The use of tricyclic proizvodnyh 1,4-dihydro-1,4 - dioxo-1h-naphthalene and new compounds, pharmaceutical composition and substituted derivatives naftalina as intermediates

 

(57) Abstract:

The invention relates to the use as a medicinal substance medications for the treatment of diseases associated with impaired venous function and/or inflammatory edema tricyclic derivatives of 1,4-dihydro-1,4-dioxo-1H-naphthalene and its new compounds of General formula I, where a is either a sulfur atom, oxygen or the radical R3N, where R3is a hydrogen atom, a C1-C5-alkyl; R1is either1-C5-alkyl, or phenyl ring, unsubstituted or substituted by one or more groups selected from methyl, methoxy, fluorine, chlorine, or 5-6-membered heteroaromatic ring having one or more heteroatoms selected from oxygen, sulfur, nitrogen, unsubstituted or substituted group selected from chlorine, bromine, nitro, amino, acetamido, acetoxymethyl, methyl, phenyl; R2is a hydrogen atom, halogen, C1-C5-alkyl, hydroxy, and methoxy; and their pharmaceutically acceptable salts. Pharmaceutical composition having anti-inflammatory action, containing the compound of formula I as active substance and a pharmaceutically prstat - the use of tricyclic derivatives of 1,4-dihydro-1,4-dioxo-1H-naphthalene and new compounds for the treatment of diseases associated with impaired venous function and/or inflammatory edema. 4 C. and 3 h. p. F.-ly, 3 PL.

The invention relates to the use of tricyclic derivatives and their pharmaceutically acceptable salts for medical products intended for the treatment of diseases associated with impaired venous function and/or inflammatory edema, and obtained new compounds. In particular, it relates to tricyclic derivatives of 1,4-dihydro-1,4-dioxo-lH-naphthalene. The invention concerns therapeutic application of these compounds.

BJ. Heterocycl. Chem. , 6(6), 909-916, the authors Caroll F. I. , J. T. Blackwell described the synthesis of 1H-naphthas[2,3-d] imidazole-4,9-diones substituted in position 2. In addition, Zh. Org. Khim. , 3(1), 162-168, 1967 the authors Efimova, A. and Efros HP describes the obtaining of 1,2-dimethyl-1H-naphthas[2,3-d] imidazole-4,9-dione. Finally, in J. Am. Chem. Soc. , 76, 4148-4152, 1954 authors Hoover J. R. E. , Day, A. R. retrieves derivatives of 1H-naftiridina-4,9-dione on the basis of 2,3-dichloro-1,4-dihydro - 1,4-deoxidation.

In an article in J. Prakt. Chem. , 319(2), 254-258, 1977 the authors Hammam Ahmed , S., Osman Abdel-Magid describes the synthesis of 2-amido-3-CHL is an intermediate for further synthesis of naphthas[2,3-d] oxazole-4,9-diones, substituted or unsubstituted in position 2. Patent US 3039925 on 19 June 1962 and patent application DE 24 April 1967 filed Gerhard Domagk, Karl W. Schellhammer, Siegfried Petersen, Hans B. Koenig, relate to the synthesis of 2-methyl-naphthas[2,3-d] oxazole-4,9-dione, made Fries K. and Ochwat P. (Berichte 56, 1926 [1923] ).

Japanese patent JP 61251675 author S. Hiroyuki, and article in Collect. Czech. Chem. Commun. , 50(1), 71-79, 1985 authors Hammam A. S. , Bayoumy B. E. and article in J. Heterocyclic Chem. , 25, 901-906, 1988 authors Katritzky A. R. , Fan, W. Q. describe the production of oil[2,3-d] thiazole-4,9-diones.

Tricyclic derivatives and their pharmaceutically acceptable salts in accordance with the present invention meet the General formula:

< / BR>
where a is either a sulfur atom, oxygen or radical3N, where R3is a hydrogen atom, a radical of the alkyl, C1-C5or substituted or unsubstituted aromatic cycle or a substituted or unsubstituted heteroaromatic cycle.

R1is either a radical of the alkyl, C1-C5,

or the radical R4NH, where R4is a hydrogen atom, a radical of the alkyl, C1-C5or substituted or unsubstituted aromatic cycle or a substituted or unsubstituted heteroaromatic cycle

or aromatics the automatic cycle, having one or more heteroatoms and substituted or unsubstituted groups of acceptors or donors;

R2is a hydrogen atom, halogen, an alkyl radical C1-C5, an oxygen atom, substituted or unsubstituted in the alkyl radical C1-C5or a radical NR5R'5where R5and R'5are, independently of each other, hydrogen atom, oxygen or monovalent organic radicals C1-C5.

In the present invention under the "groups of acceptors or donors understand the radical of alkyl, C1-C5or halogen atom, an oxygen atom, substituted or unsubstituted radical of the alkyl, C1-C5or a radical NR6R'6where R6and R'6are, independently of each other, hydrogen atom, oxygen or monovalent organic radicals C1-C5.

The invention relates also to the following new products:

sulfate 4,9-dihydro-4,9-dioxo-1,2-dimethyl-1H-naphthas[2,3-d] imidazole,

- 4,9-dihydro-4,9-dioxo-2-(2-forfinal)-1H-naphthas[2,3-d] imidazole,

- 4,9-dihydro-4,9-dioxo-2-(2-forfinal)-naphthas[2,3-d] oxazole,

- 4,9-dihydro-4,9-dioxo-2-(3-forfinal)-naphthas[2,3-d] oxazole,

- 4,9-dihydro-4,9-dioxo-2-(9-dioxo-2-(3-were-naphthas[2,3-d] oxazole,

- 4,9-dihydro-4,9-dioxo-2-(4-methoxyphenyl)-naphthas[2,3-d] oxazole,

- 2-(2-chlorophenyl)-4,9-dihydro-4,9-Diakonoff[2,3-d] oxazole,

- 2-(4-chlorophenyl)-4,9-dihydro-4,9-Diakonoff[2,3-d] oxazole,

- 4,9-dihydro-4,9-dioxo-2-(2-thienyl)-naphthas[2,3-d] oxazole,

- 4,9-dihydro-4,9-dioxo-2-(2-forfinal)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(3-forfinal)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(4-forfinal)-oil[2,3-d] thiazole,

- 2-(2,4-debtor-phenyl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(3-pyridyl)-oil[2,3-d] thiazole,

sulfate 4,9-dihydro-4,9-dioxo-2-(4-pyridyl)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(3-furyl)-oil[2,3-d] thiazole,

- 2-(5-chlorofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(2-thienyl)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(3-thienyl)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-phenylamine-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-8-methoxy-2-phenyl-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-5-methoxy-2-fined-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-7-methoxy-2-phenyl-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-6-methoxy-2-phenyl-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-8-hydroxy-2-phenyl-oil[2,3-d] thiazole,

- 4,9-Digue is R>
- 2-(4,5-dibromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole,

- 2-(3-bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole,

- 2-(4-bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(5-nitrofuran-2-yl)-oil[2,3-d] thiazole,

- 2-(5-aminopurin-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole,

- 2-(5-acetamidophenyl-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(5-hydroxymethylene-2-yl)-oil[2,3-d] thiazole,

- 2-(5-acetoxymethyl-2-yl)-4,9-dihydro-4,9-diaconate [2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(5-methyl-2-furyl)-oil[2,3-d] thiazole,

- 4,9-dihydro-2-(4,5-dimethyl-2-furyl)-4,9-dioxo-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(5-phenyl-2-oxazolyl)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(2-thiazolyl)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-6-fluoro-2-(2-furyl)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-7-fluoro-2-(2-furyl)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-6-fluoro-2-phenyl-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-7-fluoro-2-phenyl-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-6-fluoro-2-(5-methyl-2-furyl)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-7-fluoro-2-(5-methyl-2-furyl)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-6-fluoro-2-(4-torfin the CSR-6-fluoro-2-(4-were)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-7-fluoro-2-(4-were)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-5-fluoro-2-(2-furyl)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-8-fluoro-2-(2-furyl)-oil[2,3-d] thiazole,

- 6-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)-oil[2,3-d] thiazole,

- 7-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(2-furyl)-5-methoxy-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(2-furyl)-8-methoxy-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(2-furyl)-5-hydroxy-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(2-furyl)-8-hydroxy-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(2-furyl)-6-methoxy-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-(2-furyl)-7-methoxy-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-furyl-6-methyl-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-furyl-7-methyl-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-6-methyl-2-phenyl-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-7-methyl-2-phenyl-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-furyl-5-methyl-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-2-furyl-8-methyl-oil[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-5-methyl-2-phenyl-NAF-To[2,3-d] thiazole,

- 4,9-dihydro-4,9-dioxo-8-methyl-2-phenyl-oil[2,3-d] thiazole,

The invention concerns also the hydro-1,4-dioxo-5-methoxynaphthalene,

- 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene,

- 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene,

- 2,3-dibromo-1,4-dihydro-1,4-dioxo-6-formatline,

- 2-amino-3-bromo-6-fluoro-1,4-dihydro-1,4-deoxidation,

- 2-amino-3-bromo-7-fluoro-1,4-dihydro-1,4-deoxidation,

- 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-formatline,

- 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-formatline,

- 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-formatline,

- 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-6-methylnaphthalene,

- 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene,

- 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene,

- 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene,

- 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methylnaphthalene.

The invention also concerns the use of tricyclic derivatives and their pharmaceutically acceptable salts that meet the General formula (I), to obtain medication intended for treatment:

- functional or organic venous insufficiency,

- hemorrhoidal pathology

- migraine headache

- osteo-articular, dermatological and cardiovascular inflammation

- shock, characterized by a significant drop in the I of the present invention correspond to General formula (I):

< / BR>
where A= -NH, -N-C6H5, -N-CH3, O, S, N,

< / BR>
< / BR>
R1= -CH3, -NH2,

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
R2= H, -OCH3, -OH, -F, C1, CH3.

The present invention also concerns salts of salt-forming compounds of formula (I). These salts include the salts of the accession of mineral acids such as hydrochloric, Hydrobromic, sulfuric, phosphoric or nitric acid, and salts of accession of organic acids such as acetic, propionic, oxalic, citric, maleic, fumaric, succinic, tartaric acid.

The invention is illustrated by the following non-limiting examples.

Examples identified by the number, meet new connections and examples, denoted by the letter correspond to known compounds.

In all examples, the analysis was conducted as follows:

The melting point was determined using a device type of "stand Kofler" LEICA REICHERT model WME, without further correction,

- Thin-layer chromatography was carried out on plates of silica gel with indicator fluorescence UV254 0.25 mm thick type MACHEREY-NAGEL (link 805023).trometry type AEI MS-50, or on the spectrometer type FISONS VG PLATRORM. The method of ionization is specified for each example,

- NMR spectra1H and13With determined either on the spectrometer type JEOL at 270 MHz and 68 MHz, respectively, or on the spectrometer type BRUKER 400 MHz and 100 MHz, respectively. Used datarecovery solvents specified for each analysis,

- Infrared range of values was determined on the spectrometer type NICOLET 205 FT-IR 1% (m/m) dispersion in KBR.

Example 1

Sulfate 4,9-dihydro-4,9-dioxo-1,2-dimethyl-1H-naphthas[2,3-d] imidazole

To a solution of 2 g (8,84 mm) 4,9-dihydro-4,9-dioxo-1,2-di-methyl-1H-naphthas [2,3-d] imidazole in 300 ml of a mixture (2/1) of methanol and dichloromethane, brought to 70oC, add 1 ml of concentrated sulfuric acid. The reaction mixture was stirred at 70oC for two hours, concentrated under reduced pressure, the obtained light-yellow precipitate was filtered, washed with dichloromethane, then ethyl ether to obtain 2 g of sulfate 4,9-dihydro-4,9-dioxo-1,2-dimethyl-1H-naphthas[2,3-d] -imidazole in the form of yellow crystals.

The output is 70%,

F (melting Point) > 260oWITH,

Rf of 0.50 (CH2CL2/methanol, 97, 5/2, 5),

NMR1H (DMSO-d6) - (ppm)

with 8.05 (dd, 2H, H-5, H-8, JH5-H6= JH7-H83)

NMR13(DMSO d6) - (ppm)

177,22; 175,44 (2C, C-4, C-9)

153,46 (1C, C-2)

138,96 (1C, C-3A)

134,10; 134,01 (2C, C-6, C-7)

132,30; 131,93 (3C, C-8A, C-9a, C-4A)

126,24; 126,13 (2C, C-5, C-8)

32,33 (1C, CH3)

12,30 (1C, CH3)

IR (infra-red spectrum (KBr) (cm-1)

3414-2400 (a wide range of NH+); 1674 (C= 0)

Example 2

4,9-dihydro-4,9-dioxo-2-(2-forfinal)-1H-naphthas[2,3-d] imidazol

In a suspension of 1.37 g (7,29 mm) 2,3-diamine-1,4-dihydro-1,4-deoxidation in 50 ml of water is added a solution of 0.77 ml (7,29 mm) 2-forventelige in 5 ml of glacial acetic acid. After 5 min of exposure under reflux obtained black solid is filtered, washed three times in 30 ml of water. The solid is then dissolved in 2 l of dichloro-methane, the organic phase is washed three times in water, dried over calcium chloride and then evaporated to dryness to obtain 1.50 g of light brown crystals. The product was then purified column for flash chromatography (carrier: silica, air conditioning: heptane, eluent: dichloromethane/95/5 heptane, then dichloromethane/methanol 99/1), after evaporation under reduced pressure, solvent gain of 1.00 g of 4,9-dihydro-4,9-dioc-with-2-(2-forfend)-1H-naphthas[2,3-d] imidazole in the form of yellow crystals.

O the/SUP>H (DMSO-d6) - (ppm)

of 14.28 (s, 1H, NH)

to 8.12 (m, 2H, H-5, H-8)

of 8.00 (m, 1H, H-6')

7,86 (m, 2H, H-6, H-7)

of 7.60 (m, 1H, H-3')

7,44 (m, 2H, H-4', H-5')

NMR13(DMSO d6) - (ppm)

179,13; 175,03 (2C, C-4, C-9)

157,41 (1C, C-2')

147,88 (1C, C-2)

133,85 (2C, C-6, C-7)

132,67 (3C, C-6, C-9a, C-3A)

130,62 (2C, C-4A, C-8A)

126,24; 124,82 (3C, C-5, C-8, C-5')

116,62; 116,31 (2C, C-1', C-3')

IR (KBR) (cm-1)

3339 (NH); 1683, 1665 (C= 0)

Example 3

4,9-dihydro-4,9-dioxo-2-(2-forfinal)-naphthas[2,3-d] oxazol

In a solution of 6.0 g (28.8 mm) 2-amino-3-chloro-1,4-dihyd-ro-1,4-deoxidation in 120 ml of nitrobenzene is added in the dark 17,70 ml (144, 0mm mm) chloride 2-verbenaceae acid. After 10 min stirring at 80oTo add to 0.20 ml of concentrated sulfuric acid. The reaction mixture was kept under reflux for 18 hours. Once completely cool, add ether to obtain a yellow precipitate, which is filtered on mitrofanna glass and washed with ether. The solid is purified by column flash chromatography (carrier: silica, air conditioning: heptane, eluent: dichloromethane/heptane 60/40) obtain 2.5 g of 4,9-dihydro-4,9-dioxo-2-(2-forfinal)-naphthas[2,3-d] oxazole in the form of yellow crystals.

Output - 30%,

F > 260oWITH,

Rf 0,60 (the -6')

to 7.95 (m, 2H, H-6, H-7)

7,76 (m, 1H, H-4')

7,52 (m, 2H, H-3', H-5')

NMR13C (DMSO d6) - (ppm)

178,22; 173,06 (2C, C-4, C-9)

161,88 (1C, C-2)

158,08 (1C, C-2')

150,67; 142,83 (2C, C-3A, C-9a)

135,37 (1C, C-6')

134,64 (2C, C-6, C-7)

132,31; 131,94 (2C, C-4A, C-8A)

130,65 (1C, C-4')

126,79; 126,47 (2C, C-5, C-8)

125,62 (1C, C-5')

117,32 (1C, C-3')

113,21 (1C, C-1')

IR (KBr) (cm-1)

1693, 1680 (C= 0)

Example 4

4,9-dihydro-4,9-dioxo-2-(3-forfinal)-naphthas[2,3-d] oxazol

Into a solution of 5.0 g (24 mm) 2-amino-3-chloro-1,4-dihyd-ro-1,4-deoxidation in 50 ml of nitrobenzene is added in the darkness of 14.6 ml (120.0 mm) chloride 3-fermenting acid, then after 5 min of mixing of 0.50 ml of concentrated sulfuric acid. After 24 hours of exposure with a reflux condenser and a complete cooling, the reaction mixture was added 200 ml of ether. The formed precipitate was filtered, then dissolved in 200 ml of dichloromethane, to which was added 100 ml of ice-cold solution of sodium hydroxide. After 6 hours of stirring at this temperature, the organic phase is extracted, washed several times with water and dried over calcium chloride. The solid obtained after evaporation of the solvent, purified on a column of medium pressure (carrier: silica, air conditioning: heptane, is chloromethane and heptane, get to 0.50 g of 4,9-dihydro-4,9-dioxo-2-(3-forfinal)-naphthas[2,3-d] oxazole in the form of yellow crystals.

Output is 7%,

F: 230oWITH,

Rf: 0.50 in (CH2C12/heptane, 95/5)

SM (I. E. ): m/z 293 (M+. )

NMR1H (CDCl3) - (ppm)

8,31 (m, 1H, H-6')

of 8.27 (m, 2H, H-5, H-8)

8,02 (s, 1H, H-2')

7,83 (m, 2H, H-6, H-7)

7,63 (m, 1H, H-5')

7,31 (m, 1H, H-4')

NMR13C (DMSO d6) - (ppm)

178; 173 (20, C-4, C-9)

162,53 (1C, C-3')

149,37 (1C, C-9a)

143,47 (1C, C-3A)

134,85; 134,46 (2C, C-6, C-7)

132,45; 132,08 (2C, C-4A, C-8A)

131,06 (1C, C-5')

127,52; 127,11 (2C, C-5, C-8)

124,74 (1C, C-6')

117,46; 117,15 (2C, C-2', C-4').

IR (KBR) (cm-1)

1695, 1680 (C= 0).

Example 5

4,9-dihydro-4,9-dioxo-2-(4-forfend)-naphthas[2,3-d] oxazol

In the solution to 6.22 g (30 mm) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation in 60 ml of nitrobenzene is added in the dark 18,00 ml (150,0 mm) chloride 4-fermenting acid. After 10 min of stirring under reflux add to 0.20 ml of concentrated sulfuric acid. After 12 hours and completely cool, add ether to obtain a yellow precipitate, which is filtered on mitrofanna glass, washed with ether and purified by column flash chromatography (carrier: silica, air conditioning: heptane, eluent: lizovyvatj in dichloromethane, get 2,90 g of 4,9-dihydro-4,9-dioxo-2-(4-forfinal)-naphthas[2,3-d] oxazole in the form of yellow crystals.

The output is 33%,

F > 260oWITH,

Rf: 0,60 (CH2C12/heptane, 80/20)

SM (I. E. ): m/z 293 (M+. )

NMR 1H (CDCl3) - (ppm)

with 8.33 (m, 2H, H-2', H-6')

of 8.28 (m, 2H, H-5, H-8)

of 7.82 (m, 2H, H-6, H-7)

7,26 (m, 2H, H-3', H-5')

NMR13With (CDCl3) - (ppm)

166,89 (1C, C-4')

143,45 (1C, C-3A)

134,42 (2C, C-6, C-7)

132,86; 132,55 (2C, C-4A, C-8A)

130,78 (2C, C-2, C-6')

127,52; 127,07 (2C, C-5, C-8)

121,50 (1C, C-1')

116,82; 116,50 (2C, C-3', C-5')

IR (KBR) (cm-1)

1689, 1669 (C= 0)

Example 6

4,9-dihydro-4,9-dioxo-2-(2-were-naphthas[2,3-d] oxazol

In a solution of 5.00 g (24 mm) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation in 37 ml (280 mm) chloride 2 - methylbenzoic acids are added in the dark 8 drops of concentrated sulfuric acid. After 7 hours of exposure under reflux and complete cooling of the formed ochre precipitate is filtered on mitrofanna glass, washed with ether and purified by column flash chromatography (carrier: silica, air conditioning: heptane, eluent: dichloromethane/heptane 50/50). The obtained yellow powder after evaporation of the solvent discolor, recrystallized in dichlormethane - 34%,

F: 212oWITH,

Rf of 0.50 (CH2C12/heptane, 80/20)

SM (I. E. ): m/z 289 (M+. )

NMR 1H (CDCl3) - (ppm)

8,30 (m, 1H, H-6')

of 8.27 (m, 2H, H-5, H-8)

7,81 (m, 2H, H-6, H-7)

7,47 (m, 1H, H-4')

7,37 (m, 2H, H-3', H-5')

2,84 (s, 3H, CH3)

NMR13C (CDCl3) - (ppm)

179,05; 173,50 (2C, C-4, C-9)

140,81 (1C, C-2')

134,77 (2C, C-6, C-7)

133,50 (1C, C-3')

132,50 (1C, C-4')

130,80 (1C, C-6')

127,91; 127,49 (2C, C-5, C-8)

125,60 (1C, C-5')

123,45 (1C, C-1')

22,50 (1C, CH3)

IR (KBr) (cm-1)

1668, 1678 (C= 0)

Example 7

4,9-dihydro-4,9-dioxo-2-(3-were-naphthas[2,3-d] oxazol

To a solution of 5 g (24 mm) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation in 70 ml of dioxane is added in the dark 32,00 ml (240 mm) chloride 3-methylbenzoic acid, and then, after 5 min stirring of 0.50 ml of concentrated sulfuric acid. After 45 min exposure with a reflux condenser and completely cool, add 200 ml of ether, the precipitate filtered. The red filtrate is evaporated to dryness, dissolved in dichloromethane, washed several times with water, dried and purified by column flash chromatography (carrier: silica, air conditioning: heptane, eluent: dichloromethane/heptane 50/50). Yellow crystals formed after evaporation process is the aft[2,3-d] oxazole in the form of yellow crystals.

The output is 43%,

F: 255oWITH,

Rf of 0.43 (CH2C12/heptane, 80/20)

SM (I. E. ): m/z 289 (M+. )

NMR1H (CDCl3) - (ppm)

compared to 8.26 (m, 2H, H-5, H-8)

8,17 (s, 1H, H-2')

8,13 (m, 1H, H-5')

of 7.82 (m, 2H, H-6, H-7)

the 7.43 (m, 2H, H-4', H-6')

2,48 (s, 3H, CH3)

NMR13With (CDCl3): (ppm)

179,13; 173,72 (2C, C-4, C-9)

166,95 (1C, C-2)

150,65; 144,17 (2C, C-3A, C-9a)

139,62 (1C, C-3')

134,81; 134,77; 134,32 (3C, C2', C-6, C-7)

132,86; 132,55 (2C, C-4A, C-8A)

129,54; 129,26 (2C, C-4', C-5')

127,91; 127,49 (2C, C-5, C-8)

125,86 (1C, C-6')

125,44 (1C, C-1')

21,71 (1C, CH3)

IR (KBr) (cm-1)

1693, 1678 (C= 0)

Example 8

4,9-dihydro-4,9-dioxo-2-(4-methoxyphenyl)-naphthas[2,3-d] oxazol

Into a solution of 5.0 g (24 mm) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation in 80 ml of dichloromethane is added in the dark at room temperature for 16 ml (120 mm) chloride 4-methoxybenzoic acid, then 0.003 ml of concentrated sulfuric acid. After 3 hours of exposure under reflux, the reaction mixture is evaporated to dryness, the obtained black oil residue is dissolved in 300 ml dichloromethane, washed with a solution of 10N sodium hydroxide, then with water, dried over calcium chloride. The product is then purified by column flash chromatography (silica 6-35 mm, condizionatore as yellow-orange crystals after recrystallization and discoloration on the animal corner.

The output is 56%,

F: > 260oWITH,

Rf of 0.44 (CH2Cl2/ethanol, 99/1)

SM (I. E. ): m/z 305 (M+. )

NMR1H (CDCl3) - (ppm)

of 8.28 (dd, 2H, H-5, H-8, JH5-H6= JH7-H8= cent to 8.85 Hz; JH5-H7= JH6-H8= 1.73 Hz)

8,24 (d, 2H, H-2', H-6, JH2'-H3'= JH5'-H6'= at 8.60 Hz)

7,80 (m, 2H, H-6, H-7)

7,05 (d, 2H, H-3, H-5, JH2'-H3'= JH5'-H6'= at 8.60 Hz)

to 3.92 (s, 3H, CH3)

IR (KBR) (cm-1)

1750, 1680 (C= 0)

Example 9

2-(2-chlorophenyl)-4,9-dihydro-4,9-dioxo-naphthas[2,3-d] oxazol

To a solution of 5 g (24 mm) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation in 60 ml of dioxane is added and 15.3 ml (120 mm) chloride 2-chlorbenzoyl acid, then after 5 min of stirring 0.5 ml of concentrated sulfuric acid. The reaction mixture was kept under reflux for 4 hours, the precipitate obtained after evaporation of the dioxane under reduced pressure, dissolved in 200 ml of dichloromethane. To the solution is added to cold 100 ml of 10N sodium hydroxide. Stirred for 2 hours. The organic phase is extracted, washed several times with water and dried over calcium chloride. The solid residue obtained after evaporation of the solvent, purified by medium-pressure column (carrier: silica, eluent: dichloromethane/heptane 40/60). Floor-(2-chlorophenyl)-4,9-dihydro-4,9-dioxo-naphthas[2,3-d] oxazole in the form of light yellow crystals.

The output is 67%,

F: 216oWITH,

Rf 0,42 (CH2C12/heptane, 80/20)

SM (I. E. ): m/z 309, 311 (M+. )

NMR1H (CDCl3) - (ppm)

compared to 8.26 (m, 3H, H-5, H-8, H-6')

of 7.82 (m, 2H, H-6, H-7)

7,53 (m, 3H, H-3, H-4', H-5')

NMR13C (CDCl3): (ppm)

134,99; 134,87 (3C, C-2', C-6, C-7)

133,78; 132,84; 132,18 (4C, C-3', C-4, C-5', C-6')

132,38; 132,04 (2C, C-4A, C-8A)

128,04; 127,63 (2C, C-5, C-8)

124,80 (1C, C-1')

IR (KBR) (cm-1)

1691, 1674 (C= 0)

Example 10

2-(4-chlorophenyl)-4,9-dihydro-4,9-dioxo-naphthas[2,3-d] oxazol

Into a solution of 5.0 g (24 mm) 2-amino-3-chloro-1,4-dihyd-ro-1,4-deoxidation in 60 ml of dioxane is added at room temperature and 15.3 ml (120 mm) chloride 4-chlorbenzoyl acid and 0.5 ml of concentrated sulfuric acid. The reaction mixture was kept under reflux for 4 hours, then evaporated to dryness, dissolved in 200 ml of dichloromethane, neutralized in the cold with 100 ml of 10N sodium hydroxide. The organic phase is washed three times with water and dried over calcium chloride. Received a red powder purified by column flash chromatography (silica 6-35 mm, air conditioning: heptane, eluent: dichloromethane/heptane 70/30). The yellow crystals obtained after evaporation of the solvent, discolor, recrystallized in dichloromethane - 4%,

F: > 260oWITH,

Rf of 0.40 (CH2C12/heptane, 80/20)

SM (I. E. ): m/z 309, 311 (M+. )

NMR1H (CDCl3) - (ppm)

of 8.28 (m, 4H, H-5, H-8, H-2', H-6')

of 7.82 (m, 2H, H-6, H-7)

at 7.55 (d, 2H, H-3', H-5', JH2'-H3'= JH5'-H6'= 8.34 per Hz).

NMR13With (CDCl3): (ppm)

178,55; 173,21 (2C, C-4, C-9)

165,31 (1C, C-2)

150,35; 144,03 (2C, C-3A, C-9a)

139,55 (1C, C-4')

134,48; 134,43 (2C, C-6, C-7)

132,38; 132,04 (2C, C-4A, C-8A)

129,65; 129,49 (4C, C-2, C-3, C-5', C-6')

127,55; 127,09 (2C, C-5, C-8)

123,63 (1C, C-1')

IR (KBr) (cm-1)

1695, 1675 (C= 0)

Example 11

4,9-dihydro-4,9-dioxo-2-(2-thienyl)-naphthas[2,3-d] oxazol

Into a solution of 5.0 g (24 mm) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation in 50 ml of dichloromethane is added in the dark at room temperature of 12.9 ml (120 mm) chloride 2-tenuiloba acid, then 3 μl of concentrated sulfuric acid. After 21 hours of exposure under reflux, the reaction mixture is evaporated to dryness, the obtained black oil residue is dissolved in 100 ml dichloromethane, washed with a solution of 10N sodium hydroxide, then with water, dried over calcium chloride. The product is then purified by column flash chromatography (silica 6-35 μm, air conditioning: heptane, eluent: dichloromethane/heptane 60/40), gain of 5.3 g of 4,9-dihydro-4,9-dioxo-2-(2-t is Mr. coal.

The output is 78%,

F: > 260oWITH,

Rf 0,41 (CH2C12)

SM (I. E. ): m/z 281 (M+. )

NMR1H (CDCl3) - (ppm)

by 8.22 (dd, 2H, H-5, H-8, JH5-H6= cent to 8.85 Hz, JH5-H7= 1.73 Hz)

of 8.06 (dd, 1H, H-5', JH5'and H4'= 3,49 Hz, JH5'-H3'= 1,00 Hz)

7,83 (m, 2H, H-6, H-7)

7,73 (dd, 1H, H-3', JH3'-H4'= 4,88 Hz, JH3'-H5'= 1,00 Hz)

7,27 (dd, 1H, H-4', JH4'-H3'= 4,88 Hz, JH4'-H5'= 3,49 Hz)

IR (KBR) (cm-1)

1687, 1667 (C= 0)

Example 12

4,9-dihydro-4,9-dioxo-2-(2-forfinal)-oil[2,3-d] thiazole

To a suspension of 5.0 g (24 mm) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation in 80 ml of water is added to 8.4 g (35 mm) sulfide nonhydrocarbon sodium. The reaction mixture was kept under reflux for 20 minutes, then add 20 ml of an aqueous solution containing 2.0 g of sodium sulfide. When the environment is fully acquire a blue color, add sequentially 1,95 ml (24 mm) 2-ftorangidridy and 6,36 ml of glacial acetic acid. After keeping under reflux for 1 hour, the obtained semi-product of the black color is filtered, dried, then purified by column flash chromatography (silica 6-35 mm, air conditioning: heptane, eluent: dichloromethane/heptane 50/50). Greenish crystals formed after waut in dichloromethane and get a 2.0 g of 4,9-dihydro-4,9-dioxo-2-(2-forfinal)-oil[2,3-d] thiazole in the form of yellow crystals.

The output is 27%,

F: > 260oWITH,

Rf 0,60 (CH2C12)

SM (I. E. ): m/z 309 (M+. )

NMR1H (CDCl3) - (ppm)

to 8.62 (m, 1H, H-6')

8,30; 8,21 (2dd, 2H, H-5, H-8, JH5-H6= JH7-H8= cent to 8.85 Hz; JH5-H7= JH6-H8= 1.73 Hz)

7,81 (m, 2H, H-6, H-7)

7,56 (m, 1H, H-4')

7,29 (m, 2H, H-3', H-5')

NMR13With (CDCl3): (ppm)

179,17 (2C, C-4, C-9)

169,20 (1C, C-2')

153,47 (1C, C-2)

134,43; 134,09 (2C, C-6, C-7)

133,70; 133,56 (2C, C-4A, C-8A)

130,02 (1C, C-6')

127,86; 126,97 (2C, C-5, C-8)

124,99 (1C, C-4')

120,00 (1C, C-5')

116,48; 115,90 (2C, C-1', C-3')

IR (KBr) (cm-1)

1683, 1661 (C= 0)

Example 13

4,9-dihydro-4,9-dioxo-2-(3-forfinal)-oil[2,3-d] thiazole

To a suspension of 5.0 g (24 mm) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation in 50 ml of water is added a solution containing an 8.4 g (35 mm) sulfide nonhydrocarbon of sodium in 50 ml of water. The reaction mixture was kept under reflux for approximately 20 minutes. When the environment becomes blue color, add sequentially 2,50 ml (24 mm) 3-forventelige and 6,36 ml of glacial acetic acid. After keeping under reflux for 2 hours, the resulting product black filtered, dissolved in dichloromethane, washed with distilled water, dried over calcium chloride, " to flash chromatography (carrier: silica, air conditioning: heptane, eluent: dichloromethane/heptane 50/50, then dichloromethane, then dichloromethane/methanol 99/1). The solid obtained after evaporation of the solvent, washed several times with methanol, ethanol and ether, then discolor and recrystallized in dichloromethane and get to 4.0 g of 4,9-dihydro-4,9-dioxo-2-(3-forfinal)-naphthol[3-d] thiazole in the form of yellow crystals.

The output is 54%,

F: > 260oWITH,

Rf 0,56 (CH2C12)

SM (I. E. ): m/z 309 (M+. )

NMR1H (CDCl3) - (ppm)

of 8.37; 8,25 (2dd, 2H, H-5, H-8, JH5-H6= JH7-H8= cent to 8.85 Hz, JH6-H8= JH5-H7= 1.73 Hz)

to 7.95 (m, 2H, H-2, H-6')

to 7.84 (m, 2H, H-6, H-7)

at 7.55 (m, 1H, H-5')

7,25 (m, 1H, H-4')

IR (KBr) (cm-1)

1676, 1661 (C= 0)

Example 14

4,9-dihydro-4,9-dioxo-2-(4-forfinal)-oil[2,3-d] thiazole

To a suspension of 5.0 g (24 mm) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation in 130 ml of water is added to 8.4 g (35 mm) sulfide nonhydrocarbon sodium. The reaction mixture was kept under reflux for 20 minutes, then add 50 ml of an aqueous solution containing 1.0 g of sodium sulfide. When the environment is fully acquire a blue color, add sequentially 2,60 ml (24 mm) 4-forventelige and 6,36 ml of glacial acetic acid is t, then purified by column flash chromatography (carrier: silica, air conditioning: heptane, eluent: dichloromethane/heptane 60/40). Yellow crystals formed after evaporation of the solvent, washed successively with isopropanol and ether, then discolor and recrystallized in dichloromethane and get a 2.0 g of 4,9-dihydro-4,9-dioxo-2-(4-forfinal)-oil[2,3-d] thiazole in the form of yellow crystals.

The output is 27%,

F: > 260oC,

Rf 0,51 (CH2C12/heptane, 90/10)

SM (I. E. ): m/z 309 (M+. )

NMR1H (CDCl3) - (ppm)

8,30; 8,21 (2dd, 2H, H-5, H-8, JH5-H6= JH8-H7= cent to 8.85 Hz, JH5-H7= JH8-H6= 1.73 Hz)

to 8.12 (m, 2H, H-2', H-6')

7,83 (m, 2H, H-6, H-7)

7,22 (m, 2H, H-3', H-5')

NMR13C (CDCl3): (ppm)

179,17 (2C, C-4, C-9)

165,21 (1C, C-4')

134,46; 134,04 (2C, C-6, C-7)

132,78; 132,43 (2C, C-4A, C-8A)

130,08; 129,96 (2C, C-2, C-6')

127,88; 126,98 (2C, C-5, C-8)

116,74; 116,42 (2C, C-3', C-5')

IR (KBr) (cm-1)

1678, 1659 (C= 0)

Example 15

2-(2,4-differenl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole

5.0 g (24,15 mm) 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphthalene in 150 ml of water, add 150 ml of an aqueous solution containing 29.0 g (120.0 mm) sulfide nonhydrocarbon sodium. The reaction mixture was kept with education is Ino 2.0 ml (18 mm) of 2,4-diferentialglea and 6.3 ml of glacial acetic acid. After keeping under reflux for 3 hours, the resulting solid precipitate is filtered, washed with distilled water, dried, then purified on filterpresses tortilla (carrier: silica, air conditioning: heptane, eluent: dichloromethane). Yellow crystals formed after evaporation of the solvent, recrystallized in dichloromethane, discolor on the animal angle and gain of 3.9 g of 2-(2,4-differenl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole.

The output is 97%,

F: > 260oWITH

Rf: 0.40 in (CH2C12)

SM (I. E. ): m/z 327 (M+. )

NMR1H (CDCls) - (ppm)

8,55 (m, 1H, H-3')

8,28, 8,24 (2dd, 2H, H-5, H-8, JH5-H6= JH7-H8= cent to 8.85 Hz, JH5-H7= JH6-H8= 1.73 Hz)

to 7.84 (m, 2H, H-6, H-7)

7,10 (m, 2H, H-5', H-6')

NMR 13With (CDCl3) - (ppm)

178,88, 177,93 (2C, C-4, C-9)

163,45 (1C, C-2)

134,87, 134,52 (2C, C-6, C-7)

133,44, 133,10, 131,61 (4C, C-3A, C-4A, C-8A, C-9a)

127,95, 127,18 (2C, C-5, C-8)

123,45 (1C, C-1')

113,53, 113,21 (2C, C-2', C-4')

105,56, 105,18, 104,79 (3C, C-3', C-5', C-6')

IR (KBr): (cm-1)

1681, 1658 (C= 0)

Example 16

4,9-dihydro-4,9-dioxo-2-(3-pyridyl)-oil[2,3-d] thiazole

To a suspension of 10.0 g (48,2 mm) 2-amino-3-chloro-1,4-dihyd-ro-1,4-dioxopiperidin in 100 ml of water add 13,88 g (74,5 mm) sulfide aching blue color at 60oC. To strengthen the color change must be added to the water of 4.00 g (16,7 mm) concentrated sodium sulfide. Then add successively 6 ml (60,6 mm) 3-pyridine-carboxaldehyde and 10 ml of glacial acetic acid. After keeping under reflux for 2 hours and completely cool, add 300 ml of ethanol. The formed precipitate is removed by filtration. The filtrate is evaporated to dryness, dissolved in dichloromethane, washed several times with ether, then with water, dried, then purified by medium pressure column (carrier: silica, air conditioning: heptane, eluent: dichloromethane/methanol from 100/0 to 99/1). Yellow crystals formed after evaporation of the solvent, washed with ethanol, then discolor and recrystallized in dichloromethane and get 10,0 g of 4,9-dihydro-4,9-dioxo-2-(3-pyridyl)-oil[2,3-d] thiazole in the form of yellow crystals.

Output is 7%,

F: 256oWITH

Rf: 0.50 in (CH2C12/methanol, 98/2)

SM (I. E): m/z 292 (M+. )

NMR1H (CDCl3) - (ppm)

was 9.33 (d, 1H, H-2', J= 1,83 Hz)

8,80 (d, 1H, H-6', JH5'-H6'= 3,36 Hz)

8,49 (d, 1H, H-4, JH4'-H5'= to 7.93 Hz)

at 8.36, compared to 8.26 (2dd, 2H, H-5, H-8, JH5-H6= JH7-H8= cent to 8.85 Hz, JH5-H7= JH6-H8= 1.73 Hz)

to 7.84 (m, 2H, H-6, H-7)

to 7.50 (dd, 1H, NS, P-2)

155,18 (1C, C-3A)

152,87, 148,58 (2C, C-2', C-6')

142,18 (1C, C-9a)

134,77, 134,31 (2C, C-6, C-7)

134,18 (1C, C-4')

132,74, 132,01 (2C, C-4A, C-8A)

128,36 (1C, C-3')

128,04, 127,16 (2C, C-5, C-8)

124,56 (1C, C-5')

IR (KBr): (cm-1)

1680, 1660 (C= 0)

Example 17

Sulfate 4,9-dihydro-4,9-dioxo-2-(4-pyridyl)-oil[2,3-d] thiazole

To a suspension of 500 mg (1,71 mm) 4,9-dihydro-4,9-dioxo-2-(4-pyridyl)-oil[2,3-d] thiazole in 60 ml of methanol, add 60 ml of methanol containing of 0.18 ml (1,74 mm) 98% sulphuric acid. After keeping under reflux for 1 h and complete cooling of the formed yellow precipitate was filtered, washed several times with ethyl ether, then dried. Receive 500 mg of sulfate 4,9-dihyd-ro-4,9-dioxo-2-(4-pyridyl)-oil[2,3-d] thiazole in the form of yellow crystals.

The yield is 75%,

F: > 260oWITH

Rf: 0.50 in (CH2C12/methanol 96/4)

IR (KBr): (cm-1)

3100 and 2725 (NH+); 1686, 1668 (C= 0)

Example 18

4,9-dihydro-4,9-dioxo-2-(3-furyl)-oil[2,3-d] thiazole

6.0 g (29 mm) 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphthalene was added 100 ml of a freshly prepared aqueous solution containing 34.8 g (145 mm) sulfide nonhydrocarbon sodium. The reaction mixture was stirred at 70oC for 20 minutes to the second acid. After stirring for 2 hours at 50oWith and within 1 h 40 min at room temperature the obtained dark yellow precipitate was filtered and washed twice in 500 ml of water. Thus obtain 7.0 g of crystals, which dissolve in 500 ml of dichloromethane, washed three times in 750 ml of water, then dried over calcium chloride and filtered. After evaporation of dichloromethane under reduced pressure, the obtained solid orange clean the filtering on a layer of silica (dichloromethane/heptane 80/20) and get 3.5 g of 4,9-dihydro-4,9-dioxo-2-(3-furyl)-oil[2,3-d] thiazole in the form of yellow crystals, which are recrystallized in ethyl acetate after bleaching at animal corner.

The output is 43%,

F: 245oWITH

Rf: 0,58 (CH2C12)

SM (I. E): m/z 281 (M+. )

NMR 1H (CDCl3) - (ppm)

a 8.34 (dd, 1H, H-5 or H-8, JH5-H6= JH7-H8= cent to 8.85 Hz, JH5-H7= JH6-H8= 1.73 Hz)

of 8.28 (dd, 1H, H-2, JH2'-H5'= 1,50 Hz, JH2'and H4'or = 0.90 Hz)

8,23 (dd, 1H, H-5 or H-8, JH5-H6= JH7-H8= cent to 8.85 Hz, JH5-H7= JH6-H8= 1.73 Hz)

7,81 (m, 2H, H-6, H-7)

7,56 (t, 1H, H-5', JH2'-H5'= 1.50 Hz)

6,98 (dd, 1H, H-4, JH2'and H4'or = 0.90 Hz, JH4'-H5'= 1.80 Hz)

NMR13C (CDCl3) - (ppm)

178,28, 177,83 (2C, C-4, C-9)

167,28 (1C, C-2)

127,86, 126,90 (2C, C-5, C-8)

120,80 (1C, C-3')

109,19 (1C, C-4')

IR (KBr): (cm-1)

1678, 1656 (C= 0)

Example 19

2-(5-chloro-furan-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole

In a solution of 1.78 g (6.3 mm) 4,9-dihydro-4,9-dioxo-2-(2-furyl)-oil[2,3-d] thiazole in 600 ml of chloroform bar-bootroot chlorine gas at 0oC for 2 min, the Reaction mixture is stirred for 10 minutes to obtain a light yellow solution. The excess chlorine is removed by passing a stream of argon. The yellow solid obtained after evaporation under reduced pressure, purified by column flash chromatography (silica 6-35 μm, air conditioning: heptane, eluent: dichloromethane/heptane 50/50) and gain of 0.43 g of light yellow crystals. After filtering on a layer of silicon dioxide obtain 0.40 g of 2-(5-chloro-furan-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole in the form of yellow crystals after recrystallization and discoloration on the animal corner.

Output - 20%,

F: 257,7oWITH

Rf: 0,42 (CH2C12)

SM (I. E): m/z 315 (M+. )

NMR1H (CDCl3) - (ppm)

with 8.33 (dd, 1H, H-5 or H-8, JH5-H6= cent to 8.85 Hz, JH5-H7= 1.73 Hz)

8,23 (dd, 1H, H-5 or H-8, JH5-H6= cent to 8.85 Hz, JH5-H7= 1.73 Hz)

7,81 (m, 2H, H-6, H-7)

the 7.43 (d, 1H, H-3', JH3'-H4'= to 3.58 Hz)

141,10 (1C, C-2')

140,78 (1C, C-3A)

139,58 (1C, C-9a)

134,40, 134,17 (2C, C-6, C-7)

133,10, 132,68 (2C, C-4A, C-8A)

127,86, 126,95 (2C, C-5, C-8)

115,65 (1C, C-3')

113,34 (1C, C-4')

IR (KBr): (cm-1)

1678, 1652 (C= 0)

Example 20

4,9-dihydro-4,9-dioxo-2-(2-thienyl)-oil[2,3-d] thiazole

In of 4.00 g (19 mm) 2-amino-3-chloro-1,4-dihydro-1,4 - deoxidation add 150 ml of a freshly prepared aqueous solution containing of 22.8 g (95 mm) sulfide nonhydrocarbon sodium. The reaction mixture is brought to 80oC for 20 minutes to obtain a blue color. Then add successively 1.8 ml (19 mm) thiophene-2-carboxaldehyde and 5.0 ml (87 mm) glacial acetic acid. After stirring for 2 hours, the obtained black-brown precipitate is filtered, dissolved in 350 ml of dichloromethane. The organic phase is washed three times with 150 ml of water, dried over calcium chloride and filtered. Orange solid substance obtained after evaporation of dichloromethane under reduced pressure, discolor on the animal angle and recrystallized in dichloromethane, receiving a 2.71 g of 4,9-dihydro-4,9-dioxo-2-(2-thienyl)-oil[2,3-d] thiazole in the form of red-orange crystals.

The output is 48%,

F: > 260oWITH

Rf: 0,58 (CH2Cl2)

SM (I. E): m/z 297 (M+. )

I
8,21 (dd, 1H, H-5 or H-8, JH5-H6= JH7-H8= cent to 8.85 Hz, JH5-H7= JH6-H8= 1.73 Hz)

of 7.82 (m, 3H, H-6, H-7, H-5')

a 7.62 (dd, 1H, H-3, JH3'-H4'= 4,88 Hz, JH3'-H5'= 1,00 Hz)

to 7.18 (dd, 1H, H-4', JH3'-H4'= 4,88 Hz, JH4'-H5'= 3,49 Hz)

NMR13C (CDCl3) - (ppm)

178,32, 177,92 (2C, C-4, C-9)

169,34 (1C, C-2)

155,14 (1C, C-3A)

135,50 (1C, C-9a)

134,37, 134,02 (2C, C-6, C-7)

132,78, 132,43 (2C, C-4A, C-8A)

130,19 (1C, C-4')

128,50 (1C, C-3')

127,84, 127,61 (2C, C-5, C-8)

126,86 (C-5')

IR (KBr): (cm-1)

1676, 1654 (C= 0)

Example 21

4,9-dihydro-4,9-dioxo-2-(3-thienyl)-oil[2,3-d] thiazole

4.0 g (19 mm) 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphthalene add 90 ml of freshly prepared aqueous solution containing of 22.8 g (95 mm) sulfide nonhydrocarbon sodium. The reaction mixture is brought to 90oC for 20 minutes to obtain a blue color. Then add successively 1.8 ml (19 mm) thiophene-3-carboxaldehyde and 5.0 ml (87 mm) glacial acetic acid. After stirring for 2 hours at 90oWith the yellow-green precipitate was filtered, washed three times in 400 ml of water and dried. The crystals are dissolved in 200 ml of isopropanol, stirred at room temperature for 1 h, then filtered, dried and recrystallized in dichloromethane is Alto-ochre crystals.

The output is 70%,

F: 258oWITH

Rf: 0,55 (CH2C12/methanol of 99.5/0.5 to)

SM (I. E): m/z 297 (M+. )

NMR1H (CDCl3) - (ppm)

of 8.37 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= cent to 8.85 Hz, JH5-H7or JH6-H8= 1.73 Hz)

8,23 (m, 2H, H-5 or H-8, H-2')

7,81 (m, 2H, H-6, H-7)

7,71 (d, 1H, H-5', JH4'-H5'= 4,88 Hz)

of 7.48 (dd, 1H, H-4', JH4'-H5'= 4,88 Hz, JH2'and H4'= 2,99 Hz)

NMR13With (CDCl3) - (ppm)

178,32, 177,92 (2C, C-4, C-9)

169,34 (1C, C-2)

155,14 (1C, C-3A)

140,69 (1C, C-9a)

134,36, 134,04 (2C, C-6, C-7)

133,09, 132,71 (2C, C-4A, C-8A)

128,23 (1C, C-4')

127,84 (1C, C-5')

127,61, 126,89, 126,59 (3C, C-5, C-8, C-2')

IR (KBr): (cm-1)

1674, 1655 (C= 0)

Example 22

4,9-dihydro-4,9-dioxo-2-phenylamine-oil[2,3-d] thiazole

In a solution of 200 mg (0.8 mm) of 2-chloro-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole in 100 ml of ethanol is added at 80oWith 730 ml (8 mm) of aniline. The reaction mixture was kept under reflux for 3.5 h, and the resulting red precipitate was filtered after cooling, then clean the filter pressey tortilla (carrier: silica 6-35 μm, eluent: dichloromethane/heptane from 20/80 to 100/0, then dichloromethane/ethyl acetate from 99.5/0.5 to 0/100). Pure fractions are collected, filtered on a Millipore filter, the solvent is evaporated at below the S="ptx2">

Output - 80%,

F: > 260oWITH

Rf: 0,44 (CH2CL2/ethyl acetate 90/10)

SM (I. E): m/z 306 (M+. )

NMR 1H (DMSO-d6) - (ppm)

11,34 (s, 1H, NH)

of 8.09 (m, 2H, H-5, H-8)

7,86 (m, 2H, H-6, H-7)

of 7.70 (m, 2H, H-2', H-6')

7,44 (m, 2H, H-3, H-5')

7,14 (m, 1H, H-4')

NMR13C (DMSO d6) - (ppm)

178,04, 177,31 (2C, C-4, C-9)

167,72 (1C, C-2)

154,61 (1C, C-3A)

of 145.95 (1C, C-9a)

139,49 (1C, C-1')

134,02, 133,93 (2C, C-6, C-7)

132,79, 132,06 (2C, C-4A, C-8A)

129,36 (2C, C-3', C-5')

126,76, 125,73 (2C, C-5, C-8)

123,68 (1C, C-4')

118,60 (2C, C-2, C-6')

IR (KBr): (cm-1)

3228 (NH); 1677, 1632 (C= 0)

Examples 23 and 24

4,9-dihydro-4,9-dioxo-8-methoxy-2-phenyl-oil[2,3-d] thiazole and

4,9-dihydro-4,9-dioxo-5-methoxy-2-phenyl-oil[2,3-d] thiazole

Intermediate compound synthesis:

1,4-dihydro-1,4-dioxo-5-methoxynaphthalene

In the solution 26,45 g (0,147 M) 1,4-dihydro-1,4-dioxo-5-hydroxynaphthalene 1300 ID dichloromethane was added dropwise 39 ml (0,303 M) iodomethane, then 73,50 g of silver oxide. The reaction mixture was stirred for 72 h, then filtered. The filtrate is dried over calcium chloride and then evaporated under reduced pressure. Get 28,50 g of orange crystals, which cleans the filter pressey tortilla (carrier: silica 40-60 mm, eluent: heptane/ethyl acetate 70/ Rf: 0.50 in (ethyl acetate/heptane 50/50)

NMR 1H (CDCl3) - (ppm)

7,72 (m, 2H, H-6, H-8)

to 7.32 (dd, 1H, H-7, JH6-H7= JH7-H8= 7,63 Hz)

to 6.88 (m, 2H, H-2, H-3)

to 4.01 (s, 3H, och3)

2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene

In a solution of 3.5 g (18.6 mm) 1,4-dihydro-1,4-dioxo-5-methoxynaphthalene in 135 ml of chloroform, add 3,05 g (37,2 mm) of sodium acetate and 3 ml (58,4 mm) of bromine. The reaction medium is stirred for 48 hours salt Formed acetate filter. The filtrate is washed with distilled water, dried over calcium chloride and then evaporated under reduced pressure and get to 7.3 g of 1,4-dihydro-1,4-dioxo-2,3-dibromo-5-methoxynaphthalene in the form of orange crystals.

The output is 100%,

F: 190oWITH

NMR1H (DMSO-d6) - (ppm)

7,80 (dd, 1H, H-8, JH7-H8= a 7.85 Hz, JH6-H8= 1,53 Hz)

7,73 (dd, 1H, H-7, JH6-H7= a 8.34 Hz, JH6-H8= a 7.85 Hz)

7,37 (m, 1H, H-6)

of 3.95 (s, 3H, och3)

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene

In a solution of 500.0 mg (1.5 mm) of 2,3-dibromo-1,4-dihyd-ro-1,4-dioxo-5-methoxynaphthalene in 25 ml of tetrahydrofuran, add a drop of ammonia. The reaction medium becomes black. Then pass the stream of ammonia for 2 h at 20oC. IP is silicon oxide, eluent: dichloromethane/heptane 80/20) and get 347,3 mg of a mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene.

Total yield: 82%.

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene

NMR1H (DMSO-d6) - (ppm)

for 7.78 (d, 1H, H-8, JH7-H8= 7,94 Hz)

to 7.67 (dd, 1H, H-7, JH6-H7= 8,54 Hz, JH7-H8= 7,94 Hz)

of 7.25 (d, 1H, H-6, JH6-H7= 8,54 Hz)

to 3.99 (s, 3H, och3)

of 1.73 (s, 2H, NH2)

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene

NMR1H (DMSO-d6) - (ppm)

7,73 (d, 1H, H-8, JH7-H8= to 8.57 Hz)

to 7.61 (t, 1H, H-7, JH7-H6= JH7-H8= to 8.57 Hz)

7,34 (d, 1H, H-6, JH6-H7= to 8.57 Hz)

of 3.97 (s, 3H, och3)

of 1.73 (s, 2H, NH2)

4,9-dihydro-4,9-dioxo-8-metakey-2-phenyl-oil[2,3-d] thiazole (Example 23) and

4,9-dihydro-4,9-dioxo-5-methoxy-2-phenyl-naphthol[2,3-d] thiazole (Example 24)

In the solution 93,70 g (389 mm) nonhydrocarbon of sodium sulfide in 400 ml of water, add 18,30 g (64,87 mm) mixture (1/1) 2-amino-3-bromo-5-methoxy-1,4-dihydro-1,4-deoxidation and 2-amino-3-bromo-8-methoxy-1,4-dihydro-1,4-deoxidation. Reaction medium was incubated under reflux to obtain a blue color. Then add sequentially to 6.6 ml (64,87 mm) benzalde the full cooling, the precipitate is filtered, washed in ethanol, dissolved in chloroform. The organic phase is washed with water, dried over calcium chloride. After evaporation of the solvents under reduced pressure get 16,50 g of yellow crystals, which are then purified by column flash chromatography (carrier: silica 40-60 mm; eluent: dichloromethane/ethyl acetate from 100/0 to 97/3) and after bleaching and recrystallization in dichloromethane get 8.90 g 4,9-dihydro-4,9-dioxo-8-methoxy-2-phenyl-oil[2,3-d] thiazole (example 23) and to 2.29 g of 4,9-dihydro-4,9-dioxo-5-methoxy-2-phenyl-oil[2,3-d] thiazole (example 24) in the form of yellow crystals.

4,9-dihydro-4,9-dioxo-8-methoxy-2-phenyl-naphthol[2,3-d] thiazole (example 23)

Yield: 42%,

F: > 260oWITH,

Rf: 0,55 (CH2C12/ethyl acetate 90/10),

SM (I. E. ): m/z 321 (M+. )

NMR1H (CDCl3) - d (ppm)

to 8.14 (dd, 2H, H-2', H-6', JH2'-H3'= JH5'-H6'= 6,10 HZ, JH2'and H4'= JH4'-H6'= 1.80 Hz)

of 7.90 (d, 1H, H-5, JH5-H6= 7,63 Hz)

7,73 (dd, 1H, H-6, JH5-H6= 7,60 Hz, JH6-H7= 8,50 Hz)

7,52 (m, 3H, H-3', H-4', H-5')

7,39 (d, 1H, H-7, JH6-H7= 8,50 Hz)

4,06 (s, 3H, och3)

NMR13C (CDCl3): d (ppm)

177,95 (1C, C-9)

177,58 (1C, C-4)

161,00 (1C, C-RMS)

135,98 (1C, C-RMS)

135,01 (1C, C-6)

132,23 (1C, C-4')

129,20 (2C, C-3', C-5')

Re-4,9-dioxo-5-methoxy-2-phenyl-oil[2,3-d] thiazole (example 24)

Yield: 11%,

F: 245oWITH,

Rf: 0,47 (CH2C12/ethyl acetate 98/2),

SM (I. E. ): m/z 321 (M+. )

NMR1H (CDCl3) - d (ppm)

of 8.15 (dd, 2H, H-2', H-6, JH2'-H3'= JH5'-H6'= 7,98 Hz, JH2'and H4'= JH4'-H6'= 1.90 Hz)

a 7.92 (d, 1H, H-8, JH7-H8= 7,60 Hz)

7,73 (t, 1H, H-7, JH7-H8= JH6-H7= 8,00 Hz)

7,53 (m, 3H, H-3', H-4', H-5')

7,39 (d, 1H, H-6, JH6-H7= 8,00 Hz)

a 4.03 (s, 3H, och3)

NMR13With (CDCl3): d (ppm)

161,50 (1C, C-5)

135,50 (1C, C-RMS)

135,08 (1C, C-7)

132,20 (1C, C-4')

129,70 (2C, C-3', C-5')

127,80 (2C, C-2', C-6')

119,75 (1C, C-6)

119,02 (10, C-8)

57,00 (1C, CO3)

IR (KBr): (cm-1)

1678, 1651 (C= 0)

Examples 25 and 26

4,9-dihydro-4,9-dioxo-7-methoxy-2-phenyl-oil[2,3-d] thiazole and

4,9-dihydro-4,9-dioxo-6-methoxy-2-phenyl-oil[2,3-d] thiazole

In a solution of 9.9 g (41,00 mm) nonhydrocarbon of sodium sulfide in 27 ml of water is added to 1.9 g (6.7 mm) mixture (1/1) 2-amino-3-bromo-6-methoxy-1,4-dihydro-1,4-deoxidation and 3-amino-2-bromo-6-methoxy-1,4-dihydro-1,4-deoxidation. The reaction medium is maintained at 50oTo obtain a blue color. Then add successively 0,685 ml (6.7 mm) benzaldehyde and 2,300 ml of glacial acetic acid. After heating for 3 h and full cooling poluchennym in 100 ml of water, dried over calcium chloride and evaporated under reduced pressure. Obtain 4.0 g of yellow crystals, which are then purified by chromatography on a column of medium pressure (carrier: silica 6-35 mm, inner diameter: 3.0 cm, height 40 cm, pressure: 30 bar, eluent: heptane/dichloromethane from 100/0 to 65/35). The obtained yellow crystals discolor and recrystallized in dichloromethane and obtain 0.2 g of 4,9-dihydro-4,9-dioxo-7-methoxy-2-phenyl-oil[2,3-d] thiazole (example 25) and 1.2 g of 4,9-dihydro-4,9-dioxo-6-methoxy-2-phenyl-oil[2,3-d] thiazole (example 26)

4,9-dihydro-4,9-dioxo-7-methoxy-2-phenyl-oil[2,3-d] thiazole (example 25)

Output: 1,5% and

F: > 260oWITH,

Rf: 0,47 (CH2C12)

SM (I. E. ): m/z 321 (M+. )

NMR1H (270 MHz, CDCl3) - d (ppm)

to 8.20 (s, 1H, H-8)

of 8.15 (dd, 2H, H-2', H-6, JH2'-H3'= JH5'-H6'= 7,21 Hz, JH2'and H4'= JH4'-H6'= 1,93 Hz)

for 7.78 (d, 1H, H-5, JH5-H6= 8,65 Hz)

7,53 (m, 3H, H-3, H-4', H-5')

from 7.24 (d, 1H, H-6, JH5-H6= 8,65 Hz)

to 4.01 (s, 3H, och3)

NMR13(270 MHz, CDCl3) - d (ppm)

132,68 (1C, C-5)

129,84 (1C, C-4')

129,69 (2C, C-3', C-5')

128,20 (2C, C-2, C-6')

120,64 (1C, C-6)

MONTHS AMOUNTS TO 111.99 (1C, C-8)

56,58 (OCH3)

IR (KBr): (cm-1)

1679 (C= 0)

4,9-dihydro-4,9-dioxo-6-methoxy-2-phenyl-oil[2,3-d] Tias (M+. )

NMR1H (270 MHz, CDCl3) - d (ppm)

8,29 (d, 1H, H-8, JH7-H8= 8,65 Hz)

to 8.14 (d, 2H, H-2', H-6', JH2'-H3'= JH5'-H6'= 7,21 Hz)

to 7.67 (d, 1H, H-5 JH5-H7= 2,67 Hz)

7,52 (m, 3H, H-3', H-4', H-5')

of 7.25 (dd, 1H, H-7 JH7-H8= 8,65 Hz, JH5-H7= 2,67 Hz)

to 4.01 (s, 3H, och3)

NMR13C (270 MHz, CDC13) - d (ppm)

164,21 (1C, C-6)

155,88 (1C, C-RMS)

135,87 (1C, C-RMS)

132,31 (1C, C-5)

130,30 (1C, C-4')

129,25 (2C, C-3, C-5')

127,79 (2C, C-2', C-6')

127,40 (1C, C-RMS)

120,27 (1C, C-7)

110,09 (1C, C-8)

56,05 (OCH3)

IR (KBr): (cm-1)

1667 (C= 0)

Example 27

4,9-dihydro-4,9-dioxo-8-hydroxy-2-phenyl-nefto [2,3-d] thiazole

A suspension of 1.00 g (0,003 M) 4,9-dihydro-4,9-dioxo-8-methoxy-2-phenyl-oil[2,3-d] thiazole (example 23) in 67 ml (1,160 M) of acetic acid and 67 ml (0,570 M) Hydrobromic acid withstand under reflux for 5 h 30 min After cooling to 10oWith the reaction medium is filtered on mitrofanna glass. The residue is dissolved in 200 g of chloroform. The organic phase is washed with 3% solution of ammonia (340 ml) and dried over calcium chloride. The yellow solid obtained after evaporation of the solvent under reduced pressure, purified by medium-pressure column (carrier: dvol/heptane 50/50 and get 0,302 g of 4,9-dihydro-4,9-dioxo-8-hydroxy-2-phenyl-oil[2,3-d] thiazole.

Yield: 33%,

F: 263,5oWITH,

Rf: 0,51 (heptane/ethyl acetate 70/30),

SM (I. E. ): m/z 307 (M+. )

NMR1H (CDCl3) - d (ppm)

8,08 (dd, 2H, H-2, H-6, JH2'-H3'= JH5'-H6'= 8,4 Hz, JH2'-H4'= JH4'-H6'= 1,4 Hz)

7,81 (dd, 1H, H-5, JH5-H7= 7,6 Hz, JH5-H6= 1,4 Hz)

to 7.67 (t, 1H, H-7)

at 7.55 (m, 3H, H-3, H-4', H-5')

to 7.35 (dd, 1H, H-6, JH6-H7= 8,4 Hz)

NMR13With (CDCl3) - d (ppm)

163,11 (1C, C-8)

136,57 (1C, C-6)

132,53 (1C, C-4')

129,32 (2C, C-3, C-5')

127,75 (2C, C-2', C-6')

125,62 (1C, C-7)

120,17 (1C, C-5)

IR (KBr): (cm-1)

1650 (C= 0)

Example 28

4,9-dihydro-4,9-dioxo-2-(1-pyrrolyl)-oil[2,3-d] thiazole

In the suspension of 2.30 g (0.01 M) 2-amino-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole in 25 ml of acetic acid is added at a high temperature of 1.3 ml (0.01 M) of 2,5-dimethoxyethane-hydrofuran. The reaction mixture was kept under reflux for 2 hours Received light brown precipitate was filtered, dissolved in dichloromethane, and then washed three times in 200 ml of distilled water. The organic phase is dried over calcium chloride, filtered and evaporated under reduced pressure, obtaining of 1.80 g of yellow solid, which was then purified by column flash chromatography (carrier: silica 6-35 mm, conditioning is the form of yellow crystals after recrystallization and discoloration on the animal corner.

Yield: 64%,

F: > 260oWITH,

Rf: 0,41 (CH2Cl2)

SM (I. E. ): m/z 280 (M+. )

NMR1H (CDCl3) - d (ppm)

8,29; 8,20 (2dd, 1H, H-5, H-8, JH5-H6= cent to 8.85 Hz, JH5-H6= 1.73 Hz)

7,79 (m, 2H, H-6, H-7)

of 7.48 (m, 2H, H-2', H-5')

6.42 per (m, 2H, H-3', H-4')

NMR13C (CDCl3) - d (ppm)

177,89; 177,47 (2C, C-4, C-9)

165,60 (1C, C-2)

153,00 (10-3A)

137,14 (10-9a)

134,30; 134,06 (2C, C-6, C-7)

132,87; 132,38 (2C, C-4A, C-8A)

127,75; 126,69 (2C, C-5, C-8)

120,52 (2C, C-2', C-5')

114,23 (2C, C-3', C-4')

IR (KBr): (cm-1)

1680, 1665 (C= 0)

Examples 29 and 30

2-(5-bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole

2-(4,5-dibromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole

10.0 g (35,6 mm, 1 EQ. ) 4,9-dihydro-4,9-dioxo-2-(furan-2-yl)-oil[2,3-d] thiazole are dissolved in 750 ml of dichloromethane, previously dried on a molecular sieve. The solution is cooled to 0oWith add small portions of 11.2 g (81,9 mm, 2.3 EQ. ) ammonium chloride.

The reaction mixture was kept under reflux, was added dropwise to 8.0 ml (126,0 mm, 3.5 EQ. ) of bromine in solution in 20 ml of dichloromethane, the reaction is carried out for 5 hours. The solution is cooled and carefully poured into a saturated solution of hydrogencarbonate sodium. The organic phase is washed several Radnevo orange color) obtained after evaporation of the solvent, purified by column flash chromatography (carrier: silica 6-35 μm, eluent: CH2Cl2/heptane 50/50, CH2Cl280/20) to give after evaporation of 4.5 g of 2-(5-bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole in the form of orange crystals and 380 mg of 2-(4,5-dibromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole in the form of yellow crystals.

2-(5-bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole

Output: 42,8%,

F: > 260oC,

Rf: 0,47 (CH2C12)

SM (I. E. ): m/z 359-361 (M+. )

NMR1H (CDCl3) - d (ppm)

a 8.34 (m, 1H, H-5 or H-8)

8,23 (m, 1H, H-5 or H-8)

7,81 (m, 2H, H-6, H-7)

7,40 (d, 1H, H-3', JH3'-H4'= 3,74 Hz)

6,59 (d, 1H, H-4, JH3'-H4'= 3,67 Hz)

NMR13C (CDCl3) - d (ppm)

178,28; 177,99 (2C, C-4, C-9)

162,67 (P-2)

162,06 (C-2')

155,35 (C-3A)

149,88 (C-9a)

140,88 (C-5')

134,58; 134,27 (2C, C-6, C-7)

133,30; 132,83 (2C, C-4A, C-8A)

127,24; 127,13 (2C, C-5, C-8)

115,23; 115,50 (2C, C-3, C-4')

IR (KBr): (cm-1)

1682, 1656 (C= 0)

2-(4,5-dibromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole

Output: 2.4 per cent,

F: > 260oWITH,

Rf: 0,63 (CH2C12)

SM (APcI-): m/z 438 (M-H),

NMR1H (CDCl3) - d (ppm)

8,35 (m, 1H, H-5 or H-8)
6, C-7)

127,92; 127,03 (2C, C-5, C-8)

117,59 (1C, C-3')

IR (KBr): (cm-1)

1685 and 1655 (C= 0)

Example 31

2-(3-bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole

150 ml of a solution of sodium hydroxide (pH of 10.7) add 5,33 g (22.2 mm, 1 EQ. ) sulfide nonhydrocarbon sodium. The solution is maintained at 90oAnd stirred in an argon atmosphere. Add 4.61 in (22.2 mm, 1 EQ. ) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation, mix the solution until obtaining a blue color. The solution is cooled to 20-25oTo add to the reaction medium to 3.89 g (22.2 mm) 3-bromo-2-furaldehyde (CAS No 14757-78-9). After 5 min replace pozirovanie argon compressed air for 1 hour, then was added dropwise 5 ml of acetic acid, is a brown-red color.

Stirring is carried out for 5 min, the resulting black precipitate was filtered on mitrofanna glass, washed with water and dried, get of 9.30 g of the product, which is purified several times on the column for PDEs-chromatography (carrier: silica 6-35 μm, diameter: 4.5 cm, height: 30 cm, eluent: dichloromethane/heptane 50/50).

After evaporation of the solvent to obtain 2.15 g of 2-(3-bromo-2-furan-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole in the form of an orange crystal>/BR>NMR1H (CDCl3) - (ppm)

at 8.36 (m, 1H, H-5 or H-8)

of 8.25 (m, 1H, H-5 or H-8)

of 7.82 (m, 2H, H-6, H-7)

the 7.65 (d, 1H, H-5', JH4'-H5'= 2,14 Hz)

to 6.75 (d, 1H, H-4, JH4'-H5'= 2,14 Hz)

NMR13C (DMSO d6) - (ppm)

147,95 (1C, C-5')

134,82; 134,42 (2C, C-6, C-7)

127,24; 126,44 (2C, C-5, C-8)

117,50 (1C, C-4')

IR (KBr): (cm-1)

1680 and 1655 (C= 0)

Example 32

2-(4-bromofuran-2-yl)-4,9-digidoc-4,9-dioxo-oil[2,3-d] thiazole

In 0,257 g (1,24 mm, 1 EQ. ) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation in 9 ml of water is added 1.19 g (4,96 mm, 4 EQ. ) sulfide nonhydrocarbon sodium. The mixture was kept under reflux until such time as the reaction medium will completely acquire a blue color. When 90oWith added 0.26 g (1,48 mm 1,19 EQ. ) 4-bromo-2-furaldehyde. The reaction medium is cooled to room temperature, then add to 0.28 ml of acetic acid. A precipitate. The reaction medium is stirred for one hour at room temperature. The precipitate is filtered, washed with water. The precipitated brown (0.35 g) is purified by column flash chromatography (carrier: aluminium hydroxide, air conditioning: dichloromethane/heptane 70/30, eluent: dichloromethane/heptane 70/30, then 80/20, then 100/0, then dichloromethane/methanol 99,6/0,4) with obrazovanog: 32%

F: > 260oWITH,

Rf: 0,23 (dichloromethane/heptane, 70/30) on the media of aluminium hydroxide.

SM (I. E. ): m/z 360 (M+. )

NMR1H (CDCl3) - (ppm)

a 8.34 (m, 1H, H-5 or H-8)

of 8.25 (m, 1H, H-8 or H-5)

7,83 (m, 2H, H-6, H-7)

to 7.64 (d, 1H, H-5', JH3'-H5'= 0,95 Hz)

7,46 (d, 1H, H-3', JH3'-H5'= 0,95 Hz)

NMR13C (CDCl3) - (ppm)

143,76 (1C, C-5')

134,48; 134,17 (2C, C-6, C-7)

127,89; 126,99 (2C, C-5, C-8)

116,07 (1C, C-3')

IR (KBr): (cm-1)

1680, 1657 (C= 0)

Example 33

4,9-dihydro-4,9-dioxo-2-(5-nitrofuran-2-yl)-oil[2,3-d] thiazole

5 g (17,8 mm) 4,9-dihydro-4,9-dioxo-2-(furan-2-yl)-oil[2,3-d] thiazole added at room temperature 20 ml of fuming nitric acid and 20 ml of concentrated sulfuric acid. The reaction mixture was kept under reflux for 72 hours, the precipitate is filtered on mitrofanna glass, washed with water and ether. The obtained dark-yellow powder is recrystallized in DMF after bleaching at animal corner. Receive 2 g of 4,9-dihyd-ro-4,9-dioxo-2-(5-nitrofuran-2-yl)-oil[2,3-d] thiazole in the form of a dark yellow solid.

Yield: 34%,

F: > 300oC,

Rf: 0,30 (CH2Cl2)

SM (APcI-): m/z 326 (M-. )

NMR1H (CDCl3) - (ppm)

8,39 B>H3'-H4'= 3,74 Hz)

IR (KBr): (cm-1)

1675, 1656 (C= 0)

Example 34

2-(5-aminopurin-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole

In a three-neck flask, 2 g (6,10 mm, 1 EQ. ) 4,9-dihydro-4,9-dioxo-2-(5-nitrofuran-2-yl)-oil[2,3-d] thiazole are dissolved in 1500 ml of absolute ethanol. Placed in an inert atmosphere, add on the tip of a spatula coal containing 30% palladium. The solution is incubated with a reflux condenser and added five receptions 360 μl (of 7.36 mm, 1.2 EQ. ) hydrazine. The reaction is carried out for 1 hour, the color of the solution changes from yellow-green to purple-black. The solution is cooled and filtered to celite. Get 1,65 g solid black after evaporation of the solvent on a rotary evaporator. The solid is purified by column flash chromatography (carrier: silica 6-35 μm, gradient eluent: dichloromethane, then dichloromethane/metamod 98/2) to give 0.36 g of 2-(5-aminopurin-2-ID)-4,9-dihyd-ro-4,9-dioxo-oil[2,3-d] thiazole in the form of blue crystals.

Yield: 20%,

F: > 260oWITH,

Rf: 0,29 (dichloromethane/ethyl acetate 99/1)

SM (APcI+): m/z 297 (M+H+)

NMR1H (DMSO-d6) - (ppm)

8,24 (m, 1H, H-5 or H-8)

8,18 Cm, 1H, H-5 or H-8)

to 7.99 (m, 2H, H-6, H-7)

of 7.60 (d, 1H, H-3, JH3'-H4'
161,0 (1C, C-5')

155,0 (1C, C-2)

138,0 (1C, C-2')

134,3; 134,1 (2C, C-6, C-7)

133,1; 132,4 (2C, C-4A, C-8A)

127,0; 126,0 (2C, C-5, C-8)

122,1 (1C, C-3')

87,5 (1C, C-4')

IR (KBr): (cm-1)

3350 (NH2); 1680 and 1625 (C= 0)

Example 35

2-(5-acetamidophenyl-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole

In a three-neck flask in 0,300 g (1,01 mm, 1 EQ. ) 2-(5-aminopurin-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole was added dropwise at room temperature, 200 ál (2,02 mm, 2 EQ. ) acetic anhydride, then 60 µl (1,01 mm, 1 EQ. ) acetic acid. The resulting suspension heated to 50oWith, acquires a reddish-maroon color. After 2 hours of reaction, the suspension is cooled and dissolved in 500 ml of dichloromethane. The solution is washed twice with a saturated solution of sodium bicarbonate, then several times with water until neutral pH of the aqueous phase. After drying the organic phase over calcium chloride and evaporation of the solvents get 0,330 g solid of the original product red-Burgundy color. The solid is purified by column flash chromatography (carrier: silica 6-35 μm, eluent: dichloromethane/methanol 98/2). The compound obtained is dissolved in dichloromethane, filtered over a Millipore filter. The filtrate is concentrated, and the QRF] thiazole in the form of a brick red crystals.

Yield: 42%,

F: > 260oWITH,

Rf; 0,34 (dichloromethane/methanol 95/5)

SM (APcI+): m/z 339 (M+H+)

NMR1H (DMSO-d6) - (ppm)

of 11.75 (s, 1H, NH)

of 8.28 (m, 1H, H-5 or H-8)

8,23 (t, 1H, H-5 or H-8)

8,03 (t, 2H, H-6, H-7)

of 7.69 (d, 1H, H-3, JH3'-H4'= to 3.73 Hz)

6,62 (d, 1H, H-4', JH3'-H4'= 3,74 Hz)

2,22 (s, 3H, CH3)

NMR13C (DMSO-d6): (ppm)

177, 9MM; 176,5 (2C, C-4, C-9)

167,5 (1C, C-5')

155, 2MM (1C, C-2)

139,0 (1C, C-2')

134,6; RUR 134.4 (2C, C-6, C-7)

132,7; to 132.6 (2C, C-4A, C-8A)

127,2; 126,4 (2C, C-5, C-8)

118,1 (1C, C-3')

97,0 (1C, C-4')

23,4 (1C, CH3)

IR (KBr): (cm-1)

3033 (N-H); 1682 and 1655 (C= 0)

Example 36

4,9-dihydro-4,9-dioxo-2-(5-hydroxymethyl-2-yl)-oil[2,3-d] thiazole

17,36 g (72,2 mm, 5 EQ. ) sulfide nonhydrocarbon sodium are dissolved in 70 ml of water. The solution is heated to 60oWith, then add 3.00 g (14.4 mm, 1 EQ. ) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation. After 30 min stirring at 60oThe solution is cooled to room temperature. In the reaction environment, acquired blue color, add 2,43 g (14.5 mm, 1 EQ. ) 5-acetoxymethyl-2-furaldehyde, then after 5 min was added dropwise 3 ml of acetic acid. Environment acquires a brown-orange color, and the formed precipitate is filtered on friter the lash-chromatography (carrier: silica 6-35 μm, diameter: 5 cm, height: 15 cm, eluent: CH2Cl2/MeOH 96/4). The obtained orange product is recrystallized in dimethylformamide, discolor on the animal angle and filtered on celite and microporous filter with getting 0,80 g of 4,9-dihydro-4,9-dioxo-2-(5-hydroxymethylene-2-yl)-oil[2,3-d] thiazole in the form of ochre crystals.

Yield: 17%,

F: > 260oWITH,

Rf: 0,60 (CH2Cl2/MeOH 96/4)

SM (I. E. ): m/z 311 (M+),

NMR1H (DMSO-d6) - (ppm)

to 8.20 (m, 1H, H-5 or H-8)

8,11 (m, 1H, H-5 or H-8)

to $ 7.91 (m, 2H, H-6, H-7)

7,46 (d, 1H, H-3, JH3'-H4'= 3.1 Hz)

of 6.65 (d, 1H, H-4', JH3'-H4'= 3.1 Hz)

of 5.55 (t, 1H, HE )

of 4.54 (d, 2H, CH2That )

NMR13(DMSO-d6): (ppm)

177,6; 176,6 (2C, C-4, C-9)

160,0 (1C, C-5')

TO 158.4 (1C, C-2)

146,6 (1C, C-2')

RUR 134.4 (2C, C-6, C-7)

132,3; 132,1 (2C, C-4A, C-8A)

127,0; 126,2 (2C, C-5, C-8)

USD 114.9 (1C, C-3')

110,5 (1C, C-4')

55,6 (1C, CH2)

IR (KBr): (cm-1)

3374 (OH); 1677 and 1656 (C= 0)

Example 37

2-(5-acetoxymethyl-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole

Of 5.00 g (24 mm) 2-amino-3-mercapto-1,4-dihydro - 1,4-dioxopiperidin added at 0oC in an atmosphere of argon, 40 ml of N-methylpyrrolidone. The reaction mixture was stirred for 10 min, then added at 0oC 4,10 g is Noah temperature. The contents of the three-neck flask was poured into 250 ml of water, and the resulting light brown precipitate was dissolved in ethyl acetate. The organic phase is extracted, dried on magnesium sulfate, filtered and evaporated under reduced pressure.

The obtained solid light brown color clear for the first time on the column (carrier: silica 6-35 μm, eluent: CH2Cl2/MeOH/AcOEt 97/1/2), receiving 3,29 g of the product.

Take a sample 0,500 g, purified a second time by preparative plates (carrier: silica, eluent: CH2CL2/Meon/t 97/1/2), receiving 0,107 mg of 2-(5-acetoxymethyl-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole in the form of yellow crystals.

Yield: 38%,

F: 204oWITH,

Rf: 0,52 (heptane/AcOEt 50/50),

SM (I. E. ): m/z 353 (M+)

NMR1H (CDCl3) - (ppm)

a 8.34 (m, 1H, H-5 or H-8)

8,24 (m, 1H, H-5 or H-8)

7,81 (m, 2H, H-6, H-7)

7,41 (d, 1H, H-3, JH3'-H4'= 3,74 Hz)

only 6.64 (d, 1H, H-4', JH4'-H3'= 3,32 Hz)

further 5.15 (s, 2H, CH2)

and 2.14 (s, 3H, CH3)

NMR13With (CDCl3) - (ppm)

134,39; 134,14 (2C, C-6, C-7)

133,30; 132,83 (2C, C-4A, C-8A)

127,86; 126,94 (2C, C-5, C-8)

114,52; 113,77 (2C, C-3', C-4, )

57,67 (1C, CH2)

20,83 (1C, CH3)

IR (KBr): (cm-1)

1734, 1686 and 1669, aderrasi 6.2 g of N3IN3and 4 g of NaOH per liter, added 4.6 g (19,3 mm) sulfide nonhydrocarbon sodium. The mixture was stirred at 15oIn an argon atmosphere until dissolved, then add 2 g (9.6 mm) of 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation. After 20 minutes, add in the reaction medium, bought the blue color of 0.96 ml (9.6 mm) 5-methyl-2-furfural.

After 4 hours stirring the contents of the three-neck flask was poured into 100 ml of ethyl acetate, and the three-neck flask rinsed with 50 ml water. The organic phase is washed three times in 80 ml of water and dried on magnesium sulfate. After evaporation of the solvent under reduced pressure to obtain 1 g of the product of orange color, which cleans the filter pressey tortilla (carrier: silica 6-35 μm, eluent: CH2CL2/heptane 50/50, 90/10 and 100) to obtain the 0,560 g of orange crystals, which are recrystallized in a mixture of AcOEt/CH2Cl270/30 after bleaching at animal corner.

Yield: 35%,

F: 254oWITH,

Rf: 0,48 (CH2C12)

SM (I. E. ): m/z 295 (M+)

NMR1H (CD2C12) - (ppm)

by 8.22 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= cent to 8.85 Hz, JH5-H7or JH6-H8= 1.73 Hz)

is 8.16 (m, 1H, H-5 or H-8)

7,80 (m, 2H, H-6, is>3With (CDCl3) - (ppm)

178,43; 178,12 (C-4, C-9)

164,07 (P-2)

157,79 (C-5')

155,00 (C-3A)

146,92 (C-2')

140,60 (C-9a)

134,54; 134,32 (C-6, C-7)

133,50; 133,04 (C-4A, C-8A)

127,72; 126,94 (C-5, C-8)

115,43; 110,16 (C-3, C-4')

14,09 (CH3)

IR (KBr): (cm-1)

1684 and 1653 (C= 0)

Example 39

4,9-dihydro-2-(4,5-dimethyl-2-furyl)-4,9-dioxo-oil[2,3-d] thiazole

200 ml of a solution of sodium hydroxide (pH 10,66) add 6,94 g (28,9 mm) sulfide nonhydrocarbon sodium. The mixture was stirred at 15oIn an argon atmosphere until dissolved, then add 3.00 g (14.4 mm) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation. After 3 hours stirring at room temperature in a reaction medium, bought the blue color and type of 1.80 g (14.4 mm) 4,5-dimethyl-2-furaldehyde, then after 5 min was added dropwise 5 ml of acetic acid, the environment becomes orange.

Stirring is continued for 5 minutes, then pozirovanie argon is replaced by compressed air for 3 minutes

The resulting black precipitate was filtered on mitrofanna glass, washed with water and dried, obtaining of 4.00 g of the product, which is purified by column flash chromatography (carrier: silica 6-35 μm, eluent: heptane/AcOEt 85/15).

Product is stilizovala in ethyl acetate to obtain 2.50 g 4,9-dihydro-2-(4,5-dimethyl-2-furyl)-4,9-dioxo-oil[2,3-d] thiazole in the form of orange crystals.

Yield: 90%,

F: 250oWITH,

Rf: 0,2 (CH2Cl2)

SM (I. E. ): m/z 309 (M+)

NMR1H (CDCl2) - (ppm)

8,31 (dd, 1H, H-5 or H-8, JH5-H6or JH5-H7= cent to 8.85 Hz, JH5-H7or JH6-H8= 1.73 Hz)

by 8.22 (dd, 1H, H-5 or H-8, JH5-H6or JH5-H7= cent to 8.85 Hz, JH5-H7or JH6-H8= 1.73 Hz)

7,80 (t, 2H, H-6, H-7)

of 7.23 (s, 1H, H-3')

of 2.35 (s, 3H, CH35')

2,17 (s, 3H, CH34')

NMR13With (CDCl3) - (ppm)

178,43; 178,12 (2C, C-4, C-9)

172 (P-2)

164,21 (C-2')

155,35 (C-3A)

153,18 (C-5')

145,32 (C-9a)

134,13; 133,97 (20, C-6, C-7)

133,24; 132,89 (2C, C-4A, C-8A)

127,72; 126,79 (2C, C-5, C-8)

118,78 (C-4')

117,51 (C-3')

12,50 (CH35')

10,00 (CH34')

IR (KBr): (cm-1)

1682, 1656 (C= 0)

Example 40

4,9-dihydro-4,9-dioxo-2- (5-phenyl-2-oxazolyl)-oil[2,3-d] thiazole

2-amino-3-chloro-1,4-dihydro-1,4-deoxidation (0.21 g - 1.0 mm) in distilled water (7 ml) is added in an argon atmosphere sulfide nonhydrocarbon sodium (0,98 g - 4.1 mm). The mixture was kept under reflux in an argon atmosphere prior to the acquisition of the reaction medium is completely blue. Then add 5-phenyl-2-oxazolinone (CAS No 96829 - 89-9) (0.21 g - 1.4 mm) in a solution of tetrahydrofuran (6 ml), then the UKS the hour. A precipitate of orange. The precipitate was filtered and washed with water. The orange residue (0.28 g) was partially dissolved in diethylether (21 ml). After filtration of insoluble matters, the filtrate was concentrated in vacuo and subjected to flash chromatography on a column (carrier: silica 6-35 μm, eluent: dichloromethane/metamod 98/2). The orange product obtained after evaporation, discolor on animal charcoal, then filtered on a Millipore filter. After evaporation obtain orange crystals (0.17 g) 4,9-dihydro-4,9-dioxo-2-(5-phenyl-2-oxazolyl)-oil[2,3-d] thiazole.

Yield: 79%,

F: > 260oWITH,

Rf: 0,64 (acetonitrile in reverse phase)

0,76 (dichloromethane/methanol 98/2)

SM (I. E. ): m/z 358 (M+), 330 (M+-FROM)

NMR1H (CDCl3) - (ppm)

at 8.36 (m, 1H, H-5 or H-8)

compared to 8.26 (m, 1H, H-5 or H-8)

the 7.85 (m, 4H, H-6, H-7, H-2", H-6")

of 7.60 (d, 1H, H-4', J= 0.9 Hz)

7,55-7,35 (m, 2H, H-3", H-5")

7,27 (d, 1H, H-4", J= 0.9 Hz)

NMR13With (CDCl3) - (ppm)

178,23; 177,36 (2C, C-4 AND C-9)

160,34 (1C, C-2)

155,20 (1C, C-2')

154,60 (1C, C-3A)

154,37 (1C, C-5')

142,98 (1C, C-9a)

134,71; 134,27 (2C, C-6 and C-7)

133,04; 132,77 (2C, C-4A and C-8A)

129,92 (1C, C-8 or C-5)

129,15 (2C, C-2" and C-6")

128,02 (1C, C-5 or C-8)

127,16 (1C, C-4')

126,51 (1C, C-1")

125,22 (2 dioxo-2-(2-thiazolyl)-oil[2,3-d] thiazole

1.12 g (5,39 mm) 2-amino-3-chloro-1,4-dihydro-1,4-deoxidation in 38 ml of water add 5,18 g (21,56 mm) sulfide nonhydrocarbon sodium. The mixture was kept under reflux until reaction when the environment is fully acquires a blue color. Then when the 90oWith added 0.73 g (6,46 mm) 2-thiazolecarboxamide, then 1.3 ml (22,75 mm) of acetic acid. Reaction medium was cooled rapidly to 0oC in an ice bath. A precipitate. The reaction medium is stirred for one hour at 0oC. the Precipitate is filtered, washed with water. Then the precipitate is partially dissolved in dichloromethane. When filtration and dissolved in dichloromethane change color: sediment light brown color becomes yellow-brown color. After filtration to remove insoluble particles and solvent evaporation obtain 0.3 g of 4,9-dihydro-4,9-dioxo-2-(2-thiazolyl)-oil[2,3-d] thiazole as a yellow-brown crystals.

Yield: 19%,

F: > 260oWITH,

Rf: 0,22 (dichloromethane)

SM (APcI-): m/z 298 (M-),

NMR1H (CDCl3) - (ppm)

at 8.36 (m, 1H, H-5 or H-8)

compared to 8.26 (m, 1H, H-8 or H-5)

8,03 (d, 1H, H-4, JH4'-H5'= 3,06 GHz)

to 7.84 (m, 2H, H-6, H-7)

to 7.67 (d, 1H, H-5', JH4'-H5'= 3,05 Hz)

NMR13With (CDCl3) - (ppm)
1675, 1652 (C= 0)

Examples 42 and 43

4,9-dihydro-4,9-dioxo-6-fluoro-2-(2-furyl)-oil[2,3-d] thiazole and

4,9-dihydro-4,9-dioxo-7-fluoro-2-(2-furyl)-oil[2,3-d] thiazole

Intermediate compound synthesis:

2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fornatale

To a solution of 1,4-dihydro-1,4-dioxo-6-formatline (CAS No 148541-61-1) (12.5 g - 71 mm) in chloroform (250 ml) is added 36 ml (710 mm) of bromine. The solution is incubated under reflux for 12 hours, then brought to room temperature. After ozonation compressed air solution concentrated under reduced pressure, and the obtained solid is washed five times in heptane. Obtain 15.0 g of a beige powder of 2,3-dibromo-1,4-dihydro-1,4-dioxo-6-formatline.

Yield: 65%,

F: 158oWITH,

Rf: 0,80 (dichloromethane)

SM (APcI-): m/z 332, 334, 336 (M+)

NMR1H (CDCl3) - (ppm)

by 8.22 (dd, 1H, H-8, JH7H8= 8,55 Hz, JH-F= 5,19 Hz)

7,81 (dd, 1H, H-5, JH-F= 8,55 Hz, JH5-H7= 2,75 Hz)

was 7.45 (td, 1H, H-7, JH-F= JH7-H8= 8,55 Hz, JH5-H7= 2,75 Hz)

IR (KBr): (cm-1)

1680 (C= 0)

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fornatale and

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-fornatale

In a solution of 6-fluoro-2,3-dibromo-1,4-dihydro-1,4-deoxidation (10,00 g - 30 mm) in tetrahit compressed air within 15 minutes After evaporation of the solvent under reduced pressure, the obtained solid is first cleaned on the cake of silica gel (carrier: silica 6-35 μm, diameter: 5 cm, height: 15 cm, eluent: dichloromethane/heptane 90/10), then purified by three successive thin-layer chromatographic columns of silica gel (carrier: silica 6-35 μm, diameter: 2 cm, height: 30 cm, eluent: dichloromethane/heptane 90/10). Get 4,78 g of powder of a red color, a mixture of 2-amino-3-bromo-6-fluoro-1,4-dihydro-1,4-deoxidation and 2-amino-3-bromo-7-fluoro-1,4-dihydro-1,4-deoxidation.

Yield: 60%, (the ratio of the isomers 75/25)

F: 190-195oWITH,

Rf: 0.40 in (dichloromethane)

SM (APcI-): m/z 270 (M-),

NMR1H (acetone-d6) - (ppm)

of 8.27 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= 8,54 Hz, JH-F= 5,18 Hz)

the 7.85 (dd, 1H, H-5 or H-8, JH-F= 8,54 Hz, JH5-H7or JH6-H8= 2,74 Hz)

7,71 (td, 1H, H-6 or H-7 minor isomer, JH-F= JH5-H6or JH7-H8= 8,54 Hz, JH5-H7or JH6-H8= 2,74 Hz)

to 7.64 (td, 1H, H-6 or H-7 major isomer, JH-F= JH5-H6or JH7-H8= 8,54 Hz, JH5-H7or JH6-H8= 2,74 Hz)

IR (KBr): (cm-1)

3357 (NH2), 1685 (C= 0)

4,9-dihydro-4,9-dioxo-6-fluoro-2-(2-furyl)-oil[2,3-d] thiazole and

4,9-digid is about-6-formatline and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-formatline add 25 ml of sodium hydroxide solution (5,10-4M) containing 1,11 g (4.6 mm to 2.5 EQ. ) sulfide nonhydrocarbon sodium. Suspension red heated for 30 minutes to 80oWith up to the moment when the solution becomes dark blue. Then add 0.3 ml (3.6 mm to 2.0 EQ. ) 2-furaldehyde. After 90 minutes of heating up to 80oWith the resulting solution was dark red to cool to room temperature. Add a few drops of glacial acetic acid, then the resulting orange precipitate was filtered, washed three times in water and dried. Obtain 0.5 g of a mixture of two isomers 4,9-dihydro-4,9-dioxo-6-fluoro-2-(2-furyl)-oil[2,3-d] thiazole and 4,9-dihydro-4,9-dioxo-7-fluoro-2-(2-furyl)-oil[2,3-d] thiazole in the form of red crystals.

The isomers separated by thin-layer chromatography on a column of silica gel (silica 6-35 μm, diameter: 4.5 cm, height 30 cm, eluent: dichloromethane), and then by the method of preparative HPLC (column: Dynamax 60-A Si 83-141C; eluent: heptane/ethyl acetate 80/20) to give 0.125 g of the least polar product and 0.375 g the most polar product.

Yield: 90% (the ratio of the isomers 75/25),

The least polar product

F: > 265oWITH,

Rf: 0,32 (heptane/ethyl acetate 80/20)

SM (APcI-): m/z 299 (M-),

NMR1H (CD2C12) - 55 Hz, JH-For JH6-H8= 2,44 Hz)

to 7.61 (m, 1H, H-5')

7,39 (td, 1H, H-6 or H-7, JH5-H6or JH7-H8= JH-F= 8,55 Hz, JH5-H7or JH6-H8= 2,44 Hz)

7,33 (d, 1H, H-3', JH3'-H4'= 3,66 Hz)

of 6.61 (dd, 1H, H-4', JH3'-H4'= 3,66 Hz, JH4'-H5'= 1,83 Hz)

IR (KBr): (cm-1)

1680 and 1655 (C= 0)

The most polar product

F: > 265oWITH,

Rf: 0,25 (heptane/ethyl acetate 80/20)

SM (APcI-): m/z 299 (M-),

NMR1H (CD2C12) - (ppm)

8,23 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= 8,54 Hz, JH-F= 5.50 Hz)

for 7.78 (dd, 1H, H-5 or H-8, JH-F= 8,54 Hz, JH-For JH6-H8= 2,75 Hz)

to 7.61 (m, 1H, H-5')

7,40 (td, 1H, H-6 or H-7, JH5-H6or JH7-H8= JH-F= 8,55 Hz, JH5-H7or JH6-H8= 2,75 Hz)

7,33 (d, 1H, H-3', JH3'-H4'= 3,66 Hz)

6,60 (dd, 1H, H-4', JH3'-H4'= 3,66 Hz, JH4'-H5'= 1,83 Hz)

IR (KBr): (cm-1)

1680 and 1660 (C= 0)

Examples 44 and 45

4,9-dihydro-4,9-dioxo-6-fluoro-2-phenyl-oil[2,3-d] thiazole and

4,9-dihydro-4,9-dioxo-7-fluoro-2-phenyl-oil[2,3-d] thiazole

In the 0.80 g (2,96 mm - 1,0 EQ. ) 75/25 mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-formatline and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-formatline add 40 ml of an aqueous solution of sulfide nonhydrocarbon sodium (1.78 g - 7,40 mm, 2.5 EQ. ). Suspension red Naga is benzaldehyde and the solution is stirred for 2 hours at 80oC. the resulting solution chestnut color is cooled to room temperature, add a few drops of glacial acetic acid. The resulting dark green precipitate was filtered, washed three times in water and dried. Get 0,820 g of a mixture of 4,9-dihyd-ro-4,9-dioxo-6-fluoro-2-phenyl-oil[2,3-d] thiazole and 4,9-di-hydro-4,9-dioxo-7-fluoro-2-phenyl-oil[2,3-d] thiazole in the form of yellow crystals.

The isomers separated by thin-layer chromatography on three consecutive columns of silica gel (carrier: silica 6-35 μm, diameter: 9.5 cm, height 25 cm, eluent: dichloromethane/heptane 70/30) to obtain 0,205 g the least polar product and of 0.615 g the most polar product.

Yield: 89% (the ratio of the isomers 75/25),

The least polar product

F: 261oWITH,

Rf: 0,48 (dichloromethane/heptane 80/20)

SM (APcI-): m/z 309 (M-),

NMR1H (CD2C12) - (ppm)

to 8.20 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= 8,54 Hz, JH-F= 5,18 Hz)

of 8.09 (m, 2H, H-2' and H-6')

of 7.90 (dd, 1H, H-5 or H-8, JH-F= 8,54 Hz, JH-For JH6-H8= 2,74 Hz)

to 7.50 (m, 4H, H-6 or H-7, H-3', H-4' and H-5')

IR (KBr): (cm-1)

1680 and 1660 (C= 0).

The most polar product

F: 241oWITH,

Rf: 0,41 (dichloromethane/heptane 80/20)

SM (APcI-): m/z 309 (M-),<9 Hz)

8,08 (dd, 2H, H-2' and H-6', JH2'-H3'= JH5'-H6'= 8,05 Hz, JH4'-H6'= JH2'and H4'= 1.65 Hz)

7,81 (dd, 1H, H-5 or H-8, JH-F= 8,54 Hz, JH-For JH6-H8= 2,44 Hz)

to 7.50 (m, 4H, H-6 or H-7, H-3' and H-4' and H-5')

IR (KBr): (cm-1)

1680 and 1660 (C= 0)

Examples 46 and 47

4,9-dihydro-4.9-dioxo-6-fluoro-2-(5-methyl-2-furyl)-oil[2,3-d] thiazole

4,9-dihydro-4,9-dioxo-7-fluoro-2-(5-methyl-2-furyl)-oil[2,3-d] thiazole

In the 0.80 g (2,96 mm - 1,0 EQ. ) 75/25 mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-formatline and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-formatline add 40 ml of an aqueous solution of sulfide nonhydrocarbon sodium (1.78 g - 7,40 mm, 2.5 EQ. ). Suspension red heated for 30 minutes to 80oTo produce a dark blue color. Then add a 0.59 ml (5,9 mm - 2.0 EQ. ) 5-methyl-2-furaldehyde, and the solution is stirred for 90 minutes at 80oC. the resulting solution was dark brown to cool to room temperature, add a few drops of glacial acetic acid. The resulting greenish precipitate is filtered, washed three times in water and dried. Get 0,705 g of a mixture of 4,9-dihydro-4,9-dioxo-6-fluoro-2-(5-methyl-2-furyl)-oil[2,3-d] thiazole and 4,9-dihydro-4,9-dioxo-7-fluoro-2-(5-methyl-2-furyl)-oil[2,3-d] tuaolo in the form of dark-red the C silica gel (carrier: silica 6-35 μm, diameter: 5 cm, height 35 cm, eluent: dichloromethane/heptane 90/10) to obtain 0,177 g the least polar product and 0,528 g the most polar product.

Yield: 76% (the ratio of the isomers 75/25),

The least polar product

F: 260oWITH,

Rf: 0.40 in (dichloromethane/heptane 80/20)

SM (APcI-): m/z 313 (M-),

NMR1H (CD2C12) - (ppm)

8,18 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= 8,54 Hz, JH-F= 5,18 Hz)

7,86 (dd, 1H, H-5 or H-8, JH-F= 8,54 Hz, JH5-H7or JH6-H8= 2,75 Hz)

7,41 (td, 1H, H-6 or H-7, JH-F= JH5-H6or JH7-H8= 8,54 Hz, JH5-H7or JH6-H8= 2,75 Hz)

of 7.25 (d, 1H, H-3', JH3'-H4'= 3,36 Hz)

6,24 (d, 1H, H-4', JH3'-H4'= 3,36 Hz)

2,39 (s, 3H, CH3)

IR (KBr): (cm-1)

1685 and 1650 (C= 0)

The most polar product

F: 238oWITH,

Rf: 0,30 (dichloromethane/heptane 80/20)

SM (APcI-): m/z 313 (M-),

NMR1H (CD2Cl2) - (ppm)

of 8.25 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= 8,54 Hz, JH-F= 5,18 Hz)

7,80 (dd, 1H, H-5 or H-8, JH-F= 8,54 Hz, JH5-H7or JH6-H8= 2,75 Hz)

7,42 (td, 1H, H-6 or H-7, JH5-H6or JH7-H8= JH-F= 8,54 Hz, JH5-H7or JH6-H8= 2,75 Hz)

of 7.25 (d, 1H, H-3', JH3'-H4'= 3,36 Hz)

6,24 (d, 1H, H-4, JH3'-H4'= 3,36 Hz)

2,39 (s, 3H, CH3)
2,3-d] thiazole and

4,9-dihydro-4,9-dioxo-7-fluoro-2-(4-forfinal)-oil[2,3-d] thiazole

In the 0.80 g (2,96 mm - 1,0 EQ. ) 75/25 mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-formatline and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-formatline add 40 ml of an aqueous solution of sulfide nonhydrocarbon sodium (1.78 g - 7,40 mm, 2.5 EQ. ). Suspension red heated for 30 minutes to 80oTo produce a dark blue color. Then added 0.63 ml (5,80 mm - 2.0 EQ. ) 4-fermented-Devida, and the solution is stirred for 90 minutes at 80oC. the resulting solution was dark brown to cool to room temperature, add a few drops of glacial acetic acid. The resulting greenish precipitate is filtered, washed three times in water and dried. Get 0,570 g of a mixture of 4,9-dihydro-4,9-dioxo-6-fluoro-2-(4-forfinal)-oil[2,3-d] thiazole and 4,9-dihydro-4,9-dioxo-7-fluoro-2-(4-forfinal)-oil[2,3-d] thiazole in the form of bright yellow crystals.

The isomers separated by thin-layer chromatography on three consecutive columns of silica gel (carrier: silica 6-35 μm, diameter: 5.5 cm, height 40 cm, eluent: dichloromethane/heptane 80/20), and then each fraction is washed several times in heptane with getting 0,143 g the least polar product and 0,427 g R> F: > 265oWITH,

Rf: at 0.42 (dichloromethane/heptane 80/20)

SM (APcI-): m/z 327 (M-),

NMR1H (CD2Cl2) - (ppm)

8,21 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= 8,54 Hz, JH-F= 5,19 Hz)

8,10 (dd, 2H, H-2 and H-6', JH2'-H3'= JH5'-H6'= cent to 8.85 Hz, JH2'-F= JH6'-F= 5,19 Hz)

7,89 (dd, 1H, H-5 or H-8, JH-F= 8,54 Hz, JH5-H7or JH6-H8= 2,75 Hz)

the 7.43 (td, 1H, H-6 or H-7, JH-F= JH5-H6or JH7-H8= 8,54 Hz, JH5-H7or JH6-H8= 2,75 Hz)

then 7.20 (t, 2H, H-3 and H-5', JH-F= JH2'-H3'= JH5'-H6'= cent to 8.85 Hz)

IR (KBr): (cm-1)

1675 1655 (C= 0)

The most polar product

F: > 265oWITH,

Rf: 0.40 in (dichloromethane/heptane 80/20)

SM (APcI-): m/z 327 (M-),

NMR1H (CD2C12) - (ppm)

of 8.28 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= 8,54 Hz, JH-F= 5,19 Hz)

8,11 (dd, 2H, H-2 and H-6', JH2'-H3'= JH5'-H6'= cent to 8.85 Hz, JH2'-F= JH6'-F= 5,19 Hz)

7,81 (dd, 1H, H-5 or H-8, JH-F= 8,54 Hz, JH5-H7or JH6-H8= 2,75 Hz)

was 7.45 (td, 1H, H-6 or H-7, JH-F= JH5-H6or JH7-H8= 8,54 Hz, JH5-H7or JH6-H8= 2,75 Hz)

then 7.20 (t, 2H, H-3' AND H-5', JH-F= JH2'-H3'= JH5'-H6'= cent to 8.85 Hz)

IR (KBr): (cm-1)

1675 1660 (C= 0)

Examples 50 and 51

4,9-dihydro-4,9-dioxo-6-fluoro-2-(4-were)-oil[2,3-d] t is about-3-bromo-1,4-dihydro-1,4-dioxo-6-formatline and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-formatline add 50 ml of an aqueous solution of sulfide nonhydrocarbon sodium (2,22 g - 9,20 mm, 2.5 EQ. ). Suspension red heated for 30 minutes to 80oTo produce a dark blue color. Then add to 0.87 ml (7,40 mm - 2.0 EQ. ) 4-methylbenzaldehyde, and the solution is stirred for 90 minutes at 80oC. the resulting solution was dark brown to cool to room temperature, add a few drops of glacial acetic acid. The resulting greenish precipitate is filtered, washed three times in water and dried. Get 0,623 g of a mixture of 4,9-dihydro-4,9-dioxo-6-fluoro-2-(4-methylphenyl)-oil[2,3-d] -thiazole and 4,9-dihydro-4,9-dioxo-7-fluoro-2-(4-were)-oil[2,3-d] thiazole in the form of yellow crystals.

The isomers separated by thin-layer chromatography on three consecutive columns of silica gel (carrier: silica 6-35 μm, diameter: 9 cm, height 35 cm, eluent: dichloromethane/heptane 70/30). The collected fractions concentrated in vacuo, the resulting solid product is washed twice mitrofanna glass in a minimal amount of methanol and five times in heptane with getting 0,467 g the most polar product and 0.156 g of the least polar product as yellow crystals.

Yield: 52% (the ratio of the isomers 75/25),

The most polar product

F: >260oWITH,

Rf: 0,42 (the SUB>H5-H6
or JH7-H8= 8,54 Hz, JH-F= 5,19 Hz)

of 7.96 (d, 2H, H-2 and H-6', JH2'-H3'= JH5'-H6'= 8,24 Hz)

7,80 (dd, 1H, H-5 or H-8, JH-F= 8,54 Hz, JH5-H7or JH6-H8= 2,75 Hz)

7,44 (td, 1H, H-6 or H-7, JH-F= JH5-H6or JH7-H8= 8,54 Hz, JH5-H7or JH6-H8= 2,75 Hz)

7,30 (d, 2H, H-3' and H-5, JH2'-H3'= JH5'-H6'= 8,24 Hz)

of 2.38 (s, 3H, CH3)

IR (KBr): (cm-1)

1670 and 1665 (C= 0)

The least polar product

F: >260oWITH,

Rf: 0,46 (dichloromethane/heptane 70/30)

SM (APcI-): m/z 323 (M-),

NMR1H (CD2C12) - (ppm)

to 8.20 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= 8,54 Hz, JH-F= 5,19 Hz)

of 7.97 (d, 2H, H-2' and H-6', JH2'-H3'= JH5'-H6'= 8,24 Hz)

7,88 (dd, 1H, H-5 or H-8, JH-F= cent to 8.85 Hz, JH5-H7or JH6-H8= 2,75 Hz)

7,42 (td, 1H, H-6 or H-7, JH-F= JH5-H6or JH7-H8= 8,54 Hz, JH5-H7or JH6-H8= 2,75 Hz)

7,31 (d, 2H, H-3 and H-5', JH2'-H3'= JH5'-H6'= 8,24 Hz)

2,39 (s, 3H, CH3)

IR (KBr): (cm-1)

1675 1655 (C= 0).

Examples 52 and 53

4,9-dihydro-4,9-dioxo-5-fluoro-2-(2-furyl)-oil[2,3-d] thiazole and

4,9-dihydro-4,9-dioxo-8-fluoro-2-(2-furyl)-oil[2,3-d] thiazole

Intermediate compound synthesis:

2,3-dibromo-1,4-dihydro-1,4-dioxo-5-fornatale

To a solution of 1,4-who stand under reflux for 12 hours, then bring to room temperature. After ozonation compressed air solution concentrated under reduced pressure, and the obtained solid product beige purified by column flash chromatography (carrier: silica, air conditioning: heptane, eluent: CH2C12/heptane) to give the 3,44 g of 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-formatline in the form of beige crystals.

Yield: 74%,

F: 100oWITH,

Rf: 0,63 (dichloromethane/heptane 80/20),

SM (I. E. ): m/z 333, 335, 337 (M++l),

NMR1H (CDCl3) - (ppm)

8,01 (d, 1H, H-8, JH7-H6= 7,94 Hz)

to 7.77 (m, 1H, H-7)

7,52 (m, 1H, H-6)

IR (KBr): (cm-1)

1704 (C= 0)

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-fornatale and

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-fornatale

In a solution of 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-formatline (33 mg, 0,098 mm) in tetrahydrofuran (5 ml) was bubbled ammonia at room temperature for 1 hour, then passed through a solution of compressed air for 15 min to remove excess ammonia. After evaporation of the solvent under reduced pressure, the obtained solid product red purified on preparative plate of silica (eluent: CH2CL2/90/10 heptane). Polictics-8-formatline.

Yield: 77%,

F: 208oWITH,

Rf: of 0.44 (dichloromethane),

SM (APcI-): m/z 269, 271, (M-),

NMR1H (CDCl3) - (ppm)

7,98 (d, 1H, H-5 or H-8, JH5-H6or JH7-H8= 7,63 Hz)

to 7.64 (m, 1H, H-6 or H-7)

7,31 (dd, 1H, H-b or H-7, JH5-H6or JH7-H8= JH-F= 8,55 Hz)

6,40-5,00 (s1, 2H, NH2)

IR (KBr): (cm-1)

3466, 3355 (NH2), 1778, 1633 (C= 0)

4,9-dihydro-4,9-dioxo-5-fluoro-2-(2-furyl)-oil[2,3-d] thiazole

4,9-dihydro-4,9-dioxo-8-fluoro-2-(2-furyl)-oil[2,3-d] thiazole

0.15 g (0.55 mm to 1.0 EQ. ) a mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-formatline and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-formatline in 25 ml of water is added 0.33 g (1,38 mm to 2.5 EQ. ) sulfide nonhydrocarbon sodium. Suspension red heated for 30 minutes to 80oTo produce a dark blue color. Then add 0.1 ml (1.1 mm to 2.0 EQ. ) 2-furaldehyde. After 90 minutes of heating at 80oWith the resulting solution was dark brown to cool to room temperature. Then add a few drops of glacial acetic acid, and the resulting brown precipitate was filtered, washed three times in water and dried. The resulting mixture of products purified preparative thin-layer chromatography (silica 2 mm, eluent: dichloromethane (silicon dioxide 2 mm, eluent: dichloromethane) to obtain the 0,020 g of a mixture of 4,9-dihydro-4,9-dioxo-5-fluoro-2-(2-furyl)-oil[2,3-d] thiazole and 4,9-dihydro-4,9-dioxo-8-fluoro-2-(2-furyl)-oil[2,3-d] thiazole in the form of orange crystals.

Output: 12% (the ratio of the isomers 47/53)

The least polar isomer

F: > 260oWITH,

Rf: 0,34 (dichloromethane),

SM (APcI+): m/z 300 (M+H+),

NMR1H (CD2C12) - (ppm)

of 8.09 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= 8,24 Hz, JH5-H7or JH6-H8= 1,22 Hz)

of 7.75 (td, 1H, H-6 or H-7, JH5-H6or JH7-H8= JH6-H7= 7,94 Hz, JH-F= 4,58 Hz)

the 7.65 (dd, 1H, H-5', JH3'-H5'= 0,92 Hz, JH4'-H5'= 1,84 Hz)

7,46 (ddd, 1H, H-6 or H-7, JH-F= 10,98 Hz, JH6-H7= 8,24 Hz, JH5-H7or JH6-H8= 1,22 Hz)

to 7.35 (d, 1H, H-3, JH3'-H4'= 3,67 Hz)

6,63 (dd, 1H, H-4', JH3'-H4'= 3,67 Hz, JH4'-H5'= 1,84 Hz)

IR (KBr): (cm-1)

1680 and 1655 (C= 0).

The most polar isomer

F: > 260oWITH,

Rf: 0,28 (dichloromethane),

SM (APcI+): m/z 300 (M+H+),

NMR1H (CD2C12) - (ppm)

8,02 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= 7,63 Hz, JH5-H7or JH6-H8= 1,22 Hz)

7,73 (td, 1H, H-6 or H-7, JH5-H6or JH7-H8= JH6-H7= 8,24 Hz, JH-F= 4,58 Hz)

to 7.64 (dd, 1H, H-5', JH3'-H5'= 0,91 Hz, JH4'-H5'= 1,83 Hz)

1H, H-3, JH3'-H4'= 3,66 Hz)

only 6.64 (dd, 1H, H-4, JH3'-H4'= 3,66 Hz, JH4'-H5'= 1,83 Hz)

IR (KBr): (cm-1)

1680 and 1655 (C= 0).

Examples 54 and 55

6-chloro-4,9-dihydro-4,9-dioxo-2-C2-furyl)-oil[2,3-d] thiazole

7-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)-oil[2,3-d] thiazole

In 435 mg (1,79 mm) 75/25 mixture of 2-amino-3,6-dichloro-1,4-dihydro-1,4-deoxidation and 2-amino-3,7-dichloro-1,4-dihyd-ro-1,4-deoxidation added at room temperature and in an atmosphere of argon 1,72 g (7,16 mm) sulfide nonhydrocarbon sodium in solution in 15 ml of sodium hydroxide with a pH of 10.6. After 30 min of incubation at 60oC in argon atmosphere in the reaction environment, which has become completely blue, add 296 μl (to 3.58 mm) 2-furaldehyde. After 15 minutes exposure under reflux stop the flow of argon, the reaction mixture is diluted with 250 ml of water and extracted three times with 150 ml of dichloromethane. The organic phase is washed with 300 ml of water and evaporated to dryness, to obtain 450 mg of a mixture of 6-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)-oil[2,3-d] thiazole and 7-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)-oil[2,3-d] thiazole in the form of orange crystals.

Both isomers share the cake of silica (silicon dioxide 40-60 mm, diameter: 7 cm height: 14 cm, eluent: dichloromethane/heptane 90/10) and peoduct

Exit 40%

F: > 260oWITH,

Rf: 0,42 (CH2Cl2/MeOH 99/1),

SM (APcI-): m/z 315 and 317 (M-),

NMR 1H (CDCl3) - (ppm)

of 8.28 (d, 1H, H-5 or H-8, JH5-H7or JH6-H8= 2,08 Hz)

8,17 (d, 1H, H-5 or H-8, JH7-H8or JH5-H6= 8,31 Hz)

of 7.75 (dd, 1H, H-6 or H-7, JH7-H8or JH5-H6= 8,31 Hz, JH5-H7or JH6-H8= 2,07 Hz)

the 7.65 (m, 1H, H-5')

7,46 (d, 1H, H-3, JH3'-H4'= 3,74 Hz)

of 6.66 (dd, 1H, H-4', JH3'-H4'= 3,74 Hz, JH3'-H5'= 1,66 GHz)

NMR13With (CDCl3) - (ppm)

146,81 (C-5')

134,72 (C-6 or 0-7)

129,31; 128,53 (2C, C-5, C-8)

114,75 and 114,11 (2C, C-3, C-4')

IR (KBr): (cm-1)

1675, 1665 (C= 0).

The most polar product

Exit 26%

F: > 260oWITH,

Rf: 0,36 (CH2Cl2/MeOH 99/1),

SM (APcI+): m/z 316 and 318 (M+H+)

NMR1H (CDCl3) - (ppm)

of 8.28 (d, 1H, H-5 or H-8, JH7-H8or JH5-H6= 8 Hz)

8,18 (d, 1H, H-5 or H-8, JH5-H7or JH6-H8= 1,84 Hz)

to 7.77 (dd, 1H, H-6 or H-7, JH7-H8or JH5-H6= 8,04 Hz, JH5-H7or JH6-H8= 1,84 Hz)

to 7.67 (1s, 1H, H-5')

7,47 (d, 1H, H-3', JH3'-H4'= 3,45 Hz)

of 6.66 (m, 1H, H-4')

NMR13With (CDCl3) - (ppm)

178,50; 177,90 (2C, C-4 C-9)

148,5 (C-2')

146,8 (C-5')

141,8 (C-6 or C-7)

134,9 (C-6 or C-7)

131,8 (2C, C-4A, C-8A)

130,09; 127,64 (2C, C-5, C-8)

114,-5-methoxy-oil[2,3-d] thiazole or

4,9-dihydro-4,9-dioxo-2-(2-furyl)-8-methoxy-oil[2,3-d] thiazole

In an inert atmosphere of 3.64 g (12.9 mm) a mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene add 140 ml of an aqueous solution containing 7,74 g (32.2mm) sulfide nonhydrocarbon sodium. The resulting suspension is heated to 82oTo get "ink" colors. Then in the reaction medium was added to 2.1 ml (25,8 mm) 2-furaldehyde. The mixture gradually becomes red-brick color. After 1.25 hours the reaction mixture was 6.73 g (38,7 mm) hydrosulfite sodium, gradually falls brown precipitate. The precipitate is filtered at high temperature in mitrofanna glass and washed with water. The original product is recrystallized in DMF. A second recrystallization is carried out in dichloromethane. After evaporation under reduced pressure the filtrate is purified by the filter pressey tortilla (carrier: silica 6-35 μm, air conditioning: CH2C12/the 80/20 heptane, eluent: CH2Cl2/MeOH from 100/0 to 90/10). The obtained solid is washed in heptane, discolor on the animal angle in dichloromethane, then filtered on a Millipore filter to obtain after evaporation when ponies-8-methoxy-oil[2,3-d] thiazole in the form of orange crystals.

Exit 8%

F: > 260oWITH,

Rf: 0,60 (CH2C12/Meon 98/2),

SM (APcI+): m/z 312 (M+H+)

NMR1H (CD2C12) - (ppm)

for 7.78 (dd, 1H, H-8 or H-5, JH7-H8= 7,63 Hz, JH6-H8= 1,22 Hz)

the 7.65 (t, 1H, H-7 or H-6, JH7-H8# JH6-H7= a 7.62 Hz)

of 7.60 (dd, 1H, H-5', JH4'-H5'= 1,53 Hz, JH3'-H5'= 0,92 Hz)

7,33 (dd, 1H, H-6 or H-7 and metoxygroup, JH6-H7= 8,24 Hz, JH6-H8or JH5-H7= 0,92 Hz)

7,31 (s, 1H, H-3')

6,59 (dd, 1H, H-4', JH3'-H4'= 3,67 Hz, JH4'-H5'= 1,83 Hz)

of 3.96 (s, 3H, )

IR (KBr): (cm-1)

3112 (C-H); 1674 (C= 0); 1655 (C= N)

Example 57

4,9-dihydro-4,9-dioxo-2-(2-furyl)-5-hydroxy-oil[2,3-d] thiazole or

4,9-dihydro-4,9-dioxo-2-(2-furyl)-8-hydroxy-oil[2,3-d] thiazole

To a solution of 4,9-dihydro-4,9-dioxo-2-(2-furyl)-5-methoxy-oil[2,3-d] thiazole or 4,9-dihydro-4,9-dioxo-2-(2-furyl)-8-methoxy-oil[2,3-d] thiazole (230 mg - 0,73 mm) in 20 ml acetic acid is added to 0.90 ml of 47% Hydrobromic acid (7,69 mm). The reaction mixture is stirred under reflux for 5 hours. After returning to room temperature, the reaction medium was added water (30 ml). The solution is then extracted with dichloromethane. The organic phase is washed with water until neutral pH. After drying over calcium chloride avouches silica 6-35 μm, eluent: CH2Cl2). The product, dissolved in dichloromethane, discolor on the animal angle. After washing with heptane get 110 ml of 4.9-dihyd-ro-4,9-dioxo-2-(2-furyl)-5(or 8)-hydroxy-oil[2,3-d] thiazole in the form of orange powder.

Output 50%

F: 257oWITH,

Rf: 0.50 in (CH2Cl2)

SM (APcI+): m/z 298 (M+N+)

NMR1H (CD2Cl2) - (ppm)

12,25 (s, 1H, )

to 7.77 (dd, 1H, H-8 or H-5, JH7-H8or JH5-H6= 7,63 Hz, JH5-H7= 1,22 Hz)

of 7.70 (dd, 1H, H-5', JH4'-H5'= 1,84 Hz, JH3'-H5'= 0,92 Hz)

to 7.68 (t, 1H, H-7 or H-6 in b hydroxy group, JH7-H8or JH5-H6= 7,63 Hz, JH6-H7= 8,23 Hz)

7,41 (d, 1H, H-3', JH3'-H4'= 3,67 Hz)

7,34 (dd, 1H, H-6 or H-7 and hydroxy-group, JH6-H7= 8,23 Hz, JH6-H8or JH5-H7= 1,22 Hz)

6,69 (dd, 1H, H-4', JH3'-H4'= 3,66 Hz, JH4'-H5'= 1,83 Hz)

NMR13(CD2C12) - (ppm)

183,72 (1C, C-4 or C-9)

177,73 (1C, C-9 or C-4)

164,31 (1C, C-5 or C-8)

163,45 (1C, C-2)

155,15 (1C, C-2')

148,41 (1C, C-3A)

146,68 (1C, C-5')

142,00 (1C, C-9a)

137,07 (1C, C-7 or C-6 hydroxy groups)

133,76 (1C, C-8A or 4A)

125,74 (1C, C-8 or C-5)

120,32 (1C, C-6 or C-7 hydroxy group)

115,69 (1C, C-4A or C-8A)

113,75 and 114,07 (2C, C-3' and C-4')

IR (KBR): (cm-1)

3400 (OH)>4,9-dihydro-4,9-dioxo-2-(2-furyl)-7-myoxidae[2,3-d] thiazole

In an inert atmosphere to a 2.00 g (7.1 mm) a mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-methoxynaphthalene and 3-amino-2-bromo-1,4-dihydro-1,4-dioxo-6-methoxynaphthalene add 75 ml of an aqueous solution containing of 4.25 g (17.7 mm) sulfide nonhydrocarbon sodium. The resulting suspension is heated to 82oWith the naphthoquinone gradually dissolved to obtain an ink color of the solution. Then in the reaction medium was added 1.2 ml (14.2 mm) 2-furaldehyde. The mixture gradually becomes red-brick color. 1.5 hours of exposure and cooling to 50oC in the reaction mixture of 2.45 g (14.2 mm) hydrosulfite sodium, roll a brown precipitate. The precipitate is filtered at high temperature in mitrofanna glass and washed with water until the washing water becomes colorless. After drying in the drying chamber to the vacuum source, the product is distilled on the cake of silica gel (carrier: silica 6-35 mm, eluent: CH2Cl2/MeOH 98/2). Get to 1.15 g (3.7 mm) of a mixture of 4,9-dihydro-4,9-dioxo-2-(2-furyl)-6-methoxy-oil[2,3-d] thiazole or 4,9-dihydro-4,9-dioxo-2-(2-furyl)-7-myoxidae[2,3-d] thiazole.

The separation of the two isomers is carried out by three consecutive chromatogra the recrystallization in dichloromethane each isomer get 0,210 g of orange crystals the most polar product and 0,300 g of orange crystals of the least polar product.

The most polar product

Output: 9,5%

F: > 260oWITH,

Rf: 0,58 (CH2Cl2/AcOEt 90/10)

SM (I. E. ): m/z 311 (M+)

NMR1H (CD2C12) - (ppm)

by 8.22 (d, 1H, H-8 or H-5, JH5-H6or JH7-H8= cent to 8.85 Hz)

7,69 (s1, 1H, H-5')

7,66 (d, 1H, H-5 or H-8 and methoxy-groups, JH5-H7or JH6-H8= 2,74 Hz)

7,40 (d, 1H, H-3', JH3'-H4'= 3,66 Hz)

7,27 (dd, 1H, H-7 or H-6, JH5-H6or JH7-H8= 8,55 Hz, JH6-H8or JH5-H7= 2,45 Hz)

of 6.68 (dd, 1H, H-4', JH3'-H4'= 3,66 Hz, JH4'-H5'= 1,83 Hz)

3,98 (s, 3H, CH3About 6 or 7)

IR (KBr): (cm-1)

1675 (C= 0), 1650 (C= N), 1589.

The least polar product

Output: 13,5%

F: > 260oWITH,

Rf: 0,68 (CH2Cl2/AcOEt 90/10)

SM (I. E. ): m/z 311 (M+)

NMR1H (CD2C12) - (ppm)

of 8.15 (d, 1H, H-8 or H-5, JH5-H6or JH7-H8= 8,55 Hz)

7,73 (d, 1H, H-5 or H-8 and methoxy-groups, JH5-H7or JH6-H8= 2,75 Hz)

to 7.68 (d, 1H, H-5, JH4'-H5'= 1,83 Hz)

7,38 (d, 1H, H-3, JH3'-H4'= 3,67 Hz)

of 7.25 (dd, 1H, H-7 or H-6, JH5-H6or JH7-H8= 8,55 Hz, JH6-H8or JH5-H7= 2,75 Hz)

of 6.68 (dd, 1H, H-4', JH3'-H4'= 3,66 Hz, JH4'-H5'= 1,83 Hz)

to 3.99 (s, 3H, CH3About 6 or 7)

IR (KBr): (cm-1)

1681 (C= 0), 1645 (C= N), 1586

Examples 60 and 61
Intermediate compounds for the synthesis of

2-amino-3-chloro-1,4-dihydro-1,4-dioxo-6-methylnaphthalene, and

2-amino-3-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene

In a solution of 6.00 g (25 mm 1.0 in EQ. ) a mixture of 2-chloro-1,4-dihydro-1,4-Diageo-6-methylnaphthalene (CAS No 87 170-60-3) and 2-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene (CAS No 87 170-61-4) and 250 ml of glacial acetic acid added at a time 2,60 g (40 mm 1.6 EQ. ) of sodium nitride in solution in 16 ml of distilled water. The medium is heated to 80oC for 5 hours, its color changes from yellow to orange. After cooling, the reaction medium is evaporated to dryness, and the obtained original product was then purified on a layer of silicon dioxide (carrier: silica 6-35 μm, diameter: 10 cm height: 5 cm, floor is solid, eluent: heptane/ethyl acetate 92/8) to give after evaporation of the solvents of 0.44 g of a mixture of 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-6-methyl-naphthalene and 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene in the form of red crystals.

Output: 8%

Rf: 0,38 (heptane/ethyl acetate 70/30)

SM (APcI+): m/z 222, 224 (M+H+)

NMR1H (CDCl3) - (ppm)

7,99 and 7,95 (2d, 2H, protons in b of CH3, J= 7,93 Hz)

7,87 (s, 2H, protons and CH3)

7,56 and of 7.48 (2d, 2H, protons and CH3)

In a solution of 1.3 g (5.4 mm to 6.0 EQ. ) sulfide nonhydrocarbon sodium and 3.2 ml of a previously prepared solution of sodium hydroxide with a pH of 10.7 add 0.2 g (0.9 mm to 1.0 EQ. ) a mixture of 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-6-methylnaphthalene, and 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene. The suspension is heated to 45oWith over 30 min acquires a blue color. Add 149 μl (1.8 mm - 2.0 EQ. ) 2-furaldehyde, then after 15 minutes 97 μl (1.7 mm and 1.9 EQ. ) glacial acetic acid at 55oC. the Reaction medium chestnut color is extracted six times with 100 ml dichloromethane. The organic phases are collected, dried on magnesium sulfate, filtered, then evaporated to dryness. The resulting product is distilled on a layer of silicon dioxide (carrier: silica 6-35 μm, diameter: 5 cm, height: 15 cm, the coating is solid, eluent: heptane/ethyl acetate 90/10) to give after evaporation of the solvents of 0.13 g of a mixture of 4,9-dihydro-4,9-dioxo-2-furyl-6-methylnaphtho[2,3-d] thiazole and 4,9-di-hydro-4,9-dioxo-2-furyl-7-methylnaphtho[2,3-d] thiazole, both isomers in the form of orange crystals.

The isomers separated on preparative plates (carrier: aluminium hydroxide, eluent dichloromethane/heptane 70/30).

Output: 48,8% (mixture of two isomers)

Naib is R1H (CD2C12) - (ppm)

to 8.20 (d, 1H, H-5 or H-8 b of CH3I , JH5-H6or JH7-H8= to 7.93 Hz)

with 8.05 (m, 1H, H-5 or H-8 and CH3)

7,73 (dd, 1H, H-5', JH4'-H5'= 1,83 Hz, JH3'-H5'= 0,61 Hz)

to 7.67 (d, 1H, H-6 or H-7, JH5-H6or JH7-H8= 7,94 Hz, and CH3)

7,44 (dd, 1H, H-3', JH3'-H4'= 3,67 Hz, JH3'-H5'= 0,61 Hz)

6,72 (dd, 1H, H-4', JH3'-H4'= 3,66 Hz, JH4'-H5'= 1,83 Hz)

to 2.57 (s, 3H, CH3)

NMR13(CD2C12) - (ppm)

146,41 (1C, C-5')

135,31 (1C, C-6 or C-7, and CH3)

127,99 (1C, C-5 or C-8)

127,55 (1C, C-5 or C-8)

113,70 (1C, C-3')

113,59 (1C, C-4')

21,94 (1C, CH3)

The least polar product

Rf: 0.50 (a dichloromethane/heptane 70/30, alumina)

SM (APcI+): m/z 296 (M+N+)

NMR1H (CD2Cl2) - (ppm)

8,01 (m, 2H, H-5, H-8)

of 7.60 (dd, 1H, H-5', JH4'-H5'= 1,83 Hz, JH3'-H5'= 0,61 Hz)

7,53 (d, 1H, H-6 or H-7, JH5-H6or JH7-H8= 7,33 Hz, and CH3)

7,31 (dd, 1H, H-3', JH3'-H4'= 3,66 Hz, JH3'-H5'= 0,61 Hz)

6,60 (dd, 1H, H-4', JH3'-H4'= 3,66 Hz, JH4'-H5'= 1,83 Hz)

the 2.46 (s, 3H, CH3)

NMR13(CD2Cl2) - (ppm)

176,28 (2C, C-0)

145,99 (1C, C-5')

134,64 (1C, C-6 or C-7, and CH3)

127,94 (1C, C-5 or C-8)

126,83 (1C, C-5 or C-8)

4,9-dihydro-4,9-dioxo-7-methyl-2-anilnetto[2,3-d] thiazole

In a solution of 1.3 g (5.4 mm to 6.0 EQ. ) sulfide nonhydrocarbon sodium and 3.2 ml of a previously prepared solution of sodium hydroxide with a pH of 10.7 add 0.5 g (0.9 mm to 1.0 EQ. ) a mixture of 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-6-methylnaphthalene, and 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene. The suspension is heated to 45oWith over 30 min acquires a blue color. In the reaction medium was added 184 MCD (1.8 mm - 2.0 EQ. ) benzaldehyde. The mixture is heated to 55oWith, acquires a green color within 30 minutes. After adding 291 μl (5.0 mm to 5.5 EQ. ) glacial acetic acid, a precipitate of brown color, which is filtered on mitrofanna glass, then washed with dichloromethane. The initial product was then purified on a layer of silicon dioxide (carrier: silica 6-35 μm, diameter: 5 cm height: 5 cm, floor is solid, eluent: heptane/ethyl acetate 90/10) to give after evaporation of the solvents 90 mg of a mixture of 4,9-dihydro-4,9-dioxo-2-furyl-6-methyl-2-anilnetto[2,3-d] thiazole and 4,9-dihydro-4,9-dioxo-2-furyl-7-methyl-2-anilnetto[2,3-d] thiazole in the form of yellow crystals. The isomers separated on preparative plates (carrier: aluminium hydroxide, eluent: dichloromethane/70/30 heptane, aluminum oxide)

SM (APcI+): m/z 306 (M+R+)

NMR1H (CD2C12) - (ppm)

8,10 (d, 1H, H-5 or H-8, JH5-H6or JH7-H8= 7,63 Hz)

8,03 (m, 2H, H-2' and H-6')

to 7.93 (bs, 1H, H-5 or H-8, and CH3)

at 7.55 (d, 1H, H-6 or H-7, JH5-H6or JH7-H8= to 7.93 Hz)

7,46 (m, 3H, H-3', H-4', H-5')

of 2.45 (s, 3H, CH3)

NMR13(CD2C12) - (ppm)

135,36 (1C, C-6 or C-7)

132,60 (1C, C-4')

129,65 (2C, C-2', C-6')

128,01 (1C, C-5 or C-8)

127,90 (2C, C-3', C-5')

127,55 (1C, C-5 or C-8)

21,93 (1C, CH3)

The least polar product

Rf: 0,62 (dichloromethane/heptane 70/30, aluminium hydroxide)

SM (APcI+): m/z 306 (M+N+)

NMR1N (CD2C12) - (ppm)

8,09 to 8.00 (m, 4H, H-5, H-8, H-2', H-6')

7,53 (d, 1H, H-6 or H-7, JH5-H6or JH7-H8= to 7.93 Hz)

7,46 (m, 3H, H-3', H-4', H-5')

the 2.46 (s, 3H, CH3)

NMR13(CD2C12) - (ppm)

134,98 (1C, C-6 or C-7)

132,59 (1C, C-4')

129,66 (2C, C-2', C-6')

128,36 (1C, C-5 or C-8)

127,90 (2C, C-3, C-5')

127,25 (1C, C-5 or C-8)

22,0 (1C, CH3)

Examples 64 and 65

4,9-dihydro-4,9-dioxo-2-furyl-5-methylnaphtho[2,3-d] thiazole and

4,9-dihydro-4,9-dioxo-2-furyl-8-methylnaphtho[2,3-d] thiazole

Intermediate compounds for the synthesis of

2,3-dibromo-1,4-dihydro who orida carbon then and 17.2 ml (337 mm - 4 EQ. ) of bromine. When the solution turns red, add 22,94 g (168 mm - 2 EQ. ) sodium acetate. After 96 hours of exposure under reflux, the reaction medium is filtered, washed with carbon tetrachloride and evaporated to dryness. The product was then purified on a pellet (diameter: 6.5 cm height: 5 cm, the coating of the solid substance carrier: silica, eluent: CH2Cl2); after evaporation to dryness receive chestnut-orange mass. After the first crystallization dichloromethane get to 8.25 g of 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene in the form of yellow crystals; after the second recrystallization with acetonitrile get 11,90 g of 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene in the form of yellow crystals.

Yield: 72%

Rf: 0,70 (ethyl acetate/heptane 50/50)

SM (APcI-): m/z 328, 330, 332 (M-).

NMR1H (CDCl3) - (ppm)

8,11 (dd, 1H, H-8, JH7-H8= 7,02 Hz, JH6-H8= 1,53 Hz)

7,63 (m, 2H, H-6, H-7)

was 2.76 (s, 3H, CH3)

IR (KBr): (cm-1)

1670 (C= 0); 1570 (C= C)

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methylnaphthalene

8 g (24 mm - 1 EQ. ) 2,3-dibromo-1,4-dihydro-1,4-deoxidation add 200 ml of glacial acetic acid (3.5 mm - 6,85 EQ. ), SAR turns red. The reaction medium is cooled and evaporated to dryness. The product was then purified on a pellet (diameter: 5 cm height: 5 cm, the coating of the solid substance carrier: silica, eluent: ethyl acetate/heptane 10/90, then 20/80). Get 525 mg of a mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene and 2-amino-3-bromo-1,4-di-hydro-1,4-dioxa-8-methylnaphthalene in the form of red-orange crystals.

Output: 8%

Rf: of 0.58 (ethyl acetate/heptane 50/50)

SM (APcI-): m/z 264, 266 (M-),

NMR1H (CDCl3) - (ppm)

to 8.12 (d, 1H, H-5 or H-8, JH7-H8or JH5-H6= to 7.32 Hz)

7,58 (t, 1H, H-6 or H-7, JH5-H6or JH7-H8= 7,63 Hz)

7,44 (d, 1H, H-6 or H-7, JH5-H6or JH7-H8= 7,63 Hz)

to 2.74 (s, 3H, CH3)

4,9-dihydro-4,9-dioxo-2-furyl-5-methylnaphtho[2,3-d] thiazole and

4,9-dihydro-4,9-dioxo-2-furyl-8-methylnaphtho[2,3-d] thiazole

In a solution of 1.35 g (5,63 mm) sulfide nonhydrocarbon sodium and 3.38 ml (1,810-1M) pre-prepared solution of sodium hydroxide with a pH of 9 add 0.25 g (0,93 mm) a mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methylnaphthalene. The suspension is heated to 45oWith, after 40 min it becomes blue. Then add 156 μl (1,87 mm) 2-furaldehyde, then after 15 minutes 102 μl (1.7 every 100 ml of dichloromethane, dried on magnesium sulfate, filtered and evaporated to dryness. Clean on the cake of aluminium hydroxide (eluent: dichloromethane/heptane, gradient concentration of from 50/50 to 70/30).

Obtain 51 mg (18%) of a mixture of 4,9-dihydro-4,9-dioxo-2-furyl-5-methylnaphtho[2,3-d] thiazole and 4,9-dihydro-4,9-Diageo-2-furyl-8-methylnaphtho[2,3-d] thiazole. The isomers are separated on a preparative plate (carrier: aluminium hydroxide, eluent: dichloromethane/heptane) to obtain the most polar and less polar products.

The least polar product

Rf: 0,61 (dichloromethane/heptane 70/30, asked aluminum)

SM (APcI+): m/z 296 (M+H+),

NMR1H (CD2C12) - (ppm)

8,07 (d, 1H, H-5 or H-8 g of CH3I , JH5-H6or JH7-H8= of 9.55 Hz)

7,58 (m, 3H, H-6 and H-7 and CH3and H-5')

to 7.32 (d, 1H, H-3', JH3'-H4'= 3,32 Hz)

6,60 (dd, 1H, H-4', JH3'-H4'= 3.1 Hz, JH4'-H5'= 1.2 Hz)

2,77 (s, 3H, CH3)

NMR13(CD2C12) - (ppm)

145,24 (1C, C-5')

137,82-132,24 (2C, C-6 and C-7)

124,90 (1C, C-5 or C-8)

112,54 AND 112,44 (2C, C-3' and C-4')

The most polar product

Rf: 0,53 (dichloromethane/heptane 70/30, aluminium hydroxide)

SM (APcI+): m/z 296 (M+H+),

NMR1H (CD2C12) - (ppm)

8,07 (d, 1H, H-5 or H-8, JH5-H6or JH7-H8= to 4.98 Hz, JH5-H7<5 (dd, 1H, H-4', JH3'-H4'= 3,32 Hz, JH4'-H5'= 1,66 GHz)

2,77 (s, 3H, CH3)

NMR13(CD2C12) - (ppm)

189,69 and 184,57 (2C, C-4 and C-9)

145,38 (1C, C-5')

129,29 (1C, C-6 or C-7 of CH3)

126,04-132,24 (1C, C-6 or C-7 and CH3)

123,45 (1C, C-5 or C-8 of CH3)

113,67 and 113,57 (2C, C-3' and C-4')

23,39 (1C, CH3)

Examples 66 and 67

4,9-dihydro-4,9-dioxo-5-methyl-2-anilnetto[2,3-d] thiazole and

4,9-dihydro-4,9-dioxo-8-methyl-2-anilnetto[2,3-d] thiazole

In a solution of 1.35 g (5,63 mm - 6 EQ. ) sulfide nonhydrocarbon sodium and 3.38 ml (890 mm - 193 EQ. ) pre-prepared solution of sodium hydroxide with a pH of 9 add 0.25 g (0,93 mm) a mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-methylnaphthalene, and 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-methylnaphthalene. The suspension is heated to 45oC, after 30 min acquires a blue color. Then add 191 ml (1,87 mm - 2 EQ. ) benzaldehyde, then after 15 minutes 102 ml (1,78 mm) glacial acetic acid at 55oC. the Reaction medium, acquired the chestnut color, is extracted with three times 100 ml of dichloromethane, washed to neutral pH and dried on magnesium sulfate, obtain 38 mg (13%) of the original product. After the separation of the two isomers by preparative plate (carrier: hydroxide is angry and 4,9-dihydro-4,9-dioxo-8-methyl-2-anilnetto[2,3-d] thiazole.

The least polar product

Rf: 0,58 (dichloromethane/heptane 70/30, alumina)

SM (I. E. ): m/z 305 (M+),

NMR1H (CD2C12) - (ppm)

8,07 (m, 3H, H-2', H-6', H-5 or H-8)

to 7.61 (m, 2H, H-6, H-7)

7,49 (m, 2H, H-3', H-5')

7,30 (m, 1H, H-4')

was 2.76 (s, 3H, CH3)

The most polar product

Rf: 0,51 (dichloromethane/heptane 70/30, alumina)

SM (I. E. ): m/z 305 (M+),

NMR1H (CD2C12) - (ppm)

8,07 (m, 3H, H-2, H-6', H-5 or H-8 g of CH3)

of 7.60 (m, 2H, H-6, H-7)

7,49 (m, 2H, H-3, H-5')

7,30 (m, 1H, H-4')

2,77 (s, 3H, CH3)

An example of a

4,9-dihydro-4,9-dioxo-2-methyl-1H-naphthas[2,3-d] imidazol

Source: C. A. 67 97905t

Yield: 76%

F > 260oWITH

Rf: 0,44 (CH2CL2/methanol 97/3)

SM (I. E. ): m/z 212 (M+. )

NMR1H (DMSO-d6) - (ppm)

13,74 (s, 1H, NH)

with 8.05 (dd, 2H, H-5, H-8, JH5-H6= JH7-H8= cent to 8.85 Hz; JH5-H7= JH6-H8= 1.73 Hz)

of 7.82 (m, 2H, H-6, H-7)

of 2.45 (s, 3H, CH3)

NMR13C (DMSO d6): (ppm)

178,15; 176,53 (2C, C-4, C-9)

153,80 (1C, C-2)

137,14 (1C, C-3A)

133,98; 133,99 (2C, C-6, C-7)

133,27; 133,10; 132,84 (3C, C-8A, C-9a, C-4A)

126,82 (2C, C-5, C-8)

14,01 (1C, CH3)

IR (KBr): (cm-1)

3134-2897 (NH), 1678, 1672 (C= 0)

Example b

4,9-dihydro-4,9-dioxo-2-methyl-1-phenyl-1H-naphthas[2,3-d] )

SM (I. E. ): m/z 288 (M+. )

NMR1H (DMSO-d6) - (ppm)

8,23 (d, 1H, H-5 or H-8, JH5-H6or JH7-H8= of 6.71 Hz)

of 7.90 (d, 1H, H-5 or H-8, JH5-H6or JH7-H8= of 6.71 Hz)

to 7.68 (m, 3H, H-3', H-4', H-5')

of 7.60 (m, 2H, H-6, H-7)

7,37 (m, 2H, H-2', H-6')

is 2.40 (s, 3H, CH3)

NMR13C (CDCl3): (ppm)

179,13; 175,03 (2C, C-4, C-9)

153,66 (1C, C-2)

143,14 (1C, C-1')

135,11 (1C, C-3A)

133,68; 133,51 (2C, C-6, C-7)

133,15; 133,01; 132,63 (3C, C-8A, C-9a, C-4A)

129,95; 129,69 (3C, C-3', C-4, C-5')

126,93; 126,76; 126,43 (40, C-2, C-6', C-5, C-8)

13,77 (1C, CH3)

IR (KBr): (cm-1)

1674, 1663 (C= 0)

Example with

Sulfate 4,9-dihydro-4,9-dioxo-2-methyl-1-phenyl-1H-naphthas [2,3-d] imidazol

Source: S. A. 68 8764b

Yield: 47%

F > 260oWITH

Rf: 0,53 (CH2C12/methanol 97,5/2,5)

NMR1H (DMSO-d6) - (ppm)

8,11 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= cent to 8.85 Hz; JH5-H7or JH6-H8= 1.73 Hz)

of 8.00 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= cent to 8.85 Hz; JH5-H7or JH6-H8= 1.73 Hz)

7,94 (m, 2H, H-6, H-7)

of 7.82 (m, 2H, H-2', H-6')

7,51 (m, 3H, H-3', H-4', H-5')

5,54 (s, 1H, NH+)

of 2.30 (s, 3H, CH3)

IR (KBr): (cm-1)

3414-2400 (a wide range of NH+), 1736, 1681 (C= 0)

Example d

4,9-dihydro-4,9-dioxo-1,2-dimethyl-1H-naphthas[2,3-d] imidazol

The source is+. )

NMR1H (CDCl3) - (ppm)

8,21; 8,09 (2m, 2H, H-5, H-8)

of 7.70 (m, 2H, H-6, H-7)

to 4.01 (s, 3H, CH3)

of 2.56 (s, 3H, CH3)

NMR13C (D13): (ppm)

179,22; 178,44 (2C, C-4, C-9)

154,46 (1C, C-2)

134,18; 134,11 (2C, C-6, C-7)

133,37; 133,17 (2C, C-4A, C-8A)

127,37; 126,75 (2C, C-5, C-8)

32,74 (1C, CH3)

13,64 (1C, CH3)

IR (KBr): (cm-1)

1674 (C= 0)

Example e

4,9-dihydro-4,9-dioxo-2-phenyl-1H-naphthas[2,3-d] imidazol

Source: S. A. 68 8764b

Yield: 34%

F > 260oWITH

Rf: 0,51 (CH2Cl2/ethyl acetate 90/10)

SM (I. E. ): m/z 274 (M+. )

NMR1H (DMSO-d6) - (ppm)

14,40 (s, 1H, NH)

compared to 8.26 (m, 2H, H-5, H-8)

to 8.12 (m, 2H, H-2', H-6')

7,87 (m, 2H, H-6, H-7)

rate of 7.54 (m, 3H, H-3', H-4', H-5')

NMR13C (DMSO d6): (ppm)

179,13; 175,03 (20, C-4, C-9)

152,60 (1C, C-2)

133,89 (2C, C-6, C-7)

132,60 (2C, C-9a, C-3A)

130,00 (2C, C-4A, C-8A)

129,03 (3C, C-3', C-4', C-5')

126,82; 126,32 (4C, C-5, C-8, C-2', C-6')

IR (KBr): (cm-1)

3232 (NH); 1681, 1664 (C= 0)

Example f

4,9-dihydro-4,9-dioxo-2-phenyl-naphthas[2,3-d] oxazol

Source: S. A. 87 53134z

Yield: 75%

F > 260oWITH

Rf: 0,60 (CH2C12/heptane 80/20)

SM (I. E. ): m/z 275 (M+. )

NMR1H (CDCl3) - (ppm)

with 8.33 (d, 2H, H-2', H-6', JH2'-H3'= JH5'-H6'= of 6.71 Hz)

of 8.27 (m, 2H, Jerusalem.
167,76 (1C, C-2)

134,52; 132,99 (2C, C-6, C-7)

129,21 (3C, C-3', C-4', C-5')

128,33 (2C, C-2', C-6')

127,50; 127,04 (2C, C-5, C-8)

IR (KBr): (cm-1)

1693, 1678 (C= 0)

Example g

4,9-dihydro-4,9-Diageo-2-(4-were-naphthas[2,3-d] oxazol

Source: S. A. 87 53134z

Yield: 44%

F > 260oC

Rf: 0.50 (a CD2C12)

SM (I. E. ): m/z 289 (M+. )

NMR1H (CHCl3) - (ppm)

of 8.27 (m, 2H, H-5, H-8)

8,23 (d, 2H, H-2', H-6', JH2'-H3'= JH5'-H6'= 8,24 Hz)

7,81 (m, 2H, H-6, H-7)

7,38 (m, 2H, H-3, H-5')

the 2.46 (s, 3H, CH3)

NMR13C (CDCl3): (ppm)

178,77; 173,80 (2C, C-4, C-9)

165,51 (1C, C-2)

143,95 (1C, C-3A)

135,80 (1C, C-4')

134,29; 132,12 (3C, C-1', C-6, C-7)

131,70; 131,38 (2C, C-4A, C-8A)

129,93; 128,28 (4C, C-2', C-3', C-5', C-6')

127,44; 126,99 (2C, C-5, C-8)

122,41 (1C, C-1')

21,81 (1C, CH3)

IR (KBr): (cm-1)

1668, 1678 (C= 0)

Example h

4,9-dihydro-4,9-dioxo-2-methylnaphtho[2,3-d] thiazole

Source: C. A. 120 270267z

Yield: 11%

F > 260oWITH

Rf: 0,41 (CH2C12/methanol 99/1)

SM (I. E. ): m/z 229 (M+. )

NMR1H (CDCl3) - (ppm)

8,33; 8,21 (2dd, 2H, H-5, H-8, JH5-H6= JH7-H8= cent to 8.85 Hz)

7,80 (m, 2H, H-6, H-7)

only 2.91 (s, 3H, CH3)

NMR13With (CDCl3): (ppm)

177,95; 176,95 (2C, C-4, C-9)

173,86 (1C, C-2)

153,10 (1C, C-3A)< 3
)

IR (KBr): (cm-1)

1677, 1655 (C= 0)

Example i

2-amino-4,9-dihydro-4,9-diaconate[2,3-d] thiazole

Source: C. A. 120 270267z

Yield: 96%

F > 260oWITH

Rf: 0,24 (CH2C12/methanol 96/4)

SM (I. E. ): m/z 230 (MB+. )

NMR1H (DMSO-d6) - (ppm)

8,56 (s, 2H, NH2)

8,03 (m, 2H, H-5, H-8)

7,83 (m, 2H, H-6, H-7)

NMR13C (DMSO d6): (ppm)

178,04; 177,31 (2C, C-4, C-9)

173,45 (1C, C-2)

154,61 (1C, C-3A)

of 145.95 (1C, C-9a)

134,34; 134,03 (2C, C-6, C-7)

133,18; 132,24 (2C, C-4A, C-8A)

126,99; 125,97 (2C, C-5, C-8)

IR (KBr): (cm-1)

3460, 3420 (NH2), 1690, 1660 (C= 0)

Example j

4,9-dihydro-4,9-dioxo-2-anilnetto[2,3-d] thiazole

Source: C. A. 67 11450f

Yield: 68%

F > 249oC

Rf: 0,45 (CH2C12)

SM (I. E. ): m/z 291 (M+. )

NMR1H (CDCl3) - (ppm)

8,30; by 8.22 (2dd, 2H, H-5, H-8, JH5-H6= JH7-H8= cent to 8.85 Hz, JH6-H8= JH5-H7= 1.73 Hz)

to 8.14 (m, 2H, H-2', H-6')

7,83 (m, 2H, H-6, H-7)

7,56 (m, MN, H-3', H-4', H-5')

NMR13With (CDCl3): (ppm)

178,45; 172,67 (2C, C-4, C-9)

134,82; 134,44 (2C, C-6, C-7)

133,50; 133,24; 132,74; 132,01 (4C, C-9a, C-1', C-4A, C-8A)

129,75; 128,01 (5C, C-2', C-3', C-4', C-5', C-6')

127,94; 127,18 (2C, C-5, C-8)

IR (KBr): (cm-1)

1675, 1660 (C= 0)

Example k

4,9-dihydro-4,9-dioxo-2-(2-pyridyl)-oil[2,3-d] t is)

SM (I. E. ): m/z 292 (M+. )

NMR1H (CDCl3) - (ppm)

8,69 (d, 1H, H-6', JH5'-H6'= 5.50 Hz)

of 8.47 (d, 1H, H-3', JH3'-H4'= 5.50 Hz)

at 8.36; compared to 8.26 (2dd, 2H, H-5, H-8, JH5-H6= JH7-H8= cent to 8.85 Hz, JH5-H7= JH6-H8= 1.73 Hz)

of 7.82 (m, 3H, H-4', H-6, H-7)

7,46 (m, 1H, H-5')

NMR13C (CDCl3): (ppm)

178,17; 177,43 (2C, C-4, C-9)

158,76 (1C, C-RMS)

151,11 (1C, C-6')

147,86 (1C, C-4')

134,77; 134,31 (2C, C-6, C-7)

133,50; 132,74 (2C, C-4A, C-8A)

128,04; 127,16 (2C, C-5, C-8)

121,15 (1C, C-3')

118,45 (1C, C-5')

IR (KBr): (cm-1)

1688, 1667 (C= 0)

Example l

4,9-dihydro-4,9-dioxo-2-(4-pyridyl)-oil[2,3-d] thiazole

Source: S. A. 109 130788t

Yield: 75%

F > 260oWITH

Rf: 0,30 (CH2C12/methanol 97/3)

SM (I. E. ): m/z 292 (M+. )

NMR1H (CDCl3) - (ppm)

8,84 (d, 2H, H-2, H-6', JH2'-H3'= JH5'-H6'= 5.50 Hz)

8,39; compared to 8.26 (dd, 2H, H-5, H-8, JH5-H6= JH7-H8= cent to 8.85 Hz, JH6-H8= JH5-H7= 1.73 Hz)

to 7.99 (d, 2H, H-3', H-5', JH2'-H3'= JH5'-H6'= 5.50 Hz)

to 7.84 (m, 2H, H-6, H-7)

NMR13With (CDCl3): (ppm)

178,17; 172,50 (2C, C-4, C-9)

151,11 (20, C-2', C-6')

134,77; 134,31 (2C, C-6, C-7)

133,50; 132,74; 132,01 (4C, C-9a, C-4', C-4a, C-8A)

128,04; 127,16 (2C, C-5, C-8)

121,04 (2C, C-3', C-5')

IR (KBr): (cm-1)

1688, 1667 (C= 0)

Example m

4,9-dihydro-4,9-dioxo-: 0,44 (CH2C12/ethanol 99/1)

SM (I. E. ): m/z 280 (M+. )

NMR 1H (CD2C12) - (ppm)

9,85 (1s, 1H, NH)

8,21; 8,17 (2dd, 2H, H-5, H-8, JH5-H6= JH7-H8= cent to 8.85 Hz, JH5-H7= JH6-H8= 1.73 Hz)

7,79 (m, 2H, H-6, H-7)

7,07 (m, 1H, H-5')

of 6.96 (m, 1H, H-3')

6.35mm (m, 1H, H-4')

IR (KBr): (cm-1)

3286 (NH); 1676, 1647 (C= 0)

Example n

4,9-dihydro-4,9-dioxo-2-(2-Farid)-oil[2,3-d] thiazole

Source: C. A. 67 11450f

Yield: 48%

F > 260oWITH

Rf: 0,55 (CH2C12/methanol of 99.5/0.5 to)

SM (I. E. ): m/z 281 (MH+. )

NMR1H (CDCl3) - (ppm)

of 8.37 (dd, 1H, H-5 or H-8, JH5-H6or JH7-H8= cent to 8.85 Hz, JH5-H7or JH6-H8= 1.73 Hz)

8,23 (m, 1H, H-5 or H-8)

7,81 (m, 2H, H-6, H-7)

the 7.65 (d, 1H, H-5', JH4'-H5'= 1.97 Hz)

7,46 (d, 1H, H-3, JH3'-H4'= 3,94 Hz)

of 6.65 (dd, 1H, H-4', JH3'-H4'= 3,94 Hz, JH4'-H5'= 1.97 Hz)

NMR13C (CDCl3): (ppm)

178,25; 177,90 (2C, C-4, C-9)

163,94 (1C, C-2)

155,25 (1C, C-2')

148,00 (1C, C-3A)

145,93 (1C, C-5')

140,62 (1C, C-9a)

134,34; 134,09 (2C, C-6, C-7)

133,13; 132,68 (2C, C-4A, C-8A)

127,83; 126,91 (2C, C-5, C-8)

113,80 (1C, C-3')

113,34 (1C, C-4')

IR (KBr): (cm-1)

1683, 1658 (C= 0)

Pharmacological properties

The study of the compounds of the present invention and their possible salts showed that they are about the tone, affecting the arterial system only at concentrations significantly greater than the activity concentration for veins, with the exception of some of the arteries, particularly of the cerebral arteries (carotid, basilar artery. . . ). Connections have no affinity or have a very weak affinity for the majority of the known pharmacological membrane receptors. In addition, they increase capillary resistance, reduce venous hyperproliferate induced some inflammatory agents. These properties have been identified in mammals, such as hamsters, rats, Guinea pigs and rabbits, in conditions in vitro (isolated vessels or vascular bed) and in vivo.

For studies in vitro of the compounds were dissolved in water, pure or containing DMSO (dimethyl sulfoxide).

For in vivo studies of the compounds were injected intravenously or intraperitoneally in the form of an aqueous solution containing or not containing DMSO, or orally as a 1% suspension in carboxymethyl cellulose, in a volume of 10 ml/kg using a probe for gastric feeding.

Model pharmacological studies

Contractility effect

Contractile effect was measured in vitro under static conditions on which I and other vein, and femoral, carotid, basilar, mesenteric arteries, thoracic and abdominal and other aortech rats (Wistar, 200-250 g), rabbit (New Zealand, 2-2,5 kg), Guinea pigs (Dunkin Hartley 250-300 g).

The ring was placed in a cell for isolated organs (25 mg for vessels with conductivity and 2.5 ml for vessels with resistance by Mulvany), held in isometric conditions using two rigid wires, inserted into the vessel so as not to damage the endothelium. The vessel was immersed in a modified Krebs solution (in mm: NaCl= 118, KCl= 4,6, CaCl2= 2,5, MgS04= l, 2, KN2P04= 1,17, Panso3= 25, glucose= 11), aeronavali in continuous mode, the gas mixture of 95% O2and 5% CO2at pH 7.4 and kept at 37oC. Rings were brought to the optimum pressure-length.

The increase in pressure generates an electric signal by a sensor power (Wheastone bridge). This signal is amplified, then either taken to a recording device CRR& Zonen, or translated into digital form for subsequent processing on a computer (IOS, CAPACIOUS). Pharmacological studies were performed after several standard pre-reduce stimulations using depolarizing solution (high staranimolinar solution. The presence of endothelium revealed by relaxation induced by increasing concentrations of acetylcholine after stabilization of the pre-reduction vessel.

The force of contractions of vascular rings in response to the action of various compounds was studied on the vessels alone or vessels stimulated electrically (5-8 Hz), using depolarizing physiological solution with a high concentration of potassium (KS1: 20, 40 mm), noradrenaline (higher concentrations), serotonin (increased concentration). . .

The magnitude of the reductions was expressed in mg strength or as a percentage of the maximal contraction in response to depolarization physiological solution with a high content of potassium.

Contractile effect was also measured in vitro under dynamic conditions (blood)current pressure perfusing vascular bed with a constant amount of current. On the mesenteric venous level selectivity was studied on the model of dual perfusion, simultaneous and separate arterial and venous networks, the model developed by T. Warner (British J. Pharmacol. 1990, 99, 427-433). The separation of the two vascular networks was carried out by incision of the blood vessels and tissues along the putting edge. The network was perfesional 2 ml/min with a solution of the Oia was measured in animals under anesthesia in basal conditions and after circulatory arrest, provoked by the introduction at the level of the right auricle catheter with an inflatable balloon. When the cardiac venous tone (mean filling pressure circulation with a constant blood volume) was calculated by the venous and arterial pressures measured in the equilibrium state and the adjustable depending on the relative differences in the elasticity of these two networks (SAMAR & COLEMAN, Am. J. Physlol. , 1978, 234: N-100; YAMAMOTO et al. , Am. J. Physiol, 1980, 238: H823-828).

In awake animals, blood pressure was measured by the classical method, derived from the Riva Rocci, by analyzing the acoustic waves transmitted by blood level and transforming the piezoelectric transducer located on the tail of the rats below the cuff will automatically inflate generator pressure.

At the microcirculatory level variations of the venous and arterial cross-section was studied in vivo in a model with an installed camera in the skin of the back awake hamster after video microscopic registration (microscope Leitz Ergolux, equipped with a halogen light source and video camera black-and-white image CDD HPR 610) and computer image analysis (software Viscap, Pack ICAP).

After anesthesia peenya surveillance camera (Prof. GEBHARD, Heidelberg) directly on the skin of the back. Both parts of the camera sew after careful selection of the thickness of the skin, intended for observation. In implanted jugular vein catheter for intravenous drugs within 48 hours after the operation.

The effect on induced hyperproliferate capillaries

Venous permeability was investigated in vivo by measuring the extravasation of albumin, the amount of which is determined by the dye binding albumin (Evans blue).

Hyperproliferate induce intradermal injection of a solution of histamine, bradykinin or zymosan.

We use the technique described BEACH & STEINETZ, J. Pharmacol. Exp. Therap. , 1961, 131, 400-406.

The abdominal wall of rats (Wistar line, 200-230 g) cut an hour before the start of the experiment. The test compound is administered intraperitoneally or orally for 1 h 40 min prior to slaughter. Rats anaesthetize mixture gaditana. Then they do intradermal injection in the belly of 0.10 or 0.15 ml (histamine 6,7 or 10 µg) inflammatory agent and intravenous injection of 1 ml of 0.5% solution of Evans blue in the veins of the penis. These injections carried out for 30 minutes before Athanasii.

After 30 minutes of these two injections rats score shifted the cabin with a glass stopper, containing 30 ml of fuming hydrochloric acid. Fermentation of the skin is carried out by keeping in water bath at 37oWith at least within one hour. Then add 3 ml of 12.8% benzalkonium chloride. Then after 30 minutes, add 7 ml of dichloromethane. Within hours of the tube periodically shaken. The aqueous phase is removed by suction, the organic phase is "dichloromethane" is filtered. The optical density estimate using absorption spectrophotometry at a wavelength of 620 nm against a control containing only dichloromethane.

Calculate the average values of optical density in the experimental and control groups of animals, then calculate the percentage of variation of the respective values in the experimental animals compared to control.

The influence of compounds on hyperproliferate induced inflammatory agents such as histamine and bradykinin, are also investigated after intravenous bolus injection in the model with the installed camera in the skin of the back of the hamster and the method developed GEMENO et A1. described above ("A new technique using intravital videomicroscopy for macromolecular permeability measurement, the 18th European Congress on microcirculation, Rome 1994"), i.e., video microscopic and by Ana(FITC-Dextran), enter bolus injection via a catheter implanted in the jugular vein (63 mg/kg for a certain volume of 1 ml/kg). The microscope is equipped with fluorescent source and filter set (initiation at blue 450-490 nm and barrier filter 515 nm).

The influence on capillary resistance

Increase capillary resistance was estimated by the change petechial index (petechial haemorrhages) (negative pressure, causing transudation of red blood cells), as measured by the method using angiosarcoma Parrot.

The study was conducted on male Wistar rats with an average weight of 200 g (age about 6 weeks). The lower region of the back shaved, then epidural with pastes, based on the derived thioglycolic and calcium hydroxide. After about 30 minutes the skin was washed and dried.

On the day of the study, the rats were in free movement. Reduced pressure at 80 mm RT. Art. If petechial haemorrhages (transudate erythrocytes) after 15 sec were observed, lowered the pressure even more, holding the vacuum extractor in the same position.

For the minimum value of the reduced pressure, p is about treatment). For each experiment was carried out two measurements on different areas of the back.

The drugs were administered to rats orally. After a certain time (usually 2, 4, 6 hours) after treatment, the test was repeated on different areas of the skin before the appearance of petechial haemorrhages, giving a new index reduced pressure. All measurements were done blindly.

The percentage variation of the capillary resistance of the treated animals in comparison with their original capillary resistance was calculated for each tested compound in each moment of treatment and compared with the control group (only excipient).

The effect on induced pleurisy in rats

Anti-inflammatory activity of the compounds was also investigated by measuring the degree of inhibition of the swelling and migration of cells after the induction of pleurisy in rats by injecting carrageenin in the pleural cavity (ALMEIDA et al. , J. Pharmacol. Exp. The rap. , 1980, 214: 74).

2 hours before injection carragenine and after 2 and 4 hours after injection, the rats were administered orally with the compounds. After a certain time (6 hours) after the induction of pleurisy in rats scored, pleural fluid was aspirated and measured its volume. Leukocytes, poscit raniwala them with the data of the control group.

Effect on septic shock

Activity in septic shock were studied in rats after the induction of shock by intravenous bolus injection of lipopolysaccharide endotoxin (LPS: 15 mg/kg) of E. Coli, a method similar to those described TERASHITA et al. , Eur. J. Pharmacol. , 1985, 109: 257-261. Blood pressure was measured depending on time and compared experimental and control (only excipient) group. Compounds were administered intravenously or orally for 5 min or 2 h, respectively, before the injection of LPS.

Examples of pharmacological effects

Compounds according to the invention and their possible salts selectively increase, in most cases, the reduction of the veins in animals caused by norepinephrine, electrostimulation or depolarizing gobernaciones solution of potassium.

To illustrate the effect of different compounds on reducing the ability of the subcutaneous veins of the legs of the rabbit, procontractor, called "physiological" depolarizing solution with a concentration of potassium equal to 40 mm; the maximum effect of each compound is expressed in percent of the maximal contraction induced by depolarizing gobernaciones solutions of potassium, and in the ED50(see tab. 1).

As the capillary resistance in rats as a rule, at doses from 0.01 to 5 mg/kg (see table. 2).

To illustrate - oral administration of some compounds according to the invention and their possible salts reduces inflammatory hyperproliferate in rats induced simhasanam in doses from 0.1 to 5 mg/kg (see table. 3).

In addition, the compounds according to the invention and their possible salts of very low toxicity. For example, after a single oral administration to mice at a dose of 500 mg/kg did not notice any visible toxic effects or mortality for most compounds, in particular for example f (1 g/kg), example j example h (1 g/kg, diarrhea), n (1 g/kg, red urine), example 3 (light diarrhea), example 5, example 6, example 13 (1 g/kg).

Most of the compounds detected the absence of cytotoxicity (cell viability is measured by counting inclusions in cells of the dye neutral red) until the concentration limits of their solubility in aqueous medium at fibroblastic cell lines mice (L929), in particular example f, example j, example 3, example 4, example 20, example 21. . .

Of the active compounds according to the invention is compound of example n.

So, the connection with the s ED50reduced 10 times, and Emaxincreases by 30%), electrical stimulation (an increase of 200% up to 0.3 microns), serotonin, in addition, reduce the observed effect in the presence of reaction to hibernate.many solution potassium. In depolarizing conditions gobernaciones solution of potassium compound causes a reduction of, for example, the jugular vein of a rabbit (ED50= 16 nm), rat (ED50= 50 nm), perfesional network mesenteric veins of the rats (ED50= 300 nm), the carotid artery of the rat (ED50= 300 nm), rabbit (ED5= 120 nm), basilar artery of the rabbit.

On models with an installed camera in the skin of the back of the hamster compound of example n (28 µg/kg intravenous bolus injection) reduces the diameter of the veins, not arteries, after intravenous injection of histamine (1 mg/kg), and reduces induced them venous hyperproliferate.

The effect on capillary resistance rats connection example n, administered orally in a dose-dependent manner in a wide range of doses and duration of at least 6 hours correlates with its concentration in plasma.

2 hours after oral administration of 0.1 mg/kg compound of example n reduces hyperproliferate induced itsnature reduces pulmonary exudate after induction in rat pleurisy introduction carragenin.

Introduced intravenous bolus injection at a dose of 28 mg/kg 5 minutes before the induction of septic shock, the compound of example n increases mean arterial pressure by 20 mm RT. Art. compared with the control group of rats.

The compound of example n does not affect blood pressure as shot rats after intravenous bolus injection, at least up to a dose of 28 mg/kg, and in awake rats after oral administration of 0.1-5-50 mg/kg)

All this shows that the compounds according to the invention and their possible salts can be used for therapeutic applications in humans and animals. They, in particular, shall be appointed by functional or organic venous insufficiency and hemorrhoidal pathology, with typical inflammatory diseases, as well as during shock States, accompanied by a significant drop in blood pressure. In the latter case, the improvement of the venous inflow able to maintain cardiac output and, therefore, blood pressure.

Functional venous insufficiency is characterized by expansion and hyperactivity external veins of the lower extremities, edema, paresthesia type Dragutanu failure, characterized by the development of varicose veins, "incontinence" valve, even in thrombophlebitis and venous disorders, ending ulcer pathological changes.

When this venous pathology of the inflammatory component appears in the early stages and becomes more apparent in advanced stages.

Due to its reducing action on the veins, anti-inflammatory activity, in particular venous hyperproliferate, and reduce the effect on the artery of the brain, the compounds according to the invention and their possible salts is also indicated for the treatment of migraine.

The present invention also concerns the use of the above compounds and their possible salts as active substances for medical drugs and pharmaceutical compositions for use in human therapy and veterinary medicine, which contain at least one of these compounds and salts with pharmacologically acceptable carrier or diluent.

The form of presentation of these drugs and the pharmaceutical compositions depends, of course, on the desired method of administration, in particular oral, parenteral, local (cazuela and fillers.

Thus, for oral administration they can be represented in the form of tablets, pills, gelatin capsules, solutions, syrups, emulsions, suspensions, powders, granules, soft capsules, liofilizatow, microcapsules, micro granules.

Tablets, pills and capsules contain the active substance together with diluents (e.g., lactose, dextrose, sucrose, mannitol, Malta, xedit, sorbitol or cellulose), lubricant (e.g., silicon dioxide, talc or stearate), a binder (e.g. starch, methylcellulose or gum Arabic), a disintegration agent (e.g., alginate) and are produced by known technologies, for example by mixing, granulating, pelletizing, coating shell, pressing, etc.

The syrups may contain as carrier glycerol, mannitol and/or sorbitol. Solutions or suspensions can contain water and other physiologically compatible solvents and carrier, such as vegetable gum, agar, sodium alginate or polyvinyl alcohol.

For parenteral administration the compounds and compositions can be presented in the form of solutions, emulsions or suspensions containing the active substance and the corresponding carrier or solven is) the use of the compounds and compositions can be presented in the form of ointments, creams or gels, in the form of emulsions or suspensions, solutions, mousses, powders.

For rectal administration the compounds and compositions can be presented in the form of capsules, creams, emulsions, gels, mousses, ointments, candles.

1. The use of tricyclic derivatives and their pharmaceutically acceptable salts of General formula

< / BR>
where a is either a sulfur atom, oxygen or radical3N, where R3is a hydrogen atom, a C1-C5-alkyl;

R1is either C1-C5-alkyl, or phenyl ring, unsubstituted or substituted by one or more groups selected from methyl, methoxy, fluorine, chlorine, or 5-6-membered heteroaromatic ring having one or more heteroatoms selected from oxygen, sulfur, nitrogen, unsubstituted or substituted by one or more groups selected from chlorine, bromine, nitro, amino, acetamido, acetoxymethyl, hydroxymethyl, methyl, phenyl;

R2is a hydrogen atom, halogen, C1-C5-alkyl, hydroxy, methoxy, with the exception of compounds in which: A is an oxygen atom or sulfur, or a group NH or N-Me, where Me denotes methyl, provided that when a represents N-Me, then R is of aroda, and R1mean 2-forfinal; when a represents an oxygen atom, then R2means a hydrogen atom, a R1mean 2-forfinal, 3-forfinal, 4-forfinal, 2-were, 3-were, 4-methoxyphenyl, 2-chlorophenyl, 4-chlorophenyl or 2-thienyl; when a represents a sulfur atom, then2means the OMe group in one of the positions 5, 6, 7, 8, and R1means phenyl or 2-furan; or R2means the hydroxyl in position 5 or 8, and R1mean 2-furan (and when R2is in position 8, R1can also mean phenyl; or R2means methyl in one of the positions 5, 6, 7, 8, and R1mean 2-phenyl or 2-furan; or R2means a hydrogen atom, and R1can be selected from 2-ftoheia, 3-ftoheia, 4-ftoheia, 2,4-dipthera, 3-pyridine, 4-pyridine, 3-furan, 5-chlorofuran-2-yl, 2-tanila, 3-tanila, 2-phenylamino, 1-pyrrole, 5-bromofuran-2-yl, 3-bromofuran-2-yl, 4-bromofuran-2-yl, 4,5-dibromofuran-2-yl, 5-nitrofuran-2-yl, 5-aminopurin-2-yl, 5-acetamidophenyl-2-yl, 5-hydroxymethylene-2-yl, 5-acetoxymethyl-2-yl, 5-methyl-2-furil, 4,5-dimethyl-2-furil, 5-phenyl-2-oxazolyl and 2-thiazole; or R2means a fluorine atom at position 6 or 7, and in this case, R1mean 2-furan; or R2means a chlorine atom in position 6 or 7, and in this case, R1mean 2-furan,

and their salts;

as active substances of the medicinal product intended for the treatment of diseases associated with impaired venous function and/or inflammatory edema.

2. Compounds of General formula (I), as defined in paragraph 1, representing

sulfate 4,9-dihydro-4,9-dioxo-1,2-dimethyl-1H-naphthas[2,3-d] imidazole,

4,9-dihydro-4,9-dioxo-2-(2-forfinal)-lH-naphthas[2,3-d] imidazole;

4,9-dihydro-4,9-dioxo-2-(2-forfinal)-naphthas[2,3-d] oxazol;

4,9-dihydro-4,9-dioxo-2-(3-forfinal)-naphthas[2,3-d] oxazol;

4,9-dihydro-4,9-dioxo-2-(4-forfinal)-naphthas[2,3-d] oxazol;

4,9-dihydro-4,9-dioxo-2-(2-were-naphthas[2,3-d] oxazol;

4,9-dihydro-4,9-dioxo-2-(3-were-naphthas[2,3-d] oxazol;

4,9-dihydro-4,9-dioxo-2-(4-methoxyphenyl)-naphthas-[2,3-d] oxazol;

2-(2-chlorophenyl)-4,9-dihydro-4,9-dioxo-naphthas[2,3-d] oxazol;

2-(4-chlorophenyl)-4,9-dihydro-4,9-dioxo-naphthas[2,3-d] oxazol;

4,9-dihydro-4,9-dioxo-2-(2-thienyl)-naphthas[2,3-d] oxazol;

4,9-dihydro-4,9-dioxo-2-(2-forfinal)-oil[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(3-forfinal)-oil[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(4-ftoh is(3-pyridyl)-oil[2,3-d] thiazole;

sulfate 4,9-dihydro-4,9-dioxo-2-(4-pyridyl)-oil[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(3-furyl)-oil[2,3-d] thiazole;

2-(5-chlorofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(2-thienyl)-oil[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(3-thienyl)-oil[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-phenylamine-oil[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-8-methoxy-2-phenyl-oil [2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-5-methoxy-2-phenyl-oil[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-7-methoxy-2-phenyl-oil[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-6-methoxy-2-phenyl-oil [2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-8-hydroxy-2-phenyl-oil[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(1-pyrrolyl)-oil[2,3-d] thiazole;

2-(5-bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil[2,3-d] thiazole;

2-(4,5-dibromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil-[2,3-d] thiazole;

2-(3-bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil-[2,3-d] thiazole;

2-(4-bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(5-nitrofuran-2-yl)-oil-[2,3-d] thiazole;

2-(5-aminopurin-2-yl)-4,9-dihydro-4,9-dioxo-oil-[2,3-d] thiazole;

2-(5-acetamidophenyl-2-yl)-4,9-dihydro-4,9-dioxo-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(5-hydroxymethylene-2-yl)-oil[2,3-d] thiazole;
4,9-dihydro-2-(4,5-dimethyl-2-furyl)-4,9-dioxo-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(5-phenyl-2-oxazolyl)-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(2-thiazolyl)-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-6-fluoro-2-(2-furyl)-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-7-fluoro-2-(2-furyl)-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-6-fluoro-2-phenyl-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-7-fluoro-2-phenyl-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-6-fluoro-2-(5-methyl-2-furyl)-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-7-fluoro-2-(5-methyl-2-furyl)-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-6-fluoro-2-(4-forfinal)-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-7-fluoro-2-(4-forfinal)-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-6-fluoro-2-(4-were)-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-7-fluoro-2-(4-were)-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-5-fluoro-2-(2-furyl)-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-8-fluoro-2-(2-furyl)-oil-[2,3-d] thiazole;

6-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)-oil-[2, 3-d] thiazole;

7-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(2-furyl)-5-methoxy-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(2-furyl)-8-methoxy-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(2-furyl)-5-gexo-2-(2-furyl)-6-methoxy-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-(2-furyl)-7-methoxy-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-furyl-6-methyl-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-furyl-7-methyl-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-6-methyl-2-phenyl-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-7-methyl-2-phenyl-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-furyl-5-methyl-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-2-furyl-8-methyl-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-5-methyl-2-phenyl-oil-[2,3-d] thiazole;

4,9-dihydro-4,9-dioxo-8-methyl-2-phenyl-oil-[2,3-d] thiazole.

3. Connection on p. 2, applicable for obtaining a medicinal product intended for the treatment of diseases associated with impaired venous function and/or inflammatory edema.

4. Derivatives substituted naftalina as intermediates for producing compounds of formula (I) under item 2, representing

1,4-dihydro-1,4-dioxo-5-methoxynaphthalene;

2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene;

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene;

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene;

2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fornatale;

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fornatale;

2-amine-5-fluoro-1,4-dihydro-1,4-deoxidation;

2-amino-3-bromo-8-fluoro-1,4-dihydro-1,4-deoxidation;

2-amino-3-chloro-1,4-dihydro-1,4-dioxo-6-methylnaphthalene;

2-amino-3-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene;

2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene;

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene;

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methylnaphthalene.

5. Application under item 1, characterized in that the drug is intended for treatment of functional or organic venous insufficiency.

6. Application under item 1, characterized in that the drug has anti-inflammatory activity.

7. Pharmaceutical composition having anti-inflammatory action, containing the active ingredient and pharmaceutically acceptable carrier, characterized in that the active substance it contains an effective amount of at least one of the compounds under item 1 or 2, and/or their pharmaceutically acceptable salts.

 

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The invention relates to new chemical compounds, in particular derivatives (1,2,3-triazolyl)-1,2,5-oxadiazole General formula I, where R = NH2or< / BR>
and, if R1= N, R2lowest hydroxyalkyl, or, if R1- lower alkyl, lower hydroxyalkyl, aryl, R2= N, the lower hydroxyalkyl or a radical of General formula-C(O)R3where R3= HE, NH2, lower alkyl or lower alkoxyl, potentiating NO-dependent activation of the soluble form of guanylate cyclase (RGC)

The invention relates to compounds of formula I:

< / BR>
where X denotes O, S, NH or NA;

Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
R2represents CrH2r-COOR3;

R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

"m" and "r" each, independently of one another, denote 0, 1, 2, 3 or 4; and

"n" represents 2, 3 or 4,

and their physiologically acceptable salts

The invention relates to the field of anhydrides of carboxylic acids, in particular, to methods selection of phthalic anhydride from a mixture flowstone
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