Synthesis of certain disubstituted thiourea and condensed thiourea derivatives for antihypertensive activity

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Author: Magda M.F.Ismail1, Nehad A.M. El-Sayed2, Heba S. Rateb1, Mohey Ellithey3 Yousry A. Ammar4

Synthesis of certain disubstituted thiourea and condensed thiourea derivatives for antihypertensive activity

Magda M.F.Ismail1, Nehad A.M. El-Sayed2, Heba S. Rateb1, Mohey Ellithey3 Yousry A. Ammar4

1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt. 2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt 3. Department of Pharmacology, National Research Center, Cairo, Egypt. 4. Department of Organic Chemistry, Faculty of Science, Al-Azhar University,Cairo,. Egypt

Summary

Some new N-substituted-N'-(4-(piperidin-1-yl-sulfonyl)phenylthiourea derivatives and condensed thiourea derivatives such as, hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one, 2-thioxo-2,3-dihydroquinazoline-4-one and thiohydantoin derivatives. have been synthesized and tested for their antihypertensive activity. Among the selected compounds, 3a can be considered more potent than the standard (nifedipine), compounds 2, 5 and 7 showed significant antihypertensive activity, while compound 3b exhibited only moderate antihypertensive activity. The detailed synthesis, spectroscopic and biological data are reported.

Keywords, N, N'-disubstituted thiourea, hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one, 2-thioxo-2,3-dihydroquinazolin-4-one, thiohydantoin, synthesis, antihypertensive activity.

Introduction

Surveying the literature, it was clear that several piperidinobenzenesulfenamide and 1-arylpiperazine-4-benzenesulfonamide [1, 2] exhibited marked antihypertensive properties. Moreover, it was reported that a variety of N, N'-disubstituted thiourea elicited an antihypertensive activity. [3-5] Moreover, quinazolines, [6] thienopyrimidinediones [7] and thiohydantoin [8] were found to be useful in treatment of hypertension Encouraged by these findings, the present work was designed to synthesize potential antihypertensive compounds using thiourea as versatile reagent, in the construction of many bioactive hybrids via two different approaches. The first one involved the incorporation of piperidinobenzenesulfonamide moiety to substituted thiourea derivatives in an open-chain form as in 3a-f, 4 and the second one involved the synthesis of new compounds carrying potent antihypertensive moieties by cyclocondensation of some newly synthesized open-chain thiourea derivatives to afford compounds 5-7.

2. Materials and methods

2.1. Materials

Elemental analyses (C, H, N) were performed on Perkin-Elmer 2400 analyzer (Perkin-Elmer, Norwalk, CT, USA) at the Microanalytical Unit of Cairo University. All compounds were within + 0.4% of the theoretical values. Melting points were determined in open capillaries on an electrothermal LA 9000 Series (Electrothermal Engineering Ltd., Essex, UK) and are uncorrected. TLC chromatography was performed on precoated silica gel 60F 254 plates (Merck CO., Sofia, Bulgaria). Infrared spectra were recorded on Pye Unicam SP 1000 IR spectrophotometer (Thermoelectron CO., Egelsbach, Germany). 1HNMR spectra were recorded on Varian Gemini EM-300 MHz NMR spectrophotometer (Varian CO., Fort Collins, USA). DMSO-d6 was used as solvent, TMS was used as internal standard and chemical shifts were measured in δ ppm. Mass spectra were recorded on Varian MAT 311-A 70 e.v.( Varian CO., Fort Collins, USA). 4-(Piperidin-1-yl sulfonyl) aniline was prepared according to the procedure described. [9]

2.2. Synthesis

2.2.1. 1-[4-(Isothiocyanato-benzene)sulfonyl]piperidine. (2)

Thiophosgen (0.003 mole, 0.5 ml) was added drop wise to equimolar amount of an alcoholic solution of 4-(piperidin-1-yl sulfonyl) aniline [10] (1, 0.70 g.) with shaking. The separated solid was filtered, dried and crystallized (Table 1). IR (KBr, cm-1): 2944, 2836 (CH-aliph.), 2094 (NCS), 1338, 1160 (SO2); 1H-NMR (CDCl3): δ 1.4-1.6 ( m, 6H, C(3)H, C(4)H, C(5)H, C5H10N); 2.9 (t, 4H, C(2)H, C(6)H); 7.3 (d, 2H, AB system, J=8.7Hz)., 7.7 (d, 2H, AB system, J=8.7 Hz). MS: m/z (%) = 282 (M+, 91.2); 198 (10.7); 134 (87.7); 149 (34.1); 84 (100, base).

2.2.2. N Aryl/Heteroaryl N'-[4-(piperidin-1-yl sulfonyl) phenyl]-thiourea (3a-f)

A mixture of equimolar amounts of (1) (0.002 mole, 0.56 g.) the appropriate amino compound and 2 drops of triethylamine (TEA) in dioxane (20 ml) was refluxed for 3 h then poured onto ice; the formed solid was filtered, dried and crystallized (Table 1). IR (KBr, cm-1) 3a: 3310, 3169 (NH), 3550 (OH), 2939, 2857 (CH-aliph), 1328, 1158 (SO2); IR ( KBr, cm-1) 3b: 3302, 3155 (NH), 2978, 2850 (CH-aliph), 1334, 1162 (SO2); 1H-NMR (DMSO-d6): δ 1.35 (m, 2H, C5H10N), 1.53 (m, 4H, C5H10N), 2.88 (m, 4H, C5H10N), 3.74 (s, 3H, OCH3), 6.91 (d, 2H, AB system, J=9 Hz), 7.79 (d, 2H AB system, J=9 Hz), 9.89 (s, 1H, NH, D2O-exchangeable), 9.99 (s, 1H, NH, D2O-exchangeable). IR ( KBr, cm-1) 3c: 3211 (NH), 2973, 2872 (CH-aliph), 1337, 1165 (SO2), 1H-NMR (CDCl3): δ 1.35 (m, 4H, C5H10N), 1.38-1.43 (m, 5H, CH3, 2H C5H10N), 3.00 (m, 4H, C5H10N), 4.04 (q, 2H, CH2), 6.88-6.92 (m, 4H, Ar-H), 7.22-7.26 (m, 4H, Ar-H), 7.45 (s, 2H, 2 NH). IR (KBr, cm-1) 3d: 3436, 3361, 3251 (OH, NH), 2947, 2835 (CH-aliph), 1639 (CO), 1308, 1148 (SO2). MS (m/z, %): 437 (M+2, 0.19), 240 (44), 230 (14.6), 175 (11.11), 92 (100). IR (KBr, cm-1) 3e: 3293, 3142 (NH), 2941, 2850 (CH-aliph), 1716 (CO), 1335, 1163 (SO2). IR (KBr, cm-1) 3f: 3446, 3328 (NH), 2195 (CN), 2933, 2837 (CH-aliph), 1336, 1161 (SO2). 1H-NMR (CDCl3): δ 1.2-1.6 (m, 10 H, aliphatic-H), 2.4-2.6 (m, 4H, aliphatic-H), 2.9-3.1 (m, 4H, aliphatic-H), 7.5 (s, 1H, NH), 7.7-7.9 (m, 4H, Ar-H), 8.2 (s, 1H, NH).

2.2.3. O-2-Naphthlenyl [4-(piperidin -1-ylsulfonyl)phenyl]thiocarbamate (4)

This compound was prepared by applying the method used for the preparation of 3 using β-naphthol (0.002 mole, 0.25 g.), instead of the appropriate amino compound dioxane (20 ml); the obtained solid was crystallized (Table 1). IR (KBr, cm-1): 3361 (NH); 2949-2835 (-CH aliphatic), 1338, 1163 (SO2). 1H-NMR (CDCl3): δ 1.2- 1.6 (m, 6H, C(4)H, C(3)H, C(5)H, C5H10N); 2.9 (t, 4H, C(2)H, C(6)H, C5H10N); 7.20 (d,2H, AB system, J=8.9Hz); 7.60-7.75(m, 2H, naphthyl-H); 7.95(d,2H, AB system, J=8.9Hz);8.1 20 (s, 1H, naphthyl-H); 9.15-9.22 (m, 4H, naphthyl-H), 9.7 (s, 1H, NH exchangeable).

2.2.4. 3-[4-(Piperidin-1-yl sulfonyl)phenyl]2-thioxo-2,3,5,6,7,8-hexahydro-1H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one (5)

The title compound was prepared as described for 3 using ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (0.002 mole, 0.40 g.). The reaction mixture was refluxed for 5h, filtered and the solid so obtained was crystallized (Table 1). IR (KBr, cm-1): 3326.7 (NH); 3113-2837 (-CH aliphatic), 1664 (C=O), 1335, 1162 (SO2); 1H-NMR (CHCl3) δ: 1.30, 1.65-1.79, 2.8, 3.03 (4 m, 18H, C5H10N, C6H8); 7.55 (d, 2H, AB system, J=8.7 Hz); 7.81 (d, 2H, AB system, J=8.7 Hz); 12.5 (s, 1H, NH, exchangeable). MS (m/z, %): 461(M+, 1.5); 313 (1.89); 281 (26.89); 267 (56.64); 206 (9.88); 179 (100, base).

2.2.5. 3[4-(Piperidin-1yl-sulfonyl) phenyl]-2-thioxo-2,3-dihydro-1H-quinazolin-4-one(6)

This compound was prepared according to the method used for the preparation of 5 using anthranilic acid (0.002 moles, 0.27 g.). The solid was crystallized (Table l). IR (KBr, cm-1): 3259 (NH); 2970-2850 (CH aliphatic); 1664 (C=O), 1341, 1172 (SO2).1H-NMR (DMSO-d6) δ: 1.4-1.6 (m, 6 H, C5H10N); 2.9 (t, 4H, C5H10N); 7.4 (t, 2H, C(6) H, C(7) H); 7.46 (d, 1H, C(5) H); 7.6 (d, 2H, AB system, J=8.4 Hz); 7.8 (d, 2H, AB system, J=8.4 Hz); 7.9 (d, 1H, C(8) H); 13.1 (s, 1H, NH).

2.2.6. 3[4-(Piperidin-1-yl-sulfonyl) phenyl]-2-thioxo-imidazolidin-4-one (7)

A mixture of 2 (0.003 mole, 0.85 g.) in ethanol (10 ml) was added to a solution of glycine (0.15mole, 0.5 g.) in sodium hydroxide solution (1 g. in 5 mL water). The reaction mixture was heated on a sand bath for 1 h where a pale yellow solid gradually separated from the clear solution. The formed solid was filtered, hydrochloric acid was then added and the reaction mixture was evaporated to dryness; the obtained residue was washed several times with water and crystallized (Table 1). IR (KBr, cm-1): 3340 (NH); 2919, 2850 (CH-aliphatic); 1729 (C=O), 1313, 1159 (SO2). MS (m/z, %): 339 (M+, 27.3); 255 (5.7); 190 (22.29); 175 (4.65); 133 (10.00); 55 (100.00, base).

2.3. Biological testing

Ninety male Sprague-Dawley rats, 230-250 gm, were randomly assigned to the experiment. Animals (Animal house colony in National Research Center, Cairo, Egypt) were provided with standard laboratory diet (Milad CO., Cairo, Egypt). The diet composition (A.O.A.C.): vitamin mix 1%, mineral mix 4%, corn oil 10%, sucrose 20%, cellulose 0.2%, casein (95% pure)10.5%, starch 54.3%), water ad lib and housed under standard hygienic conditions. Animals were acclimatized for 1 week in the animal facility that has 12h light / dark cycles with the temperature controlled at 21-23 ºC. All the animal experiments have been conducted in blind conditions and approved from the National Research Center, Cairo, Egypt.

2.3.1. Antihypertensive activity

Assessment of hypertensive animal model (DOCA-salt hypertension model

Eighty- four rats were injected with 10 mg / kg of deoxycorticosterone acetate (DOCA) subcutaneously and the animal fed high diet (8 % NaCl) for 3- 4 weeks. These animals were divided into equal 8 groups (6 rats each) as follows: Group 1: was served as hypertensive control (positive-control) rats of this group were orally administered 4 ml saline / kg b. wt. Groups 2-7: were given 2 mg / kg b. wt. of the standard drug (nifedipine) and tested compounds 2, 3a, 3b, 5 and 7 orally. Group 8: this group was kept normal Bl.p. (non-hypertensive, negative-control) and rats were given 4 ml saline / kg b. wt. orally. Two hours later, blood pressure was recorded for all groups, the left carotid artery was cannulated by a pp50 SILASTIC brand tubing for measurement of blood pressure (Ugo basily, Milano, Italy), the catheter was inserted during pentobarabital anesthesia (60 mg / kg ip ). The catheter was connected to a Gould - Statham P50 pressure transducer and via a custom built amplifier, the artery blood pressure signals were continuously recorded by a Watanabe Mark IV four channel hot stylus recorder adjusted to a speed of 10 mm / min. .[11]

Statistical analysis:

Data are given as means + SE. P < 0.05 was considered to be significant. Statistical analysis was performed by analysis of variance (ANOVA) and least significant difference (LSD). [12]

3. Results

3.1. Chemistry

The preparation of thiourea derivatives was achieved by reaction of isothiocyanate (2) with aromatic and heterocyclic amines in dioxane and triethylamine (TEA) for 2 h. to afford N-substituted-N'-(4-(piperidin-1-ylsulfonyl) phenylthiourea derivatives (3a-f). Unfortunately, reaction of 2 with β-naphthol in the same previous reaction conditions yielded a compound which could not be separated. A convenient route to separate the desired compound 2-naphthyl-4-(piperidin-1-ylsulfonyl) phenylthiocarbamate (4), was performed by changing the reaction medium to dimethylformamide and triethylamine (DMF/TEA) Elemental, as well as spectral analyses were consistent with the structures. On the other hand, cyclocondensation of our starting isothiocyanate (2) with either ethyl 2-amino-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate or with anthranilic acid in dioxane/TEA afforded the desired products; the tricyclic structure, 3-[4-(piperidin-1-ylsulfonyl)phenyl]-2-thioxo-2,3,5,6,7,8-hexahydro-1H benzo[4,5]thieno-[2,3-d]-pyrimidin-4-one (5) and the bicyclic one, 3-[4-(piperidin-1-ylsulfonyl)phenyl]-2-thioxo-2,3-tetrahydroquinazolin-4-one (6). Moreover, the required thiohydantoin derivative, 3-[4-(piperidin-1-yl-sulfonyl) phenyl]-2-thioxo-imidazolidin-4-one (7) was prepared via the reaction of 2 with glycine in presence of sodium hydroxide. The suggested mechanism for these reactions proceeds most probably via elimination of ethanol or water molecule respectively.

3.2. Antihypertensive activity

Comparative pharmacological study of the results drawn from Table 2 revealed that, the open-chain diarylthiourea derivative 3a was more potent than standard drug, while its counterpart 3b was less potent than nifedipine, it exhibited only moderate antihypertensive activity when compared with hypertensive control group. The first thiourea, 3a bearing C6H4-OH-4 on N while, 3b having C6H4-OCH3-4 and both have the active moiety; 4-(piperidin-1-yl sulfonyl) phenyl on N', so the polar hydroxyl group in 3a may contribute to the activity of this hyprid. On the other hand, compounds 2, 5 and 7 exhibited less potent effect than nifedipine but, still show a significant antihypertensive activity when compared to hypertensive control group. Therefore, hyprids of 4-(piperidin-1-yl sulfonyl) phenyl moiety (2) with cyclized thiourea (5-7) does not confer any antihypertensive activity.

4. Conclusion

Hyprids of open chain thiourea having polar electron-releasing group on N and 4-(piperidin-1-ylsulfonyl) phenyl moiety on N' might display higher antihypertensive activity than the standard, nifedipine. However, those of cyclized thiourea with 4-(piperidin-1-ylsulfonyl) phenyl moiety did not enhance the activity.

References

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