PL173517B1 - Novel pyrrolo (1,2-c) [1,3] thiazines, method of obtaining them and and anticonvilsive agent - Google Patents

Abstract

1. A new pyrrolo (1,2-c) [1,3] thiazine of formula general 1 is shown in the figure where R1 is hydrogen, alkyl, cycloalkyl, benzyl, phenyl, substituted phenyl. 2. The method of producing new pyrroles (1,2- c) [1,3] thiazines of general formula I wherein R1 is hydrogen, alkyl, cycloalkyl. benzyl phenyl, substituted phenyl, characterized in which 2- (2-hydroxyethyl) pyrrolidine is reacted of general formula 2 with isothiocyanate of the general formula 3 in which R1 has the meaning given above, in a solvent medium organic at 30 to 60 ° C, then after completion of the reaction after distilling off the solvent added to inorganic acid residues and heated the mixture to reflux for 2 to 15 hours and further distillation to remove excess inorganic acid, then isolates the obtained salt or neutralized and crystallized from properly selected solvent.

Description

The present invention relates to novel pyrrolo (1,2-c) [1,3] thiazines of general formula 1 and a process for the preparation of new pyrrolo (1,2-c) [1,3] thiazines.

There are no known organic compounds containing heterocyclic systems of the pyrrole (1,2-c) [1,3] thiazine type.

The new pyrrole (1,2-c) [1,3] thiazines represent a new class of organic compounds.

The new pyrrolo (1,2-c) [1,3] thiazines are represented by the general formula 1, wherein R 1 is hydrogen, alkyl, cycloalkyl, benzyl, phenyl, substituted phenyl.

The process according to the invention consists in reacting a 2- (2-hydroxyethyl) pyrrolidine of the general formula 2 with an isothiocyanate of the general formula 3, in which R 1 is as defined above, in an organic solvent medium at a temperature of 30 to 60 ° C then, after the reaction is completed, after distilling off the solvent, inorganic acid is added to the residue and the mixture is refluxed for 2 to 15 hours, distillation is continued to remove the excess inorganic acid, then the salt obtained is isolated or neutralized and crystallized from a suitably selected solvent. In this way, the new pyrrolo (1,3-c) [1,3] thiazines of general formula I are obtained in which R 1 is hydrogen, alkyl, cycloalkyl, benzyl, phenyl, substituted phenyl.

Preferably, an organic solvent in the form of methanol, ethanol, isopropanol, heptane or benzene is used as the reaction medium of the 2- (2-hydroxyethyl) pyrrolidine with the isothiocyanate.

Preferably, hydrochloric acid, hydrobromic acid or sulfuric acid is used as the inorganic acid.

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Good results are obtained if the neutralization of salts, an aqueous solution of NaOH or KOH or K2CO3 or Na CO ₃ "or NaHCO" or KHCO3.

Preferably, an ethanol or nitromethane solvent is used for the crystallization of the salt.

The new compounds obtained according to the invention have an anticonvulsant effect, especially marked in the minimum doses of pentatresol and are shown in the table, items 1 to 6.

The subject matter of the invention is illustrated in the following examples.

Example 1 To 0.05 mol of 2- (2-hydroxyethyl) pyrrolidine in 50 cm 3 of ethanol, 0.05 mol of methyl isothiocyanate was added with stirring. The temperature of the mixture rises to 50 ° C and after 15 minutes the heating is removed and the contents remain for a further 30 minutes. Then, after ethanol has been distilled off under reduced pressure, 45 cm3 of 48% hydrobromic acid are added to the oily liquid and heated to reflux for 2 hours. Subsequently, the hydrobromic acid was distilled off under reduced pressure and the resulting solid hydrobromide was crystallized from ethanol. The obtained hydrobromide is shown in table 1, item 1.

Example II. To 0.01 mol of 2- (2-hydroxyethyl) pyrrolidine in 100 cm3 of isopropanol, 0.1 mol of cyclohexyl isothiocyanate was added with stirring. The mixture was heated at 30 ° C for 1 hour. After the isopropanol has been distilled off under reduced pressure, 45 ml of 48% hydrobromic acid are added to the residue and heated to the boil under reduced pressure. The resulting hydrobromide precipitate is crystallized from ethanol. The obtained hydrobromide and its physical and chemical properties are presented in Table 1, item 3.

Example III. To 0.01 mol of 2- (2-hydroxyethyl) pyrrolidine in 100 cm 3 of benzene, 0.12 mol of isothiocyanate was added with stirring and the mixture was stirred for a further 30 minutes at 60 ° C. After the benzene has been distilled off under reduced pressure, 100 cm3 of 48% hydrobromic acid are added to the residue and heated under reflux for 5 hours. Then the excess of hydrobromic acid is distilled off and the obtained hydrobromide, after crystallization from ethanol, is neutralized with 10% aqueous sodium hydroxide solution. The obtained precipitate crystallizes from nitromethane. The physico-chemical data of the obtained product are presented in Table 1, item 4.

Example IV. 0.05 mole of p-methoxyphenyl isothiocyanate is added to 0.05 mole of 2- (2-hydroxyethyl) pyrrolidine in 50 cm "of methanol. The reaction is carried out at 50 ° C for 30 minutes. After the methanol has been distilled off, 100 ml of concentrated hydrochloric acid are added and the reaction mixture is heated for 2 hours at the reflux temperature. After the excess hydrochloric acid had been distilled off, the salt obtained was neutralized with a 20% aqueous KOH solution. The separated precipitate is crystallized from nitromethane. Properties of the obtained compound are presented in table 1, item 8.

Example 5 To 0.05 mole of 2- (2-hydroxyethyl) pyrrolidine in 50 cm "ethanol, 0.05 mole of p-chlorophenyl isothiocyanate is added and the contents of the reactor are stirred for 30 minutes at 50 ° C. After the ethanol has been distilled off, the residue is treated with 100 ml of 20% sulfuric acid and heated to reflux for 1 hour. The excess sulfuric acid is then distilled off and the resulting product precipitate is crystallized from ethanol. The obtained pyrrolo (1,2-c) [1,3] thiazine is shown in Table 1, item 7.

Example VI. P-Bromophenyl isothiocyanate is added to 0.05 mole of 2- (2-hydroxyethyl) pyrohidine in 50 cm "heptane. The reaction is carried out at 40 ° C for 30 minutes, then heptane is distilled off and 45 cm ^T 48% hydrobromic acid is added to the residue. The reaction mixture is refluxed for 6 hours. The excess hydrobromic acid is then distilled off under reduced pressure. The obtained hydrobromide is neutralized with NaHCO "or KHCO3 and the resulting precipitate is crystallized from nitromethane. The physical and chemical properties of the obtained product are presented in Table 1, item 6.

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For this example, the anticonvulsant tests performed in mice are presented:

- spontaneous mobility of mice, table 2,

- maximum electric doses, table 3,

- duration of anticonvulsant action in maximum electrical convulsions, table 4

- minimal pentatresol convulsions, table 5,

- maximum pentatresol convulsions, table 6,

- test of four plates, table 6.

Table 1

No. R1 Mp, ° C IR (cm ^-1) KBr performance, % 1 CH3 164-165 1600 (C = N) 45 2 c ₂ h ₅ 209-211 3180- 2750 (NH) ⁵⁰ 3 c-CeHn 161 - 163 3250 - 2750 (NH) 1600 (C = N) 45 4 C ₆ H ₅ -CH ₂ 192-194 3150-2750 (NH) 1600 (C = N) 55 5 c ₆ h ₅ 155 - 157 1560 (C = N) 58 ⁶ p-BrCeHł 16: 2- 164 1560 (C = N) 50 7 p-ClC ₆ H4 161-163 1560 (C = N) 51 8 p-CH ₃ OC ₆ H4 125 - 127 1590 (C = N) 54

Table 2

Spontaneous mobility of mice

Relationship symbol Dose mg / kg p o Number of counter strokes +/- SE Action % Control - 603 2 (61 48) - Tab 1, pos. 6 100 432.6 (63 36) -28 300 202.3 (42.89) * -66 *

n = 12 * p <0.01

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Table 3

Maximum electrical shocks

And a symbol of relationship Dose mg / kg p.o Number of animals in which there was no tonic phase seizures Action shielding % control - 0 - 1 tab. 1, item 6 300 10 100 - * 55 200 7 70 - "" 150 4 40 and 133.3 4 40 B _B 88.8 4 40 - "55 75 4 40 B "55 59 1 ¹⁰

ED50 = 128.22 / 96 4 - 170.4 mg / kg p.o. ID = 11.7 phenytoin ED50 = 12 0/8 5 - 16 8 / mg / kg p.o.

ID = 21.6

Number of animals per dose = 10

LD50

ED50

Table 4

The duration of the anticonvulsant effect of the compound tab. 1 item 6 in maximum electric shocks

1 Dose, mg / kg p.o. % of animals free of tonic convulsions | 1 hour 3 hours 6 hours from serving 1 1 control 0 0 0 200 70 60 100

r = 10

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Table 5

Minimal pentatresol seizures

Relationship symbol Dose mg / kg after. ENumber of mice developing clonic seizures Action % control - 30 (30) * - control 300 3 (10) * 100 tab.l item 6 150 0 (10) * 70 ~ 55 " 75 3 (10) * 70 1 37.5 5 (10) * 50 1 ”55 ~ 18.75 8 (10) * twenty

ED50 = 46 41 / 27.65 - 77.88 / mg / kg p o ID = 32 3 diazepam ED50 = 1.1. / 0.85 - 1.40 / mg / kg p o.

ID = 854 phensuximide ED = 46 0/26. (5-71.3/ mg / kg p.o.

ID = 16.9 (x) *

ID - LD50 ^J ED50

Table 6

Maximum pentatresol seizures

| Relationship symbol Dose mg / kg po ENumber of mice developing clonic seizures Action J% J control - 10 (10) * - I J tab, item 6 150 4 (10) * 63 6 1 55 " 75 _7 (10) * 30.0 |

orient ED50 ~ 115 / mg / kg p.o. ID = 32.3 phenytoin

ED50 = 20 / 14.9 - 26 8 / mg / kg after ID5- = 13 (x) * 7 r \ ..LD50 ¹ “ED50

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MODEL 1

ch ₂ ch ₂ oh

PATTERN 2

R — N = C = S

MODEL 3

Publishing Department of the UP RP. Circulation of 90 copies. Price PLN 2.00

Claims (6)

Patent claims 1. The new pyrrolo (1,2-c) [1,3] thiazines of general formula 1 are shown in the figure, wherein R ¹ is hydrogen, alkyl, cycloalkyl, benzyl, phenyl substituted phenyl. 2. A method for the preparation of new pyrrolo (1,2-c) [1,3] thiazines of general formula 1, in which R ¹ is hydrogen, alkyl, cycloalkyl. benzyl, pephenyl, substituted phenyl, characterized by reacting 2- (2-hydroxyethyl) pyrrolidine of the general formula 2 with an isothiocyanate of the general formula 3, in which R 1 is as defined above, in an organic solvent at a temperature of 30 to 60 ° C, then, after the solvent has been distilled off, inorganic acid is added to the residue and the mixture is heated to boiling for 2 to 15 hours, distillation is continued to remove excess inorganic acid, then the obtained salt is isolated or neutralized and crystallized from selected solvent. 3. The method according to p. The process of claim 2, wherein an organic solvent in the form of methanol, ethanol, isopropanol, heptane or benzene is used as the reaction medium of the 2- (2-hydroxyethyl) pyrrolidine with the isothiocyanate. 4. The method according to p. The process of claim 2, wherein the inorganic acid is hydrochloric acid, hydrobromic acid or sulfuric acid. 5. The method according to p. 2, characterized in that for the neutralization of salts, an aqueous solution of NaOH or KOH or K2CO3 or Na ₂ CO ₃ or KHCO 3 or NaHCO. 6. The method according to p. The method of claim 2, characterized in that an ethanol or nitromethane solvent is used for the crystallization of the obtained salt.