SU1380610A3 - Method of producing spiroheteroazolydindiones or pharmaceutically acceptable salts thereof - Google Patents

Abstract

The invention relates to heterocyclic substances, in particular the preparation of spiroheteroazolidinediones of the general formula -NH U CHiln x o where a) U-NH; p O or 1; XH, Br, benzyl, C-alkyl or dimethyl, provided that X is dimethyl, then Y-H, halogen, N0, C-alkoxy or C-alkyl; Z-H, halogen, C. -alkyl under the condition that Y N07, then Z is H; b) and - oxygen; n 1, X - C-alkyl; Y is halogen; Z-H, or their pharmaceutically acceptable salts, which are capable of inhibiting the activity of aldose reductase and can be used to treat complications of diabetes, including complications of the visual organs. The goal is to create new more active substances of the specified class. Their synthesis is carried out by cyclization, for example, 2,5-dioxo-4-phenyl-4-imidazolidinacetic acid under the action of polyphosphoric acid or conc. at 70-150 ° C. The degree of inhibition of the indicated enzyme. In new substances it is 81-91% without signs of toxicity. 3 tab. SU) 00 o O) cm

Description

The invention relates to a method 11oluche u1 new biologically active chemical compounds, namely to a process for preparing spirogeteroazo- lidindionov, spirooksazolidindionov or spiromidazolidindionov or pharmaceutically acceptable salts thereof which possess the ability sorbed inhibition of aldose reductase activity and can be used for the treatment of certain chronic diabetic complications, including complications of the visual organs.

The purpose of the invention is to obtain new derivatives of the spiroheteroazolidinediones, which have an increased inhibitory activity against the aldose reductase enzyme.

Example 1, SpiroCimidazole din-4,1 -indan-3-it) 2,5-dione.

2,5-dioxo-4-phenyl-A-imidazolidine acetic acid is suspended in 15 m of polyphosphoric acid at 150 ° C. Dissolving occurs gradually, and after 2 hours, the reaction mixture is cooled to and diluted with 15 ml of water. A solid is formed slowly, which is collected by filtration, washed with water, dried and recrystallized from the hearth, yielding 0.210 g (A0% yield) of the title compound, mp. 268-270 С

Calculated,%: C 61.11, H 3.73,

N 12.96.

With ,, nonM, 0 ,.

Found,%: C 60.89, H 3.87, N 12.98.

Example. Spiro (imidazolidin-4,1 -3 N-1, 2-d1 hydronaphthalen-4 - -one) 2,5-dione.

2,5-dioxo-A-phenyl-4-imidazolidinopropionic acid (2.48 g, 10 mmol) is heated in 25 ml of concentrated sulfuric acid first, first for 1 hour, and then at 120 ° C for 45 minutes and poured into 200 g of ice. The resulting solid is collected by filtration and dried under vacuum at 100 ° C for 60 hours to obtain 1.85 g of the crude product, m.p. 144-149 ° C. The substance is decoloured in a solution of isopropanol with activated carbon and recrystallized from isopropanol to obtain 1.11 g (487 yield) of the target compound, mp. 261-263 S.

2

%: C 62.60, H 4.38,

С ,, Н, „N7О,

Found,%: C 62.34, H 4.51, N 12.16.

Example 3. Spiro (imidazolidin-4, G-3 H-1, 2-dihydronaphthalen-4-one) 2,5-dione.

2,5-dioxo-4-phenyl-4-imidazolidine-propionic acid (2.43 g, 10 mmol) is suspended in 25 ml of polyphosphoric acid at 150 ° C. Dissolution gradually takes place and after 135 minutes the reaction mixture is cooled to 25 ° C. Water (75 ml) is added, the resulting crude solid is separated by filtration. This solid material is provided with activated carbon as a solution in isopropanol and recrystallized from

isopropanol to obtain 450 mg (17% yield) of the desired compound, m.p. 262-263 S.

NMR (DMCO-dt), ppm: 10.98 (bp, 1H), 8.65 (bp, 1H), 8.03-7.30 (m, 4H) and 3.07-2.23 (m, 4H).

Example 4.7-Fluoro-spiro (imidazolidin-4,1 -ZH-1, 2 -dihydronaphtalen-4 it) -2,5-dione.

2,5-Dioxy-4-m-fluorophenyl-4-imidazolidin-propionic acid (1.33 g, 5 mmol) with 15 ml of polyphosphoric acid is heated at 150 ° C for

1.5h The reaction mixture is cooled to 0 ° C and diluted with water. The dark solid is collected by filtration and distributed between ethyl acetate and dilute aqueous sodium hydroxide (pH 8). The ethyl acetate layer is extracted with aqueous 10% sodium hydroxide, and the combined aqueous layers are decolorized with activated charcoal.

and adjusted to pH 3 with concentrated hydrochloric acid. The water is evaporated in vacuo, and the resulting white solid is triturated with boiling isopropane to remove sodium chloride. The isopropanol solution is filtered and concentrated in vacuo to give 115 mg of the title compound as a white foam. NMR (DMSO-dj), million dollars: 8.55 (s.s., 1H) 8.02 (q, 1H), 7.37 (m, 1H), 7.17 (q, 1H), 3.15-2.96 (m, 1H), 2.752 .6 (m, 1H) and 2.45-2.3 (m, 2H). Example 5. 7-Fluoro-spiro (imidazolidin-4, 1 -Z H-1, 2 -dihydronaphtalen-4-one) -2, 5-dione.

2,5-dioxo-A-m-fluorophenyl-4-imidazolidinopropionic acid (68.55 g, 0.26 mmol) with 500 ml of concentrated sulfuric acid is heated at 75-77 ° C and poured into ice to precipitate a solid which is separated by filtration. The solid is dissolved in 800 ml of methanol and decolorized with activated charcoal. The methanol is removed in vacuo to give a solid, which is triturated with 75 ml of methanol, then collected by filtration. After washing with 30 ml of water, the solid was dried in vacuo at 80 ° for 20 hours to obtain 52.07 g (81% yield) of the title compound, mp. 229-231 s.

Calculated,%: C 58.07, H 3.65, N 11.29.

ScN g FN-jO 3.

Found,%: C 57.86, H 3.59, N 11.39.

Example 6. 7-Methyl-spiro (imidazolidin-) A, 1 (-Z H-1, 2-dihydronaphthalen-4-it) 2,5-dione.

2,5-dioxo-4-m-tolyl-4-imidazolidinopropionic acid (d, g, 5.3 mmol) is combined with 25 ml of concentrated sulfuric acid and heated for 30 minutes. The reaction mixture is drunk on ice and the resulting solid is collected by filtration and decolorized with hot charcoal in hot water and crystallized from water to give 420 mg (32% yield) of the title compound, mp. .

Calculated,%: C 63.93, H 4.95, N 11.47.

C, iH ,, N, 03.

Found,%: C 63.57, H 4.91, N 11.45.

The spent black carbon is dried and extracted with methanol at reflux with a reflux condenser to obtain an additional 110 mg (8.5% yield of the desired product, mp 202 C.

Example 7. 5.7-Dimethyl-β-spiro (imidazolidine-4,1 -3 H -1, 2-β-dihydronaphthalen-4-one) 2,5-dione.

2,5-dioxo-4-m-xylyl-4-imidazolidinopropionic acid (1.0 g, 3.7 mmol) is mixed with 20 ml of concentrated sulfuric acid and heated at 85 ° C for 45 minutes, cooled to and poured on ice. The resulting red precipitate is collected by filtration, dried, and

five

0

five

Q

with

five

0

0

200 ml of methanol is heated at reflux and decolorized with activated carbon. The methanol solution is concentrated in vacuo, and the residue is triturated with 10 ml of water. The resulting solid is collected by filtration and dried to give 630 mg (70% yield) of the title compound, m.p. 260-261 ° C.

Calculated,%: C 65.11, H 5.46, N 10.85.

C ,, N ,, K, Oz,

Found: C, 64.80; H, 5.48; N, 10.73.

Example B, 6-Chloro-spiro (dazolidin-4,1 -3 H-1, 2 -dihydronaphthalen-4-one) -2,5-dione.

2,5-dioxo-4-p-chlorophenyl-4-imidazolidinopropionic acid (5.0 g, 18 mmol) is mixed with 90 ml of concentrated sulfuric acid and heated at 1 for 16 h. The reaction mixture is cooled to 25 ° C and poured onto 800 J of ice and stirred for 2 hours. Activated carbon was added and stirring continued for 1.5 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was washed with 400 ml of water, and then the filtered solid, activated carbon and diatomaceous earth is mixed with 500 ml of methanol while heating with reverse holo Ilnyk. After stirring for 30 minutes, the slurry (or suspension) is again filtered through diatomaceous earth, the pure substance is concentrated under vacuum to obtain 1.1 g of material which, according to NMR data, is a 1: 1 mixture of the starting material and the target compound, 1.1 g the substances are suspended in methanol and filtered to obtain 0.31 g (6%) of the title compound, mp 258-261 ° C. An analytical sample recrystallized from water to give the title compound, so pl. 265-266 C.

Calculated,%: C 54.46, H 3.43, N 10.58.

C, H ,, C1,

Found,%: C 54.21, H 3.41, N 10.40.

Example 9, (17-Chloro-3, 3-dimethyl-spiro (imidazolidin-4, 1 -1, -dihydronaphthalen-4-one) 2,5-dione.

2,5-dioxo-3, 3-dimethyl-4- (m-chlorophenyl) -4-imidazolidinopropionic acid (0.62 g, 2 mmol) is mixed with 4 ml of concentrated sulfuric acid

513

You are heated at 70 ° C for 4 hours. The reaction mixture is poured onto ice, and the solid that is formed is collected by filtration, washed with water and dried to give 412 ml of solid. This solid is added to hot acetonitrile, is provided with activated carbon with admixed earth mixed with it, and the harder substance, which is formed upon cooling, is collected by filtration and dried to obtain 140 kg of the desired compound, mp. 264-26b with.

Calculated,%: C 57.44, H 4.48, N 9.57.

C ,, H ,, 0, N, F.

Found,%: C 57.26, H 4.51, N 9.63.

Example 10. (1) 3, 3 -Dimethyl-spiro (imidazolidin-4,1-1, 2 - 2-dihydronaphthalen-4 it) 2,5-dione,

2,5-dioxo-3, 3-dimethyl-4-phenyl-4-imidazolidinopropionic acid (26.94 g, 0.1 mol) is combined with 135 ml of concentrated sulfuric acid and heated at 70 ° C for 5 hours and then poured onto ice. A solid is formed, which is collected by filtration and dried, yielding 21.04 g of crude product. The crude product (19.35 g) is dissolved in 150 ml of 1 sodium hydroxide and decolorized with activated charcoal mixed with diatomaceous earth. The basic solution is adjusted to pH 7 with hydrochloric acid, and the resulting solid is collected by filtration and washed twice with water. This procedure is repeated again, and the solid B obtained as a result is distributed between 75 ml of dilute hydrochloric acid and 400 ml of ethyl acetate. The ethyl acetate layer is washed with brine, dried over anhydrous sodium sulfate and concentrated.

12.54 g of the title compound were obtained, m.p. 229-231 s.

N

Calculated,%: C 65.10, H 5.46, 10.85.

five

Q

0

5 n

five

0

five

0

2,5-dioxo-3-methyl-4- (m-chlorophenyl) -4-imidazolidinopropionic acid (10.72 g, 36.1 mmol) is combined with 55 ml of concentrated sulfuric acid and heated at 70 ° C in for 5 hours. The reaction mixture is poured into ice-water, and the resulting solid is collected by filtration, washed with water and dried to obtain 7.96 g of the crude product. The crude product (7.76 g) is dissolved in 400 ml of boiling acetonitrile and decolorized with activated carbon, filtered and allowed to cool to 25 ° C. The resulting solid is collected by filtration and dried to give 4.48 g of the title compound, m.p. 232-234 C (partial melting), 255-257 C (decomposition).

Calculated,%: C 56.02, H 3.98, N 10.05.

..

Found,%: C 56.17, H 4.08, N 10, 13.

Example 12. Spiro (imidazolidin-4, 1 -indan-3-it) 2,5-dione.

Melting point 253-256 C.

NMR (DMCO-dj), ppm: 11.13 (i.e., 1H), 8.50 (bp, 1H), 7.97-7.43 (m, 4H) and 3.0 (d, 2H).

Calculated,%: C 61.11, H 3.73, N12.96.

C, iHgNiOj

Found,%: N 13.09.

Pr and m-e p 13. 6 -Fluoro-spiro (imidazolidin-4,1 -indan-3-one) 2,5-dione.

Melting point, with decomposition.

C 56.42, H 3.01,

C 60.54, H 4.02,

C 55.85, H 3.22,

Calculated, N 11.96.

C ,, H, FN, Oj.

Found,%: N 12.06.

Example 14. Spiro (imidazolidin-4, 1 -Z H-1, 2 -dihydronaphthalen-4-one) 2,5-dione.

Melting point 256-258 s.

Calculated,%: C 62.60, H 4.38, N 12.17.

C ,,, N ,.

Found,%: C 54.74, H 5.53, N 10.74.

Example 11. (t) 7-Chloro-3 - -methyl-spiro (imidazolidin-4,1 -Z H- -1, 2 -dihydronaphthalen-4-one) 2, 5-dione.

P

Found%:

12.15.

Example

C 62.84, H 4.75,

15. 3 -Bromo-spiro (imidazolidin-4,1 -ZH-1, 2 -dihydronaphthalen-4 -one) -2,5-dione.

Melting point 221-224 ° C.

Calculated,%: C 46.63, H 2.93, N 9.06.

С „Н, ВгЫ, 0 ,.

Found,%: C 46.42, H 3.10, N 9.12.

Example 16. 7 -Methoxy-spiro (imidazolidin-4,1 -ZH-1, 2-dihydronaphthalen-4 -one) -2,5-dione.

2,5-Dioxo-4-m-methoxyphenyl-4-imidazolidinopropionic acid (8.35 g, 30 mmol) is reacted with 60 ml of polyphosphoric acid for 1 hour. The reaction mixture is cooled to 25 ° C and diluted with water . The resulting solid is collected by filtration and is decolorized with activated carbon in an aqueous solution and crystallized from water to give 2.9 g (37% yield) of the desired compound; melting point 250-251 ° C

Calculated,%: C 60.00, H 4.65, N 10.76.

, 0 ,.

Found,%: C 59.83, H 4.71, N 10.79.

Example 17. 7 -Nitro-spiro (imidazolidin-4,1 -3 Н-1, 2 -dihydro naphthalene-4-it) 2,5-dione.

The procedure of Example 5 is used to prepare the target compound using 2,5-dioxo-4-m-nitrophenyl-4-imidazolidine propionic acid as a starting material instead of m-fluorophenyl compound.

Example 18. 7-Chloro-b-methyl-spiro (imidazolidin-4,1 -Z H-1, 2 - -dihydronaphthalen-4-one) 2,5-dione.

4- (m-Chloro-p-methylphenyl) -2,5-dioxo-4-imidazolidinpropionic acid (10.0 g, 34 mmol) is mixed with 150 ml of concentrated sulfuric acid and heated at 80 ° C for 2 hours. The reaction mixture is cooled down and drunk on ice. The resulting white solid is collected and rinsed with water and dried, yielding 8.78 g (94% yield) of the crude product; m.p. 260-265 ° C. The crude product is recrystallized from isopropanol-water to obtain 5.80 g of the title compound; m.p. 277-278 C.

Calculated,%: C 56.03, H 3.98, N 10.05.

, 0, Cl.

five

0

five

0

five

0

five

five

Found,%: C 55.63, H 4.01, N 9.96.

Example 19. 6-Methyl-spiro (imidazolidin-4,1-3 H-1, 2 -dihydronaphthalen-4-one) 2,5-dione.

2,5-dioxo-4-p-tolyl-4-imidazolidinopropionic acid (2.85 g, 10.9 mmol) is mixed with 25 ml of concentrated sulfuric acid and heated at 95 ° C for 1.5 hours. the mixture was poured onto ice, and the resulting solid was collected by filtration, washed with water and dried to give 1.88 g (71% yield) of the crude product, mp. 206-214 s. The crude material (1.76 g) is recrystallized from isopropanol to obtain 1.12 g of the title compound, m.p. 245-248 C.

Calculated,%: C 63.93, H 4.95, N 11.47.

C, H „K, Oz.

Found,%: C 63.56, H 5.15, N 11.24.

Example 20. 7-Chloro-spiro (imidazolidin-4,1 -3 N-1, 2 -dihydronaphthalen-4-it) 2,5-dione.

2,5-dioxo-4- (m-chlorophenyl) -4-imidazolidinpropionic acid (5.42 g, 20.0 mmol) is mixed with 40 ml of concentrated sulfuric acid, heated at 90 ° C for 3 hours, and then cooled to 25 ° C and poured onto ice. The resulting solid is collected, dried and recrystallized from water to give 2.61 g of the substance, m.p. 202-230 ° C. NMR analysis shows that the substance is a mixture of the original propionic acid and the desired product. Respectively, 2.4 g of this substance is combined with 25 ml of concentrated sulfuric acid and heated at 120 ° C for 3 hours. The reaction mixture is cooled to 25 ° C, poured onto ice, and the resulting solid is collected by filtration and recrystallized from water, yielding 700 mg (14% yield) of the title compound, m.p. 279-280 ° C.

Calculated,%: C 54.58, H 3.41, N 10.60.

With iHgNlOjCl.

Found: C, 54.42; H, 3.60; N, 10.42.

Example 21. Using the techniques described, 3-methyl 913 is obtained.

- -fluoro-spiro (imidazolidin-A, 1 - -3 H-1, 2 -dihydronaphthalen-4-it) 2,5-dione.

Melting point 224-225 C.

Calculated,%: C 59.5A, H 4.23, N 10.68.

GI, H ,, FNjOj.

Found,%: C 59.41, H 4.32, N 10.68.

NMR (DMSO-dfe, 250 MHz) shows a diastereomeric pair in a ratio of 94GB; main component, million, dollars: 11.07 (i.e., 1H), 8.60 (s., 1H), 8.05 (m, 1H), 7.39 (m, 1H), 7.24 (m, 1H), 3.34 (m, 1H), 2.5 (t, 1H), 2.18 (t, 1H) and 1.15 (d., MN), component in a smaller amount, ppm: a, 94 (s., 1H), 3.0 (m, 1H) and 1.18 (d., ZN).

Example 22. Salt (+) 7 -fluoro-α-spiro (imidazolidin-4,1 -Z H-1, 2- -dihydronaphthalen-4-one (2,5-dione.

(t) 7-Fluoro-spiro (imidazolidin-4,1 -3 Н-Г, 2 -dihydronaphthalen-4 - -he) 2,5-dione (24.62 g, 0.099 mol) is dissolved in 700 ml of bale reflux of acetonitrile. 42.96 g (, 0.0998 mol) of brucine dihydrate is added to this solution. The acetonitrile mixture is filtered hot to remove traces of insoluble matter and the filtrate is allowed to cool to 25 ° C. The resulting solid is collected by filtration and dried to give 26.83 g of salt, m.p. 229-230 C with decomposition: fo J j) +30.7 (methanol). This salt is recrystallized from acetonitrile to give 18.8 g of purified salt, m.p. 230 ° C with decomposition, d +32.0 (methanol).

The purified salt (17.8 g) is decomposed with 500 ml of chloroform with stirring. First, most if dissolved, and then a new solid is formed. This solid new substance is collected by filtration and the substance is obtained to obtain 6.32 g of the target compound, m.p. 263-264 ° C; Go +203.5 (methanol).

The absolute configuration at 4, l center is attributed to S based on the X-ray analysis of a single crystal.

Example 23. 3-Bromo-7-fluoro-spiro (imidazolidin-4,1 -Z H-1, hydronaphthalen-4-one) 2,5-dione. Melting point 223-224 ° C.

ten

ten

Calculated,%: C 44.06, H 2.47, N 8.56.

With ,, HjNjOjBrF.

Found,%: C 43.61, H 2.61, N 8.31.

Example 24. (+) 7-Fluoro-3 - -methyl-spiro (imidazolidin-4,1 -3 Н-1, 2 -dihydronaphthalen-4-it) 2,5- -dione.

Melting point 250-25 ° C; Ul +231, G (methanol,).

Calculated,%: C 59.54, H 4.23, N 10.68.

С „Н„ М, 0, Г.

Found,%: C 59.36, H 4.38, N 10.70.

The absolute configurations at 4.1 and 3 centers are defined as S and R, respectively, on the basis of X-ray analysis of a single crystal.

Example 25. (-) 7 -Fluoro-3 - -methyl-spiro (imidazolidin-4,1 -Z H- -1, 2 -dihydronaphthalen-4-one) 2,5-dio

Melting point 149-150, C with decomposition; , -223.4 (methanol, С

one).

Example 26. (1) 7 -Fluoro-3 - -methyl-spiro (imidazolidin-4,1 -z H- -1, 2 -dihydronaphthalen-4-one) 2,5-dioH.

The melting temperature is 196-199 s.

Calculated,%: C 59.54, H 4.23, N 10.68,

C 1, H ,,.

Found,%: C 59.22, H 4.29, N 10.53.

Both p and mr 27. (+) 7 -Fluoro-3 - -benzyl-spiro (imidazolidin-4,1 -3 H- -1, 2 -dihydronaphthalen-4-it) 2,5-dione.

Melting point 225-226 ° C. LoiT 120 (methanol, C 1).

High resolution mass spectrum. Calculated for C ,, H «Nj05F: 338, 1067. Found: 338, 1067.

The main diastereomer is selected as follows. When using 672 mg (2 mmol) of (+) 7-fluoro-3 - -benzylidene-spiro (imidazolidin-4 -. -1, 2 -dihydronaphthalen-4-one) 2,5-dione and the hydrogenation conditions described above, the crude product consisting predominantly of one diastereomer. Recrystallization from isopropanol yields 460 mg of the basic diastereomer; m.p. 238-240 C, d -31 (methanol, C 1). (

1113

Example 28. (f) 7-Ftop-3-methyl (3, A-dihydronaphthalen-1) 2H (5-oxazolidine) 2, A-trion.

The title compound is obtained as a brown gummy solid, which, when subjected to a high vacuum, is converted to a foam of the title compound.

Macc-cneifTp high resolution. Calculated for C H, jN04F: 263,0594. Found: 263, 0572.

The infrared spectrum of the chloroform foam solution has an absorption at 1820, 1750 and 1690 cm-.

Example 29. The compounds of Examples 1-28 were tested for their ability to inhibit the activity of the aldose reductase enzyme using the procedure.

Compounds are tested against al-dose-reductase isolated from human placenta.

Inhibition of aldose reductase isolated from human placenta when -. conducted in table 1.

As comparative compounds, they test:

A.Spiroinuan (1,5) oxazolidine

21 I I, 4-dion.

B.1, 2, 3, 4 -tetrahydro-interio-oxazolidine (5, 1) naphthalene 2,4-dione.

C.Rel 1,5, ZP-7-fluorop-3-methylspi-, 4-dihydronaphthalen-1 (2H), 5 -oxazolidine 2, 4 -dione.

(concentration ongrol ° - 25P5bo1ka

(sorbitol concentration)

The results of inhibition of sorbitol are given in Table 3.

The results show that only compound D has sufficient inhibitory activity in the sciatic nerve.

The proposed compounds in the tested doses show no signs of toxicity and can be classified as low-toxic compounds.

Claims (1)

Invention Formula Method for preparing spiroheteroazolidinediones of formula ten 12 D. Pe1 1,3, 3,7-fluoro-3-methylspiro 3, 4-dihydronaphthalen-1 (2H), 5-oxazolidine 2, 4-dione. Compounds A and B are tested against aldose reductase isolated from the calf's eye lens, and C and D against aldose reductase derived from human placenta. These two enzymes give the same inhibition percentage values and, if they differ, only in that the human placenta is more difficult to inhibit according to the method of Choristopher A, Lipinski and Nancy I. Test data are given in table 2. The results of Table 2 for compounds A-D show that D is the most active. The compounds are also tested for their ability to inhibit sorbitol accumulated in the sciatic nerve and the lens of a diabetic rat. Following the previously described method, m.I. Peterson single dose of streptozotocin was intravenously administered to rats (85 mg / kg). The test compound is fed to the rats 4, 7 and 24 hours after the administration of streptozotocin. Twenty-seven hours after administration of streptozotocin, the animals were sacrificed and the lens of the eyes and sciatic nerves were removed for the sorbitol test. The control animals BBO / 1JT only streptozotocin, without the introduction of the tested compounds. The percentage of sorbitol inhibition is calculated by the following formula: control where, when U is an NH group, p O or 1; X is hydrogen or bromine, benzyl, C, -C 4 alkyl or dimethyl with the condition X is dimethyl, p 1; Y is hydrogen, halo, nitro, C 1 -C-alkoxy or C, -C4-alkyl; Z is hydrogen, halo or C, -Cd-alkyl with the proviso Y is a nitro group, Z is hydrogen; when and - oxygen, p 1; X is C, -alkyl, Y is halogen; Z is hydrogen, or their pharmaceutically acceptable lei, characterized in that the compound of the formula  tO X about g de p, and, Y, Z and X are indicated, are subjected to interaction with polyphosphoric or concentrated sulfuric acid at 70-150 ° C. Table 1 79 61 11 79 61 11 81 54 5 91 91 Continued table. 87 86 five 87 66 five 87 66 five 82 71 18 3 17 15 sixteen nineteen 138061018 Continuation of table 1 82 71 18 3 97 95 76 16 87 77 23 89 87 60 14 73 73 nineteen 23 1380610 20 Continuation of table 1 90 77 48 88 77 21 81 53 16 9A 97 77 49 25 91 75 25 3 86 76 31 91 76 28 3 83 60 U 3 23 26 138061024 Continuation of table 1 X 83 45 86 64 12 89 62 eight 59 10 92 59 3 25 Main diastereomer 138061026 Continuation of table 1 64 27 95 91 72 18 271380610 table 2 28 Continuation of table 2