HU209839B

HU209839B - Process for producing ureido-thiazol derivatives and pharmaceutical compositions containing them

Info

Publication number: HU209839B
Application number: HU178689A
Authority: HU
Inventors: Donka Minkova Mondeshka; Tashka Koleva Atanassova; Ljudmila Vutova Petkova; Anton Ivanov Nakov; Zoja Tancheva Ivanova
Original assignee: T Kom Za Promishlena Mikrobiol
Priority date: 1989-04-13
Filing date: 1989-04-13
Publication date: 1994-11-28

Abstract

A találmány tárgya eljárás az (I) általános képletű, új ureido-tiazol-származékok és e vegyületeket tartalmazó gyógyászati készítmények előállítására. Az (I) általános képletben R jelentése (a) vagy (b) képletű csoport, R2 jelentése hidrogénatom vagy rövid szénláncú alkil- csoport; és X jelentése íz/n-(metoxi-imino)-csoport, >C=O vagy -CH2-csoport. Az (I) általános képletű vegyületek gyulladáscsökkentő hatást mutatnak. R-CONK Λ X—COOR 2 CO ο P (o HU 209 839 B A leírás terjedelme: 8 oldal (ezen belül 1 lap ábra)The present invention relates to a process for the preparation of novel ureido-thiazole derivatives of the formula I and pharmaceutical compositions containing these compounds. In formula (I), R is a group of formula (a) or (b), R2 is hydrogen or lower alkyl; and X is a flavor / n- (methoxyimino) group,> C = O or -CH 2. The compounds of formula (I) exhibit anti-inflammatory activity. R-CONK Λ X — COOR 2 CO ο P (o HU 209 839 B Scope of description: 8 pages (including 1 sheet))

Description

Scope of the description: 8 pages (including 1 page figure)

HU 209 839 Β

The present invention relates to novel ureidothiazole derivatives having anti-inflammatory activity and to pharmaceutical compositions containing them.

2-Aminothiazole derivatives having a C 1 -C 4 alkyl group and having an immunomodulatory effect are known in the art; therefore, they can be used in immunodeficient diseases.

More particularly, the present invention relates to a process for the preparation of novel ureido-thiazole derivatives of formula (I).

In formula (I), R is a group of formula (a) or (b),

R ₂ is hydrogen or lower alkyl; and

X is a methoxyimino group> C = O or a -CH ₂ - group.

According to the present invention, compounds of formula I are prepared by reacting a compound of formula I wherein X is as defined above, Z is hydrogen, lower alkyl or -Si (CH ₃ ) ₃ , and Y is hydrogen. or -Si (CH ₃ ) ₃ - with a carbamoyl chloride R-COCl (Π) where R is as defined above in anhydrous medium, a hydrogen chloride-binding agent, 0 ° C and the solvent used for the acylation reaction reaction temperature and optionally deprotecting.

Suitable solvents for the acylation reaction include: halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; esters of lower fatty acids such as ethyl acetate or butyl acetate; lower dialkyl ketones such as acetone and methyl ethyl ketone; cyclic ethers such as tetrahydrofuran; and hydrocarbons such as benzene and toluene.

Compounds of formula (Π) in which Y and Z are both -Si (CH ₃ ) ₃ or Y is hydrogen and Z is -Si (CH ₃ ) ₃ are known by the known silylation techniques well known in the art. silylating agents.

Suitable compounds for the capture of the hydrochloride formed in the acylation reaction (hydrogen chloride acceptor) are, for example, triethylamine, dimethylaniline, pyridine; however, a mixture of N-silyl derivatives of the corresponding amides or ureas and triethylammonium chloride may also be used.

The components of the acylation reaction may be used in equimolar amounts, or, in order to increase the yield of the final product and more economically utilize the compounds of formula (II), the carbamoyl chlorides of formula (ΙΠ) may be used in a 0.1-0.3 molar excess. depending on the reaction conditions. After the reaction, the unreacted carbamoyl chloride is converted into readily water-soluble neutral products by isolation of the corresponding ureido-thiazole derivative, which simplifies the isolation and purification of the final product.

The acylation of the compounds of formula (II) with the carbamoyl chlorides of formula (III) can be carried out over a wide range of temperatures, from 0 ° C to the boiling point of the solvent of choice, for a period of from 2 to 28 hours. Low temperatures reduce the yield of the acylation reaction.

By controlling the conditions for the acylation reaction and isolating the resulting ureido-thiazole derivative, it is possible to obtain the color configurations of the compounds of the present invention which are prepared using compounds of formula II wherein X is a methoxyimino group.

The novel ureido-thiazole derivatives of the present invention have anti-inflammatory activity.

The following non-limiting embodiments of the present invention are described in more detail below.

Example 1

Preparation of 2- [2- (2-Oxo-imidazolidine-1-carboxamido) -4-thiazolyl] -2-syn (methoxyimino) -acetic acid methyl ester

A mixture of 4- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid methyl ester (4.3 g, 20 mmol) in dichloromethane (60 mL) was cooled to 0-5 ° C and A mixture of 5 g (24 mmol) of 1- (chlorocarbonyl) -2-imidazolidinone and 3.3 ml of triethylamine was added, then refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was washed with dilute hydrochloric acid solution, then with aqueous sodium bicarbonate solution, and finally with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Addition of diisopropyl ether to the residue afforded 5.7 g of the title compound as a precipitate.

Analysis for C ₁₁ H ₁₂ N ₅ O ₅ (MW 327.31): Calculated: C 40.36%, H 4.00%, N 21.40%;

Found: C, 40.38%, H4, II%, N, 21.44%.

1 H NMR (CDCl ₃ , δ ppm):

3.18, 3.60 (4H, m), _4-CH2 and _5-CH2;

3.65 (3H, s) and 3.85 (3H, s), -CO ₂ CH ₃ and -NOCH ₃ ;

7.04 (1H, s), 5-H;

7.70 (1H, s, broad), 2-CONH;

11.10 (1H, s, broad), 2-CONH.

IR (KBr): 3300, 3180, 1720, 1690, 1525, 1260 and 1020 cm ^-1 .

Example 2

Preparation of 2- [2- (2,3-Dioxo-4-ethylpiperazine-1-carboxamido) 4-thiazolyl] -2-syn (methoxyimino) acetic acid methyl ester

The title compound was prepared according to the procedure of Example 1, using 4.3 g (20 mmol) of methyl 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid, m.p.

Triethylamine (3.6 mL, 26 mmol) and 2,3-dioxo-4-ethylpiperazine-1-carbonyl chloride (5.3 g, 26 mmol) were reacted. After concentration in vacuo, the residue is chromatographed on a silica gel column using ethyl acetate / tetrahydrofuran as eluent. The eluate was concentrated in vacuo

5.8 g of the expected product are obtained.

Analysis based on C ₁₄ Hi ₇ N ₅ O ₆ S (relative molecular weight 383.38):

H, 208.839; calculated: C, 43.86; H, 4.47; N, 18.27;

Found: C 43.77%, H4.39%, N 18.31%.

1 H-NMR (CDCl ₃ , δ ppm):

I, 14 (3H, t) and 3.36 (2H, q), -NC ₂ H ₅ ;

3.45 (2H, m) and 4.00 (2H, m), 5-and 6-CH ₂ CH _2;

3.73 (3H, s) and 3.85 (3H, s), -N-OCH ₃ and -COOCH ₃ ;

6.94 (1H, s), 5'-H;

II, 82 (1H, broad exchangeable, D ₂ O), CONH 2;

IR (KBr): 3400, 3180, 1730, 1690, 1438,

1525.1720, 1280, 1038 cm ^-1 .

Example 3

Preparation of 2- [2- (2-Oxo-imidazolidine-1-carboxamido) -4-thiazolyl] -2-syn (methoxyimino) -acetic acid 4.0 g (20 mmol) of 2- (2-amino-4 -thiazolyl) -2- (methoxyimino) acetic acid and 30 ml of chloroform

Triethylamine (6.7 mL, 44 mol) and trimethylchlorosilane (5.6 mL, 44 mmol) were added. The reaction mixture was refluxed for 3 hours, filtered, and the filtrate was cooled to -5 ° C, triethylamine (2.9 mL, 21 mmol) and l-chloro-carbonyl (3.1 g, 21 mmol). 2-Imidazolidinone is added and the mixture is stirred at room temperature for 8 hours and then given birth. Water (30 mL) was added to the filtrate and stirring was continued for an additional 20 minutes. At this time, the pH of the reaction mixture was adjusted to 1.5 and the phases were separated. The chloroform layer was washed with dilute hydrochloric acid solution, then with water, dried over anhydrous sodium sulfate and concentrated in vacuo. 5 g of the title compound are obtained.

Analysis for C ₁₀ H _N N ₅ O ₅ Calc'd (molecular weight 313.29): calculated: C 38.34%, H3,54% N, 22.36%;

Found: C, 38.39; H, 3.61; N, 22.41.

1 H-NMR Spectrum (DMSO-d ₆ , δ ppm):

3.26 and 3.72 (4H, m), 4'- and 5'-CH ₂ CH _2;

3.72 (3H, s), -N-OCH ₃ ;

7.16 (1H, s), 5-H;

7.82 (1H, s, replaceable by _D2 O), 2'-CONH;

11.24 (1H, s, broad, interchangeable with D ₂ O), 2CONH.

Example 4

Preparation of 2- [2- (2,3-Dioxo-4-ethylpiperazine-1-carboxamido) 4-thiazolyl] -2-syn (methoxyimino) acetic acid

Hexamethyldisilazane (4.6 mL, 22 mmol) was added to a suspension of 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid (4.0 g, 20 mmol) in dichloromethane (15 mL) and the reaction mixture was refluxed for 4 hours with stirring and then cooled to -5 ° C. Triethylamine (3.0 mL, 22 mmol) and 2,3-dioxo-4-ethylpiperazine-carbonyl chloride (4.5 g, 22 mmol) were added with cooling, and the reaction mixture was stirred at room temperature for 6 hours and then filtered. Water (30 ml) was added to the filtrate, hydrolysed for 20 minutes, then the pH was adjusted to 1.5 and the phases were separated. The organic phase is concentrated in vacuo and the crude product is chromatographed on a silica gel column. Elution was carried out with an 18: 2 mixture of chloroform and tetrahydrofuran. Concentration of the eluate gave 5.6 g of the title compound.

Analysis calculated for C ₁₃ H ₁₅ N ₅ O ₆ S (MW 369.38): Calculated: C 42.28%, H4.09%, N 18.96%;

Found: C, 42.25; H, 4.12; N, 18.77.

1 H-NMR Spectrum (DMSO-d ₆ , δ ppm):

1. 17 (3H, t) and 3.40 (2H, q), -N ~ C ₂ H ₅ ;

3.50 (2H, m) and 4.08 (2H, m), 5-CH ₂ and 6-CH ₂ ;

3.72 (3H, s), - N-OCH ₃ ;

7.02 (1H, s), 5-H;

II, 6 (1H, s broad, interchangeable with D ₂ O), 2-CONH.

Example 5

Preparation of 2- [2- (2-Oxo-imidazoline-1-carboxamido) -4-thiazolyl] -acetic acid ethyl ester This compound was prepared according to the procedure described in Example 1, 1.9 g (10 mmol). - (2-amino-4-thiazolyl) -acetic acid ethyl ester and 1.6 g (11 mmol) of 1- (chlorocarbonyl) -2-imidazolidinone in 1.5 ml (11 mmol) of triethylamine as hydrogen, in the presence of chloride-binding agent. 2.2 g of the expected product are obtained.

Analysis for C] jH ₁₄ N ₄ O _O4 (molecular weight 298.31): calculated: C 44.29%, H4,73%, N 18.78%;

Found: C, 44.32; H, 4.80; N, 18.82.

1 H-NMR Spectrum (DMSO-d ₆ , δ ppm):

I, 10 (3H, t), 3.9 (2H, q) -OC ₂ H _5;

3.47 (2H, s), _4-CH2;

3.24 and 3.69 (4H, m), 4'-CH ₂ and 5'-CH ₂ ;

6.67 (1H, s), 5-H;

7.75 (1H, s, broad), 2'-CONH;

II, 13 (1H, s, br, exchangeable with D ₂ O) 2CONH;

IR (KBr) 3295, 3175, 1735, 1720, 1680, 1410, 1425, 1435, 1350, 1250, 1020 cm @ ^-1 .

Example 6

Preparation of 2- [2- (2,3-Dioxo-4-ethylpiperazine-1-carboxamido) 4-thiazolyl] -acetic acid ethyl ester

This compound was prepared according to the procedure of Example 2 by adding 1.9 g (10 mmol) of ethyl 2- (2-amino-4-thiazolyl) acetic acid in 2.7 g (13 mmol) of 2,3-dioxo. 4-ethylpiperazine-1-carbonyl chloride was reacted in the presence of triethylamine (1.8 mL, 13 mmol) as the hydrochloride acceptor. Yield: 2.9 g.

Analysis (relative molecular mass 354.34) calculated for C ₁₄ H _g N ₄ O ₅ S _Calc'd: C, 47.45% H5,12%, N 14.81%;

Found: C, 47.48; H, 5.11; N, 15.79.

1 H-NMR Spectrum (DMSO-d ₆ , δ ppm):

1.03 (3H, t) and 3.27 (2H, q), -NC ₂ H ₅ ;

I, 12 (3H, t), 3.92 (2H, q), COOC ₂ H _5;

3.50 and 3.88 (4H, m), 5-and 6-CH ₂ CH _2;

3.54 (2H, s), 4-CH ₂ ;

6.81 (1H, s), H-5;

II, 28 (1H, br s, exchangeable with D ₂ O); -CONH;

IR spectrum (KBr): 3390, 1710, 1680, 1520, 1410,

1425, 1435, 1350, 1285, 1138 cm -1.

HU 209 839 Β

Example 7

Preparation of 2- [2- (2-Oxo-imidazolidine-1-carboxamido) -4-thiazolyl] -acetic acid

This compound was prepared according to the procedure of Example 3 by first adding 3.2 g (20 mmol) of 2- (2-amino-4-thiazolyl) acetic acid in 5.6 mL (44 mmol) of chlorotrimethylsilane 6, 1 ml (44 mmol) of triethylamine was silylated in the presence of the hydrochloride acceptor and the resulting silyl ester was acylated with 3.1 g (21 mmol) of l-chlorocarbonyl-2-imidazolidinone. 3.9 g of the title compound are obtained.

Analysis calculated for C ₉ H ₁₀ N ₄ O ₄ S (relative molecular weight 270.26): Calculated: C 39.99%, H 3.73%, N 20.73%;

Found: C, 40.01; H, 3.78; N, 20.76.

1 H-NMR Spectrum (DMSO-d ₆ , δ ppm):

3.53 (3H, s), 3.28 (2H, q) and 3.72 (4H, m), 4'-CH ₂ and 5'-CH ₂ ;

6.67 (1H, s), 5-H;

7.78 (1H, broad);

11.13 (1H, s broad, interchangeable with D ₂ O), 2'-CO 2 NH and 2-CONH.

Example 8

2- [2- ^(2,3-t5: .jxo-4-ethyl-piperazin -] - carboxamido) -4-thiazolyl] acetic acid

This compound was prepared according to the procedure described in Example 4 by silylation of 2- (2-amino-4-thiazolyl) acetic acid (3.2 g, 20 mmol) with hexamethyldisilazane (4.6 mL, 22 mmol). The silyl ester thus obtained was acylated with 4.5 g (22 mmol) of 2,3-dioxo-4-ethylpiperazine-1-carbonyl chloride in the presence of a hydrogen chloride acceptor. 4.8 g of the title compound are obtained.

Analysis calculated for C ₁₂ H ₁₄ N ₄ O ₅ S (MW 326.32): Calculated: C 44.17%, H4.32%, N 17.7%;

Found: C, 44.21; H, 4.35; N, 17.27.

1 H NMR (DMSO-d ₆ , δ ppm):

1.07 (3H, t), 3.25 (2H, q), -NC ₂ H ₅ ;

3.35 and 3.78 (4H, m), 5-CH ₂ and 6-CH ₂ ;

3.54 (2H, s), 4-CH ₂ ;

6.81 (2H, s), 5-H;

II, 27 (1H, s broad, interchangeable with D ₂ O) -CONH.

Example 9

Preparation of 2- [2- (2-Oxoimidazolidine-1-carboxamido) -4-thiazolyl) -glyoxylic acid ethyl ester

A mixture of 4.0 g (20 mmol) of 2- (2-amino-4-thiazolyl) glyoxylic acid and 50 ml of tetrahydrofuran was cooled to 0-5 ° C, 3.2 ml of triethylamine and 3.3 g (23 mmol) were added. 1- (Chlorocarbonyl) -2-imidazolidinone is added and the reaction mixture is refluxed for 5-6 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated in vacuo to give tetrahydrofuran. The residue was dissolved in chloroform (50 mL) and the solution was washed with dilute hydrochloric acid solution, aqueous sodium bicarbonate solution, water, dried over anhydrous sodium sulfate and concentrated in vacuo. Addition of diisopropyl ether to the residue afforded 4.6 g of the title compound as a precipitate.

Analysis calculated for ChH ₁₂ N ₄ O ₅ S (relative molecular weight 312.30): Calculated: C 42.30%, H 3.87%, N 17.94%;

Found: C, 42.43; H, 3.92; N, 18.03.

1 H-NMR Spectrum (DMSO-d ₆ , δ ppm):

1.22 (3H, t), 4.19 (2H, q) -OC ₂ H _5;

3.24 and 3.27 (4H, m), _4'-CH2 and ^5-CH2;

8.15 (1H, s), 5-H;

7.90 (1H, br s) and 11.58 (1H, br, D ₂ O exchangeable), 2'-CONH and CONH 2.

Example 10

Preparation of 2- [2- (2,3-Dioxo-4-ethylpiperazine-1-carboxamido) 4-thiazolyl] glyoxylic acid ethyl ester

This compound was prepared according to the procedure described in Example 9 so that 4.0 g (20 mmol) of 2- (2-amino-4-thiazolyl) glyoxylic acid ethyl ester was 4.9 g (24 mmol) 2.3 g. -dioxo-4-ethylpiperazine-1-carbonyl chloride and 3.3 ml (24 mmol) of triethylamine. The chloroform solution was concentrated in vacuo and the residue chromatographed on a silica gel column. The eluate was evaporated in vacuo to give 6.1 g of the title compound.

Analysis calculated for C ₄ H ₁₆ N ₄ O ₆ S Calcd (molecular weight 368.36): calculated: C 45.65%, H, 4.38%; N, 15.21%;

Found: C, 45.74; H, 4.41; N, 15.17.

1 H-NMR Spectrum (DSMO-d ₆ , δ ppm):

1.05 (3H, t) and 3.30 (2H, q); -NC ₂ H ₅ ;

1.25 (3H, t), 4.18 (2H, q), COOC ₂ H _5;

3.50 (2H, m) and 3.89 (2H, m), 5-CH ₂ and 6-CH ₂ ;

3.18 (1H, s), 5-H;

11.68 (1H, br s, exchangeable with D ₂ O), CONH.

Example 11

The anti-inflammatory activity of the novel ureido-thiazole derivatives of the present invention was investigated by the test method of Winter et al. In carrageenan edema; our results are presented in Tables 1, 2, 3, 4, 5 and 6.

Table 1

Effect of 2- [2- (2-Oxoimidazolidine-1-carboxatnido) 4-thiazolyl] -2-syn-methoxyimino-acetic acid methyl ester (Example 1 compound)

Dose Manual value 1 hour 2 o'clock 3 hours 4 o'clock 5 hours 24 hours after 1 mg 1 1.29 129% 1.52 152% 1.58-158% 1.67 167%, 1.59 159% 1.41 141% 3 mg 0.96 1.40 146% 1.37 143% 1.57-164% 1.66 173% 1.57-164% 1.38 144% 5 mg 1.06 1.31 123% 1.46 138% 1.64 154% 1.72 166% 1.73 165% 1.23 115% 10 mg 1.04 1.21 116% 1.27 122% 1.47 141% 1.61 155% 1.58 152% 1.17 113%

HU 209 839 B

Control 0.91 1.28 141% 1.58 174% 1.72 189 = 1.77 195% 1.80 198 = 1.38 152%.

Control 0.93 1.31 140% 1.69 174% 1.75 188% 1.80 193% 1.85 199% 1.35 146%

Table 2

Methyl 2- [2- (2,3-Dioxo-4-ethyl-piperazine-1-carboxamido) -4-thiazolyl] -2-syn (methoxyimino) -acetic acid (Example 2) effect

Dose Manual value 1 hour 2 o'clock 3 hours 4 o'clock 5 hours 24 hours after 1 mg 0.96 1.27 132% 1.55-161% 1.60 166% 1.66 172% 1.63 169% 1.45 151% 3 mg L0 1.39 139% 1.40 140% 1.57157% 1.67 167% 1.62 162% 1.35 135% 5 mg 1.04 1.29 124% 1.46 140% 1.62 155% 1.72 165% 1.74 167% 1.25 120% 10 mg 1.06 1.22 115% 1.25 117% 1.46 137% 1.63 154% 1.60 151% 1.15 108% Control 0.92 1.29 140% 1.61 175% 1.71 185% 1.77 192% 1.83 199% 1.43 155%

Table 5

Effect of ethyl 2- [2- (2-oxo-imidazolidine-1-carboxamido) -4-thiazolyl) -glyoxylic acid (Example 9)

Dose Manual value 1 hour 2 o'clock 3 hours 4 o'clock 5 hours 24 hours after 1 mg 0.96 1.32 135% 1.54-160% 1.72 179% 1.62 169% 1.56-163% 1.31 147% 3 mg 0.97 1.32 136% 1.57 162% 1.67 165% 1.57 162% 1.67 172% 1.27 131% 5 mg 1.11 1.38 124% 1.63 147% 1.73 158% 1.75 158% 1.69 152% 1.34 121% 10 mg 1.05 1.36 130% 1.68-160% 1.85 176% 1.68-160% 1.73 164% 1.25 119% Control 1.01 1.28 127% 1.42 141% 1.72 171% 1.71 171% 1.69-168% 1.35 134%

Table 3

Effect of 2- [2- (2-oxo-imidazolidine-1-carboxamido) 4-thiazolyl] -acetic acid ethyl ester (compound of Example 5)

Dose Initial value 1 hour 2 o'clock 3 hours 4 o'clock 5 hours 24 ^hours 1 mg 0.87 1.23 141% 1.36 156% 1.39-160% 1.53 175% 1.47 169% 1.16 133% 3 mg 0.91 1.29 142% 1.18 130% 1.25 137% 1.45 159% 1.30 143% 1.18 130% 5 mg 0.94 1.08 115% 1.20 128% 1.31 139% 1.43 152% 1.49 159% 1.14 121% 10 mg 0.95 1.06 113% 1.20 126% 1.33 140% 1.46 154% 1.54 162% 1.07 113% Control 0.91 1.28 141% 1.58 174% 1.72 189% 1.77 195% 1.80 198% 1.38 152%

Table 6

Effect of 2- [2- (2,3-dioxo-4-ethylpiperazine-1-carboxamido) 4-thiazolyl] -glyoxylic acid ethyl ester (Example 10 compound)

Dose Manual value 1 hour 2 o'clock 3 hours 4 o'clock 5 hours 24 hours after 1 mg 0.90 1.30 144% 1.54-171% 1.61 179% 1.67 186% 1.57 174% 1.27 141% 3 mg 0.95 1.15 121% 1.26 133% 1.55-163% 1.59-167% 1.64 173% 1.21 127% 5 mg 0.96 1.21 126% 1.30 135% 1.55-161% 1.52 158% 1.61-168% 1.15 120% 10 mg 0.95 1.07 112% 1.34 141% 1.33 140% 1.44 152% 1.54 162% 1.12 118% Control 1.01 1.28 127% 1.42 141% 1.72 171% 1.72 171% 1.69-168% 1.35 134%

Table 4

Effect of 2- [2- (2,3-dioxo-4-ethylpiperazine-1-carboxamido) 4-thiazolyl] -acetic acid ethyl ester (compound of Example 6)

Dose Initial value 1 hour 2 hours 3 hours 4 hours 5 hours

Claims

PATENT CLAIMS

A process for the preparation of the ureido-thiazole derivatives of formula (I), wherein R is a group of formula (a) or (b),

R ₂ is hydrogen or lower alkyl; and

X is a methyl (methoxyimino) group> C = O or

_-CH2 group, wherein a compound of formula (II) - wherein X is as defined above, Z is hydrogen, lower alkyl or -Si (CH3) _₃ group, and Y is hydrogen or -Si (CH ₃ ) Acylation of ₃ groups with a carbamoyl chloride of the formula R-COCl of formula III wherein R is as defined above and optionally deprotecting.

HU 209 839 Β

Process according to Claim 1, characterized in that the acylation is carried out in an anhydrous organic solvent, preferably a halogenated hydrocarbon or a lower fatty acid ester.

The process according to claim 1, wherein the acylation is carried out in the presence of a hydrogen chloride-binding agent (hydrogen chloride acceptor).

The process according to claim 1, wherein the acylation is carried out at a temperature ranging from 0 ° C to the boiling point of the solvent used for the acylation.

5. A process for the preparation of a pharmaceutical composition having an anti-inflammatory effect, characterized in that:

A ureido-thiazole derivative of the Formula I, as defined in claim 1, wherein R, R ₂ and X are as defined in Claim 1, is formulated with a pharmaceutically acceptable carrier and excipient to form a pharmaceutical composition.