R 4, R 5 and Ar have the above formation of a compound of formula d wherein the addition agent such as N, N'-dicyclohexylcarbodiimide in a solvent such as dimethylformamide is stirred approximately at room temperature until the reaction is complete as monitored by thin layer chromatography to give a compound of formula III wherein n, m, R 1, R 1, R 5 and Ar are as defined above.

The reaction mixture containing the compound of formula III and anhydrous potassium carbonate is suspended in a solvent such as anhydrous methanol and then refluxed until it is established by thin layer chromatography that a compound of formula I wherein R 1 is oxygen is formed during the reaction. or hydroxy, R 3 is NHCOOR 6 in which R e is as defined above, an, m, R 4, R 5 and Ar are as defined above.

A compound of formula I wherein R 1 is oxygen or hydroxy and R 3 is NHCOOR 6 wherein R 8 and other symbols are as defined above may optionally be used to prepare a compound of formula I wherein R 8 is NHR wherein R is the above meaning, other than COORs, using conventional methods known in the art.

In a similar manner, a compound of formula I wherein R 1 is S or SH may be prepared using known methods, and a compound of formula I wherein R 1 is oxygen or hydroxy is used as the starting compound and the other symbols are as defined above.

The preparation of compounds of formulas IV, II, III and I can be carried out in a single step. However, it is also possible, if desired, to carry out the separation or the separation of the components. separating and purifying each of the compounds of formula (IV), (II), (III) or (I) according to a conventional method known in the art.

The compounds of the invention exhibit significant enzyme inhibitory activity and cytotoxic activity. Purine nucleoside phosphorylase (PMP-4) enzyme assay provides complete inhibition at a concentration of less than about 300 micromoles of certain compounds of the present invention. This PNP-4 activity was measured by the radiochemical method by detecting the formation of [ ¹⁴ C] hypoxanthine, from [ ¹⁴ C] inosine [see Biomedicine, 33, 39 (1980)] using human erythrocytes as an enzyme source. Using the standard assay (HTBA-1) [Science, 214, 1137, (1981)], the same compounds were found to be selectively cytotoxic to T cells in the presence of 2'-deoxyguanosine in a similar concentration range and nontoxic to B- cells in the presence of the same amount of 2'-deoxyguanosine. Representative examples are given in the following table for potency values.

Example number

TABLE

Efficiency value

Ar ¹ PNP-4

IC50 (μΜ)

HTBA-1 (T-cells + dGuo (10 μΜ) IC50 (^ M)

10 3-Py 21.9 54.1 2 or or 2-Th 0.17 0.83 11 12 2-Th-5-Et 0.93 4.15 2b 2-Fu 0.25 2.57 2 c 3-Th 0,085 0.49 2d 2-Th-3-CH 3 4.05 8.6 9Ad 3-Th-2-CH 3 1.72 18.2 9Ae CH ₂ -2-Th 6.25 17.6 9Ak 3-Th-5-CH 3 0.63 2.8 9Ag 8.45 > 12.5 "> X 2e (ort 140 9Af 2-Py 4.6 lp _y = * pyridine Th = thiophene Fu = furan

Since T cells play a major role in the immune response of a compound of the invention, they can be used for immunoregulation of autoimmune diseases such as rheumatic arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, myastemia, transplantation, juvenile diabetes , tumors and viral diseases. The compounds obtainable according to the invention make it possible to produce compositions comprising a compound of formula I for the treatment of diseases, such as autoimmune diseases, characterized by an abnormal immune response in warm-blooded animals. Therefore, the properties of the compounds of the invention can be utilized when administered to warm-blooded animals in effective doses in the form of pharmaceutical compositions containing the active ingredient in an amount of at least about 0.1% by weight based on the total weight of the composition comprising at least one compound of the invention.

The pharmaceutical compositions may be prepared by any suitable method, preferably with an inert carrier for oral, parenteral, ophthalmic, topical or suppository administration.

For example, the compounds of the invention may be prepared in unit dosage forms, such as tablets or syrups, mixed with an inert pharmaceutical carrier, such as lactose or conventional syrup, using methods known in the art. For injectable dosage forms, the compounds of the invention are mixed with excipients such as water, propylene glycol, peanut oil, sesame oil and the like. In such dosage forms, the active ingredient content is in the range of about 0.05 to 0.5 grams per unit dose.

The invention will be further illustrated by means of examples.

Example 1A

2-Amino-9 - [(2-thienyl) methyl] -6-chloropurine

A mixture of 2-amino-6-chloropurine (Aldrich Chemical Co.) (7.47 g, 0.44 mol), potassium carbonate (6.64 g, 0.048 mol) and 3-thenyl bromide (see US Patent 3,746,724) (7.8 g, 0.044 mol) in dimethylformamide (200 mL) was stirred under nitrogen at room temperature for 48 hours, then the mixture was filtered and the filtrate was evaporated to dryness under vacuum. The resulting precipitate was collected by filtration to give a mixture

7-substituted and 9-substituted chlorpurine. A sample of the pure 9-isomer was prepared by silica gel chromatography using 5% methanol in methylene chloride as eluent. In this way, the 9-isomer was separated from the 7-isomer. A sample of ana284281 lytic quality was obtained by crystallization from a mixture of acetone and methanol. The yield was

2.36 g, softening point 185 ° C (dec.) And then melting at 203-204 ° C (dec.).

Example 1B

The procedure of Example 1A was repeated to prepare these 2-amino-9 - [(heteroaryl) methyl] -6-chloropurines or 2-amino-9 - [(substituted heteroaryl) methyl] -6-chloropurines starting from suitable heteroarylmethyl halides or substituted heteroarylmethyl halides:

2-amino-9 - [(2,5-dimethyl-3-thienyl) methyl] -6-chloropurine, m.p. 190-192 ° C [starting compound, i.e. 2,5-dimethyl-3-thenyl chloride, was Buu-Hoi and Nguyen-Hoan, Rec. Trav. Chim., 68.5 (1949)].

2-Amino-9- (3-furanylmethyl) -6-chloropurine [starting compound, i.e. 3-furyl chloride, was prepared according to literature procedures. Tanis, S. P., Tet. Letts., 23, 3115 (1982)].

Example 1 a d 2

If the above procedure is followed, 8-amino-9 - [(3-pyridyl) methyl] guanine is produced having a melting point greater than 300 ° C.

In addition, the following compounds a) to e) were prepared analogously:

(a) 8-amino-9- (2-thenyl) guanine or 8-amino-9 - [(2-thienyl) methyl] guanine in the form of the hydrochloride salt of 0,5 HzO, m.p. decomposition)

(b) 9-amino-9- (2-furanylmethyl) guanine monohydrochloride monohydrate, m.p. 197-199 ° C (dec.);

(c) 8-amino-9 - [(3-thienyl) methyl] guanine monohydrochloride monohydrate, m.p. 275-278 ° C (dec.);

d) 8-amino-9 - [(3-methyl-2-thienyl) methyl] guanine. 0.25 H2O, mp 290 ° C (dec.),

e) 8-amino-9 - [(benzo [b] thien-3-yl) methyl] guanine. 0.5 H / O, mp &gt; 300 ° C (dec.).

The starting compounds used in these processes are generally commercially available (e.g., Aldrich Chemical Company).

Example 3

Process for the preparation of 2-amino-4 [((2-thienyl) methyl) amino] -5- (formamido) -6-pyrimidinol

2-Amino-6-chloro-4-pyrimidine monohydrate (85%, 100.0 g, 0.5197 mol) was suspended in methoxyethanol (700 mL) and 2-thiophenomethylamine (96 mL) was added. The mixture was heated to reflux for 2 hours, then 73 mL of triethylamine (d = 0.726, 0.52 mol) was added and heating was continued. The reaction was followed by thin layer chromatography using 20% methanol / trichloromethane and the reaction mixture was poured into ice water (1000 mL), diluted with acetic acid ( 400 ml) and then treated with a solution of sodium nitrite (80 g, 1.16 mol) in water (300 ml) and stirred for 4 hours at room temperature to give the resulting red-colored nitroso compound corresponding to Scheme o. The general formula (X) was then separated by filtration and finally washed with water (the reaction was observed by observing a color change during the formation of a precipitate).

The thus obtained crude nitrosopyrimidine of the general formula X, a compound mentioned above in the reaction scheme, wherein n is 1, m is zero, R4 and R5 each represent hydrogen and Ar represents a 2-thienyl group, was then divided into two batches, of these batches were reduced with sodium dithionite (less than 90%, 70 g, 0.36 mol) in formamide (300 mL) and 90% formic acid (300 mL) at 80 ° C, then boiling for 20 min. minutes. At this stage of the treatment, the temperature was about 130-140 ^° C. The reaction was complete when the red color completely disappeared and the inorganic salt precipitated. The reaction mixture was then diluted with water (300 mL) and boiled for an additional 30 minutes, the reaction mixture was filtered while hot and then crystallized in a cooling box. The progress of the reaction was monitored only after completion of thin layer chromatography (silica, 20% methanol in irichloromethane). The crude N-formyl derivative, i.e. 2-amino-4 [((2-thienyl / methyl) amino] -5- (formamido) -6-pyrimidinol (100 g)) was then filtered off, washed water and dried, which compound was used for the next step without further purification.

Example 3 A

The procedure described in Example 3 was repeated to prepare 2-amino - [(3-thienyl) methyl] amino] -5- (formamido) -6-pyrimidinol. Starting from 3-thiophenomethylamine and 2-amino-6-chloro-4-pyrimidinol.

Example 4

Process for the preparation of 2-amino-4 - [([2-furanylmethyl] amino)) - 5- (formamido) -6-pyrimidinol

A mixture of 2-amino-6-chloro-5-nitro-4-pyrimidinol (J. Chem. Soc., 1962, p. 4 186) (31.5 grams, 0.15 mol), methanol (1200 mL) and furfurylamine (29.1 g, 0.3 mol) was stirred and refluxed under nitrogen for 6 hours. The reaction mixture was cooled, filtered, washed with water and air dried to give 34.43 g of a yellow solid, m.p. 286 ^DEG- 289 ^DEG C. (dec.), Which was used for the next reaction. .

Crude nitropyrimidine (33.9 g, 0.135 mole) was suspended in formamide (290 mL) and 88% formic acid (145 mL) and then heated to 80 ° C. To this hot slurry at 80-85 ° C was added sodium dithionite (57 grams, 0.327 mol) slowly over 50 minutes, and then the temperature of the mixture was maintained at about 85 ° C for an additional 30 minutes, further diluted with boiling water. (1200 mL) and was again heated at about 85 ° C for an additional 20 minutes to form red-yellow crystals. The product was filtered, washed with water and dried over phosphorus pentoxide under vacuum overnight. Yield: 23.4 g, m.p. 246 ^DEG- 247 ^DEG C. (dec.). In most cases, these compounds were converted by reaction steps without characterization.

Example 4 A

The procedure of Example 1 was repeated to prepare the following 2-amino-4 - [((heteroaryl) methyl) amino] -5- (formamido) -6-pyrimidinols or 2-amino-4 - [(/ substituted heteroaryl) methyl jamino] -5- (formamido) -6-pyrimidinols (see Table 1), starting from suitable heteroarylmethylamines or substituted heteroarylmethylamines and 2-amino-6-chloro-5-nitro-4-pyridinol.

Ar (name)

Ar (formula)

2-thienyl

3-thienyl

3-furanyl (2-thienyl) methyl

3-methyl-2-thienyl

2-methyl-3-thienyl

‘CHs

5-methyl-2-thienyl

Ar (formula)

Ar (name) or

2-Pyridinyl benzo [b] thien-2-yl

2-thiazolyl

4-thiazolyl (3-thienyl) methyl

5-methyl-3-thienyl

5-methyl-2-furanyl

4-methyl-3-thienyl

4-methyl-2-thienyl

Example 5

A process for the preparation of 2,5-diamino-4 - [(2-thienylmethyl) amino] pyrimidin-6-ol dihydrochloride compound of formula IVa wherein n is 1, m is zero, R 1 and R 5 are hydrogen and Ar is thienyl.

The crude N-formyl derivative prepared according to Example 3 (40 g, 0.1508 mol) was suspended in anhydrous methanol (500 ml) and a gaseous stream of dry hydrogen chloride was passed through the solution while heating to boiling. This reaction was carried out for 2.5 hours to give a clear solution from which a crystalline precipitate crystallized. The mixture was cooled in an ice bath and then filtered to give the desired salt, i.e. 2,5-diamino-4 - [(2-thienylmethyl) amino] pyrimidin-6-ol dihydrochloride (28.6 g). Evaporation of the mother liquor gave an additional amount of this salt (8.65 g). The overall yield was 37.25 g (79%). This material was used without further purification.

Alternatively, the N-formyl derivative was heated to reflux with a 5% methanolic hydrogen chloride solution to give the desired diaminodihydrochloride salt.

Example 5

The procedure of Example 5 was repeated and the following 2,5-diamino- ((heteroaryl or substituted heteroaryl / methyl) amino) pyridine-6-dl-dihydrochlorides were prepared (see Table 2). These procedures were based on the appropriate 2-amino-4 - [([heteroaryl or substituted heteroaryl] methyl) amino] -5- (formamido) -6-pyrimidinols (see Table 1).

AND

TABLE 2

NH, they weren't

HCl

NH

L

Ar

Ar (name)

3-thienyl

2-furanyl

3-furanyl (2-thienyl) methyl

3-Methyl-2-thienyl

2-methyl-3-thienyl

5-methyl-2-thienyl

2-Pyridinyl benzo [b] thien-2-yl

2-thiazolyl

4-thiazolyl (3-thienyl) methyl

5-methyl-3-thienyl

5-methyl-2-furanyl

4-methyl-3-thienyl

4-methyl-2-thienyl

Ar (formula)

Example 6

A process for the preparation of methyl [(2-amino-1,6-dihydro-6-oxo-4- ([2-thienyl] amino) -5-pyrimidinyl) amino] thioxomethylcarhamate (compound of formula II wherein R6 is methyl) a group, n is 1, m is zero, R 4 and R 5 each represent a hydrogen atom and Ar represents a 2-thienyl group).

The crude dihydrochloride salt, prepared as described in Example 5 (37.2 g, 0.12 mol), was suspended in water (300 mL) and then basified with 3: 1 concentrated ammonium hydroxide and 97% hydrazine (in 40 mL). ) to obtain the free base which was dried with phosphorus pentoxide for 20 hours. The yield was 26.1 g (97%) of the base, which is referred to in the above reaction scheme as a compound of formula IVb, wherein n, m, R 5, R 5 and Ar are as defined above. This free base was unstable.

A suspension of potassium thiocyanate (18.1 g, 0.186 mol) in acetonitrile (250 mL) was treated with methylcloroformate (99%), (13.8 mL, 0.177 mol), and the mixture was refluxed for one hour. It was then cooled and filtered to remove inorganic salts. The light yellow filtrate was stirred overnight at room temperature under a nitrogen atmosphere. It should be noted that all methyl chloroformate should be reacted before further processing. To the thus obtained solution of methoxycarbonyl isothiocyanate was added the dried base (26.1 g) while stirring was continued for another 36 hours at room temperature under a nitrogen atmosphere. The progress of this reaction was followed to determine the completion of the reaction by thin layer chromatography (silica, methanol in trichloromethane). The obtained product was filtered and jaromyt with methanol to give the thiourea derivative, i.e. methyl (1- [2-amino-1,6-dihydro-6-oxo-4- ((2-thionylmethyl) aino) -5-pyrimidinyl] aminojthioxomethyl) Yield: 37.4 g (96%), m.p. 225 ^DEG- 226 ^DEG C. (96.6% purity by high pressure liquid chromatography).

Alternatively, the nitropyrimidines or nitrosopyrimidines were catalytically reduced, and then immediately reacted with ethoxycarbonyl isothiocyanate to form the thiourea derivative.

This material was used in the next step without renumbering.

Example 6 A

The procedure as described in Example 6 is repeated to give methyl (or ethyl) - (([2-amino-1,6-dihydro-6-oco-4- ([heteroaryl or substituted heteroaryl / methyl) amino]) -5-pyrimidinylamino) thioxomethyl] carbamates (Table 3), starting from the appropriate 2,5-diamino-4 - {[(heteroaryl) methyl] amino] pyrimidine-6-dichlorides or 2,5-diamino-4 - {[(substituted heteroaryl) methyl] amino [ipyrimidin-6-ol-dihydrochloride (Table 2).

TABLE 3

nh-c-nhcoor ₆ 'NH.

—Ar

Ar (name) or Ar (formula)

Re

2-thienyl -O ethyl 3-thienyl CH3 2-furanyl CH3 3-furanyl 4 CH3 m.p. 246-249 (dec.)

IB 4 28 1

Ar (name) or Ar (formula)

Re (2-thienyl) methyl

2-methyl-3-thienyl

5-methyl-2-thienyl

2-methyl-2-thienyl

2-Pyridinyl benzo [b] thien-2-yl, 2-thiazolyl

4-thiazolyl (3-thienyl) methyl

5-methyl-3-thienyl

5-methyl-2-furanyl

4-methyl-3-thienyl

4-methyl-2-thienyl

CH3 mp 234-239 ° C (dec.)

CH3 mp 235 to 237 ^Q C (decomposition)

CH 3 melting point 227-230 ° C (dec.) Ethyl

CH3

CH3

Mp 214-215 ^° C

CH 3 melting point 217-218 ° C

CHs

CHs

CHs mp 228-229 ° C (dec.)

CH 3, ethyl

CH 3, ethyl

Example 7

A process for the preparation of methyl 5-amino-7 - [(2-thlenylmethyl) amino] oxazolo (5,4-d) pyrimidin-2-yl [carbamate (compound of formula III wherein R 6 is methyl, n is 1, m is zero, Rd and R5 are each hydrogen and Ar is 2-thienyl).

A mixture of the thiourea derivative prepared according to Example 6 (35 g, 0.096 mol) and N, N'-dicyclohexylcarbodiimide (59.4 g, 0.288 mol) was suspended in anhydrous dimethylformamide (1800 ml) and stirred at room temperature for 24 hours . Progress of the reaction was monitored by thin layer chromatography (silica, 20% methanol in trichloromethane). The dimethylformamide used was completely evacuated under vacuum, the residue was then triturated twice with methylene chloride. The desired kanbamate, i.e. methyl {5-amino-7 - [(2-thienylmethyl) amino] oxazolo (5,4-d) 264281 pyrimidin-2-ylcarbamate, was obtained in a yield of 27.8 g (90%), temperature mp 300 ° C. The purity of the product by high pressure liquid chromatography was 97.6%.

This material was used in the next step without further purification.

Example 7 A

The procedure of Example 14 was repeated to prepare methyl) - or (ethyl) - (5-amino-7 - {[(heteroaryl or substituted heteroaryl) methyl amino] oxazolo (5,4-d] pyrimidin-2-yl) carbamates (Table 4) using appropriate starting methyl- (or ethyl) - [({2-amino-1,6-dihydro-6-oxo-4 - [([heteroaryl or substituted heteroaryl] methyl] amino] -5-pyrimidinyl} amino) thioxomethyl] carbamates (Table 3).

Ar (name)

2-thienyl

3-thienyl

2-furanyl

3-furanyl (2-thienyl) methyl

2-methyl-3-thienyl

5-methyl-2-thienyl

2-Pyridinyl benzo [b] thien-2-yl

2-thiazolyl

4-thiazolyl

TABLE 4 was not

í: <

WITH.-

Re ethyl

CHe

CH3

CH3 mp 288-291 ° C (dec.)

CH3 melting point> 270 ° C (dec.)

CH3 melting point> 270 ° C (dec.)

CH 2, ethyl melting point> 250 ^c C (dec.)

CH3

CH3

CHs

CH3

Ar (name) or Ar (formula)

R 6 (3-thienyl) methyl

5-methyl-3-thienyl

CH3

CH3

5-methyl-2-furanyl

CH3

5-methyl-2-thienyl

5-methyl-3-thienyl

4-methyl-2-thienyl

CH 3, ethyl

CH3 ethyl melting point> 260 ° C (dec.)

Example 8

A process for the preparation of methyl [2-amino-6,9-dihydro-6-oxo-9- (2-thienylmethyl-1H-purin-8-yl) carbamate (a compound of formula I wherein R 3 is NHCOOR 6, where R 6 denotes a methyl group, n is zero, m is zero, R 1 and R 5 each represent a hydrogen atom and Ar represents a 2-thienyl group).

A mixture of oxazolocarbamate, prepared as described in Example 7 (25 g, 0.078 mol) and anhydrous potassium carbonate, was suspended in anhydrous methanol, and the mixture was heated to reflux for 8 hours. The progress of the reaction was followed by thin layer chromatography analogous to that used in the previous example. The reaction mixture was then evaporated to dryness under reduced pressure and the residue was dissolved in a solution of ammonium chloride (16.8 g, 0.312 mol) in water (200 mL). The resulting precipitate was collected and dried to give 24.39 g of methyl [2-amino-6,9-dihydro-6-oxo-9- (2-thienylmethyl) -1H-pyrid-8-yl] carbamate, which was was partially contaminated with the 8-amino compound. In this example, 89.58% of the carbamate and 9.54% of the 8-amino compound, i.e. 8-amino-9 - [(2-thienyl) methyl] guanine of formula I, wherein R 3 is amino and the other substituents above, were obtained this meaning.

This material was used in the next step without further purification.

Example 8 A

The procedure of Example 8 was repeated to prepare the following methyl (or ethyl) - (2-amino-6,9-dihydro-6-oxo-9 - [(heteroaryl or substituted heteroaryl) methyl-1H-purine-8- yl]} carbamates (Table 5), starting from the appropriate methyl (or ethyl) - (5-amino-7 - {((heteroaryl or substituted heteroaryl) methyl] amino) oxazolo (5,4-d) pyrimidin-2-yl ) carbamates (Table 4).

Ar (name)

TABLE 5

O

V ” ^{NH C00Re} h ₂ ^nW

L.Ar or Ar (formula)

R &

2-thienyl

3-thienyl

2-furanyl

3-furanyl (2-thienyl) methyl

2-methyl-3-thienyl

5-methyl-2-thienyl

2-pyridinyl

benzo [b] thien-2-yl

2-thlazolyl

4-thiazolyl (3-thienyl) methyl

5-methyl-3-thienyl

5-methyl-2-furanyl

JÍA

n.

CH,

ethyl melting point 250 ° C (dec.)

CHs

CH3 melting point> 300 ° C (dec.)

CH3 melting point> 270 ° C (dec.)

CHs

CH3

CH3, ethyl melting point> 250 ° C (dec.)

CH3

CHs

CH3

CH3

CH3

CH3

CHs mp 250 ° C (dec.)

Example 9

A process for preparing 8-amino-9 - [(2-thienyl) methyl] guanine (a compound of formula I wherein R 3 is amino, n is 1, m is zero, each of R 4 and R 5 is hydrogen and Ar is thienyl] .

The crude carbamate prepared in Example 8 (89.5% carbamate and 9.5% 8-amino compound, 20.39 g, 0.064 mol) was suspended in isopropanol (125 mL) and 1N hydrochloric acid (125 mL, 0.125 mol). wherein the mixture was heated to reflux for about 20 hours. The progress of this reaction was followed by thin layer chromatography (silica, 20% methanol in trichloromethane, CH 3 CN: acetic acid: water 8: 1: 1) until a clear solution was formed. After cooling, the product crystallized from this solution. The yield was 15.1 g (76%). The purity of the product, determined by high pressure liquid chromatography, was 98%, mp 219-222 ° C (dec.).

Hydrolysis was also carried out in a 10% methanolic sodium hydroxide solution at reflux, followed by neutralization and recrystallization from a suitable solvent.

Example 9 A

The procedure of Example 9 was repeated to prepare the following 8-amino-9 - [(heteroaryl) methylguanines or 8-amino-9 - [(substituted heteroaryl) methylguanines (Table 6). The preparation was based on suitable methyl (or ethyl) -12-amino-6,9-dlhydro-6-oxo-9 - [(heteroaryl) methyl-1H-purin-8-yl] carbamates or methyl (or ethyl) 1- {2-amino-6,9-dihydro-6-oxo-9 - [(substituted heteroaryl) methyl] -1H-purin-8-yl] carbamates (Table 5).

TABLE 6

Compound

Ar (name) or

X

Melting point (° C)

2-furanyl HCl 253—257 and 3-thienyl HCl. H2O 275—278 (with decomposition)

b 3-furanyl 0 HCl 293—294 (with decomposition) C (2-thienyl) methyl HCl. H2O 153—155 (with decomposition) d 2-Methyl-3- -thienyl Hey HCl 266—268 (with decomposition)

4 2 Β 1

Compound

Ar [name] or

Ar (formula)

Melting point (° C) of 5-methyl-2-thienyl

_CH,

HCl. 0.25 HzO

260 f of 2-pyridinyl

1.5 HCl. 0.25-270-272 (dec.) G benzo (b) thien-2-yl

0.25 HzO> 300 (dec.) H 2-thiazolyl-4-thiazolyl (3-thienyl) methyl to 5-methyl-3-thienyl

1.2 HCl. 1.2 HzO > 250 1.1 HCl. 0.3 H2O > 250 0.9 HCl. HzO 177-183 (with decomposition) HCl. 0.5 H2O 212—215 (with decomposition)

5-methyl-2-furanyl

HCl. 1.15 HzO ch ₃

212-214 (dec.) M 4-Methyl-3-thienyl

CH,

0.9 HCl. 1.25 H2O

240 (dec.) N 4-methyl-2-thienyl

Example 10

Process for preparing 9 - [(3-pyridinyl) methyl] guanine

Pyridylmethylamine (15.8 mL, 0.1517 mol) was added to a suspension of 2-amino-6-chloro-4-hydroxy-5-nitropyrimidine (14.45 g, 0.0758 mol) in isopropanol (600 mL) . The mixture was heated to reflux for 2 hours and then stirred overnight at room temperature. Thereby, the product crystallized, i.e. 2-amino-4-hydroxy-6 - [(3-pyridyl) methylamino] -5-nitropyrimidine. The product was then filtered, washed with water and air dried.

Crude nitropyrimidine (25.32 g) in the above step was suspended in formamide (150 mL) and 90% formic acid (50 mL) and the suspension was heated to 70 ° C in a water bath. The reaction mixture was then diluted with hot water (300 mL), treated with charcoal and then heated to boiling for 20-25 minutes, filtered (celite). ), cooled and finally evaporated under reduced pressure to give formamide-pyridine which was collected by filtration, washed with acetone and dried under vacuum at 56 ° C.

The above product was then resuspended in formamide (100 mL) and formic acid (8 mL) and then heated to reflux for 3.5 hours. The mixture was then poured into 400 ml of water and ice and finally filtered. After two crystallizations from boiling water, an analytical sample of the desired product (4.5 g) with a melting point of more than 300 ° C was collected.

Example 11

The procedure described in Example 1 was repeated to obtain the following 9- (heteroaryl) methylguanines or 9- (substituted heteroaryl) methylguanines, starting from suitable hetenoarylmethylamines or substituted heteroarylmethylamines:

9- (2-thienylmethyljguanin melting point higher than 300 ^C,

9 - [(2-pyridinyl) methyl] guanine, melting point above 300 ° C,

9- (2-furanylmethyl) guanine, m.p. 296-299 ° C (dec.), [Known compound, see J. Am. Chem. Soc., 81, 3046 (1959)],

9 - [(3-temperature-2-thienyl) methyl] guanine, m.p. &gt; 250 ° C (dec.),

9 - [(2-methyl-3-thienyl) methyl] guanine, m.p.> 270 ° C (dec.),

9 - [(benzo [b] thienyl-3-yl) methyl] guanine, m.p. &gt; 300 DEG C. (dec.),

9- (3-thienylmethyl) guanine, m.p. 320 ^DEG- 322 ^DEG C. (dec.).

Example 1 a d 12

A method for preparing 9 - [(5-ethyl-2-thienyl) methyl] guanine

2-Amino-6-chloro-4-primidinol monohydrate (22.96 g, 0.1193 mol) was suspended in methoxyethanol (300 mL) and 5-ethyl-2-thienylamine (16.58 g) was added to the suspension. g, 0.1193 mol), which was prepared from 2-ethylthiophene according to the literature procedure [J. Am, Chem. Soc., 70, 4,018 (1948)]. The resulting solution was heated at reflux for one hour, then added

16.8 ml of triethylamine and refluxed for an additional 18 hours. The reaction mixture was poured into ice-water (600 mL), diluted with acetic acid (100 mL) and then treated with a solution of sodium nitrite (16 grams) in water (100 mL), then stirred at room temperature for 1 h. The resulting salmon-colored nitroso compound was then collected by filtration and washed with water.

The crude nitrosopyrimidine was then reduced with sodium dithionite ive formamide (200 mL) and 90% formic acid (100 mL) at 70 ° C and then boiled for 20 minutes, and the reaction mixture was diluted with water (300 mL). The crude N-formyl derivative (28 g), which was collected by filtration, washed with water and air-dried, was finally subjected to filtration. cyclization reaction with formic acid (10 mL) and formamide (100 mL at reflux for 4 hours. The hot reaction mixture was poured into 500 mL of ice water to give crude guanine, which was then purified by dissolving in boiling 1.5N. chlorovoďkové acid, then treatment was performed with ¹ clktivním charcoal and finally precipitating with ammonium hydroxide. the crude guanine was then redissolved in hot iN R The reaction mixture was treated with charcoal, filtered, and the filtrate acidified with acetic acid to give the desired product.

Claims (7)

A process for the preparation of purine derivatives of the general formula I wherein R 1 represents a sulfur atom, a hydroxy group or a group of the formula SH, y n A 1 e u R @ 2 represents a hydrogen atom or a group of the formula NHR in which R represents a hydrogen atom or a group of the formula COR5 in which Rg represents a C1 -C4 alkyl group, an aryl group selected from unsubstituted phenyl or phenyl substituted by fluorine, chlorine , bromine or iodine or a (C1-C4) alkyl, hydroxy, (C1-C4) alkoxy or trifluoromethyl or arylalkyl group, wherein the aryl group is as defined above and the alkyl chain contains 1 to 4 carbon atoms, R 8 represents a hydrogen atom, a hydroxy group 264281 nu, a mercapto group, a bromine atom or a group of the formula NHR in which R represents a hydrogen atom or a group of the formula COR 5 in which R 5 is as defined above; 3, with the proviso that m or n is at least 1, R 4 and R 5 are each independently hydrogen, C 1 -C 4 alkyl, aryl selected from unsubstituted phenyl or phenyl substituted by fluorine, chlorine, bromine or iodine or C 1 -C 4 alkyl, hydroxy, alkoxy C 1 -C 4 or trifluoromethyl or arylalkyl, wherein the aryl group is as defined above and the alkyl chain contains 1 to 4 carbon atoms, or the C 3 -C 6 cycloalkyl, the C 1 -C 4 hydroxyalkyl, and Ar represents 2- or 3-furanyl, 2- or 3-thienyl, 2-, 3- or 4-pyrldyl or 2-, 4 or 5-thiazolyl, which groups are optionally substituted by C1-C4 alkyl, or their pharmaceutically acceptable acid addition salts or basic salts with the exception of compounds wherein R 1 is hydroxy, R 1 is amino, R 3 is hydrogen, n is zero, m is one, and Ar is 2-furanyl, wherein the compound of formula (III) (III) wherein: R 1, R 5, R e, n, m and Ar are as defined above, reacted at room temperature with a base such as potassium carbonate in an alcoholic solvent such as methanol to form a compound of formula I wherein: R 1 is hydroxy and R 3 represents a group of the formula NHCOR 5 wherein R e is a C 1 -C 4 alkyl, aryl group as defined above or arylalkyl group as defined above, whereupon optionally converting the compound of formula I, wherein R 1 is hydroxy and the other symbols as defined above, to a compound of formula I, wherein R 1 is a group of formula S or SH and the other symbols are as defined above, or optionally to a pharmaceutically acceptable acid addition salt or base salt. 2. A process according to claim 1, wherein the compound of formula III is reacted with a base at room temperature to form a derivative of formula I wherein: R1 is OH or SH, R2 represents a hydrogen atom or an amino group, R3 is hydrogen, hydroxy, mercapto, bromo or amino, n is zero or 1, m is zero or 1, wherein n or m must be one, R 4 and R 5 independently of one another represent a hydrogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 hydroxyalkyl group, and Ar is 2-furanyl or 3-furanyl, 2-thienyl or 3-thienyl, or 2-pyridyl, 3-pyridyl or 4-pyridyl or also 2-furanyl or 3-furanyl, 2 -thienyl or 3-furanyl, 2-thienyl or 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl or 2-thiazolyl, 4-thiazolyl or 5-thiazolyl substituted with alkyl C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy, -C = C-C = C-bond attached to adjacent carbon atoms to form a benzo group, or halogen, whereupon the compound is optionally converted to its pharmaceutically acceptable addition an acid salt or a basic salt. 3. A process according to claim 2, wherein the compound of formula III is reacted with a base at room temperature to form a derivative of formula I, wherein: R 1 is hydroxy, R3 is hydrogen, hydroxy, mercapto, bromo or amino, n is 1, m is 1 and Ar is 2-furanyl or 3-furanyl, 2-thienyl or 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, or furthermore represents 2-furanyl or 3-furanyl, 2-thienyl or 3-thienyl, 2-pyridyl 264281, 3-pyridyl or 4-pyridyl, 2-thiazolyl, 4 a thiazolyl group or a 5-thiazolyl group, these groups being substituted by a methyl group or an ethyl group or by a bond of --C = C - C = C - attached to adjacent carbon atoms to form a benzo group. 4. The process of claim 3 wherein the corresponding compound of formula III is reacted at room temperature with a base to form a derivative of formula I wherein Ar is 2-furanyl or methyl-substituted 3-furanyl; or ethyl and other substituents have the meaning given in point 3. 5. The process of claim 3, wherein the compound of formula III is reacted with a base at room temperature to form a derivative of formula I wherein Ar is 2-thienyl or 3-thienyl substituted with me38 thyl. or ethyl, and the other substituents have the meaning given in point 3. 6. The process of claim 3 wherein the corresponding compound of formula III is reacted at room temperature with a base to form a derivative of formula I wherein Ar is 2-pyridyl, 3-pyridyl or 4-pyridyl. a methyl or ethyl substituted group; and the other substituents are as defined in point 3. 7. The process of claim 3 wherein the compound of formula III is reacted at matt temperature with a base to form a derivative of formula I wherein Ar is 2-thiazolyl, 4-thiazolyl or 5-thiazolyl. a methyl or ethyl substituted group; and the other substituents are as defined in point 3.