CHROMAN COMPOUNDS AND THEIR USE

Abstract: Novel chroman compounds which have excellent antiox­ idant activity and/or analgesic activity or serve as precursors for such active compounds are provided. There are also provided uses of these active compounds as an antioxidant and/or analgesic.

Description: This invention relates to novel chroman compounds, and to the use of these compounds as analgesics or precursors for the compounds having analgesic activity. It is known that compounds having a chroman skeleton such as 2-(N,N-dimethylamino)ethyl 2-(2,2,5,7,8-pentamethyl-6-chromanyloxy)isobutyrate, 2-(2,2,5,7,8-pentamethyl-6-chromanyloxy)isobutyl nicotinate, etc. have cholesterol lowering activity [Japanese Laid-Open Patent Publication No. 94382/1980] JP-A-57 145 871 describes a chromanolcarboxylic acid derivative of formula wherein R is a hydrogen atom or a lower alkyl group and an antioxidant containing said derivative as an active ingredient. In E.Schröder, C.Rufer, R.Schmiechen (Hrsg.), Pharmazeutische Chemie, Verlag G.Thieme, 1982, page 639, it is described that α-tocopherol (vitamine E) has an antioxidant and an antithrombic activity. US-A-4321270 describes chroman derivatives of formula and salts and hydrates thereof which are useful as anti-inflammatory agents, for inhibition of blood platelet aggregation, as antiallergy and as antihypertensive agents. It is an object of the invention to provide novel chroman compounds which are either analgesics or useful as precursors for such analgesic compounds. It is a further object of the invention to provide pharmaceutical compositions which contain the chroman compounds as active ingredients for use as analgesics. In accordance with this invention, there are provided compounds of general formula (I) wherein R is a hydrogen atom or a hydroxymethyl or carboxyl group, R¹ is a hydrogen atom or a C₁-C₄ alkyl group, R² and R³ are the same or different and each is a hydrogen atom or a C₁-C₄ alkyl or alkoxy group or R² and R³ combinedly represent a -CH=CH-CH=CH- group, R⁴ is a hydrogen atom or a protective group and n is an integer of 0-2, inclusive of the ester and/or salt forms thereof [hereinafter collectively referred to as "chroman compounds (I)"]. Further in accordance with this invention, there are provided pharmaceutical compositions with analgesic activity said compositions being composed of (1) an analgetically effective amount of a compound of general formula (I-2) therein R, R¹, R², R³ and n are as defined above relative to general formula (I), inclusive of the pharmaceutically acceptable ester and/or salt forms thereof [hereinafter collectively referred to as "chroman compounds (I-2)"], and (2) a pharmaceutically acceptable diluent or carrier. Referring to the above general formula (I), R is a hydrogen atom or a hydroxymethyl or carboxyl group. R¹ is a hydrogen atom or a lower alkyl group such as methyl, ethyl, propyl or butyl, R² and R³ are the same or different and each is a hydrogen atom, a lower alkyl group such as methyl, ethyl, propyl or butyl, or a lower alkoxy group such as methoxy, ethoxy, propoxy or butoxy, or R² and R³ combinedly form a -CH=CH-CH=CH-group. R⁴ is a hydrogen atom or a protective group. Said protective group may be any of conventional protective groups if only protection of hydroxyl group can be attained, and may be exemplified by acyl groups (e.g. acetyl, propionyl, butyryl or benzoyl), methyl, tert-butyl, triphenylmethyl, benzyl or trimethylsilyl, n is an integer of 0-2. The compounds of general formula (I) may be grouped, according to the substituent R, into the following three classes: The esters and salts of the α-amino acids of general formula (I-a) include such ester forms as an alkyl ester, e.g. methyl ester, ethyl ester, propyl ester, butyl ester, octyl ester, tetradecyl ester or stearyl ester; and such salt forms as an alkali metal salt, e.g. lithium salt, sodium salt or potassium salt, or a mineral acid salt, e.g. hydrochloride, sulfate or nitrate, or an organic sulfonic acid salt, e.g. p-toluenesulfonate or methanesulfonate. The α-amino acids of general formula (I-a) can be produced by reacting an aldehyde of general formula wherein R¹, R², R³ and n each have the same meanings as in general formula (I), and R⁵ is the same as or different from R⁴ in general formula (I) and represents a hydrogen atom or a protective group, with ammonium carbonate and an alkali metal cyanide and then hydrolyzing the thus-obtained hydantoin of general formula wherein R¹, R², R³, R⁵ and n each have the same meanings as in general formula (II). Said alkali metal cyanide is, for example, sodium cyanide, potassium cyanide or lithium cyanide. The reaction of the aldehyde of general formula (II) with ammonium carbonate and the alkali metal cyanide can be carried out under conditions which are generally known to be adequate for hydantoin syntheses. Thus, for instance, the aldehyde of general formula (II), about 1-10 moles, preferably about 1-3 moles, per mole of aldehyde, of ammonium carbonate and about 1-10 moles, preferably about 1-3 moles, per mole of aldehyde, of the alkali metal cyanide are reacted in a solvent such as water, methanol, ethanol or tetrahydrofuran, at a temperature between room temperature and 100°C, preferably in the range of 40-60°C. The reaction mixture is then concentrated, a small amount of concentrated hydrochloric acid is added to the concentrate, and the mixture is heated at about 80-100°C for about 1-10 minutes, whereby the hydantoin of general formula (III) is obtained. Hydrolysis of the thus-obtained hydantoin by the conventional method gives the α-amino acid of general formula (I-a). The hydrolysis is carried out, for example, by reacting the hydantoin and about 1-5 moles, per mole of hydantoin, of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in an aqueous medium at a temperature of 80-150°C, preferably 100-130°C, followed by neutralization of the alkali being in the system with a mineral acid such as hydrochloric acid or sulfuric acid. When subjected to the generally known esterification and/or salt formation reaction, the α-amino acids of general formula (I-a) are converted to esters or salts of said α-amino acids or salts of said α-amino acid esters. Thus, for example, reacting the α-amino acids of general formula (I-a) with an alkyl alcohol such as methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, octyl alcohol or stearyl alcohol, in the presence of hydrogen chloride, sulfuric acid or thionyl chloride in an amount at least equivalent to said α-amino acid at about -20°C to +40°C, followed by neutralization of the reaction mixture, for example, with an aqueous sodium bicarbonate, gives the corresponding α-amino acid ester. The α-amino acid of general formula (I-a) or esters thereof are converted to the corresponding salts by dissolving said α-amino acids or esters thereof in water, methyl alcohol, ethyl alcohol, propyl alcohol, tetrahydrofuran or diethyl ether and then adding to the solution an approximately equivalent amount, to the α-amino acid or ester thereof, of a mineral acid such as hydrogen chloride, sulfuric acid, nitric acid, or an organic sulfonic acid such as p-toluenesulfonic acid or methanesulfonic acid, or an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide. The α-amino acid of general formula (I-a) or esters thereof, inclusive of salt forms produced in the above manner can be separated and recovered by any of the methods generally known for the separation and recovery of amino acids and esters thereof, and salts thereof. When in the salt form, the α-amino acids of general formula (I-a) and esters thereof are fairly soluble, so that separation of the salts from fat-soluble impurities from the reaction process can be done with ease. The salts deprived of fat-soluble impurities can be converted to highly pure α-amino acids by the conventional neutralization with an acid such as hydrochloric acid, sulfuric acid, etc. These α-amino acids can further be converted to highly pure esters of said α-amino acids by subjecting the acids to the conventional esterification. The amino alcohols of general formula (I-b) can be produced by reducing the α-amino acids of general formula (I-a), for example, with about 1-3 moles, per mole of α-amino acid , of lithium aluminium hydride in a solvent such as tetrahydrofuran, under refluxing. The amino alcohols of general formula (I-b), when subjected to per se known general esterification and/or salt formation reaction, give esters or salts of said amino alcohols, or salts of the ester. The amino alcohols of general formula (I-b) and esters thereof and their salts thus obtained can be separated and recovered by conventional methods. The amines of general formula (I-c) can be produced by reacting the aldehyde of general formula (II) with about 1-2 moles, per mole of aldehyde, of hydroxyamine in an aqueous alcohol such as methyl alcohol, ethyl alcohol, etc. at a temperature of 0°C to room temperature and then reducing the thus-obtained oxime of general formula wherein R¹, R², R³, R⁵ and n each have the same meanings as in general formula (II), for example, with about 0.75-2 moles, per mole of oxime, of lithium aluminium hydride in a solvent such as tetrahydrofuran under refluxing. The amines of general formula (I-c), when subjected to per se known general salt formation reaction, give salts of said amine. The thus-obtained amines and salts thereof can be separated and recovered by conventional methods. The starting aldehydes of general formula (II) can be prepared easily by oxidizing alcohols of general formula (V) given below, which are known compounds, for example, with chromic anhydride in the presence of pyridine [cf. Helvetica Chimica Acta, 61 , 837-843 (1978)]. Among the chroman compounds (I), the chroman compounds (I-2) show excellent analgesic activity. In addition, these compounds have low toxicity. For example, β-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl) alanine hydrochloride has such low acute toxicity that the LD₅₀ value (oral administration) is 2,624 g/kg for male mice. So, the chroman compounds (I-2) can be used as analgesics. Among the chroman compounds (I-2), the pharmaceutically acceptable esters of the compounds in which R in general formula (I-2) is a hydroxymethyl group include such ester forms as a lower fatty acid ester, e.g. acetic acid ester or propionic acid ester; a higher fatty acid ester, e.g. palmitic acid ester or oleic acid ester; a phosphoric acid ester or an ester of monomannosyl phosphate And the pharmaceutically acceptable esters of the compounds in which R in general formula (I-2) is a carboxyl group include such ester forms as an alkyl ester, e.g. methyl ester, ethyl ester, propyl ester, butyl ester, octyl ester, tetradecyl ester or stearyl ester. The pharmaceutically acceptable salts of the compounds of general formula (I-2) include such salt forms as an alkali metal salt, e.g. lithium salt, sodium salt or potassium salt; hydrochloride, nitrate or methanesulfonate. The compounds in which R⁴ is a protective group in general formula (I) can be converted to the above-mentioned analgesic chroman compounds (I-2) by replacing the protective group with a hydrogen atom by the conventional method. The pharmaceutical compositions of the invention which contain the chroman compounds as analgesics can be formulated into various dosage forms by using means known per se . For example, the dosage forms may be those suitable for oral administration such as tablets, granules, powders, coated tablets, hard capsules, soft capsules and oral liquid preparations and those suitable for injection such as suspensions, liquid preparations, and oily or aqueous emulsions. The pharmaceutical compositions of the invention may contain various pharmaceutically acceptable liquid or solid diluents or carriers known per se . Examples of such diluents or carriers include syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, magnesium stearate, talc, polyethylene glycol, silica, lactose, sucrose, corn starch, calcium phosphate, glycine, potato starch, calcium carboxymethylcellulose, sodium laurylsulfate, water, ethanol, glycerol, mannitol and phosphate buffer. The pharmaceutical compositions of the invention may further include adjuvants conventionally used in the field of pharmaceutical production, such as coloring agents, flavors, corrigents, antiseptics, dissolution aids, suspending agents and dispersing agents. The pharmaceutical compositions of the invention may be in a form filled in a large dosage container as well as in a fixed dosage form such as tablets, capsules, coated tablets or ampoules as exemplified hereinabove. The pharmaceutical compositions of the invention contain an analgetically effective amount of a compound of general formula (I-2) and its pharmaceutically acceptable ester and/or salt. Its dosage can be varied properly depending upon the condition of the subject, the purpose of administration, etc. For example, it is about 50 to about 2,000 mg, preferably about 100 to about 500 mg, per day for an adult. The pharmaceutical compositions of the invention can be administered through various routes, for example, orally or by injection (e.g., intravenous, subcutaneous, intramuscular). Oral administration and intravenous injection are especially preferred. The following examples, test examples and formulation examples illustrate the invention in more detail. It is to be noted, however, that these examples, test examples and formulation examples are by no means limitative of the invention. (1) To a solution of 3.38 g of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)acetaldehyde in 25 ml of ethanol, there were added 14 ml of water, 4.52 g of ammonium carbonate and 0.98 g of sodium cyanide, followed by heating at 50-55°C with stirring for 4 hours. The reaction mixture was concentrated under reduced pressure, 2 ml of concentrated hydrochloric acid was added to the residue, and the mixture was heated at 90°C for 5 minutes. The reaction mixture was cooled, water was added, and the resulting precipitate was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 3.42 g (83.8% yield) of 5-[(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)methyl]imidazolidine-2,4-dione characterized by the following: (2) A mixture of 3.15 g of 5-[(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)methyl]imidazolidine-2,4-dione obtained by the above procedure (1), 1.6 g of sodium hydroxide and 30 ml of water was heated with stirring in a sealed tube at 120°C for 15 hours. Water was then added to the reaction mixture, the insoluble matter was filtered off, the filtrate was washed with diethyl ether, and the aqueous layer was neutralized with diluted hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give 2.41 g (78.7% yield) of β-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)alanine characterized by the following: (3) β-(6-Benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benopyranyl)alanine (2.30 g) obtained by the above procedure (2) was dissolved in 200 ml of ethanol, followed by addition of 12 ml of 1 N hydrochloric acid and 2.0 g of 5% palladium-on-activated carbon. The mixture was stirred at room temperature in a hydrogen atmosphere for 2 days. The reaction mixture was filtered, water was added to the filtrate, and low boiling components were distilled off under reduced pressure. The residue was dissolved in ethanol, followed by recrystallization by addition of diethyl ether. There was thus obtained 1.21 g (61.2% yield) of crystalline β-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)alanine hydrochloride characterized by the following: Using 3.52 g of 3-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)propionaldehyde in place of 3.38 g of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)acetaldehyde, the procedure of Example 1-(1) was followed for reaction, separation and recovery. There was obtained 3.17 g (75.1% yield) of 5-[2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)ethyl]imidazolidine-2,4-dione characterized by the following: The procedure for reaction, separation and recovery as described in Example 1-(2) was followed except that 3.26 g of 5-[2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)ethyl]imidazolidine-2,4-dione was used in place of 3.15 g of 5-[(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)methyl]imidazolidine-2,4-dione. There was obtained 2.41 g (78.6% yield) of 2-amino-4-[2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)butyric acid characterized by the following: The procedure for reaction, separation and recovery as described in Example 1-(3) was followed except that 2.38 g of 2-amino-4-[2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)]butyric acid was used in place of 2.30 g of β-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)alanine. There was obtained 1.26 g (61.1% yield) of crystalline 2-amino-4-[2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)] butyric acid hydrochloride characterized by the following: FD mass spectrum: [M] + 307 Examples 3 - 10 The procedure for reaction, separation and recovery as described in Example 1-(1) was followed using 10 millimoles of each aldehyde specifically given in Table 1 in place of 3.38 g (10 mmol) of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)acetaldehyde, to give the corresponding hydantoin. The results thus obtained are shown in Table 1. The procedure for reaction, separation arid recovery as described in Example 1-(2) was followed using 7.7 millimoles of each hydantoin specifically given in Table 2 as obtained by the same method as above in place of 3.15 g (7.7 mmol) of 5-[(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)methyl]imidazolidine-2,4-dione, to give the corresponding α-amino acid. The results thus obtained are shown in Table 2. The procedure for reaction, separation and recovery as described in Example 1-(3) was followed using 6 millimoles of each α-amino acid specifically given in Table 3 as obtained by the same method as above in place of 2.30 g (6 mmol) of β-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)alanine, to give the corresponding α-amino acid hydrochloride. The results thus obtained are shown in Table 3. To a mixture of 0.36 g of lithium aluminium hydride and 30 ml of tetrahydrofuran was added by portions 2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)alanine hydrochloride under refluxing. The reaction mixture was poured into a small amount of water, acidified with hydrochloric acid, and washed by diethyl ether. The aqueous layer was concentrated under reduced pressure and the residue was extracted with ethanol. The ethanol extract was basified with aqueous sodium bicarbonate and concentrated under reduced pressure. The resultant residue was extracted with dichloromethane and the extract was dried and evaporated under reduced pressure to give 1.05 g of 2-amino-3-[2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)]-1-propanol characterized by the following: (1) To a mixture of 3.31 g of hydroxyamine hydrochloride in 3 ml of water, 2.59 g of sodium carbonate in 6 ml of water and 50 ml of ethanol, there was added 15.7 g of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)acetaldehyde in 100 ml of ethanol on ice bath, and the resulting mixture was stirred at room temperature overnight. Saturated aqueous solution of sodium chloride was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The ether extract was dried with anhydrous sodium sulfate and evaporated to give 16.0 g of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)acetaldoxime. (2) A solution of 15.0 g of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)acetaldoxime obtained by the above procedure (1) in 100 ml of tetrahydrofuran was added to a mixture of 2.42 g of lithium aluminium hydride and 100 ml of tetrahydrofuran under refluxing. After the reaction was completed, the reaction mixture was poured into ice-water, acidified with hydrochloric acid, and extracted with dichloromethane. The extract was dried and evaporated under reduced pressure. Aqueous solution of sodium hydroxide was added to the resultant residue, and the resulting mixture was extracted with diethyl ether. The ether extract was dried and evaporated to give 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)ethylamine characterized by the following: (3) A mixture of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)ethylamine obtained by the above procedure (2), 1.0 g of 5% palladium-on-activated carbon, 20 ml of 2 N hydrochloric acid and 100 ml of ethanol was stirred at room temperature overnight under hydrogen atmosphere. After the reaction was competed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol, and precipitated by addition of n-hexane. The precipitate was collected by filtration, washed with n-hexane and dried to give 8.6 g of 2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl) ethylamine hydrochloride characterized by the following: (1) To a mixture of 3.31 g of hydroxyamine hydrochloride in 3 ml of water, 2.59 g of sodium carbonate in 6 ml of water and 50 ml of ethanol, there was added 15 g of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)carbaldehyde in 100 ml of ethanol on ice bath, and the resulting mixture was vigorously stirred at room temperature overnight. Saturated aqueous solution of sodium chloride was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The extract was dried with anhydrous sodium sulfate and evaporated, and the residue was purified by silica gel column chromatography to give 14 g of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)carbaldoxime. (2) A solution of 14 g of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)carbaldoxime obtained by the above procedure (1) in 100 ml of tetrahydrofuran was added to a mixture of 2.4 g of lithium aluminium hydride and 100 ml of tetrahydrofuran under refluxing. After the reaction was completed, the reaction mixture was poured into ice-water, acidified with hydrochloric acid, and extracted with dichloromethane. The extract was dried and evaporated under reduced pressure. Aqueous solution of sodium hydroxide was added to the resultant residue, and the resulting mixture was extracted with diethyl ether. The ether extract was dried, and hydrogen chloride was bubbled into the extract. After evaporation under reduced pressure, the resultant residue was dissolved in dichloromethane and precipitated by addition of n-hexane. The precipitate was collected by filtration and dried to give 7.0 g of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)methylamine hydrochloride characterized by the following: (3) A mixture of 7.0 g of 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)methylamine hydrochloride obtained by the above procedure (2), 1.0 g of 5% palladium-on-activated carbon, 20 ml of 2N hydrochloric acid and 100 ml of ethanol was stirred at room temperature overnight under hydrogen atmosphere. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol, and precipitated by addition of n-hexane. The precipitate was collected by filtration and dried to give 4.3 g of 2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)methylamine hydrochloride characterized by the following: NMR spectrum (90 MHz) δ HM / DM S / SO -d6 : 1.27 (s, 3H); 1.6-1.9 (m, 2H); 2.01 (s, 6H); 2.03 (s, 3H); 2.4-2.6 (m, 2H); 2.8-3.1 (m, 2H) Test Example 1 Pharmacological tests β-(2,3-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)alanine hydrochloride was evaluated for analgesic activity in the writhing test [cf. Koster et al., Fed. Proc., 18 , 412 (1959)], local anesthetic activity in the tail pinch test [cf. Bianchi, C., Brit. J. Pharmacol., 11 , 104 (1956)] and bronchodilator activity in lung perfusion [cf. Luduena, F. P., Arch. Int. Pharmacodyn., 111 , 392 (1957)]. The results are shown in Table 4. β-(2,3-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)alanine hydrochloride is active in the test for analgesic activity causing 84% inhibition of writhing, and also demonstrated a local anesthetic activity. An inhibition of isoprenaline-induced bronchodilation is also observed. Test Examples 2-5 Analgesic activity testing β-(23-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)alanine hydrochloride [referred to as "Compound (1)"], 2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)methylamine hydrochloride [referred to as "Compound (2)"], 2-amino-3-(2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)]-1-propanol [referred to as "Compound (3)"] and Aspirin were evaluated for analgesic activity. Male ddY strain mice in groups of ten each were used for the evaluation of analgesic activity by acetic acid writhing test [Koster et al., Federation Proc., 18 , 412 (1959)]. The results are shown in Table 5. Specific examples of formulating the analgesic of the invention are shown below. It should be understood, however, that these examples are not limitative. Formulation Example 1 Injectable preparation:- Compound (1) (100 mg) was dissolved in 3 ml of physiological saline and put aseptically in a 3 ml. ampoule. The ampoule was sealed up by melting and heat sterilized to form an injectable preparation which was aseptic and did not contain a pyrogenetic substance. The above ingredients were mixed and directly tableted by a tableting machine to form tablets each weighing 300 mg.

Claims: Compounds of the general formula wherein R is a hydrogen atom or a hydroxymethyl or carboxyl group, R¹ is a hydrogen atom or a alkyl C₁-C₄ alkyl group, R² and R³ are the same or different and each is a hydrogen atom or a C₁-C₄ alkyl or alkoxy group or R² and R³ combinedly represent a -CH=CH-CH=CH- group, R⁴ is a hydrogen atom or a protective group and n is an integer of 0-2, or their esters or salts. The compounds of Claim 1, which are compounds of the general formula wherein R is a hydrogen atom or a hydroxymethyl or carboxyl group, R¹ is a hydrogen atom or a C₁-C₄ alkyl group, R² and R³ are the same or different and each is a hydrogen atom or a C₁-C₄ alkyl or alkoxy group or R² and R³ combinedly represent a -CH=CH-CH=CH- group and n is an integer of 0-2, or their esters or salts. The compounds of Claim 2, wherein R¹, R² and R³ in the general formula each are a methyl group. A compound of Claim 3, which is β-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl) alanine or a salt thereof. A compound of Claim 3, which is 2-amino-4-[2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)]butyric acid or a salt thereof. A compound of Claim 3, which is 2-amino-3-[2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)]-1-propanol or a salt thereof. A compound of Claim 3, which is 2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)ethylamine or a salt thereof. A compound of Claim 3, which is 2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyranyl)methylamine or a salt thereof. Pharmaceutical compositions which are composed of (1) an analgetically effective amount of a compound of the general formula wherein R is a hydrogen atom or a hydroxymethyl or carboxyl group, R¹ is a hydrogen atom or a C₁-C₄ alkyl group, R² and R³ are the same or different and each is a hydrogen atom or a C₁-C₄ alkyl or alkoxy group or R² and R³ combinedly represent a -CH=CH-CH=CH- group and n is an integer of 0-2, or its pharmaceutically acceptable ester or salt and (2) a pharmaceutically acceptable diluent or carrier. Pharmaceutical compositions with analgesic activity which are composed of (1) an analgetically effective amount of a compound of the general formula wherein R is a hydrogen atom or a hydroxymethyl or carboxyl group, R¹ is a hydrogen atom or a C₁-C₄ alkyl group, R² and R³ are the same or different and each is a hydrogen atom or a C₁-C₄ alkyl or alkoxy group or R² and R³ combinedly represent a -CH=CH-CH=CH- group and n is an integer of 0-2, or its pharmaceutically acceptable ester or salt and (2) a pharmaceutically acceptable diluent or carrier.

Inventors: FUJITA, YOSHIJI, NISHIDA, TAKASHI, SHIONO, MANZO
Applicants: KURARAY CO., LTD.
Application year: 1984
Main classification: C07D311
IPC codes: C09K15, C07D311