Thiocarbamoylacetonitrile compounds

Abstract: There is disclosed a thiocarbamoylacetonitrile compound represented by the formula: wherein R¹ represents hydrogen, a C₁ to C₆ alkyl, a C₃ to C₆ cycloalkyl or -(CH₂) n -A (where A represents a C₆ to C₁₂ aryl, a 5- or 6-membered heterocyclic group or a fused heterocyclic group constituted by 9 or 10 atoms, each of which may be substituted by at least one selected from a C₁ to C₆ alkyl and a halogen, and n is 0 or an integer of 1 to 6), R² represents a C₁ to C₁₀ alkyl, and Ar represents an aryl, a 5- or 6-membered heterocyclic group or a fused heterocyclic group, each of which may be substituted by at least one substituent selected from the group consisting of a C₁ to C₆ alkyl, a C₁ to C₆ alkoxy, a C₂ to C₇ alkylcarbonyl, a C₇ to C₁₃ arylcarbonyl, a C₁ to C₆ alkylamino, a C₂ to C₆ dialkylamino, amino, formylamino, a C₂ to C₇ alkylcarbonylamino, a halogen, cyano, nitro, hydroxyl, a C₁ to C₆ alkylthio, a C₆ to C₁₂ arylthio, a C₁ to C₆ alkylsulfinyl, a C₆ to C₁₂ arylsulfinyl, a C₁ to C₆ alkylsulfonyl, a C₆ to C₁₂ arylsulfonyl, aminosulfonyl, a C₁ to C₆ alkylaminosulfonyl, a C₂ to C₆ dialkylaminosulfonyl, trifluoromethyl and imidazolyl.

Description: This invention relates to a novel thiocarbamoylacetonitrile derivative having an antihypertensive activity. There have been proposed various compounds having antihypertensive activity. For example, there has been known that a thioformamide derivative having a heterocyclic group such as pyridine or quinoline is capable of lowering a pressure of artery of spontaneous hypertension rat (SHR) (see Japanese Provisional Patent Publications No. 42687/1982, No. 38281/1983, No. 7188/1984 and No. 232281/1984). However, the compound which can be practically applied as an antihypertensive agent is not necessarily sufficient and it has been desired to develop an antihypertensive agent having further effective activity. Similar carbamoyl compounds are disclosed in EP-A-257882 ; they are useful for treating immune diseases. SUMMARY OF THE INVENTION The present inventors have intensively studied to provide a novel compound having good antihypertensive activity and as the results, they have found that by using a thiocarbamoylacetonitrile derivative with which a specific aryl group is replaced at α-position of the acetonitrile, the above object can be accomplished whereby completed the present invention. That is, a thiocarbamoylacetonitrile derivative of the present invention comprises a compound represented by the following formula: wherein R¹ represents hydrogen, a C₁ to C₆ alkyl, a C₃ to C₆ cycloalkyl or -(CH₂) n -A (where A represents a C₆ to C₁₂ aryl, a 5- or 6-membered heterocyclic group or a fused heterocyclic group constituted by 9 or 10 atoms, each of which may be substituted by at least one selected from a C₁ to C₆ alkyl and a halogen, and n is 0 or an integer of 1 to 6), R² represents a C₁ to C₁₀ alkyl, and Ar represents an aryl, a 5- or 6-membered heterocyclic group or a fused heterocyclic group, each of which may be substituted by at least one substituent selected from the group consisting of a C₁ to C₆ alkyl, a C₁ to C₆ alkoxy, a C₂ to C₇ alkylcarbonyl, a C₇ to C₁₃ arylcarbonyl, a C₁ to C₆ alkylamino, a C₂ to C₆ dialkylamino, amino, formylamino, a C₂ to C₇ alkylcarbonylamino, a halogen, cyano, nitro, hydroxyl, a C₁ to C₆ alkylthio, a C₆ to C₁₂ arylthio, a C₁ to C₆ alkylsulfinyl, a C₆ to C₁₂ arylsulfinyl, a C₁ to C₆ alkylsulfonyl, a C₆ to C₁₂ arylsulfonyl, aminosulfonyl, a C₁ to C₆ alkylaminosulfonyl, a C₂ to C₆ dialkylaminosulfonyl, trifluoromethyl and imidazolyl. DESCRIPTION OF THE PREFERRED EMBODIMENTS In the following, the present invention will be explained. In the above formulae, R¹ represents hydrogen; C₁ to C₆-straight or branched alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl; C₃ to C₆-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; or -(CH₂) n -A (each A represents C₆ to C₁₂ aryl such as phenyl and naphthyl; a 5- or 6-membered heterocyclic group such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyradinyl, pyrimidinyl, pyridazinyl, thienyl, thiazolyl, isothiazolyl, furyl, oxazolyl and isoxazolyl; or a fused heterocyclic group constituted by 9 to 10 atoms such as indolydinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, benzothienyl, isobenzothienyl, benzothiazolyl, isobenzothiazolyl, benzofuranyl, isobenzofuranyl, benzoxazolyl, isobenzoxazolyl and benzimidazolyl; each of which may be substituted by at least one substituent selected from a halogen such as fluorine, chlorine and bromine; and a lower alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl; and n represents 0 or an integer of 1 to 6.); R² represents C₁ to C₁₀ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-heptyl, n-octyl, n-nonyl and n-decyl; Ar represents a C₆ to C₁₂ aryl such as phenyl, tolyl, xylyl and naphthyl; a 5- or 6-membered heterocyclic group such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, thiazolyl, isothiazolyl, furyl, oxazolyl and isoxazolyl; or a fused heterocyclic group constituted by 9 to 10 atoms such as indolydinyl, indolyl, isoindolyl, quinolyl, isoquinolyl, benzothienyl, isobenzothienyl, benzothiazolyl, isobenzothiazolyl, benzofuranyl, isobenzofuranyl, benzoxazolyl, isobenzoxazolyl and benzimidazolyl; each of which may be substituted by at least one selected from a C₁ to C₆ alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl; a C₁ to C₆ alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy and n-hexyloxy; a C₂ to C₇ alkylcarbonyl such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl; a C₇ to C₁₃ arylcarbonyl such as benzoyl and naphthoyl; a C₁ to C₆ alkylamino such as methylamino, ethylamino, n-propylamino, isopropylamino and n-butylamino; a C₂ to C₆ dialkylamino such as dimethylamino, diethylamino and methylethylamino; amino; formyl; a C₂ to C₇ alkylcarbonylamino such as acetylamino, propionylamino and butyrylamino; a halogen such as fluorine, chlorine and bromine; cyano; nitro; hydroxyl; a C₁ to C₆ alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio; an arylthio such as phenylthio and naphthylthio; a C₁ to C₆ alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl and n-hexylsulfinyl; a C₆ to C₁₂ arylsulfinyl such as phenylsulfinyl and naphthylsulfinyl; a C₁ to C₆ alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl; a C₆ to C₁₂ arylsulfonyl such as phenylsulfonyl and naphthylsulfonyl; aminosulfonyl; a C₁ to C₆ alkylaminosulfonyl such as methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n-butylaminosulfonyl, tert-butylaminosulfonyl, n-pentylaminosulfonyl and n-hexylaminosulfonyl; a C₂ to C₆ dialkylaminosulfonyl such as dimethylaminosulfonyl and diethylaminosulfonyl; trifluoromethyl and imidazolyl. In the present invention, preferred are compounds wherein R¹ represents hydrogen, aforesaid C₁ to C₆ alkyl, a C₃ to C₆ cycloalkyl or -(CH₂) n -A (where A represents a phenyl, pyridyl, thienyl, benzimidazolyl or benzothiazolyl, each of which may be substituted by at least one selected from a C₁ to C₃ alkyl and a halogen, and n is 0 or an integer of 1 to 3), R² represents the aforesaid C₁ to C₆ alkyl, and Ar represents phenyl, naphthyl, pyridyl, thienyl, pyrrolyl, imidazolyl, pyradinyl, pyrimidinyl, indolyl, benzothiazolyl, benzimidazolyl or quinolyl, each of which may be substituted by at least one substituent selected from the group consisting of a C₁ to C₆ alkyl, a C₁ to C₆ alkoxy, a C₂ to C₇ alkylcarbonyl, a C₇ to C₁₃ arylcarbonyl, a C₁ to C₆ alkylamino, a C₂ to C₆ dialkylamino, amino, formylamino, a C₂ to C₇ alkylcarbonylamino, a halogen, cyano, nitro, hydroxyl, a C₁ to C₆ alkylthio, a C₆ to C₁₂ arylthio, a C₁ to C₆ alkylsulfinyl, a C₆ to C₁₂ arylsulfinyl, a C₁ to C₆ alkylsulfonyl, a C₆ to C₁₂ arylsulfonyl, aminosulfonyl, a C₁ to C₆ alkylaminosulfonyl, a C₂ to C₆ dialkylaminosulfonyl, trifluoromethyl and imidazolyl. Of these compounds, more preferred compounds are those wherein R¹ represents hydrogen, aforesaid C₁ to C₆ alkyl, a C₅ to C₆ cycloalkyl, or phenyl, benzyl, phenethyl or phenylpropyl each of which may have at least one halogen; R² represents the aforesaid C₁ to C₆ alkyl, and each of Ar represents phenyl, naphthyl, pyridyl, thienyl, pyrrolyl, benzothiazolyl or benzimidazolyl, each of which may be substituted by at least one substituent selected from the group consisting of a C₁ to C₆ alkyl, a C₁ to C₆ alkoxy, amino, a halogen, cyano, nitro, a C₁ to C₆ alkylthio, a C₆ to C₁₂ arylsulfonyl, aminosulfonyl, trifluoromethyl and imidazolyl. Specific examples of such compounds of the present invention may be mentioned, for example, those as shown in the following Table 1. Next, the process for producing the compound of the present invention will be explained. The compound (I) of the present invention can be produced by, for example, the following Route (1) or (2). Route (1) Route (2) wherein R¹, R² and Ar have the same meanings as defined above. In the reaction of Route (1), the compound represented by the formula (I) of the present invention can be prepared by reacting the compound represented by the above formula (II) with an isothiocyanate of the formula (III) in an anhydrous polar solvent such as tetrahydrofuran, N,N-dimethylformamide or hexamethylphosphorylamide or a mixture thereof in the presence of a base such as potassium tert-butoxide, lithium diisopropylamide or sodium hydride at -80 °C to 50 °C. In the reaction of Route (2), by reacting the compound represented by the formula (II) and carbon disulfide in a polar solvent such as tetrahydrofuran or N,N-dimethylformamide in the presence of a base such as potassium tert-butoxide or sodium hydride at -80 °C to 50 °C for several minutes to several hours, and then reacting the resulting solution by adding methyl iodide at -80 °C to 50 °C, the compound of the above formula (IV) can be obtained. The compound represented by the above formula (I) of the present invention can be obtained by reacting the compound (IV) and ammonia or the compound represented by the formula R²-NH₂ (V) in a polar solvent such as water, methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran or ether, or a mixture thereof, or in an aromatic hydrocarbon such as benzene, toluene or xylene, or in the absence of a solvent at 0 °C to 200 °C. As the preparation method of the compound represented by the formula (II), for example, the following Reaction routes (3) to (5) may be mentioned. Route (3) Route (4) Route (5) wherein R¹ and Ar have the same meanings as defined above, X represents a halogen atom, an eliminatable group such as -OSO₂CH₃, and M represents an inorganic residue such as metal ion. In Reaction route (3), the compound represented by the above formula (VI) and the compound represented by the formula (VII) are reacted in a polar solvent such as methanol, ethanol N,N-dimethylformamide, dimethylsulfoxide or tetrahydrofuran in the presence of a base such as sodium hydroxide, sodium ethoxide, potassium tert-butoxide, sodium hydride or lithium diisopropylamide at a temperature of -80 °C to 100 °C to obtain the compound represented by the above formula (II). In Reaction route (4), the compound represented by the above formula (VIII) and an inorganic cyan compound represented by M-CN are reacted in a polar solvent such as water, methanol, ethanol, acetone, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide or hexamethylphosphorylamide or a mixture thereof, or in a high boiling point solvent such as ethylene glycol and ether thereof or tetrahydrofurfuryl alcohol, or in the absence of a solvent at 0 °C to 200 °C to obtain the compound represented by the above formula (II). In Reaction route (5), from the compound represented by the above formula (IX) and p-toluenesulfonylmethylisocyanide (TosMic), the compound represented by the above formula (II) can be obtained by the method described in a literature (for example, Oldenziel O.H. and van Leusen A.M., Tetrahedron Letters, No. 16, p. 1357 (1973)). Further, in the preparation of the compound (I) of the present invention, when Reaction routes (3) and (1) are used, the compound (1) of the present invention can also be obtained from the compound represented by the formula (VI) with one step without isolating the compound represented by the above formula (II) which is an intermediate. When an asymmetric carbon is present in the compound (I) of the present invention thus obtained, there exist optical isomer(s), but the compound of the present invention includes these isomers. The thiocarbamoylacetonitrile derivative of the present invention has vasodilating activity and hypotensive activity so that it is effective for treatment of hypertensive. When the compounds according to the present invention are to be used for antihypertensive agent, it can be applied orally or non-orally to a man according to the conventional manner. As a shape for oral administration, there may be mentioned granules, fine granules, powder, tablets, hard capsules, soft capsule, syrups, emulsions, suspensions or liquids. Also, as a shape for non-oral administration, there may be mentioned injections, suppositories and endermic agents. The compounds represented by the above formula (I) and pharmaceutically acceptable salts thereof are contained in the above medical agents in combination with solid or liquid carriers for medicine or additives for medicine conventionally employed such as excipients, stabilizers, lubricants, edulcorants, preservatives and suspending agents. Examples of the solid carriers to be used may include lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, acacia, stearic acid, magnesium stearate, lecithin and sodium chloride. Examples of the liquid carriers may include syrup, glycerin, peanut oil, polyvinyl pyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol and water. When the compounds of the present invention are used orally, a dose for an adult man is 0.01 mg to 1000 mg per day, preferably 0.1 mg to 100 mg per day, which may be preferably and optionally increased or decreased depending on the age, sex, condition of the disease, symptoms, and presence or absence of the simultaneous treatment. Also, a number of the administration may be once per day or several times per day with an optional interval. When a solid preparation is prepared, as an excipient, for example, lactose, starch, talc, cellulose, dextrin, caolin or calcium carbonate may be used. In the case of a liquid preparation for oral administration, i.e. syrups, emulsions, suspensions or liquids, the above liquid carriers generally employed are used in combination with a suitable auxiliary agent such as humectants, suspension auxiliary, edulcorants, aromatics, colorants or preservatives. EXAMPLES Example 1 Synthesis of N-methyl 2-(4-chlorophenyl)-2-cyano-5-phenyl-thiovaleroamide (Compound No. 14 in Table 1) (1) 2 ml of an aqueous sodium hydroxide (1.08 g) solution was added to a 10 ml solution of dimethylsulfoxide containing 1.0 g (6.6 mmole) of 4-chlorophenylacetonitrile and 1.3 g (6.6 mmole) of 1-bromo-3-phenylpropane at room temperature. After stirring for 2 hours under the same conditions, water was added to the reaction mixture and the mixture was extracted with 10 ml of n-hexane, dried, and condensed under reduced pressure to obtain 1.78 g (yield: quantitative) of 2-(4-chlorophenyl)-5-phenylvaleronitrile. 1 H-NMR (CDCl₃): 1.7 - 2.0 (m, 4H), 2.6 - 2.7 (m, 2H), 3.7 (dd, 1H), 7.0 - 7.4 (m, 9H) (2) To a tetrahydrofuran solution containing 1.78 g (6.6 mmole) of 2-(4-chlorophenyl)-5-phenylvaleronitrile was added a tetrahydrofuran solution containing 0.77 g (6.9 mmole) of potassium tert-butoxide at 0 °C. After stirring for 30 minutes, a tetrahydrofuran solution containing 0.5 g (6.8 mmol) of methyl isothiocyanate was added to the mixture and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried and condensed under reduced pressure, and then purified by silica gel chromatography to obtain 1.19 g (yield: 52.4 %) of N-methyl-2-(4-chlorophenyl)-2-cyano-5-phenylthiovaleroamide as a crystal. 1 H-NMR (CDCl₃): 1.65 (m, 1H), 1.82 (m, 1H), 2.35 (tt, 1H), 2.70 (m, 3H), 3.14 (d, 3H), 7.1 - 7.5 (m, 9H), 7.9 (brs., 1H) IR₁: 3380, 2230, 1640, 1530 cm⁻¹ Melting point: 125.5 - 126 °C Example 2 Synthesis of N-methyl-2-(4-chlorophenyl)-2-cyanothiopropionamide (Compound No. 2 in Table 1) (1) To a 100 ml N,N-dimethylformamide suspension containing 4.0 g (0.10 mole) of 60 % oily sodium hydride was added a 200 ml N,N-dimethylformamide solution containing 15.2 g (0.10 mole) of 4-chlorophenylbenzylcyanide under ice-cooling. Stirring was continued for 0.5 hour under the same conditions, and then a 20 ml N,N-dimethylformamide solution containing 6.2 ml (0.10 mole) of methyl iodide was added to the mixture and the mixture was stirred for further 2 hours. The solvent was removed from the reaction mixture under reduced pressure, water was added to the residue and the mixture was extracted with 150 ml of dichloromethane, dried and condensed, and then purified by silica gel column chromatography to obtain 7.8 g (yield: 47.1 %) of 4-chlorophenylmethylbenzylcyanide. 1 H-NMR (CDCl₃): 1.6 (d, 3H), 3.8 - 3.9 (dd, 1H), 7.2 - 7.3 (dd, 4H) (2) To a 10 ml tetrahydrofuran solution containing 1.00 g (6 mmole) of 4-chlorophenylmethylbenzylcyanide was added a 3.2 ml tetrahydrofuran solution containing 2 M of lithium diisopropylamide at - 60 °C. After stirring for 30 minutes under the same conditions, a 5 ml tetrahydrofuran solution containing 0.44 g (6 mmol) of methyl isothiocyanate was added to the mixture and the mixture was allowed to stand at room temperature overnight. The solvent was removed from the reaction mixture under reduced pressure and water was added to the residue. The mixture was extracted with 50 ml of ethyl acetate, dried and condensed under reduced pressure, and then purified by silica gel chromatography and recrystallized from hexane to obtain 0.45 g (yield: 31.4 %) of N-methyl-2-(4-chlorophenyl)-2-cyano-thiopropionamide. 1 H-NMR (CDCl₃) ppm: 2.1 (s, 3H), 3.1 (d, 3H), 7.3 - 7.5 (dd, 4H), 7.9 (brs., 1H) IR (KBr): 3325, 2250, 1645, 1540 cm⁻¹ Melting point: 91.5 °C Example 3 Synthesis of N-methyl-2-(1,3-benzothiazol-2-yl)-2-cyanothiopropionamide (Compound No. 97 in Table 1) To a tetrahydrofuran solution containing 1.74 g (10 mmole) of 2-cyanomethyl-1,3-benzothiazole was added a tetrahydrofuran solution containing 1.42 g (10 mmole) of methyl iodide at - 70 °C in the presence of 1.12 g (10 mmole) of potassium tert-butoxide. After the addition, the temperature was gradually raised to 0 °C and the mixture was stirred at the same temperature for one hour. Then, 1.35 g (12 mmole) of potassium tert-butoxide was added to the mixture and the mixture was further stirred for one hour, 0.88 g (12 mmole) of methyl isothiocyanate was added thereto and the mixture was stirred at room temperature overnight. After addition of water, the mixture was extracted with ethyl acetate, dried and condensed under reduced pressure, and then purified by silica gel chromatography to obtain 0.59 g (yield 22.6 %) of N-methyl-2-(1.3-benzothiazol-2-yl)-2-cyano-thiopropionamide as a crystal. Melting point: 159 - 161 °C 1 H-NMR (CDCl₃) ppm: 2.3 (s, 3H), 3.2 (d, 3H), 7.4 - 7.6 (m, 2H), 7.9 (dd, 1H), 8.1 (dd, 1H), 9.1 (brs., 1H) IR (KBr): 3250, 2250, 1640, 1540 cm⁻¹ Example 4 Synthesis of N-methyl-2-(4-cyanophenyl)-2-cyano-thiopropionamide (Compound No. 64 in Table 1) (1) 1.40 g (1.25 mmole) of potassium tert-butoxide was added to a 17 ml ethyleneglycol dimethyl ether solution containing 0.73 g (5 mmole) of 4-acetylbenzonitrile, 0.5 ml of ethanol and 1.27 g (6.5 mmole) of p-toluenesulfonylmethylisocyanide under ice-cooling, and then the mixture was stirred at room temperature for 0.5 hour and then at 40 °C for further one hour. After the reaction mixture was cooled by allowing to stand, it was filtered under reduced pressure and the filtrate was purified by silica gel chromatography to obtain 0.55 g (yield: 70.4 %) of 2-(4-cyanophenyl)ethylcyanide. 1 H-NMR (CDCl₃) ppm: 1.6 (d, 3H), 3.9 - 4.0 (dd, 1H), 7.4 - 7.7 (dd, 4H) IR (neat): 2330 cm⁻¹ (2) To a 10 ml tetrahydrofuran solution containing 0.53 g (3.3 mmole) of 2-(4-cyanophenyl)ethylcyanide was added a 5 ml tetrahydrofuran solution containing 0.38 g (3.3 mmole) of potassium tert-butoxide under ice-cooling. The mixture was stirred under the same conditions for 0.5 hour, a 2 ml tetrahydrofuran solution containing 0.26 g (3.5 mmole) of methyl isothiocyanate was added thereto and the mixture was stirred under the same conditions for further 2 hours. Water was added to the reaction mixture and the mixture was extracted with 20 ml of ethyl acetate, dried and condensed. The residue was then purified by silica gel chromatography and further recrystallized from hexane to obtain 0.40 g (yield: 52.9 %) of N-methyl-2-(4-cyanophenyl)-2-cyanothiopropinonamide. 1 H-NMR (CDCl₃) ppm: 2.1 (s, 3H), 3.1 - 3.2 (d, 3H), 7.7 (s, 4H), 7.9 (brs., 1H) IR (KBr): 3295, 2440, 1640, 1535 cm⁻¹ Melting point: 135.5 - 136 °C Example 5 Synthesis of N-methyl-2-[4-(1-imidazolyl)-phenyl]-2-cyanothiopropionamide (Compound No. 106 in Table 1) (1) To a 25 ml ethylene glycol solution containing 1.86 g (10 mmole) of 4-(1-imidazolyl)-acetophenone, 1 ml of ethanol and 3,00 g (15.4 mmole) of p-toluenesulfonylmethyl isocyanide was added 1.70 g (15.1 mmole) of potassium tert-butoxide under ice-cooling, and the mixture was stirred at room temperature for 0.5 hour and further at 40 °C for 2 hours. After the reaction mixture was cooled by allowing to stand, water was added and the mixture was extracted with 25 ml of ethyl acetate, dried and condensed, and then purified by silica gel chromatography to obtain 1.02 g (yield: 52 %) of 2-[4-(1-imidazolyl)-phenyl]propionitrile as an oily product. 1 H-NMR (CDCl₃) ppm: 1.69 (d, 3H), 3.98 (dd, 1H), 7.22 (s, 1H), 7.27 (s, 1H), 7.41 - 7.51 (m, 4H), 7.86 (s, 1H) IR (KBr): 2250 cm⁻¹ (2) To a 10 ml tetrahydrofuran solution containing 1.00 g (5.1 mmole) of 2-[4-(1-imidazolyl)-phenyl]propionitrile was added a 10 ml tetrahydrofuran solution containing 0.69 g (6.2 mmole) of potassium tert-butoxide at 0 °C. After stirring for 0.5 hour, a 5 ml tetrahydrofuran solution containing 0.45 g (6.2 mmole) of methyl isothiocyanate was added to the mixture and the mixture was stirred at room temperature for 2 hours. Water was added to the mixture and the mixture was extracted with 20 ml of ethyl acetate, dried and condensed under reduced pressure, and then purified by silica gel chromatography and condensed. The resulting condensate was suspended in 30 ml of toluene and the suspension was refluxed under heating for 0.5 hour and a solid was collected by filtration to obtain 0.75 g (yield: 54 %) of N-methyl-2-[4-(1-imidazolyl)-phenyl]-2-cyanothiopropionamide as a crystal. 1 H-NMR (CDCl₃) ppm: 2.18 (s, 3H), 3.21 (d, 3H), 7.21 (s, 1H), 7.28 (s, 1H), 7.41 (d, 2H), 7.68 (d, 2H), 7.80 (s, 1H), 8.20 (brs., 1H) IR (KBr): 3250, 2250, 1640 cm⁻¹ Melting point: 183 - 184.5 °C Example 6 According to the same manner as in Examples 1 to 5, the compounds listed in Table 2 were prepared (Compound No. corresponds to that in Table 1). Test example To hypertension spontaneously occurred rats (OKAMOTO-AOKI series) showing an average blood pressure of 150 mmHg or higher was administered 10 mg/kg of the compound of the present invention, and then the blood pressure and heart rate were measured by the direct method described in Nakao K., H and Takayanagi K., Japanese Journal of Pharmacology, Vol. 25, p. 25 (1975). The results after 2 hours of the administration are shown in Table 3 below. The compounds of the present invention show good hypotensive activity so that they can be used as a antihypertensive agent effectively.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, SE A thiocarbamoylacetonitrile compound represented by the formula (I): wherein R¹ represents hydrogen, a C₁ to C₆ alkyl, a C₃ to C₆ cycloalkyl or -(CH₂) n -A (where A represents a C₆ to C₁₂ aryl, a 5- or 6-membered heterocyclic group or a fused heterocyclic group constituted by 9 or 10 atoms, each of which may be substituted by at least one selected from a C₁ to C₆ alkyl and a halogen and n is 0 or an integer of 1 to 6), R² represents a C₁ to C₁₀ alkyl, and Ar represents an aryl, a 5- or 6-membered heterocyclic group or a fused heterocyclic group, each of which may be substituted by at least one substituent selected from the group consisting of a C₁ to C₆ alkyl, a C₁ to C₆ alkoxy, a C₂ to C₇ alkylcarbonyl, a C₇ to C₁₃ arylcarbonyl, a C₁ to C₆ alkylamino, a C₂ to C₆ dialkylamino, amino, formylamino, a C₂ to C₇ alkylcarbonylamino, a halogen, cyano, nitro, hydroxyl, a C₁ to C₆ alkylthio, a C₆ to C₁₂ arylthio, a C₁ to C₆ alkylsulfinyl, a C₆ to C₁₂ arylsulfinyl, a C₁ to C₆ alkylsulfonyl, a C₆ to C₁₂ arylsulfonyl, aminosulfonyl, a C₁ to C₆ alkylaminosulfonyl, a C₂ to C₆ dialkylaminosulfonyl, trifluoromethyl and imidazolyl. The compound according to Claim 1, wherein said 5- or 6-membered heterocyclic residue represented by A or Ar forms a ring of pyrrol, imidazole, pyrazole, pyridine, pirazine, pyrimidine, pyridazine, thiophene, thiazole, isothiazole, furan, oxazole or isoxazole; and said fused heterocyclic ring residue constituted by 9 or 10 atoms forms a ring of indolizine, indole, isoindole, quinoline, isoquinoline, benzothiophene, isobenzothiophene, benzothiazole, isobenzothiazole, benzofuran, isobenzofuran, benzoxazole, isobenzoxazole or benzimidazole. The compound according to Claim 2, wherein R² represents a C₁ to C₆ alkyl. The compound according to Claim 3, wherein R¹ represents hydrogen, a C₁ to C₆ alkyl, a C₅ to C₆ cycloalkyl or -(CH₂)n-A (where A represents phenyl, pyridyl, thienyl, benzimidazolyl or benzothiazolyl, each of which may be substituted by at least one substituent selected from a C₁ to C₃ alkyl and a halogen, and n represents 0 or an integer of 1 to 3). The compound according to Claim 4, wherein Ar represents phenyl, naphthyl, pyridyl, thienyl, pyrrolyl, imidazolyl, pyrazinyl, pyrimidinyl, indolyl, benzothiazolyl, benzimidazolyl or quinolyl, each of which may be substituted by at least one substituent selected from a C₁ to C₆ alkyl, a C₁ to C₆ alkoxy, a C₂ to C₇ alkylcarbonyl, a C₇ to C₁₃ arylcarbonyl, a C₁ to C₆ alkylamino, a C₂ to C₆ dialkylamino, amino, formylamino, a C₂ to C₇ alkylcarbonylamino, a halogen, cyano, nitro, hydroxyl, a C₁ to C₆ alkylthio, a C₆ to C₁₂ arylthio, a C₁ to C₆ alkylsulfinyl, a C₆ to C₁₂ arylsulfinyl, a C₁ to C₆ alkylsulfonyl, a C₆ to C₁₂ arylsulfonyl, aminosulfonyl, a C₁ to C₆ alkylaminosulfonyl, a C₂ to C₆ dialkylaminosulfonyl, trifluoromethyl and imidazolyl. The compound according to Claim 5, wherein R′ represents hydrogen, a C₁ to C₆ alkyl, a C₅ to C₆ cycloalkyl, or phenyl, benzyl, phenethyl or phenylpropyl, which may have at least one halogen atom. The compound according to Claim 6, wherein Ar represents phenyl, naphthyl, pyridyl, thienyl, pyrrolyl, benzothiazolyl or benzimidazolyl, each of which may be substituted by at least one substituent selected from a C₁ to C₆ alkyl, a C₁ to C₆ alkoxy, amino, a halogen, cyano, nitro, a C₁ to C₆ alkylthio, a C₆ to C₁₂ arylsulfonyl, aminosulfonyl, trifluoromethyl and imidazolyl. A pharmaceutical composition comprising, as active substance, at least one of the compounds of anyone of Claims 1 to 7, and a pharmaceutically acceptable carrier. A pharmaceutical composition according to Claim 8, wherein said composition is employed for antihypotensive treatment. A method for preparing a thiocarbamoylacetonitrile compound (I) according to Claim 1, which comprises reacting a compound represented by the formula (II): wherein R¹ and Ar have the same meanings as defined in Claim 1 with an isothiocyanate of the formula (III): R²NCS (III) wherein R² has the same meaning as defined in Claim 1, in an anhydrous polar solvent in the presence of a base at -80 °C to 50 °C. A method for preparing a thiocarbamoylacetonitrile compound (I) according to Claim 1, which comprises reacting a compound represented by the formula (II): wherein R¹ and Ar have the same meanings as defined in Claim 1, and carbon disulfide in a polar solvent in the presence of a base at -80 °C to 50 °C for several minutes to several hours, then reacting the resulting compound with methyl iodide at -80 °C to 50 °C to obtain a compound of the formula (IV): wherein R¹ and Ar have the same meanings as defined in Claim 1, and then reacting the compound (IV) and ammonia or the compound represented by the formula: R²-NH₂ (V) wherein R² has the same meaning as defined in Claim 1, in a polar solvent or an aromatic hydrocarbon, or in the absence of a solvent at 0 °C to 200 °C Claims for the following Contracting States : ES, GR A method for preparing a thiocarbamoylacetonitrile compound of the formula (I): wherein R¹ represents hydrogen, a C₁-C₆ alkyl, a C₃-C₆ cycloalkyl or -(CH₂) n -A (where A represents a C₆-C₁₂ aryl, a 5- or 6-membered heterocyclic or a fused heterocyclic group constituted by 9 or 10 atoms, each of which may be substituted by at least one selected from C₁-C₆ alkyl and a halogen and n is 0 or an integer of 1-6), R² represents a C₁-C₁₀ alkyl, and Ar represents an aryl, a 5- or 6-membered heterocyclic group or a fused heterocyclic group, each of which may be substituted by at least one substituent selected from the group consisting of a C₁ to C₆ alkyl, a C₁ to C₆ alkoxy, a C₂ to C₇ alkylcarbonyl, a C₇ to C₁₃ arylcarbonyl, a C₁ to C₆ alkylamino, a C₂ to C₆ dialkylamino, amino, formylamino, a C₂ to C₇ alkylcarbonylamino, a halogen, cyano, nitro, hydroxyl, a C₁ to C₆ alkylthio, a C₆ to C₁₂ arylthio, a C₁ to C₆ alkylsulfinyl, a C₆ to C₁₂ arylsulfinyl, a C₁ to C₆ alkylsulfonyl, a C₆ to C₁₂ arylsulfonyl, aminosulfonyl, a C₁ to C₆ alkylaminosulfonyl, a C₂ to C₆ dialkylaminosulfonyl, trifluoromethyl and imidazolyl, which comprises reacting a compound represented by the formula (II): wherein R¹ and Ar are as defined above, with an isothiocyanate of the formula (III): R²NCS (III) wherein R² is as defined above, in an anhydrous polar solvent in the presence of a base at -80°C to 50°C. A method for preparing a thiocarbamoylacetonitrile compound of the formula (I): wherein R¹ represents hydrogen, a C₁-C₆ alkyl, a C₃-C₆ cycloalkyl or -(CH₂) n -A (where A represents a C₆-C₁₂ aryl, a 5- or 6-membered heterocyclic or a fused heterocyclic group constituted by 9 or 10 atoms, each of which may be substituted by at least one selected from C₁-C₆ alkyl and a halogen and n is 0 or an integer of 1-6), R² represents a C₁-C₁₀ alkyl, and Ar represents an aryl, a 5- or 6-membered heterocyclic group or a fused heterocyclic group, each of which may be substituted by at least one substituent selected from the group consisting of a C₁ to C₆ alkyl, a C₁ to C₆ alkoxy, a C₂ to C₇ alkylcarbonyl, a C₇ to C₁₃ arylcarbonyl, a C₁ to C₆ alkylamino, a C₂ to C₆ dialkylamino, amino, formylamino, a C₂ to C₇ alkylcarbonylamino, a halogen, cyano, nitro, hydroxyl, a C₁ to C₆ alkylthio, a C₆ to C₁₂ arylthio, a C₁ to C₆ alkylsulfinyl, a C₆ to C₁₂ arylsulfinyl, a C₁ to C₆ alkylsulfonyl, a C₆ to C₁₂ arylsulfonyl, aminosulfonyl, a C₁ to C₆ alkylaminosulfonyl, a C₂ to C₆ dialkylaminosulfonyl, trifluoromethyl and imidazolyl, which comprises reacting a compound of the formula (II): wherein R¹ and Ar are as defined above, and carbon disulfide in a polar solvent in the presence of a base at -80°C to 50°C for several minutes to several hours, then reacting the resulting compound with methyl iodide at -80°C to 50°C to obtain a compound of the formula (IV): wherein R¹ and Ar have the same meanings as defined above, and then reacting the compound (IV) and ammonia or the compound represented by the formula: R²-NH₂ (V) wherein R² is as defined above, in a polar solvent or an aromatic hydrocarbon, or in the absence of a solvent at 0°C to 200°C. The process according to claim 1 or 2, wherein said 5- or 6-membered heterocyclic residue represented by A or Ar forms a ring of pyrrol, imidazole, pyrazole, pyridine, pirazine, pyrimidine, pyridazine, thiophene, thiazole, isothiazole, furan, oxazole or isoxazole; and said fused heterocyclic ring residue constituted by 9 or 10 atoms forms a ring of indolizine, indole, isoindole, quinoline, isoquinoline, benzothiophene, isobenzothiophene, benzothiazole, isobenzothiazole, benzofuran, isobenzofuran, benzoxazole, isobenzoxazole or benzimidazole. The process according to claim 3, wherein R² represents a C₁ to C₆ alkyl. The process according to claim 4, wherein R¹ represents hydrogen, a C₁ to C₆ alkyl, a C₅ to C₆ cycloalkyl or -(CH₂)n-A (where A represents phenyl, pyridyl, thienyl, benzimidazolyl or benzothiazolyl, each of which may be substituted by at least one substituent selected from a C₁ to C₃ alkyl and a halogen, and n represents 0 or an integer of 1 to 3). The process according to claim 5, wherein Ar represents phenyl, naphthyl, pyridyl, thienyl, pyrrolyl, imidazolyl, pyrazinyl, pyrimidinyl, indolyl, benzothiazolyl, benzimidazolyl or quinolyl, each of which may be substituted by at least one substituent selected from a C₁ to C₆ alkyl, a C₁ to C₆ alkoxy, a C₂ to C₇ alkylcarbonyl, a C₇ to C₁₃ arylcarbonyl, a C₁ to C₆ alkylamino, a C₂ to C₆ dialkylamino, amino, formylamino, a C₂ to C₇ alkylcarbonylamino, a halogen, cyano, nitro, hydroxyl, a C₁ to C₆ alkylthio, a C₆ to C₁₂ arylthio, a C₁ to C₆ alkylsulfinyl, a C₆ to C₁₂ arylsulfinyl, a C₁ to C₆ alkylsulfonyl, a C₆ to C₁₂ arylsulfonyl, aminosulfonyl, a C₁ to C₆ alkylaminosulfonyl, a C₂ to C₆ dialkylaminosulfonyl, trifluoromethyl and imidazolyl. The process according to claim 6, wherein R′ represents hydrogen, a C₁ to C₆ alkyl, a C₅ to C₆ cycloalkyl, or phenyl, benzyl, phenethyl or phenylpropyl, which may have at least one halogen atom. The process according to claim 7, wherein Ar represents phenyl, naphthyl, pyridyl, thienyl, pyrrolyl, benzothiazolyl or benzimidazolyl, each of which may be substituted by at least one substituent selected from a C₁ to C₆ alkyl, a C₁ to C₆ alkoxy, amino, a halogen, cyano, nitro, a C₁ to C₆ alkylthio, a C₆ to C₁₂ arylsulfonyl, aminosulfonyl, trifluoromethyl and imidazolyl. The use of a thiocarbamoylacetonitrile compound represented by the formula (I): wherein R¹ represents hydrogen, a C₁ to C₆ alkyl, a C₃ to C₆ cycloalkyl or -(CH₂) n -A (where A represents a C₆ to C₁₂ aryl, a 5- or 6-membered heterocyclic group or a fused heterocyclic group constituted by 9 or 10 atoms, each of which may be substituted by at least one selected from a C₁ to C₆ alkyl and a halogen and n is 0 or an integer of 1 to 6), R² represents a C₁ to C₁₀ alkyl, and Ar represents an aryl, a 5- or 6-membered heterocyclic group or a fused heterocyclic group, each of which may be substituted by at least one substituent selected from the group consisting of a C₁ to C₆ alkyl, a C₁ to C₆ alkoxy, a C₂ to C₇ alkylcarbonyl, a C₇ to C₁₃ arylcarbonyl, a C₁ to C₆ alkylamino, a C₂ to C₆ dialkylamino, amino, formylamino, a C₂ to C₇ alkylcarbonylamino, a halogen, cyano, nitro, hydroxyl, a C₁ to C₆ alkylthio, a C₆ to C₁₂ arylthio, a C₁ to C₆ alkylsulfinyl, a C₆ to C₁₂ arylsulfinyl, a C₁ to C₆ alkylsulfonyl, a C₆ to C₁₂ arylsulfonyl, aminosulfonyl, a C₁ to C₆ alkylaminosulfonyl, a C₂ to C₆ dialkylaminosulfonyl, trifluoromethyl and imidazolyl, for preparing a medicament effective in antihypotensive treatment.

Inventors: BESSHO HIDEKI, HAYASHI JUNKO, KOBAYASHI MAKIO, OKUSHIMA HIROMI, SEINO ASAMI, SHIMPUKU TETSURO, TOBE AKIHIRO, BESSHO, HIDEKI, HAYASHI, JUNKO, KOBAYASHI, MAKIO, OKUSHIMA, HIROMI, SEINO, ASAMI, SHIMPUKU, TETSURO, TOBE, AKIHIRO
Applicants: MITSUBISHI CHEM IND, MITSUBISHI KASEI CORPORATION
Application year: 1991
Main classification: C07C327
IPC codes: A61K31, C07D233, C07D241, C07D237, C07D207, C07D239, A61P9, C07D235, C07C327, C07D333, C07D521, C07D277, C07D209, C07D213, C07D215