CONDENSED IMIDAZOPYRIDINE DERIVATIVES

Abstract: (wherein R is phenyl optionally substituted by one or two members selected from the group consisting of trifluoromethyl, C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ alkylthio, nitro, amino C₁-C₅ alkanoylamino and C₁-C5 alkoxycarbonyl or 5- or 6-membered heterocyclic group optionally substituted by one or two members selected from the group consisting of halogen, C₁-C₅ alkyl and C₁-C₅ alkoxy, Q is hydrogen, C₁-C₅ alkyl, C₁-C₁₀ acyl, C₁-C₅ alkylsulfonyl or C₅-C₁₀ arylsulfonyl, R¹, R², R³, and R⁴ each is hydrogen, halogen C₁-C₅ alkyl, C₁-C₅ alkoxy or C₁-C₅ haloalkyl, Q is present on the nitrogen atom of the 1,3 or 5- position and the dotted line indicates the presence of three double bonds at the position of 2, 3; 3a, 3b; 4, 5 / 1, 3b; 2, 3; 3a, 4 / or 1, 2; 3a, 3b; 4, 5) or its salt, being useful as psychostimulants or anxiolytics, is provided.

Description: The present invention relates to condensed imidazopyridine derivatives. More particularly, this invention is directed to condensed imidazopyridine derivatives which have been found to be particularly effective in the treatment of depression or anxiety, to their preparation, to their use and to pharmaceutical and veterinary formulations containing the compounds. USSR pat. No. 509,588 discloses that 1H-2-oxo-3-phenyl-7-methyl-imidazo[4,5-c]quinoline is useful as a synthetic intermediate to biologically active materials. Abbasi et al, [Monatsh. Chem., 111 , 963 (1980)] disclose 3-hydroxy-2-hydroxymethyl-8-methoxy-9-nitro-4-styryl-2H-imidazo[4,5-c]quinoline and its analogs as synthetic intermediates to biologically active materials. Further European Pat. Appln. No. 145,340 describes 2-hydroxyalkyl-1H-imidazo[4,5-c]quinolines useful as bronchodilators or antiviral agents. The condensed imidazopyridine derivatives of the present invention are those having a 2-position phenyl optionally substituted by one or two members selected from trifluoromethyl, C₁-C₅ alkyl, C1-C5 alkoxy, C₁-C₅ alkylthio, nitro, amino, C₁-C₅ alkanoylamino and C₁-C₅ alkoxycarbonyl, or a 5- or 6-membered heterocyclic group optionally substituted by one or two members selected from halogen, C₁-C₅ alkyl and C₁-C₅ alkoxy. According to the present invention there is provided a condensed imidazopyridine derivative of the formula: wherein R is isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, furyl, pyridyl or thienyl optionally substituted by one or two of halogen, C₁-C₅ alkyl and C₁-C₅ alkoxy; Q is hydrogen, C₁-C₅ alkyl, C₁-C₅ alkanoyl, C₇-C₁₁ aroyl, C₁-C₅ alkylsulfonyl or C₆-C₁₀ arylsulfonyl, R¹, R² and R⁴ are each independently hydrogen, halogen, C₁-C₅ alkyl, C₁-C₅ alkoxy or C₁-C₅ haloalkyl; R₃ is halogen, C₁-C₅ alkyl, C₁-C₅ alkoxy or C₁-C₅ haloalkyl; Q is present on the nitrogen atom at the 1, 3 or 5-position, and the dotted line indicates the presence of three double bonds at the position of 2, 3; 3a, 3b; 4, 5/1, 3b; 2, 3; 3a, 4/ or 1, 2; 3a, 3b; 4, 5 or an acid addition salt. The compounds of the present invention have an excellent psychotropic activity such as psychostimulant or anxiolytic activity with no undesirable side effects. Accordingly, the compound may be used in a psychotropic formulation comprising as an active ingredient 0.1 to 95% by weight of a compound of the formula (I) associated with at least one carrier, diluent or excipient therefor. The compounds of the invention may be used in the treatment of a patient suffering from depression or anxiety by the administration to the patient of a pharmacologically effective amount of a compound of the formula (I). The invention further provides a process for preparing a compound of the formula (I) which comprises reacting a compound of the formula: wherein Q' is hydrogen or C₁-C₅ alkyl, and is as defined above with an acylating agent to give a compound of the formula: wherein Q'and R each is as defined above and cycling the compound (III) and when Q' is hydrogen, applying the cyclized product to alkylation, acylation or sulfonylation, if necessary, The term "C₁-C₅ alkyl" herein employed may include a straight or branched saturated aliphatic hydrocarbon radical such as methyl, ethyl, propyl, isopropyl, hutyl, isobutyl, tert-butyl, pentyl, neopentyl or 1-methylisobutyl. The term "C₁-C₅ alkoxy" may include an alkoxy group containing a C₁-C₅ alkyl moiety such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentyloxy. The term C₁-C₅ alkanoyl, includes formyl, acetyl, propionyl, butyryl, valeryl or isovaleryl and C₇-C₁₁ aroyl such as benzoyl, toluoyl or propylbenzoyl. The term "C₁-C₅ alkylsulfonyl" includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, isobutylsulfonyl and pentylsulfonyl. The term "C₈-G₁₀ arylsulfonyl" includes phenylsulfonyl, tolylsulfonyl, xylylsulfonyl and naphthylsulfonyl. The term "C₁-C₅ haloalkyl" includes fluoromethyl, chloroethyl, bromopropyl, iodobutyl and trifluoromethyl. The term "halogen" includes fluorine, chlorine, bromine and iodine. The process for preparing the compound (I) may be shown by the scheme as follows: SCHEME (wherein Q' is hydrogen or C₁-C₅ alkyl, and Q and R are as defined above). Step (1) The amide (III) can be prepared by reacting the diamine (II) with an acylating reagent. The reaction may be performed at a comparatively lower temperature (e.g. -10 to 5°C) generally in an appropriate solvent, using an acylating agent containing a necessary acyl group. The solvent includes illustratively dimethylformamide, acetonitrile, chloroform, hexamethylphosphoramide, ether, tetrahydrofuran or mixtures thereof. The acylating reagent refers to an acid halogenide such as acid chloride or acid bromide; a mixed acid anhydride; a mixture of carboxylic acid with thionyl chloride; a mixture of carboxylic acid with a condensing agent such as DCC or polyphosphoric acid. Step (2) The compound (Ia) can be prepared by heating the amide (III) in a solvent at a temperature from about 50°C to 250°C, preferably 100°C to 250°C in the presence or absence of cyclizing agent such as polyphosphoric acid, polyphosphoric ester, sulfuric acid, acetic acid or phosphorus pentoxide. The solvent includes illustratively hexamethylphosphoramide, diphenyl ether, glycerin triethyl ether, butyl ether, isoamyl ether, diethylene glycol, triethylene glycol or Dowtherm A (Dow Chemical Co.). Step (3) As necessary, the compound (Ia) (Q'=Hydrogen) may be subjected to alkylation, acylation or sulfonylation. The reaction may be performed with an alkylating, acylating or sulfonylating agent in an appropriate solvent in the presence of a base such as alkali metal hydride. (e.g. sodium hydride, potassium hydride) or alkali metal alkoxide (e.g. sodium methoxide, potassium ethoxide, sodium isopropoxide) at a temperature of 30 to 120°C. The alkylating agent includes alkyl halide such as methyl iodide, ethyl bromide, propyl chloride or butyl iodide and dialkyl sulfate such as dimethyl sulfate or diethyl sulfate. The acylating agent includes acyl halide such as acetyl chloride, propionyl bromide, butyryl chloride or benzoyl chloride and acid anhydride such as acetic anhydride or propionic anhydride. The sulfonylating agent includes mesyl chloride, butylsulfonyl chloride and tosyl chloride. As solvents there are exemplified tetrahydrofuran, dioxane, diglyme, dimethylformamide, chloroform and ethanol. The diamine (II) usable as a starting material can be prepared, as shown below, in accordance with the methods of G. B. Bachman et al., J. Am. Chem. Soc., 69 , 365 (1947) and A. R. Surrey et al., J. Am. Chem. Soc., 73 , 2413 (1951). (wherein Ac is acetyl; and Q' are as defined above.) The compound (I) includes the following three compounds (I a , I b and I c ): (wherein Q' and R are as defined above). The compound (I) can be converted into its physiologically acceptable acid addition salts. Such acids illustratively include an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid and an organic acid such as acetic acid, maleic acid, malic acid, citric acid, lactic acid, succinic acid or methanesulfonic acid. The invention further relates to a pharmaceutical or veterinary formulation comprising a compound of formula (I) formulated for pharmaceutical or veterinary use, respectively. The formulation may be in unit dosage form and/or may further comprise a pharmaceutically or veterinarily acceptable carrier, diluent or excipient. The compound of formula (I) and its salts may be of general use in the treatment of disease. The invention includes the use of the compound of formula (I) and its salts in the manufacture of a medicament for the treatment of anxiety or depression. The compounds (I) or acceptable acid addition salts thereof have a high affinity to benzodiazepine receptors, and they are useful as psychotropic agents such as psychostimulants or anxiolytics. The compounds (I) can be administered orally or parenterally to human beings or other animals. They can be formulated as tablets, capsules, pills, granules, injections, suppositories, and syrups As acceptable carriers, diluents or excipients there are exemplified lactose, sucrose, wheat starch, potato starch, magnesium stearate, gelatin, methyl cellulose, agar, water, and the like. As necessary, appropriate stabilizers, emulsifiers, spreaders, buffers and other adjuvants can be added. Appropriate daily dosage of the compound (I) is 0.1 to 500 mg in oral route and 0.1 to 300 mg in injection. The present invention may be explained in more detail by the following non-limiting Examples, Referential Examples and Formulations. The abbreviations used in Examples, Referential Examples and Tables have the following meanings. HMPA : Hexamethylphosphoramide Me : Methyl Et : Ethyl PPA : Polyphosphoric acid MeCN : Acetonitrile MeOH : Methanol EtOH : Ethanol Et₃O : Ether AcOEt : Ethyl acetate AcOH : Acetic acid DMF : Dimethylformamide (d) : Decomposition When Q is hydrogen, the compound (Ia) and (Ib) being a tautomer of each other will be named conveniently as said formula (Ia). For example, 2-(3-trifluoromethylphenyl)-1H-imidazo[4,5-c]quinoline C₁ (Example 1) may be also named as 2-(3-trifluoromethylphenyl)-3H-imidazo[4,5-c[quinoline. Example 1 2-(3-Trifluoromethylphenyl)-1H-imidazo[4,5-c]quinoline C₁ To a solution of 500 mg of 3-trifluoromethylbenzoic acid in 6 ml of anhydrous hexamethylphosphoramide (HMPA) and 0.6 ml of anhydrous acetonitrile is added dropwise 305 mg of thionyl chloride at -5 - 0°C under nitrogen. After stirring at the same temperature for 30 minutes, 380 mg of 3,4-diaminoquinoline is added and stirred at 0 -5°C for 3 hours. The mixture is diluted with ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting crystals are filtered, washed with water, and dried to give 780 mg of 4-amino-3-(3-trifluoromethylbenzoylamino)quinoline B₁ as a crude product. It is suspended in 15 g of polyphosphoric acid and heated at 120°C for 4 hours with stirring. The mixture is poured into ice-water and neutralized uith 1N soium hydroxide. The resulting solid is filtered, washed with water and dried. it is chromatographed on silica gel with chloroform - methanol (10:1 v/v) as eluent, yielding 350 mg (47%) of C₁ as colorless crystals. Example 2 According to the method illustrated by Example 1, the compound C₂ is prepared under the conditions shown in Table 1. Table 3 shows the physical properties of these compounds. Example 4 2-(5-Methylthien-2-yl)-1H-imidazo[4,5-c]quinoline C₄ To a solution of 555 mg of 5-methylthiophene-2-carboxylic acid in 9 ml of anhydrous hexamethylphosphoramide and 0.9 ml of anhydrous acetonitrile is added dropwise 455 mg of thionyl chloride at -5 - 0°C under nitrogen. After stirring at the same temperature for 30 minutes, 570 mg of 3,4-diaminoquinoline is added and stirred at 0 -5°C for 4 hours. THe same work-up as described in Example 1 gives 900 mg of 4-amino-3-(5-methylthien-2-ylcarbonylamino)quinoline B₄ as a white solid. It is suspended in 15 g of polyphosphate ester and heated at 125°C with stirring for 3 hours. The mixture is diluted with ice-water and neutralized with 1N sodium hydroxide and extracted with ethyl acetate. The extract is washed with water and saturated sodium chloride, dried over magnesium sulfate, and evaporated. The residue is chromatographed on silica gel with chloroform - methanol (10:1 v/v) as eluent to give 456 mg (48%) of C₄ as pale yellow crystals. Example 5 2-(Pyridin-4-yl)-1H-imidazo[4,5-c]quinoline C₅ To a solution of 325 mg of isonicotinic acid in 8 ml of anhydrous hexamethylphosphoramide and 0.8 ml of anhydrous acetonitrile is added dropwise 305 mg of thionyl chloride at -5 - 0°C under nitrogen. After stirring for 45 minutes, 380 mg of 3,4-diaminoquinoline A₁ is added and the mixture is stirred at 0°C for 4.5 hours. The same work-up as described in Example 1 gives 560 mg of crude crystals of B₅ . It is dissolved in 10 ml of acetic acid and refluxed for 4 hours. The mixture is concentrated under reduced pressure and mixed with ice-water and neutralized with saturated sodium bicarbonate. The resulting crystals are filtered and dried to yield 510 mg (87%) of C₅ as white crystals. Example 6 2-(4-Trifluoromethylphenyl)-1H-imidazo[4,5-c]quinoline C₅ To a solution of 395 mg of 4-trifluoromethylbenzoic acid in 5 ml of anhydrous hexamethylphosphoramide and 0.5 ml of anhydrous acetnoitrile is added dropwise 240 mg of thionyl chloride at -5 - 0°C under nitrogen. After stirring at the same temperature for 30 minutes, 300 mg of 3,4-diaminoquinoline A₁ is added and stirred at 0 - 5°c for 4 hours. The same work-up as described in Example 1 gives 605 mg of the crude crystals of B₆ . It is suspended in 10 ml of hexamethylphosphoramide and 2.5 ml of acetic acid, and stirred at 155°C for 15 minutes under nitrogen. The cooled mixture is diluted with water and neutralized with saturated aqueous sodium bicarbonate. The resulting solid is chromatographed on silica gel with chloroform - methanol (10:1 v/v) as eluent to give 440 mg (75%) of C₆ as white crystals. Example 7-12, 15, 17, 23, 25, 34-35, 37-39, 41-93 According to the method illustrated by Example 6, Compounds C₇ - C₁₂ , C₁₅ , C₁₇ , C₂₃ , C₂₅ , C₃₄ - C₃₅ , C₃₇ - C₃₉ , and C₄₁ - C₉₃ are prepared under the conditions shown in Table 2. Table 3 shows the physical properties of these compounds. Example 98 1-Ethyl-2-(5-methylthien-2-yl)-1H-imidazo[4,5-c]quinoline C₉ ₈ To a solution of 270 mg of 5-methylthiophene-2-carboxylic acid in 5 ml of anhydrous hexamethylphosphoramide and 0.5 ml of anhydrous acetonitrile is added dropwise 215 mg of thionyl chloride at -5 -0°C under nitrogen. After stirring at the same temperature for 30 minutes, a solution of 320 mg of 3-amino-4-ethylaminoquinoline A₁ ₆ in 0.5 ml of anhydrous hexamethylphosphoramide is added and stirred at 0 -5°C for 3 hours. The same work-up as described in Example 1 gives 510 mg of B₉₈ as a white solid. It is suspended in 10 ml of acetic acid and refluxed for 1 hour. The mixture is concentrated and the residue is shaken with ethyl acetate-saturated aqueous sodium bicarbonate. The organic layer is separated, washed successively with water and saturated aqueous sodium chloride, and dried. The solvent is evaporated and the residue is chromatographed on silica gel with chloroform - methanol (20:1 v/v) as eluent to give 380 mg (76%) of C₉₈ as colorless crystals. Example 99 2-(4-Methyloxazol-5-yl)-1H-imidazo[4,5-c]quinoline C₉₉ To a solution of 300 mg of 4-methyloxazole-5-carboxylic acid in 4 ml of hexamethylphosphoramide and 0.4 ml of acetonitrile is added 268 mg of thionyl chloride at -5 - 0°C under nitrogen. After stirring at the same temperature for 30 minutes, 340 mg of 3,4-diaminoquinoline A₁ is added and stirred at 0 - 5°C for 3 hours. The mixture is diluted with ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting solid is filtered and washed with water to give 425 mg of 4-amino-3-(4-methylisoxazole-5-ylcarbonylamino)quinoline as crude crystals. It is suspended in 12 ml of Dowtherm A (Dow Chemical Co.) and refluxed for 2.5 hours. The cooled mixture is diluted with 50 ml of n-hexane and the resulting solid is collected by filtration. It is chromatographed on silica gel with dichloromethane - methanol (20:1 v/v) as eluent to yield a crude solid which is recrystallized from ethyl acetate - methanol, giving 297 mg of C₉₉ as pale yellow crystals. Example 100 2-(3-Methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline hydrochloride C₁₀₀ To an ethanolic solution of 300 mg of 2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline C₄₅ is added ethanolic hydrogen chloride at room temperature. The mixture is evaporated and the residue is washed with acetone to give C₁₀₀ as crystals melting at 248.5 - 252°C (dec.). Example 101 3-Methanesulfonyl-2-(3-methylisoxazol-5-yl)-3H-imidazo[4,5-c]quinoline C₁₀₁ To a solution of 300 mg of 2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline C₄₅ in 20 ml of tetrahydrofuran is added 50 mg of 60% sodium hydride in mineral oil and stirred at 75°C for 2 hours under nitrogen. To the cooled mixture is added dropwise 180 mg of methanesulfonyl chloride and stirred at 0 - 5°C for 2 hours. The mixture is concentrated under reduced pressure and the residue is poured into ice-water. The resulting solid is collected by filtration and chromatographed on silica gel with dichloromethane - methanol (50:1 v/v) as eluent, yielding 159 mg (40%) of C₁₀₁ as white crystals. Example 102 1-Methyl-2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline C₁₀₂ To a solution of 245 mg of 3-methylisoxazole-5-carboxylic acid in 20 ml of hexamethylphosphoramide and 0.4 ml of acetonitrile is added 226 mg of thionyl chloride at -5 - 0°C. After stirring at the same temperature for 30 minutes, 330 mg of 3-amino-4-methylaminoquinoline A₁₅ is added and stirred at 0 - 5°C for 5 hours. The mixture is diluted with 50 ml of ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting solid is filtered and washed with water to give 361 mg (67%) of 4-methylamino-3-[(3-methylisoxazole-5-ylcarbonyl)amino]quinoline. It is suspended in 4 ml of hexamethylphosphoramide and 1 ml of acetic acid and stirred at 180°C (bath temperature) for 40 minutes. The cooled mixture is poured into ice-water and neutralized with aqueous sodium bicarbonate. The resulting solid is filtered, washed with water and chromatographed on silica gel with dichloromethane - methanol (25:1 v/v) as eluent. The product obtained is recrystallized from dichloromethane - methanol to give 294 mg of C₁₀₂ as white crystals melting at 281 - 284°C (dec.). Example 104 3-Methyl-2-(3-methylisoxazol-5-yl)-3H-imidazo[4,5-c]qinoline C₁₀₅ , 1-Methyl-2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline C₁₀₂ and 5-Methyl-2-(3-methylisoxazol-5-yl)-5H-imidazo[4,5-c]qiniline C₁₀₅ To a solution of 450 mg of 2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline C₄₅ in 39 ml of tetrahydrofuran is added 80 mg of 60% sodium hydride in mineral oil and stirred at 60°C for 1.5 hours under nitrogen. To the cooled mixture is added dropwise 385 mg of methyl iodide in 2 ml of tetrahydrofuran at 0 - 5°C. After stirring at 0 - 5°C for 30 minutes and then at 40°C for 4 hours, the mixture is evaporated and the residue is chromatographed on silica gel with dichloromethane - methanol (50:1 v/v) as eluent, to give 58 mg (12%) of 3-methyl derivative C₁₀₂ as white crystals. The further elution with the same solvent yields 42 mg (9%) of 1-metyl derivative C₁₀₂ which is identical with the compound described in Example 102. Then the eluate with dichloromethane - methanol (25:1 v/v) affords 322 (68%) of 5-methyl derivative C₁₀₅ as white crystals. Example 106 2-(Thien-2-yl)-7-methyl-1H-imidazo[4,5-d]thieno[2,3-b]pyridine F₂ To a solution of 212 mg of thiophene-2-carboxylic acid in 4 ml hexamethylphosphoramide and 0.4 ml of acetonitrile is added dropwise 188 mg of thionyl chloride at -5 - 0°C under nitrogen. After stirring at 0 - 5°C for 30 minutes, 269 mg of diaminothienopyridine D₁ is added and stirred at 0 - 5 °C for 3 hours. The same work-up as described in Example 105 gives 403 mg of E₂ as crude crystals. It is suspended in 20 ml of Dowtherm A (Dow Chemical Co.) and refluxed for 3 hours under nitrogen. The cooled mixture is diluted with n-hexane and the resulting crystals are filtered. It is chromatographed on silica gel with chloroform - methanol (25:1 v/v) as eluent to give 286 mg (70%) of F₂ as colorless crystals. Example 107-110 and 114 According to the method illustrated by Example 106, Compounds F₃- F₆ and F₁₀ are obtained under the conditions shown in Table 4. Table 5 shows the physical properties of these compounds. Example 115 2-Phenyl-1H-imidazo[4,5-d]thieno[3,4-b]pyridine H₁ To a solution of 187 mg of benzoic acid in 5 ml of anhydrous hexamethylphosphoramide and 0.5 ml of anhydrous acetonitrile is added dropwise 174 mg of thionyl chloride at 0°C under nitrogen. After stirring at 0°C for 30 minutes, 239 mg of diaminothienopyridine D₃ is added and stirred for 3 hours. The mixture is diluted with ice-water and neutralized with aqueous sodium bicarbonate. The resulting crystals are filtered, washed with water and dried to give 280 mg of G₁ . It is suspended in 4.2 ml of hexamethylphosphoramide and 1.1 ml of acetic acid, and heated at 170°C for 30 minutes. The cooled mixture is diluted with ice-water and extracted with ethyl acetate, and the extract is washed with water and dried. After the solvent is evaporated, the residue is chromatographed on silica gel with chloroform - methanol (50:2 v/v) to give 170 mg (51%) of H₁ as colorless crystals. Example 117 2-(5-Chlorothien-2-yl)-1H-imidazo[4,5-d]thieno[3,4-b]pyridine H₃ According to the method illustrated by Example 115, 259 mg of H₃ is obtained from 325 mg of 5-chlorothiophene-2-carboxylic acid and 300 mg of diaminothienopyridine D₃ Example 118 2-(4-Methoxylphenyl-1H-imidazo[4,5-d]thieno[3,2-b]pyridine K₁ To a solution of 233mg of 4-methoxbenzoic acid in 4 ml of bexamethylphosphoramida and 0.4 ml of acetonitrile is added 174 mg of thionyl chloride at 0°C under nitrogen. After stirring at 0°C for 30 minutes, 230 mg of diaminothienopyridine D₄ is added and stirred at 0°C for 4 hours. The mixture is diluted with ice-water and neutralized with aqueous sodium bicarbonate. The resulting crystals are filtered, washed with water and dried to yield 348 mg (84%) J₁ The mixture of J₁ and 6.6 ml of Dowtherm A (Dow Chemical Co.) is refluxed for 2 hours. The cooled mixture is diluted with n-hexane and allowed to stand to give 300 mg (95%) of K₁ as colorless crystals. Example 122 - 123 According to the method illustrated by Example 118, Compounds K₂- K₆ are prepared under the conditions shown in Table 6. Table 7 shows the physical properties of these compounds. 3,4-Diaminoquinolines The starting 3,4-diaminoquinolines are prepared by sequential chlorination, amination and reduction of 3-nitro-4-hydroxyquinolines according to the literature [G. B. Bachman et al., J . Am . Chem . Soc ., 69, 365 (1947) and A. R. Surrey et al., J . Am . Chem . Soc ., 73, 2413 (1951)]. The following table shows their melting points. Referential Example 1 3-Amino-4-methylaminoquinoiline A₁₅ To a suspension of 2.0 g of 4-chloro-3-nitroquinoline in 20 ml of dry ethanol is added 15 ml of 30% methylamine in ethanol. The mixture is stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is triturated with excess water. The resulting crystals are collected by filtration and washed repeatedly with water. The crystals are dried over pbosphorus pentoxide in vacuo to afford 1.82 g (93%) of 4-methylamino-3-nitroquinoline. An analytical sample is recrystallized from ethyl acetate to give yellow crystals melting at 172 - 173°C. A suspension of 1.7g-of 4-methylamino-3-nitroquinoline in 75 ml of ethanol is hydrogenated in the presence of 300 mg of 10% palladium on carbon at atmospheric pressuue. After hydrogen absorption is complete, the catalyst is removed by filtration and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel. Elution with chloroform - methanol (2:1 v/v) affords 600 mg (41%) of 3-amino-4-methylaminoquinoline A₁₆ as an oil. Referential Example 2 3-Amino-4-ethylaminoquinoline A₁₆ To a stirred suspension of 1.40 g of 4-chloro-3-nitroquinoline in 30 ml of dry ethanol is introduced excess amount of gaseous ethylamine at room temperature for 3 hours. Treatment of the reaction mixture as in Example 98 yielded 1.41 g (97%) of 4-ethylamino-3-nitroquinoline. Recrystallization from ethyl acetate - n-hexane affords yellow crystals melting at 151 -152°C. A suspension of 1.34 g of 4-ethylamino-3-nitroquinoline in 40 ml of ethanol is hydrogenated in the presence of 10% palladium on carbon according to the procedure of Referential Example 1, followed by purification to give 0.95 g (82%) of 3-amino-4-ethylaminoquinoline A₁₆ as an oil. Referential Example 3 (1) 5-Nitro-2-methylthieno[2,3-b]pyridin-4(7H)-one 2 To a solution of 1.65 g of 2-methylthieno[2,3-b]pyridin-4(7H)-one 1 in 45 ml of acetic is added dropwise a solution of 1.24 g of concentrated nitric acid (d=1.38) in 5 ml of acetic acid at 110°C. The mixture is heated with stirring at the same temperature for 10 minutes and left on cooling. The resulting crystals are collected by filtration and washed with ethyl acetate to give 1.07 g (51%) of Compound 2 as pale yellow crystals melting at 280 - 282°C(dec.). (2) 4-Chloro-5-nitro-2-methylthieno[2,3-b]pyridine 3 A mixture of 2.26 g of 5-nitro-2-methylthieno[2,3-b]pyridin-4(7H)-one 2 and 10 ml of phosphorus oxychloride is refluxed for 1 hour. The reaction mixture is concentrated to dryness in vacuo and the residue is taken up in the ethyl acetate. The organic phase is dried over magnesium sulfate and treated with activated charcoal. The mixture is filtered and the solvent is evaporated in vacuo . The crude product is recrystallized from ethyl acetate - n -hexane to give 1.90 g (68%) of Compound 3 as colorless melting at 96-98°C. (3) 4-Amino-5-nitro-2-methylthieno[2,3-b]pyridine 4 To a stirred solution of 1.60 g of 4-chloro-5-nitro-2-methylthieno[2,3-b]pyridine 3 in 50 ml of 2-propanol is introduced excess amount of anhydrous ammonia at 55°C during 3 hours. The reaction mixture is concentrated in vacuo . The residue is washed with ether and suspended in 7 ml of 1N sodium hydroxide solution with stirring. The resulting crystals are collected by filtration and washed with water and a small amount of ethanol to yield 1.37 g (93%) of Compound 4 as orange crystals melting at 238 - 240°C. (4) 4,5-Diamino-2-methylthieno[2,3-b]pyridine D₁ A suspension of 1.25 g of 4-amino-5-nitro-2-methylthieno[2,3-b]-pyridine is hydrogenated under atmospheric pressure at room temperature in the presence of 360 mg of 10% palladium carbon for 2 hours. After removal of catalyst, the filtrate is concentrated and the residue is triturated with chloroform to give 866 mg (81%) of Compound D₁ as colorless crystals melting at 204 - 209°C. Referential Example 4 (1) 5-Nitrothieno[2,3-b]pyridin-4(7H)-one 6 To a solution of 3.4 g of thieno[2,3-b]pyridin-4(7H)-one 5 in 105 ml of propionic acid is added 2.79 g of concentrated nitric acid (d=1.38) at 100°C, and then the mixture is stirred at 130°C (bath temperature) for 1 hour. After cooling the reaction mixture, the resulting precipitate is collected by filtration and washed successively with water, methanol and acetone to afford 3.4 g (77%) of Compound 6 as pale yellow crystals melting at 288 - 291°C. (2) 4-Chloro-5-nitrothieno[2,3-b]pyridine 7 A mixture of 3.4 g of 5-nitrothieno[2,3-b]pyridin-4(7H)-one 6 and 34 ml of phosphorus oxychloride is heated at 115°C (bath temperature) for 1 hour and evaporated to dryness in vacuo . The residue is taken up in chloroform and washed with water. The organic phase is dried over magnesium sulfate and concentrated in vacuo . The residue is purified by column chromatography on silica gel. Elution with dichloromethane - ether (50:1 v/v) affords 3.51 g (94%) of Compound 7 as crystals melting at 110 - 113°C. (3) 4-Amino-5-nitrothieno[2,3-b]pyridine 8 To a stirred suspension of 3.35 g of 4-chloro-5-nitrothieno[2,3-b]pyridine 7 in 160 ml of 2-propanol is introduced excess amount of anhydrous ammonia at 45 - 50°C during 4 hours. After removal of the solvent, the residue is suspended in water. The solid is washed with water and cold ether, affording 2.65 g (87%) of Compound 8 as crystals. Recrystallization from methanol - ether gives a pure sample melting at 227 - 228.5°C. (4) 4,5-Diaminothieno[2,3-b]pyridine D₂ A mixture of 2.57 g of 4-amino-5-nitrothieno[2,3-b]pyridine 8 and 11.1 g of stannous chloride in 240 ml of ethanol is stirred at 75°C for 3 hours. The reaction mixture is treated with activated charcoal and filtered. After concentration of the filtrate, the residue is taken up in ethyl acetate and suspended in 185 ml of 5% aqueous sodium bicarbonate. The organic layer is extracted with dilute hydrochloric acid. The aqueous layer is treated with activated charcoal and filtered. The filtrate is basified to pH=10 with 10% sodium hydroxide and extracted with ethyl acetate. The extract is dried over megnesium sulfate and evaporated in vacuo. The residue is recrystallized from ethyl acetate - ether to afford 1.65 g (76%) of Compound D₂ as pale yellow crystals melting at 159 - 160.5°C Referential Example 5 (1) 3-Nitrothieno[3,4-b]pyridin-4(1H)-one 10 To a suspension of 4.00 g of thieno[3,4-b]pyridin-4(1H)-one 9 in 120 ml of acetic acid is added 3.00 g of nitric acid (d=1.38). The reaction mixture is stirred at 70°C for 3 minutes and cooled to room temperature. The resulting crystals are collected by filtration, and then washed with water and methanol - ether , affording 2.51 g (48%) of Compound 10 . An analytical sample is recrystallized from dimethylsulfoxide - methanol to give yellow crystals melting at 329 - 332°C. (2) 4-Chloro-3-nitrothieno[3,4-b]pyridine 11 A mixture of 3.00 g of 3-nitrothieno[3,4-b]pyridin-4(1H)-one 10 and 9 ml of phosphorous oxychloride is stirred at 105°C (bath temperature) for 1 hour and evaporated to dryness in vacuo . The residue is taken up in chloroform and washed with aqueous ammonia and water. The organic phase is dried over magnesium sulfate and evaporated. The residue is purified by column chromatography on silica gel. Elution with dichloromethane - ether (50:1 v/v) affords 2.02 g (60%) of Compound 11 . Recrystallization from ether - petroleum ether affords colorless crystals melting at 139 - 140°C. (3) 4-Amino-3-nitrothieno[3,4-b]pyridine 12 To a stirred suspension of 1.25 g of 4-chloro-3-nitrothieno[3,4-b]pyridine 11 in 37 ml of 2-propanol is introduced anhydrous ammonia at room temperature during 3 hours. The mixture is concentrated in vacuo and the residue is suspended in water with stirring. The crystals are collected by filtration, washed with water and dried to give 1.09 g (96%) of Compound 12 . An analytical sample is recrystallized from chloroform - methanol, giving yellow crystals melting at 307 - 309°C. (4) 3,4-Diamino[3,4-b]pyridine D₃ A mixture of 620 mg of 4-amino-3-nitrothieno[3,4-b]pyridine and 3.59 g of stannous chloride dihydrate in 50 ml of ethanol is stirred at 70°C for 1 hour. After evaporation of the solvent in vacuo , the residue is partitioned between ethyl acetate and aqueous sodium bicarbonate. The resulting solid is filtered off and washed with ethyl acetate. The combined extracts are dried and evaporated in vacuo . The residue is purified by column chromatography on neutral alumina. Elution with chloroform - methanol (20:1 v/v) affords 490 mg (93%) of Compound D₃, which is recrystallized from ether - methanol to afford colorless crystals melting at 140 - 144°C. Referential Example 6 (1) 6-Nitrothieno[3,2-b]pyridin-7(4H)-one 14 To a solution of 3.1 g of thieno[3,2-b]pyridin-7(4H)-one 13 in 90 ml of propionic acid is added 1.5 ml of fuming nitric acid at 110°C with stirring and the mixture is refluxed for 1 hour. The cooled mixture is diluted with 50 ml of ether and the resulting crystals are collected by filtration, washed with water and ether - methanol, and dried to give 3.13 g (78%) of Compound 14 . Recrystallization from dimethyl sulfoxide - methanol affords colorless crystals melting at 328 - 331°C (dec.). (2) 7-Chloro-6-nitrothieno[3,2-b]pyridin-7(4H)-one 15 A mixture of 2.7 g of 6-nitrothieno[3,2-b]pyridin-7(4H)-one 14 and 30 ml of phosphorous oxychloride is stirred at 115°C for 1 hour. The reaction mixture is evaporated to dryness in vacuo . The residue is taken up in dichloromethane, washed successivly with aqueous ammonia and water, and then dried over magnesium sulfate. The solvent is removed in vacuo and the crude crystals are purified by column chromatography on silica gel. Elution with dichloromethane -ether (50:1 v/v) affords 2.64 g (90%) of Compound 15 . Recrystallization from ether gives colorless crystals melting at 124 - 125.5°C. (3) 7-Amino-6-nitrothieno[3,2-b]pyridine 16 To a suspension of 2.55 g of 7-chloro-6-nitrothieno[3,2-b]pyridine 15 in 130 ml of 2-propanol is introduced excess anhydrous ammonia at 45°C (bath temperature) during 4 hours and the mixture is evaporated in vacuo . The residue is suspended in water, collected by filtration, and then washed with water and ether to give 2.30 g (99%) of Compound 16 . An analytical sample is recrystallized from chloroform methanol, affording yellow crystals melting at 266 - 268.5°C. (4) 6,7-Diaminothieno[3,2-b]pyridine D₄ A mixture of 2.3 g of 7-amino-6-nitrothieno[3,2-b]pyridine 16 and 12.5 g of stannous chloride dihydrate in 160 ml of ethanol is heated with stirring at 70°C for 3 hours. The mixture is evaporated in vacuo and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The resulting solid is filtered off and washed with ethyl acetate. The combined extracts are dried and evaporated in vacuo. The residue is purified by column chromatography on silica gel. Elution with chloroform - methanol (10:1 v/v) affords 1.91 g (97%) of Compound D₄, which is recrystallized from methanol - ether to give colorless crystals melting at 157-159°C. Preparation The above components are mixed each other to prepare a capsule. Effect of the Invention The compounds of the present invention show high affinity to a benzodiazepine receptor. `The drugs bound to this receptor are classified as three groups according to the difference of the efficacy. Thus, agonists can be utilized as anxiolytics or anticonvulsants, antagonists can be agents for treating benzodiazepine intoxication and accidental supernumerary uptake, and inverse agonists are expected as psychostimulants. Experiments for assessing biological activities of the compounds of the present invention are shown below; the number of the test compound nearly corresponds to the number used in Examples and Tables respectively. Experiment 1 Binding test to benzodiazepine receptor This test was carried out in the modified method of Möhler et al. Science, 198 , 849-851 (1977). Receptor preparation was provided from the cerebral cortex of Wistar rats (male, 11 to 13 weeks age). Inhibitory action of the test compound on the specific binding of tritium labeled diazepam to the receptor was evaluated as follows. 2nM tritium labeled diazepam and an aqueous solution of the test compound at 5 or 6 concentrations were incubated with the receptor preparation at 0°C for 6 minutes. The 50% inhibitory concentration (IC₅₀) was measured by the concentration-response curve. The inhibitory constant (Ki) was calculated according to the following equation, in which Kd is the dissociation constant of the tritium labeled diazepam and L is the concentration of the labeled ligand. Experiment 2 Antagonism of Pentyleneterazole-Induced Convulsion Agonistic activity was evaluated in this test. Groups of 8-16 male mice were challenged with a dose of 125 mg/kg, s.c. of Pentylenetetrazole immediately after intravenous injection of the test compound. The dose required to prevent tonic convulsion and death in 50% of the animal during a 2-h observation period was calculated by the probit method. Experiment 3 Potentiation of Pentylenetetrazole-Induced Convulsion Inverse agonist activity was evaluated in this test. Groups of 8-16 mice were challenged with a dose of 90 mg/kg. s.c. of plentylenepetrazole (a subconvulsive dose) immidiately after intraveonous injection of the test compound. The dose required to produce tonic convulsion and death in 50% of the animal during a 2-h observation period was calculated by the probit method. Experiment 4 Traction test The modified method of Courvoisier et al. (in "Psychotropic Drugs", ed. by S. Garattini & R. Ducrot. p 373. Elsevier Publishing Co., Amsterdam 1957) was employed. Groups of 10 mice were made to hang onto a horizontal metal wire (diameter : 1 mm) by grasping and holding with their forepaws 30 minutes after oral administration of the test compound, and the number of mice gripping the wire with hindpaws within 10 sec was counted. The ED₅₀ was calculated by the probit method. Experiment 5 Anticonflict test The modified method of Geller and Seifter (Psychopharmacol, 1 , 482, 1960) was employed. Groups of 5 or more male Wistar rats with well-established conflict behavior were used. A dose was determined as positive when the number of electric shocks (punishment) exceeded more than 12 during a 1 hour observation period starting 30 minutes after oral administration of the test compound. The ED₅₀ was calculated by the probit method. The pharmacological activities described above suggest that the dissociation of anxiolytic action and muscle relaxation action, both being specific to drugs of benzodiazepine type, was achieved. Thus, the compound of the present invention can be an anxiolytic drug not accompanying with a side effect such as dizziness.

Claims: A compound of the formula: wherein R is isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, furyl, pyridyl or thienyl optionally substituted by one or two of halogen, C₁-C₅ alkyl and C₁-C₅ alkoxy; Q is hydrogen, C₁-C₅ alkyl, C₁-C₅ alkanoyl, C₇-C₁₁ aroyl, C₁-C₅ alkylsulfonyl or C₆-C₁₀ arylsulfonyl, R¹, R² and R⁴ are each independently hydrogen, halogen, C₁-C₅ alkyl, C₁-C₅ alkoxy or C₁-C₅ haloalkyl; R₃ is halogen, C₁-C₅ alkyl, C₁-C₅ alkoxy or C₁-C₅ haloalkyl; Q is present on the nitrogen atom at the 1, 3 or 5-position, and the dotted line indicates the presence of three double bonds at the position of 2, 3; 3a, 3b; 4, 5/1, 3b; 2, 3; 3a, 4/ or 1, 2; 3a, 3b; 4, 5 or an acid addition salt. A compound as claimed in Claim 1, wherein A compound as claimed in Claim 1 or Claim 2, wherein R is isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, thienyl or furyl optionally substituted by one or two of halogen, C₁-C₅ alkyl and C₁-C₅ alkoxy. e.g. 2-thienyl or 3-methyl-5-isoxazolyl. 7-Chloro-2-(2-thienyl)-1H-imidazo[4,5-c]quinoline; 2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline; 7-fluoro-2-(3-methylisoxazol-5-yl)-1H-imidazo [4,5-c]quinoline; or 8-fluoro-2-(3-methylisoxazol-5-yl)-1H-imidazo [4,5-c]quinoline. A process for preparing a compound as claimed in Claim 1, which comprises reacting a compound of the formula: wherein Q' is hydrogen or C₁-C₅ alkyl and is as defined in Claim 1. with an acylating agent to give a compound of the formula: wherein Q' and R each is as defined in Claim 1 and cyclizing the compound (III), and when Q is hydrogen, applying the cyclized product to alkylation, acylation or sulfonylation, if necessary. A pharmaceutical or veterinary formulation comprising a compound as claimed in any one of claims 1 to 5 formulated for pharmaceutical or veterinary use, respectively, optionally in unit dosage form and/or further comprising a pharmaceutically or veterinarily acceptable carrier, diluent or excipient. A compound as claimed in any one of claims 1 to 5 or a compound which has been prepared by a process as claimed in claim 6, for use in the treatment of disease. The use of a compound as claimed in any one of claims 1 to 5 or a compound which has been prepared by a process as claimed in claim 6, for the manufacture of a medicament for the treatment of anxiety or depression. A method of making a pharmaceutical or veterinary formulation which comprises mixing a compound as claimed in any one of claims 1 to 5 or a compound which has been prepared by a process as claimed in claim 6, with a pharmaceutically or veterinarily acceptable carrier, diluent or excipient. Claims for the following Contracting State : ES A process for the production of a pharmaceutically or veterinarily acceptable formulation which comprises admixing a compound of the formula: wherein R is isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, furyl, pyridyl or thienyl optionally substituted by one or two of halogen, C₁-C₅ alkyl and C₁-C₅ alkoxy; Q is hydrogen, C₁-C₅ alkyl, C₁-C₅ alkanoyl, C₇-C₁₁ aroyl, C₁-C₅ alkylsulfonyl or C₆-C₁₀ arylsulfonyl, R¹, R² and R⁴ are each independently hydrogen, halogen, C₁-C₅ alkyl, C₁-C₅ alkoxy or C₁-C₅ haloalkyl; R₃ is halogen, C₁-C₅ alkyl, C₁-C₅ alkoxy or C₁-C₅ haloalkyl; Q is present on the nitrogen atom at the 1, 3 or 5-position, and the dotted line indicates the presence of three double bonds at the position of 2, 3; 3a, 3b; 4, 5/1, 3b; 2, 3; 3a, 4/ or 1, 2; 3a, 3b; 4, 5 or an acid addition salt with one or more pharmaceutically or veterinarily acceptable carriers or diluents. A process for preparing a compound as claimed in claim 1, which comprises reacting a compound of the formula: wherein Q' is hydrogen or C₁-C₅ alkyl and is as defined in claim 1 with an acylating agent to give a compound of the formula: wherein Q' and R each is as defined in claim 1 and cyclizing the compound (III), and when Q is hydrogen, applying the cyclized product to alkylation, acylation or sulfonylation, if necessary. A process as claimed in claim 2 wherein the starting materials are chosen such that the resulting compound is 7-chloro-2-(2-thienyl)-1H-imidazo[4,5-c]-quinoline; 2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]quinoline; 7-fluoro-2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]-quinoline; or 8-fluoro-2-(3-methylisoxazol-5-yl)-1H-imidazo[4,5-c]-quinoline. A process as claimed in claim 2 or claim 3 wherein the resulting compound is isolated and admixed with one or more pharmaceutically or veterinarily acceptable carriers or diluents to form a pharmaceutically or veterinarily acceptable formulation. A process as claimed in claim 4 wherein the formulation is formed into unit dosage form. A process as claimed in claim 4 or claim 5 wherein the pharmaceutically or veterinarily acceptable formulation is for use in the treatment of anxiety or depression.

Inventors: EIGYO, MASAMI, FUJISHITA, TOSHIO, MATSUSHITA, AKIRA, SASATANI, TAKASHI, TAKADA, SUSUMU
Applicants: SHIONOGI & CO., LTD.
Application year: 1986
Main classification: C07D471
IPC codes: C07D495, C07D471