PL229086B1 - 1-substituted-3-benzenesulfonyl urea derivatives and process for their preparation - Google Patents

Abstract

The invention relates to 1-substituted-3-benzenesulfonyl urea derivatives of general formula I, where R is preferably an aromatic substituent, phenyl and its substituted analogs, in particular 2-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl 4-chlorophenyl . The compounds of general formula I are obtained by condensation of appropriately substituted 1-aryl-2-aminoimidazoline-2 with benzenesulfonyl isocyanate in a dichloromethane atmosphere under nitrogen atmosphere at room temperature for 4-8 hours using a molar ratio of 1: 1, and then the solvent is distilled off is dissolved and the residue is dissolved hot in propan-2-ol.

Description

The invention relates to 1- (1-arylimidazolidin-2-ylidene) -3-benzenesulfonyl urea derivatives of the general formula I, where R is preferably an aromatic substituent, phenyl and its substituted analogs, especially 2-methoxyphenyl, 4-methoxyphenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl and the method of their preparation.

In the known art, there is a five-membered heterocyclic system containing two nitrogen atoms in the 1,3 position linked to the N1 of the urea. Research on these compounds was conducted towards the effects on the Central Nervous System [D. Matosiuk et al. European Journal of Medicinal Chemistry 36 (2001) 783-796].

The 1- (1-arylimidazolidin-2-ylidene) -3-benzenesulfonyl urea derivatives which are the subject of the invention constitute a group of novel compounds not described in the source literature so far.

The compounds obtained according to the invention show pharmacological activity in the Central Nervous System and are characterized by moderate toxicity (1363 mg / kg ^-1 ) and may have potential use as active substances in medicinal preparations.

Compounds of the general formula I where R is phenyl and the substituted analogues thereof, especially 2-methoxyphenyl, 4-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, are obtained by the process of the invention by condensation of the appropriately substituted 1-aryl-2-aminoimidazolines-2 of the formula general 2, in which R is as defined above, with benzenesulfonyl isocyanate of general formula 3. The condensation is carried out in an organic solvent, preferably dichloromethane, under a nitrogen atmosphere at room temperature for 8 hours. After completion of the reaction, the solvent is removed by distillation and the residue is dissolved hot in propan-2-ol. After cooling, the separated precipitate is filtered off and purified by crystallization from a polar solvent, preferably from methyl alcohol or propan-2-ol or a 1: 1 methanol: propan-2-ol mixture.

1-phenyl-3- (1-arylimidazolin-2-yl) ureas with antimicrobial activity are known from the description of the invention PL 181 837.

P r z k ł a d 1

In a 250 cm ³ conical flask there were placed 1.61 g (0.01 mol) of 2-phenyl-2-aminoimidazoline-2 dissolved in 50 cm ^{3 of} dichloromethane 1.83 g (0.01 mol) of benzenesulfonyl isocyanate in 30 cm 3. ^{3 of} dichloromethane. The flask was then purged with nitrogen gas and the contents were stirred for 8 hours at room temperature. After this time, dichloromethane was distilled off, a small amount of propane-2-ol was added to the oily residue. The obtained precipitate was purified by crystallization from a mixture of methanol: propan-2-ol (1: 1 ratio). The 1- (1-phenyl-imidazolidin-2-ylidene) -3-benzenesulfonylurea formula 1 was obtained.

1.55 g (45% yield) of a solid with mp. 200-202 ° C.

Elemental analysis for the formula C17H14N4O4S (MW 370.39) Calculated:% C = 55.80% H = 4.68% N = 16.27% S = 9.31 Determined:% C = 55.63% H = 4.56% N = 16.39% S = 9.44

¹ H NMR spectrum (D 6 - DMSO, δ, ppm, TMS)?

9.17 (s, 1H, NH), 8.82 (s, 1H, NH), 7.05-7.74 (m, 10H, Car.), 3.69-3.77 (m, 4H, 2CH2)

The physicochemical data of the remaining 1- (1-arylimidazolidin-2-ylidene) -3-benzenesulfonyl urea derivatives are presented in Table No. 1.

The results of pharmacological studies of 1- (1-arylimidazolidin-2-ylidene) -3-benzenesylfonyl urea derivatives are presented on the example of 1- [1- (4-phenyl) imidazolidin-2-ylidene] -3-benzenesulfonyl urea and are presented in Table No. 2.

PL 229 086 Β1

Table 1

Physicochemical data of 1- (1-arylimidazolidin-2-ylidene) -3-benzenesulfonyl urea derivatives

No related R Sum formula. Particle mass Ed. [%] mp. [° C] Analysis (calculated / recognized) 1 H NMR Spectra (δ, ppm, DMSO-dd against TMS) C. H. Cl S. 1. 2-OH ₃ C17H18N4O4S 374.43 57 product oily 54.53 54.61 4.84 4.91 8.56 8.97 (s, 1H, NH), 8.82 (s, ΙΗ, ΝΗ), 6.85-7.64 (m, 9H, Car.), 3.22-3.50 (m, 4H, 2 CH _2), 3.53-3.66 (s, 3H, OH ₃ ) 2. 4-OH ₃ Ci7Hi _g N ₄ O ₄ S 374.43 45 212-214 54.53 54.61 4.84 4.88 8.56 8.54 9.06 (s, 1H, NH), 8.54 (s, ΙΗ, ΝΗ), 6.95-7.54 (m, 9H, Car.), 3.44-3.65 (m, 4H, 2 CH _2), 3.22- 3.40 (t, 3H, OH ₃ ) 3. 2-C1 C ₁₆ H, 5N4O ₃ C1S 378.85 39 126-127 50.73 50.80 3.99 4.11 9.36 9.32 8.46 8.48 9.37 (s, ΙΗ, ΝΗ), 8.61 (s, ΙΗ, ΝΗ), 6.85-7.44 (m, 9H, Car.), 3.59-3.71 (m, 4H, 2CH ₂ ) 4. 3-C1 Ci ₆ H _{! 5} N ₄ O ₃ C1S 378.85 141-142 53 50.73 50.81 3.99 3.85 9.36 9.27 8.46 8.30 9.51 (s, ΙΗ, ΝΗ), 8.93 (s, ΙΗ, ΝΗ), 7.15-7.80 (m, 9H, Car.), 3.65-3.75 (m, 4H, 2CH ₂ ) 5. 4-C1 C _I6 Hi ₅ N4O ₃ CIS 378.85 170-172 42 50.73 50.51 3.99 3.64 9.36 9.44 8.46 8.55 9.17 (s, ΙΗ, ΝΗ), 8.82 (s, ΙΗ, ΝΗ), 7.05-7.74 (m, 9H, Car.), 3.69-3.77 (m, 4H, 2CH ₂ )

PL 229 086 Β1

Table 2

The results of pharmacological studies of 1- (1-arylimidazolidin-2-ylidene) -3-benzenesulfonyl urea derivatives are presented on the example of 1- [1- (4-methoxyphenyl) imidazolidin-2-ylidene] -3-benzenesulfonylurea

l- [l- (4- methoxyphenyl) imidazoIidyn-2- ylidene] -3- benzene sulfonylurea ED50 (mg / kg) i.p. 1363 Motor coordination a) in the chimney test - Motor coordination b) in the rotary bar test - Influence on spontaneous mobility - Effect on amphetamine hyperactivity - Antinociceptive activity a) in the drag test * a, * b Antinociceptive activity b) in the naloxone drag test - Effect on body temperature 190-180 '** Inhibition of 5-HTP induced head shake J. ns Protective effect in the pentetrazole seizure test

Legend:

a - after administration of the compound at a dose corresponding to 1/10 LD ₅₀ , b - after administration of the compound at a dose corresponding to 1/20 LD ₅₀ , ** - p <0.01, * - p <0.05,

T - increase,

T - reduction, - no effect.

PL 229 086 B1

The compound obtained according to the invention has a low toxicity. The ED50 dose of this compound, determined on the basis of the observation of the loss of the righting reflex in the tested animals, is 1363 mg / kg i.p. In the conducted tests, this compound significantly decreased (p <0.01) the body temperature of normothermic animals from the 90th to 180th minutes after administration, and clearly, though not statistically significant, inhibited head shaking episodes caused by the administration of 5-hydroxy-L-tryptophan, which may suggest the participation of the serotonin system in the depressive effect on the CNS. It also showed antinociceptive activity in the "writhing" test, manifested by statistically significant inhibition of dragging episodes (non-reverse administration of naloxone). It did not affect the spontaneous mobility of the animals, nor the hyperactivity caused by the administration of amphetamines, and it did not disturb the coordination in both tests used (the rota-rhodium test and the funnel test).

The compound was tested in the following tests:

- the locomotor activity was measured in photoresistors for 30 minutes as:

a) spontaneous mobility;

b) amphetamine hyperactivity: mice were administered subcutaneously (s.c.) 5 mg / kg amphetamine 30 min before the test;

- body temperature of normothermic mice was measured in the rectum of the mice with a thermistor thermometer.

Claims (3)

1. 1- (1-arylimidazolidin-2-ylidene) -3-benzenesulfonyl urea derivatives of the general formula I, where R is an aromatic substituent, preferably phenyl and its substituted analogs, especially 2-methoxyphenyl, 4-methoxyphenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl. 2. Method for the preparation of 1- (1-arylimidazolidin-2-ylidene) -3-benzenesulfonyl urea derivatives of the general formula I, where R is an aromatic substituent, preferably phenyl and its substituted analogs, especially 2-methoxyphenyl, 4-methoxyphenyl, 2 -chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, characterized in that the appropriately substituted 1-aryl-2-aminoimidazoline-2 derivatives of the general formula 2, in which R is as defined above, are condensed with benzenesulfonyl isocyanate of the general formula 3 in the presence of a solvent of organic, preferably dichloromethane, at room temperature for 8 hours in a 1: 1 molar ratio. the solvent is removed by distillation. The obtained precipitate is purified by crystallization from a polar solvent, preferably methyl alcohol or propan-2-ol or a mixture of methanol: propan-2-ol in the ratio 1: 1. 3. The method according to claim. 2. A method according to claim 2, characterized in that the separated precipitate is purified by crystallization from a polar solvent propan-2-ol or a mixture of methanol: propan-2-ol in the ratio 1: 1