JPH0436156B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a novel amine having a chroman skeleton and a salt thereof. The amines and salts thereof provided by the present invention have an analgesic effect or are precursors of compounds having an analgesic effect, and are useful as analgesics or synthetic intermediates thereof. [Prior Art] Conventionally, it has been discovered that some compounds having a chroman skeleton have pharmacological effects. For example, 2,2,5,7,8-pentamethyl-6-(2-guanidinoethoxy)chroman has a hypotensive effect [Cesk,
Farm, Vol. 29, No. 5, p. 125 (1980)], and 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, and the like have a cholesterol-lowering effect (see JP-A-55-94382). Furthermore, vitamin E, which has a chroman skeleton, is known to be involved in various physiological actions in vivo. [Problem to be solved by the invention] Many analgesics such as aspirin are currently in clinical use, but this drug has superior analgesic effects and higher safety than the analgesics currently in clinical use. At present, there is a desire to develop new analgesics. One of the objects of the present invention is to provide a novel chroman compound that has excellent analgesic effect and is highly safe. Another object of the present invention is to provide a precursor of the novel chroman compound. [Means for solving the problem] According to the present invention, the above object is achieved by solving the general formula () (In the formula, R represents a hydrogen atom or a hydroxymethyl group. ^{R 1} represents a hydrogen atom or a lower alkyl group. ^{R 2} and R ³ are the same or different, a hydrogen atom,
Represents a lower alkyl group or a lower alkoxy group, or R ² and R ³ together represent -CH=CH-CH
Forms a =CH- group. R ⁴ represents a hydrogen atom or a protective group. n represents an integer from 0 to 2. ) or a salt thereof. R ¹ , R ² , R ³ and R ⁴ in the above general formula ()
will be explained in detail next. R ¹ represents a hydrogen atom or a lower alkyl group such as a methyl group, ethyl group, propyl group, butyl group. R ² and R ³ are the same or different and each represents a hydrogen atom; a lower alkyl group such as a methyl group, an ethyl group, a propyl group, or a butyl group; or a lower alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, or a butoxy group; or ^R2
and R ³ together form a -CH=CH-CH=CH- group. R ⁴ represents a hydrogen atom or a protective group.
As the protecting group, any commonly used protecting group may be used as long as it achieves the purpose of protecting the hydroxyl group.
For example, acyl groups such as acetyl group, propionyl group, butyryl group, benzoyl group, methyl group, t
-butyl group, triphenylmethyl group, benzyl group, trimethylsilyl group, etc. In addition, the salts of the amines represented by the general formula () are specifically pharmacologically acceptable salts, such as mineral acid salts such as hydrochlorides, hydrobromides, sulfates, and nitrates. Salts; salts of organic sulfonic acids such as p-toluenesulfonate, methanesulfonate; acetate, succinate, maleate, fumarate, citrate, tartrate, malate, benzoate Examples include salts of organic carboxylic acids such as. The amine represented by the general formula () is divided into the following two types depending on the substituent R. A method for producing the amine represented by general formula (-a) will be described below. First, the general formula () [In the formula, R ¹ , R ² , R ³ and n have the same meanings as in the general formula (), and R ⁵ is the same as or different from R ⁴ in the general formula () and represents a hydrogen atom or a protective group. ] By reacting the aldehyde represented by the formula with ammonium carbonate and an alkali metal cyanide, the general formula () is obtained. [In the formula, R ¹ , R ² , R ³ , R ₅ and n have the same meanings as in the general formula (). ] By obtaining a hydantoin represented by the formula () and then hydrolyzing the hydantoin, the general formula () is obtained. [In the formula, R ¹ , R ² , R ³ , R ⁵ and n have the same meanings as in the general formula (). ] An α-amino acid represented by the following is produced. here,
Examples of the alkali metal cyanide include sodium cyanide, potassium cyanide, and lithium cyanide. The reaction of the aldehyde represented by the general formula () with ammonium carbonate and an alkali metal cyanide can be carried out under conventionally known general hydantoin synthesis reaction conditions.
For example, an aldehyde represented by the general formula (), about 1 to 10 times the mole of this aldehyde, preferably about 1 to 3 times the mole of ammonium carbonate, and about 1 to 10 times the mole of the aldehyde, preferably about 1
~3 times the mole of alkali metal cyanide is reacted in a solvent such as water, methanol, ethanol, or tetrahydrofuran at a temperature of room temperature to 100°C, preferably 40 to 60°C, and then the resulting reaction mixture is concentrated. , add a small amount of concentrated hydrochloric acid to this concentrate and make about 80
A hydantoin represented by the general formula () can be obtained by reacting at ~100°C for about 1 to 10 minutes. The α-amino acid represented by the general formula () can be produced by hydrolyzing the hydantoin thus obtained according to a conventional method. In this hydrolysis reaction, for example, hydantoin and an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in an amount of about 1 to 5 times the mole of hydantoin are mixed in an aqueous solvent at 80 to 150°C, preferably 100 to 130°C.
The reaction is carried out at a temperature of .degree. C., and then the alkali present in the system is neutralized with a mineral acid such as hydrochloric acid or sulfuric acid. The thus obtained α-amino acid represented by the general formula () is heated under reflux in a solvent such as tetrahydrofuran using lithium aluminum hydride in an amount of about 1 to 3 times the mole of the α-amino acid. The amine represented by general formula (-a) can be produced by reduction. A salt of the amine represented by the general formula (-a) can be obtained by subjecting it to a conventionally known general salt-forming reaction. The amine represented by the general formula (-a) and its salt thus produced are separated and recovered by conventional methods. The amine represented by the general formula (-b) is an aldehyde represented by the general formula (), methyl alcohol,
By reacting about 1 to 2 times the mole of hydroxyamine with respect to the aldehyde in an aqueous alcohol such as ethyl alcohol under ice cooling or at a temperature below the general formula () [In the formula, R ¹ , R ² , R ³ , R ⁵ and n have the same meanings as in the general formula (). ] The oxime is obtained, and then the oxime is reduced under heating under reflux in a solvent such as tetrahydrofuran using about 0.75 to 2 times the mole of lithium aluminum hydride relative to the oxime. A salt of the amine represented by the general formula (-b) can be obtained by subjecting the amine represented by the general formula (-b) to a conventionally known general salt-forming reaction. The general formula (-b) and its salts thus obtained are separated and recovered by conventional methods. The aldehyde represented by the general formula () used as a raw material is a known compound represented by the following general formula ()
It can be easily obtained by oxidizing the alcohol represented by, for example, with chromic anhydride in the presence of pyridine [Helvetica Chimica Acta vol. 61, 837-
See page 843 (1978)]. Among amines and their salts represented by general formula (), amines in which R ⁴ in general formula () is a hydrogen atom, that is, general formula (') (In the formula, R, R ¹ , R ² , R ³ and n are as defined above.) Amines and salts thereof [hereinafter, these compounds are collectively referred to as amines (')]
has an excellent analgesic effect as is clear from the test examples described below. It was also confirmed that amine (') has low toxicity. For example, 2-amino-3-
(2,3-dihydro-6-hydroxy-2,5,
7,8-tetramethyl-2H-benzopyran-2
-yl)-1-propanol, (2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)methylamine hydrochloride and (2,3-dihydro- The acute toxicity value [LD ₅₀ (male mouse, oral)] of 6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)ethylamine hydrochloride is 2 g/Kg.
That's all. Amine (') as an analgesic can be administered by various methods such as intravenous injection, subcutaneous injection, intramuscular injection, etc., or oral administration, but particularly preferred are oral administration, It is an intravenous injection. When used for adults, the effective amount of amine (') is approximately 50 to
Doses can range from 2000 mg, preferably from about 100 to 500 mg. Analgesics can be prepared by appropriately selecting methods commonly used for preparing various preparations.
Suitable examples of oral preparations include tablets, granules, powders, hard capsules, soft capsules, and oral liquid preparations. Tablets and capsules for oral administration are fixed dose forms, with binders such as syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone and the like; excipients such as lactose, sugar, corn starch, calcium phosphate, etc. , sorbitol, glycine, etc.; lubricants such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants such as potato starch, calcium carboxymethyl cellulose, etc.; or acceptable wetting agents such as sodium lauryl sulfate. It's okay. The tablets may be coated by methods well known in the art. Coloring agents, flavoring agents, flavoring agents, etc. can be added as necessary. Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc., or they may be dry products that are redissolved in water or other suitable vehicle before use. . Such liquid formulations may contain commonly used additives such as suspending agents such as sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats, etc. emulsifiers such as lecithin, sorbitan monooleate, gum arabic, etc.; non-aqueous vehicles such as almond oil, fractionated coconut oil, oil esters, propylene glycol, ethyl alcohol, etc.; preservatives such as methyl p-hydroxybenzoate, p- - May contain propyl hydroxybenzoate, sorbic acid, etc. As an injectable preparation, it can be packaged in fixed-dose ampoules or in multi-dose containers with additives such as preservatives and solubilizing agents. The formulations may be suspensions, solutions, oily or aqueous emulsions and may contain additives such as suspending or dispersing agents. Among amines and their salts represented by the general formula (), the amines and their salts in which R ⁴ in the general formula () is a protecting group can be obtained by replacing the protecting group with a hydrogen atom using a conventional method. Derived from amines and their salts that have analgesic effects. [Examples] The present invention will be specifically explained below using Examples, Test Examples, and Formulation Examples. Note that the present invention is not limited to these Examples. Example 1 (1) A solution of 2.59 g of sodium carbonate in 6 ml of water and 50 ml of ethanol were added to a solution of 3.31 g of hydroxylamine hydrochloride in 3 ml of water, and then (6-benzyloxy-2,3-dihydro-2,5,7,8- Tetramethyl-2H-benzopyran-2-yl)
A solution of 15 g of carbaldehyde in 100 ml of ethanol was added dropwise under ice cooling. After the dropwise addition, vigorous stirring was continued at room temperature overnight. Brine was added to the resulting reaction solution, extracted with diethyl ether, and the extract was dried over anhydrous sodium sulfate. From this extract, low-boiling substances were distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl -2H-benzopyran-2-yl)carbaldoxime 14.0
g (yield 89.2%). (2) (6-benzyloxy-
14.0 g of 2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)carbaldoxime and 100 ml of tetrahydrofuran
A solution consisting of lithium aluminum hydride
It was added dropwise to a mixture of 2.4 g and 100 ml of tetrahydrofuran while heating under reflux. After the reaction, the resulting reaction solution was poured into ice water, made acidic with hydrochloric acid, and then extracted with methylene chloride. Low-boiling substances were distilled off from the extract, and an aqueous sodium hydroxide solution was added to the resulting residue, followed by extraction with diethyl ether.
After drying the extract with anhydrous sodium sulfate,
Hydrogen chloride gas was blown into the solution, and then low boilers were distilled off from the extract. The obtained residue was dissolved in methylene chloride, n-hexane was added little by little to this solution to reprecipitate it, and the precipitate was filtered and dried to form a compound (6-benzyloxy-2,3- dihydro-2,5,
7,8-tetramethyl-2H-benzopyran-
7.0 g of 2-yl)methylamine hydrochloride was obtained. FD mass spectrum: [M-HCl] ⁺ 325 NMR spectrum (98MHz) δ ^HMS _DMSO-d6 : 1.24 (s, 3H); 1.7-2.0 (m, 2H); 2.05, 2.09, 2.12 (each s, 9H); 2.4-2.7 (m, 2H); 2.8-3.1 (m, 2H); 4.61 (s, 2H); 7.3-7.6 (m, 5H) (3) (6-benzyloxy-
2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)methylamine hydrochloride 7.0 g, 5% palladium-carbon 1.0
A mixture of 20 ml of 2N hydrochloric acid and 100 ml of ethanol was stirred overnight at room temperature under a hydrogen atmosphere. Palladium-carbon was separated from the reaction solution, and the solution was concentrated. The obtained residue was dissolved in ethanol, and n-hexane was gradually added to this solution to cause reprecipitation. By filtering and drying the formed crystals, (2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)methylamine hydrochloride having the following physical properties is obtained. 4.3g of salt was obtained. FD mass spectrum: [M-HCl] ⁺ 235 NMR spectrum (90MHz) δ ^HMS _DMSO-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) Example 2 (1) In Example 1-(1), instead of 15 g of (6-benzyloxy-2,5,7,8-tetramethyl-2,3-dihydro-2H-benzopyran-2-yl)carbaldehyde, (6 The reaction and reaction were carried out in the same manner as in Synthesis Example 1-(1), except that 15.7 g of -benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetaldehyde was used. By performing separation and recovery, (6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-
benzopyran-2-yl)acetaldoxime
16.0g was obtained. (2) (6-benzyloxy-
15.0 g of 2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetaldoxime and 100 g of tetrahydrofuran
ml mixture of lithium aluminum hydride
It was added dropwise to a mixture of 2.42 g and 100 ml of tetrahydrofuran while heating under reflux. After the reaction, the resulting reaction solution was poured into ice water, made acidic with hydrochloric acid, and then extracted with methylene chloride. After drying the extract, low-boiling substances were distilled off, and an aqueous sodium hydroxide solution was added to the resulting residue, followed by extraction with diethyl ether. By drying and concentrating the ether extract, 2-
(6-benzyloxy-2,3-dihydro-2,
5,7,8-Tetramethyl-2H-benzopyran-2-yl)ethylamine was obtained. FD mass spectrum: [M] ⁺ 339 NMR spectrum (90MHz) δ ^HMS _CDCl3 : 1.17 (s, 3H); 1.5-2.0 (m, 4H); 1.92 (s, 3H); 2.07 (s, 3H); 2.14 ( s, 3H); 2.3-2.6 (m, 2H); 4.0-4.4 (m, 2H); 4.62 (s, 2H) 7.2-7.5 (m, 5H) (3) 2- obtained in (2) above (6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)ethylamine, 5% palladium-carbon 1.0 g, 2N-
A mixture of 20 ml of hydrochloric acid and 100 ml of ethanol was stirred overnight at room temperature under a hydrogen atmosphere. After the reaction, palladium-carbon was separated from the reaction solution, and the solution was concentrated under reduced pressure. The obtained residue was dissolved in ethanol, and n-hexane was gradually added to this solution to cause reprecipitation. The resulting crystals were filtered, washed with n-hexane, and then dried under reduced pressure to obtain 2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetra) having the following physical properties. methyl-2H-benzopyran-2-yl)
8.6g of ethylamine hydrochloride was obtained. FD mass spectrum: [M-HCl] ⁺ 249 NMR spectrum (90MHz) δ ^HMS _D2O : 1.24 (s, 3H); 1.6-2.0 (m, 4H); 2.03, 2.06.2.09 (each s, 9H); 2.4- 2.8 (m, 2H); 2.8-3.2 (m, 2H) Example 3 (1) (6-benzyloxy-2,3-dihydro-
14 ml of water, 4.52 g of ammonium carbonate and 0.98 g of sodium cyanide were added to a solution of 3.38 g of 2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetaldehyde and 25 ml of ethanol, and the mixture was heated at 50 to 55°C. The mixture was heated and stirred for 4 hours. The resulting reaction solution was concentrated under reduced pressure, and 2 ml of concentrated hydrochloric acid was added to it.
was added and heated at 90°C for 5 minutes. Cool the reaction solution, add water to it, filter the formed precipitate,
After washing with water and diethyl ether,
By drying under reduced pressure, 5-[(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-) having the following physical properties was obtained.
3.42g of benzopyran-2-yl)methyl]imidazolidine-2,4-dione was obtained (yield: 83.8
%). FD mass spectrum: [M] ⁺ 408 NMR spectrum (90MHz) δ ^HMS _DMSO-d6 : 1.21 (s, 3H); 1.5-2.7 (m, 15H); 3.26 (s, 2H); 4.0-4.3 (m, 1H) ); 4.6 (s, 2H); 7.25-7.6 (m, 5H) (2) 5-[(6-benzyloxy-2,3-dihydro-2,5,7,8 A mixture of 3.15 g of -tetramethyl-2H-benzopyran-2-yl)methyl imidazolidine-2,4-dione, 1.6 g of sodium hydroxide, and 30 ml of water was heated at 120°C for 15 hours in a sealed tube. Stirred. Water was added to the resulting reaction solution, filtered to remove insoluble matter, the solution was washed with diethyl ether, and the aqueous layer was neutralized with dilute hydrochloric acid. The formed precipitate was filtered, washed with water and diethyl ether, and then dried under reduced pressure to obtain β-(6-benzyloxy-
2.41 g of 2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)alanine was obtained (yield 78.7%). FD mass spectrum: [M] ⁺ 383 NMR spectrum (90MHz) δ ^HMS _DMSO-d6 : 1.2 (s, 3H); 1.5-2.7 (m, 15H); 3.8-4.1 (m, 1H); 4.59 (s, 2H) ); 7.25-7.57 (m, 5H); 7.6-9.5 (br.s,
3H) (3) 2.30 g of β-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)alanine obtained in (2) above. Dissolve in 200 ml of ethanol, add 12 ml of 1N hydrochloric acid and 5% palladium/
2.0 g of activated carbon was added, and the mixture was stirred at room temperature for 2 days under a hydrogen atmosphere. The resulting reaction solution was filtered, water was added to the solution, and then low-boiling substances were distilled off from the solution under reduced pressure. By dissolving the residue in ethanol and recrystallizing it by adding diethyl ether, β-
(2,3-dihydro-6-hydroxy-2,5,
7,8-tetramethyl-2H-benzopyran-
1.21 g of crystals of 2-yl)alanine hydrochloride were obtained (yield 61.2%). FD mass spectrum: [M-HCl] ⁺ 293 NMR spectrum (90MHz) δ ^HMS _DMSO-d6 : 1.5 (s, 3H); 1.6-2.65 (m, 15H); 3.8-4.1 (m, 1H); 7.4 (br .s, 1H); 8.5 (br.s, 3H) (4) A mixture of 0.46 g of lithium aluminum hydride and 30 ml of tetrahydrofuran was heated to reflux, and β- obtained in the same manner as in (3) above was added. (2,
3-dihydro-6-hydroxy-2,5,7,
8-tetramethyl-2H-benzopyran-2-
3.0 g of alanine hydrochloride was added little by little.
The resulting reaction solution was poured into a small amount of water, made acidic with hydrochloric acid, and then washed with diethyl ether. The aqueous layer was concentrated under reduced pressure, and the resulting residue was extracted with ethanol. The ethanol extract was neutralized with aqueous sodium bicarbonate and concentrated under reduced pressure. The resulting residue was extracted with methylene chloride, the extract was dried, and low-boiling substances were distilled off from the extract under reduced pressure to obtain 2-amino-3-(2,
3-dihydro-6-hydroxy-2,5,7,
8-tetramethyl-2H-benzopyran-2-
1.05g of yl)-1-propanol was obtained. FD mass spectrum: [M] ⁺ 279 NMR spectrum (90MHz) δ ^HMS _D2O : 1.36 (s, 3H); 1.8-2.2 (m, 4H); 2.15, 2.17, 2.22 (each s, 9H); 2.6-2.9 ( m, 2H); 3.7 to 4.1 (m, 3H) Examples 4 to 10 In Example 3-(1), (6-benzyloxy-2,3-dihydro-2,5,7,8-
Tetramethyl-2H-benzopyran-2-yl)
The corresponding hydantoins were obtained by carrying out the reaction and separation and recovery in the same manner as in Example 3-(1), except that 10 mmol of the aldehyde shown in Table 1 was used instead of 3.38 g (10 mmol) of acetaldehyde. The results are shown in Table 1.

【table】

[Table] In Example 3-(2), 5-[(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)methyl]
3.15g imidazolidine-2,4-dione
The reaction and separation and recovery were carried out in the same manner as in Example 3-(2), except that 7.7 mmol of the hydantoin shown in Table 2 obtained by the same method as above was used instead of (7.7 mmol). The corresponding α-amino acid was obtained. The results are shown in Table 2.

【table】

[Table] In Example 3-(3), β-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)alanine 2.30 g (6 mmol) Instead of α-amino acids shown in Table 3 obtained by the same method as above,
The corresponding hydrochloride of the α-amino acid was obtained by carrying out the reaction and separation and recovery in the same manner as in Example 3-(3) except that 6 mmol was used. The results are shown in Table 3. In addition, the reaction in Example 6 is 5
The same procedure as in Example 3-(3) was followed except that the reaction was carried out in the absence of % palladium/activated carbon in a nitrogen atmosphere.

【table】

[Table] In Example 3-(4), β-[2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)alanine hydrochloride 3.0 Carry out the reaction and separation and recovery in the same manner as in Example 3-(4), except that 9.1 mmol of the amino acid hydrochloride shown in Table 4 obtained by the same method as above was used instead of g (9 mmol). The corresponding amines were obtained. The results are shown in Table 4.

【table】

[Table] Test Examples 1 to 4 For the following compound groups of the present invention and aspirin as a control, 10 ddY male mice were used in each group, and the acetic acid writing method [Koster etal.Federation]
Proc., vol. 18. 412 (1959)]). The results are shown in Table 5. Compound (1) (2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)
Methylamine hydrochloride Compound (2) 2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)ethylamine hydrochloride Compound (3) 2-amino -3-(2,3-dihydro-6-hydroxy-2,5,7,
8-tetramethyl-2H-benzopyran-2-yl)-1-propanol

〔Effect of the invention〕

R ⁴ in the general formula () provided by the present invention
As is clear from the results of the above-mentioned test examples, amines in which is a hydrogen atom and salts thereof have superior analgesic effects to aspirin and are less toxic. Further, as is clear from the Examples, the amines and salts thereof provided by the present invention in which R ⁴ in the general formula () is a protecting group can be easily derived into the amines and salts thereof having the above-mentioned analgesic effect.

Claims (1)

[Claims] 1. General formula (In the formula, R represents a hydrogen atom or a hydroxymethyl group. ^{R 1} represents a hydrogen atom or a lower alkyl group. ^{R 2} and R ³ are the same or different, a hydrogen atom,
Represents a lower alkyl group or a lower alkoxy group, or R ² and R ³ together represent -CH=CH-CH
Forms a =CH- group. R ⁴ represents a hydrogen atom or a protective group. n represents an integer from 0 to 2. ) An amine or a salt thereof.