JP3255411B2 - Hair growth promoter - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a hair growth promoting agent containing one or more benzopyran derivatives or pharmaceutically acceptable salts thereof having an excellent hair growth promoting effect.

INDUSTRIAL APPLICABILITY The present invention is used in the field of medicine or cosmetics for alopecia areata, alopecia areata, postpartum alopecia and androgenetic alopecia due to anticancer agents. Further, it is also used as a hair growth promoter in fields requiring hair and fur such as sheep and mink.

BACKGROUND ART Alopecia is roughly classified into congenital alopecia and acquired alopecia. Of these, acquired alopecia is broadly classified into those with scars and those without skin lesions. Furthermore, alopecia without scars and skin lesions is alopecia due to drugs, traumatic alopecia, alopecia due to malnutrition and metabolic disorders, and hair loss telogen due to endocrine abnormalities (hair loss after high fever, postpartum hair loss) androgenetic alopecia The disease is divided into seven. Most of the conventional hair restorer or hair restorer only targets male pattern baldness.

The physiological characteristics of androgenetic alopecia are as follows. First, testosterone, the main body of the male hormone, is activated by 5α-reductase in the hair follicle cells, the target organ, and 5α-dihydrotestosterone (hereinafter, referred to as “the male hormone”).
5α-DHT). This 5α-DHT binds to an intracellular receptor and acts on the nucleus to suppress the division of hair cells in the hair bulb portion of the hair, prevent the growth of hair, and promote hair removal and hair loss. Therefore, for male pattern baldness,
Anti-androgens have been used which have a reductase inhibitory action or an action of inhibiting the binding of 5α-DHT to a receptor. Such antiandrogens include oxendrone, chlormadinone acetate, 11α-hydroxyprogesterone, 4α-androsten-3-one-17β carboxylic acid, cyproteinacetate and the like. However, all of these antiandrogens are derivatives of steroid hormones, and when administered to the living body, they or their metabolites exhibit hormonal effects. And there was a problem in terms of safety. From this point, 5 of flavonoids which do not have a steroid skeleton
Although α-reductase inhibitors have also been found, they are all adapted only to androgenetic alopecia and only stop the progression of alopecia by the mechanism.

On the other hand, unlike these drugs, carpronium chloride (hereinafter referred to as MTB) having an effect of enhancing cutaneous vasoactivity is applicable to other acquired alopecia. However, this MTB also has only a mere effect of increasing blood flow, and has no promoting effect on hair growth of C3H mice described below.

More recently, diazoxide, a hypotensive agent, has been shown to have a hair growth promoting effect. However, the effect of promoting hair growth is very weak when used in a small amount, and there is a problem that side effects such as hyperglycemia occur when used in a large amount in order to obtain the effect. Minoxidil, which also acts as a hypotensive agent, has also been shown to have a hair growth promoting effect. Minoxidil, unlike conventional drugs, is a drug that has not only the vasodilatory effect of the MTB but also a hair follicle stimulating effect. Therefore, unlike the above-mentioned antiandrogens, it is effective not only for male pattern baldness but also for alopecia areata. However, since its action is not expressed unless minoxidil is sulfated in the body, individual differences in its metabolic ability are problematic. Furthermore, since the transdermal absorption rate into the body is high, there is a concern about the antihypertensive effect as a side effect, and the hair growth promoting effect is not sufficient.

Among the above-mentioned diazoxides and minoxidil, diazoxide has a problem of hyperglycemia, and minoxidil is not activated unless it is sulfated, and its hair growth promoting effect is not sufficient. Therefore, without the side effect of hyperglycemia, there is no need to be activated by metabolism in the body,
It has been desired to develop a drug having a stronger hair growth promoting effect and a low transdermal absorption.

Under these circumstances, the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that there is a substance having an excellent effect among benzopyran derivatives, and completed the present invention based on this finding. did.

In addition, International Application Publication No. WO90 / 14346 (International filing date 19
(May 15, 1990; International Publication Date November 29, 1990) describe compounds including benzopyran derivatives used in the present invention. The above specification states that the compound has a smooth muscle relaxing action and is therefore effective in treating respiratory disorders, hypertension, gastrointestinal spasm, cardiovascular disorders, epilepsy, etc. It does not mention or suggest that it has a hair promoting action and is effective as a hair growth promoting agent.

BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1, 3 and 5 to 19 are graphs showing the hair growth effect of mice when a benzopyran derivative or the like is applied and applied.

2 and 4 are photographs showing the hair growth status of mice 14 days after the start of the test.

BEST MODE FOR CARRYING OUT THE INVENTION The hair growth-promoting agent of the present invention contains one or more benzopyran derivatives represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. Do

In the above formula, X represents OO, SS, ＮNZ or CHCHNO ₂ , wherein Z is a hydrogen atom, a lower alkyl group, an aryl group, a hydroxyl group, a lower alkoxy group, a cyano group, a carbamoyl group or a sulfamoyl. Y represents —NR ₈ R ₉ , —OR ₁₀ or —SR ₁₁ , wherein R ₈ and R ₉
May be the same or different and include a hydrogen atom, a hydroxyl group, a lower alkoxy group, a cyano group, an amino group which may have a substituent, a lower alkyl group which may have a substituent, A good unsaturated lower alkyl group, a cycloalkyl group optionally having substituent (s), an aryl group optionally having substituent (s), a heteroaryl group optionally having substituent (s), or R ₈ and R ₉ together with a nitrogen atom represent an optionally substituted substituent, R ₁₀ and R 9
₁₁ is a hydrogen atom, a lower alkyl group or an aryl group; R ₁ is a hydrogen atom, or a lower alkyl group or an aryl group, or forms a single bond directly bonded to the R _2: R ₂ and R ₃ The same or different and represent a hydrogen atom or a hydroxyl group, or together form ＝ O, or
R ₂ is directly bonded to R ₁ to form a single bond; R ₄ and R ₅ are the same or different and represent a hydrogen atom, a lower alkyl group which may have a substituent, or taken together; R ₆ and R ₇ are the same or different and represent a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a halogen atom, a lower alkoxy group, a lower haloalkoxy group, an amino group, an acylamino group, a nitro group, a cyano group , An ester group, a lower alkylsulfonyl group or an arylsulfonyl group, or together show = N-ON-.

In the definition of the compound represented by the formula (I), the lower alkyl group means an alkyl group having 1 to 6 carbon atoms, and preferably an alkyl group having 1 to 4 carbon atoms. Examples of such lower alkyl groups include methyl, ethyl, n
-Propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group and the like.

The aryl group means a monovalent substituent obtained by removing one hydrogen atom from an aromatic hydrocarbon, and specifically includes a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group, and a phenanthryl. And the like. Particularly preferred is a phenyl group. The carbon atom on the ring of the aryl group may be substituted by one or more groups such as a halogen atom, a lower alkyl group, an amino group, a nitro group and a trifluoromethyl group. The heteroaryl group is an aryl group containing a hetero atom, and specific examples include a pyridine group, a pyrimidinyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a thiadiazole group, and a tetrazolyl group. Further, these rings may have a substituent.

The lower alkoxy group means an alkoxy group having 1 to 6 carbon atoms, preferably an alkoxy group having 1 to 4 carbon atoms. Examples of such lower alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy and the like. .

Halogen atom means chlorine, bromine, fluorine and iodine, and chlorine is particularly preferable.

The cycloalkyl group preferably has 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

Examples of the nitrogen-containing heterocycle include an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazyl group, and a morpholino group.

As the substituent, a halogen atom, a lower alkyl group,
Examples include a lower alkoxy group, an amino group, a nitro group, a lower haloalkyl group, a lower haloalkoxy group, and a cyano group.

The compound represented by the general formula (I) can be produced, for example, as follows.

General formula (II) Wherein R ₄ , R ₅ , R ₆ and R ₇ have the same meaning as described above;
₁₂ represents a hydrogen atom, a lower alkyl group or an aryl group.] A benzopyran-based compound represented by the general formula (III) Wherein X and Y have the same meanings as described above; L represents a leaving group such as a halogen atom, —OR ₁₃ , —S (O) _n R ₁₄ , wherein R ₁₃ and R ₁₄ are hydrogen Atom, lower alkyl group or aryl group, n represents an integer of 0 to 2] in the presence of a base in an inert solvent.

As the base used here, for example, sodium hydride, sodium alkoxide, potassium alkoxide,
Examples thereof include alkyl lithium, potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide.

In addition, the compound of the present invention represented by the general formula (I) can be obtained by adding a compound represented by the general formula (II) to a general formula (IV) X = C = W (IV) (where X has the same meaning as described above) It represents; W is an oxygen atom, a sulfur atom or N-R _15, wherein R ₁₅ is a hydrogen atom,
Hydroxyl group, lower alkoxy group, cyano group, amino group which may have a substituent, lower alkyl group which may have a substituent, unsaturated lower alkyl group which may have a substituent, A cycloalkyl group which may have a group, an aryl group which may have a substituent, and a heteroaryl group which may have a substituent). Can also. Examples of the compound represented by the general formula (IV) include methyl isothiocyanate.

The compound of the general formula (I) may also have the general formula (V) (Wherein X, Y, R ₄ , R ₅ , R ₆ , R ₇ and R ₁₂ have the same meanings as described above), by reducing the compound represented by the general formula (VI) (Wherein X, Y, R ₄ , R ₅ , R ₆ and R ₇ have the same meanings as described above). It can also be obtained by reducing the bond.

The reduction reaction is carried out in an inert solvent in a reducing agent such as NaBH ₄ , KBH
₄ , borohydride or metal hydride such as LiBH ₄ , NaBH ₃ CN, LiAlH ₄ or the like, or catalytic reduction using palladium carbon, Raney nickel or the like.

The dehydration reaction uses an acid such as paratoluenesulfonic acid or hydrogen chloride in an inert solvent, or an acid halide such as paratoluenesulfonyl chloride or acetyl chloride or an acid anhydride such as acetic anhydride in the presence of a base. It is done by using. As the base used here, pyridine, an organic base such as triethylamine, or sodium hydride, sodium alkoxide,
Examples include potassium alkoxide, alkyl lithium, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like.

Further, the compound (I) of the present invention can also be obtained by applying a specific production method described in Examples.

The blending amount of the benzopyran derivative is about 0.001 to 10% by weight (hereinafter, the weight% is simply referred to as%) in the hair growth promoter of the present invention. If it is less than 0.001%, the effect of promoting hair growth may not be exhibited. Also, the greater the blending amount, the greater the hair-growing effect, but it is preferably 10% or less in consideration of the appearance of side effects when used in large amounts. More preferably, it is 0.01 to 5%.

In addition to the above-mentioned benzopyran derivative, the hair growth promoting agent according to the present invention includes a fungicide such as salicylic acid, resorcin and hexachlorophene, which is generally used for a hair restorer, nicotinic acid, vitamin E, vitamin A, pantothenic acid, biotin Other vitamins, fatty acids, amino acids, menthol, lower alcohols such as ethanol, higher alcohols such as cetanol, polyethylene glycol,
Polyhydric alcohols such as propylene glycol, celluloses such as hydroxypropylcellulose, animal, vegetable and synthetic fats and oils, petrolatum, wax, silicone, surfactants, diluents such as zinc oxide, and humectants , A thickener, a suspending agent, a preservative, an antioxidant, a fragrance, a coloring agent and the like.

The hair growth promoter according to the present invention can be applied to any externally used dosage form such as liquid, emulsion, ointment, cream, gel, aerosol, and can be applied to shampoo and rinse.

Hereinafter, the present invention will be described more specifically with reference to Production Examples and Examples. However, these production examples and examples do not limit the scope of the present invention.

Production Examples 1-42 illustrate the methods for producing the benzopyran derivatives described in Table 1 below.

Production Example 1 N-methyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1
-To a mixture of 1.5 g of benzopyran-3-one, 0.6 g of methyl isothiocyanate and 15 m of dry N, N-dimethylformamide, 0.93 g of potassium tert-butoxide under ice-cooling and stirring
Was added and the mixture was stirred under ice cooling for 4 hours. Ice water was added to make the mixture acidic, and the mixture was extracted with ether. The ether layer was washed with water and dried over sodium sulfate. After the ether layer was distilled off, the residue was recrystallized from ethanol, and N-methyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran having a melting point of 186 to 187 ° C and represented by the following formula: -4-carbothioamide 1.
4 g were obtained.

NMR (CDCl ₃ ): 1.5 (6H, s), 3.3 (3H, d), 7.0 (1H, d),
7.4 (1H, dd), 7.5 (1H, d), 7.6 (1H, br.s), 13.5 (1H,
s) MS: 274 (M ⁺ ). Production Example 2 cis-N-methyl-6-cyano-3,4-dihydro-3-
Hydroxy-2,2-dimethyl-2H-1-benzopyran-
4-carbothioamide; and trans-N-methyl-6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide N-methyl-6-cyano- 3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide
1.4 g, tetrahydrofuran 15 m and methanol 15 m
Was added to sodium borohydride (NaBH ₄ ) (0.23 g) under stirring at −10 ° C., followed by stirring at −10 ° C. for 2 hours and then at room temperature for 2 hours. The reaction solution was distilled off under reduced pressure, and made acidic with acetic acid by adding ice water, and then extracted with ether and ethyl acetate. The organic layers were combined, dried over Na ₂ SO ₄ and evaporated.
The residue is subjected to silica gel chromatography (developing solution CH ₂ Cl ₂ : A
cOEt = 2: 1), and cis-N-methyl- having a melting point of 170-173 ° C.
6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide
0.1 g was obtained.

NMR (CDCl ₃ ): 1.3 (3H, s), 1.5 (3H, s), 3.25 (3H, d),
4.1 (1H, d), 4.5 (1H, d), 6.9 (1H, d), 7.4 (2H), 8.4
(1H, br.s).

MS: 276 (M ⁺ ) Then, trans-N-methyl-6-cyano- represented by the following formula having a melting point of 213 to 214 ° C from the distilled fraction:
3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-
0.1 g of 1-benzopyran-4-carbothioamide was obtained.

NMR (CDCl ₃ ): 1.2 (3H, s), 1.5 (3H, s), 3.25 (3H, d),
3.5 (1H, br.s), 4.0 (1H, d), 4.25 (1H, d), 6.9 (1H,
d), 7.4 (2H), 8.3 (1H, br.s) MS: 276 (M ⁺ ) Production Example 3 N-methyl-6-cyano-2,2-dimethyl-2H-1-
Benzopyran-4-carbothioamide N-methyl-6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-
A mixture of 0.44 g of carbothioamide, 0.07 g of paratoluenesulfonic acid monohydrate and 30 m of toluene was heated under reflux for 10 hours. The solvent was distilled off, and the residue was purified by silica gel chromatography (developing solution: CH ₂ Cl ₂ ) to give N-methyl-6-cyano-2,2-dimethyl- having a melting point of 139 to 141 ° C. and represented by the following formula. 2H-1-benzopyran-4-carbothioamide 0.
18 g were obtained.

NMR (CDCl ₃ ): 1.5 (6H, s), 3.25 (3H, d), 5.8 (1H, s),
6.8 (1H, d), 7.4 (1H, dd), 7.7 (1H, d), 7.8 (1H, br.
s) MS: 258 (M ⁺ ). Production Example 4 6-cyano-3-hydroxy-2,2-dimethyl-2H-1
-Benzopyran-4-dithiocarboxylic acid methyl ester 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1
To a mixture of 2.0 g of benzopyran-3-one, 2.3 g of carbon disulfide and 20 m of dry N, N-dimethylformamide, 1.3 g of potassium tert-butoxide was added under ice-cooling and stirring, and after stirring for 30 minutes, methyl iodide 1.56 g and dry N, N-dimethylformamide (8 m) were added dropwise, and the mixture was stirred for 1 hour under ice cooling. Ice water was added, and the mixture was extracted with ether. The ether layer was washed with water and dried over sodium sulfate. After distilling off the ether layer,
Silica gel chromatography of the residue (developing solution CH ₂ Cl ₂ )
To give 1.2 g of 6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-dithiocarboxylic acid methyl ester represented by the following formula as a yellow oily substance.

NMR (CDCl ₃ ): 1.5 (6H, s), 2.7 (3H, s), 7.0 (1H, d),
7.45 (1H, dd), 8.15 (1H, d), 14.65 (1H, s) MS: 291 (M ⁺ ) Production Example 5 N-phenyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1
0.5 g of benzopyran-3-one, 0.37 g of phenylisothiocyanate and 5 m of dry N, N-dimethylformamide
To a mixture of potassium tert-butoxide 0.31 under ice-cooling and stirring.
g was added and the mixture was stirred for 5 hours under ice cooling. Ice water was added, the mixture was acidified with acetic acid, and extracted with ether. The ether layer was washed with water and dried over sodium sulfate, and the ether was distilled off. The residue was purified by silica gel chromatography (developing solution CH ₂ Cl ₂ ),
N-phenyl-6-cyano-3-hydroxy- represented by the following formula having a melting point of 300 ° C. or more (solidified after softening at around 140 ° C.)
0.4 g of 2,2-dimethyl-2H-1-benzopyran-4-carbothioamide was obtained.

_{NMR (CDCl 3): 1.5 (} 6H, s), 7.0 (1H, d), 7.25-7.65 (7
H), 8.75 (1H, br.s), 13.55 (1H, br, s) MS: 336 (M ⁺ ) Production Example 6 N-phenyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carboxamide 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1
To a mixture of 0.5 g of benzopyran-3-one, 0.39 g of potassium tert-butoxide and 5 m of dry N, N-dimethylformamide, a mixture of 0.42 g of phenylisocyanate and 1.5 m of dry N, N-dimethylformamide was stirred under ice-cooling. It was dropped. Stir for 4 hours under ice-cooling, add ice water to acidify acetic acid,
Extracted with ether. The ether layer was washed with water and dried over sodium sulfate, and the ether was distilled off. The residue was purified by silica gel chromatography (developing solution: CH ₂ Cl ₂ ).
0.17 g of N-phenyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by the following formula at ~ 170 ° C was obtained.

_{NMR (CDCl 3): 1.5 (} 6H, s), 7.05 (1H, d), 7.25-7.75
(8H), 14.1 (1H, s). MS: 320 (M ⁺ ) Production Example 7 N, 2-dimethyl-6-cyano-2-ethyl-2H-1-benzopyran-4-carbothioamide N, 2-dimethyl-6-cyano-2-ethyl-3-hydroxy-2H-1-benzopyran -4-carbothioamide
To a mixture of 0.8 g and 20 m of methanol, 0.24 g of sodium borohydride (NaBH ₄ ) was added under ice-cooling and stirring, followed by stirring at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, water was added, and the mixture was extracted with ether. After the organic layer was washed with water and dried, the solvent was distilled off to obtain 0.43 g of N, 2-dimethyl-6-cyano-3,4-.
Dihydro-2-ethyl-3-hydroxy-2H-1-benzopyran-4-carbothioamide was obtained. Next, 0.1 g of paratoluenesulfonic acid monohydrate and toluene
After adding 30 m and heating under reflux for 3 hours, the solvent was distilled off. The residue was purified by silica gel chromatography (developing solution: CH ₂ Cl ₂ ), and N, 2-dimethyl-6-cyano-2-ethyl-2H-1-benzopyran- represented by the following formula having a melting point of 139 to 141 ° C. 0.2 g of 4-carbothioamide was obtained.

NMR (CDCl ₃ ): 1.0 (3H, t), 1.45 (3H, s), 1.75 (2H,
m), 3.3 (3H, d), 5.8 (1H, s), 6.85 (1H, d), 7.4 (1H, d)
d), 7.7 (1H, d), 7.8 (1H, br.s) Production Example 8 N, 2,2-trimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide N, 2,2-trimethyl-3,4-dihydro-3-hydroxy-6-nitro-2H-1 A mixture of -benzopyran-4-carbothioamide (7.0 g), paratoluenesulfonic acid monohydrate (3.0 g) and toluene (300 m) was heated to reflux for 1 hour. The solvent is distilled off, the residue is purified by silica gel chromatography (developing solution CH ₂ Cl ₂ ), and recrystallized from a mixed solvent of CH ₂ Cl ₂ , ether and hexane, and represented by the following formula having a melting point of 147 to 148 ° C. 3.25 g of N, 2,2-trimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide were obtained.

NMR (CDCl ₃ ): 1.5 (6H, s), 3.3 (3H, d), 5.9 (1H, s),
6.85 (1H, d), 7.9 (1H, br, s), 8.0 (1H, dd), 8.3 (1H,
d) MS: 278 (M ⁺ ) Production Example 9 N-ethyl-6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide N-ethyl-6-cyano-2,2-dimethyl-2H-1-
Benzopyran-4-carbamide 0.14 g, Lawson's reagent
A mixture of 3.45 g and 10 m of benzene was refluxed for 1 hour. The insolubles were removed by suction filtration, washed with methylene chloride, the mother liquor and the washing were combined, and the solvent was distilled off. The residue was purified by silica gel chromatography (developing solution CH ₂ Cl ₂ ) to give N-ethyl- having a melting point of 151 to 153 ° C. and represented by the following formula.
6-cyano-2,2-dimethyl-2H-1-benzopyran-
0.12 g of 4-carbothioamide was obtained.

_{NMR (CDCl 3): 1.33 (} 3H, t), 1.49 (6H, s), 3.56-4.10
(2H, m), 5.81 (1H, s), 6.85 (1H, d), 7.40 (1H, dd),
7.75 (1H, d), 7.82 (1H, br.s) MS: 272 (M ⁺ ) Production Example 10 N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbamide (1) 6-nitro-3,4-dihydro-2,2-dimethyl-2H
To a mixture of 3.2 g of -1-benzopyran-3-one, 1.2 g of methyl isocyanate and 40 m of dry N, N-dimethylformamide, 1.9 g of potassium tert-butoxide was added with stirring under ice-cooling, followed by stirring for 3 hours under ice-cooling. It was left for another 12 hours. The mixture was acidified with hydrochloric acid by adding ice water, and extracted with methylene chloride. The organic layer was re-extracted with 2N NaOH. The aqueous layer was acidified with hydrochloric acid and extracted again with methylene chloride. The organic layer is dried over magnesium sulfate, concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (developing solution, n-hexane: ethyl acetate = 10: 1).
And recrystallized from a mixture of methylene chloride and n-hexane to give N-methyl-6-nitro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4 having a melting point of 148-149 ° C. -2.33 g of carbothioamide were obtained.

NMR (CDCl ₃ ): 1.5 (6H, s), 3.25 (3H, d), 6.9 (1H, d),
7.85 (1H, dd), 8.0 (1H, d), 7.4-8.2 (1H, br), 13.5
(1H, s). MS: 294 (M ^<+> ) (2) N-methyl-6-nitro-3-hydroxy-2,2
A mixture of 2.08 g of dimethyl-2H-1-benzopyran-4-carbothioamide and 50 m of methanol was added at 1.3 ° C. with stirring at −10 ° C., and gradually increased from −10 ° C. to room temperature for 24 hours. Stirred. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixture of methylene chloride and n-hexane to give N-methyl-6-nitro-3,4-dihydro-3-hydroxy- having a melting point of 203-207 ° C.
0.6 g of 2,2-dimethyl-2H-1-benzopyran-4-carbothioamide was obtained.

NMR (CDCl ₃ , CF ₃ CO ₂ D): 1.25 (3H, s), 1.55 (3H, s), 3.
3 (3H, s), 4.1 (1H, d), 4.35 (1H, d), 6.9 (1H, d), 7.9
(1H, d), 8.1 (1H, dd) MS: 296 (M ⁺ ) (3) N-methyl-6-nitro-3,4-dihydro-3-
Hydroxy-2,2-dimethyl-2H-1-benzopyran-
A mixture of 0.42 g of 4-carbothioamide, 0.58 g of p-toluenesulfonyl chloride and 30 m of pyridine was heated under reflux for 3 hours. The reaction mixture was concentrated, 2N hydrochloric acid was added, extracted with dichloromethane, dried over magnesium sulfate, purified by silica gel column chromatography (CH ₂ Cl ₂ ), recrystallized with ethyl acetate, and melted at 166-168 ° C. 0.25 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbamide represented by the following formula: was obtained.

NMR (CDCl ₃ ): 1.5 (6H, s), 2.95 (3H, d), 6.0 (1H, s),
6.8 (1H, d), 8.0 (1H, dd), 8.45 (1H, d), 5.6-6.4 (1
H, m) MS: 262 (M ⁺ ) Production Example 11 N ² - cyano -N ^1, N ¹ - obtained according dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine (1) Preparation 10 (3) N- Methyl-6
-Nitro-2,2-dimethyl-2H-1-benzopyran-4
0.88 g of sodium hydride was added to a mixture of 5.25 g of carboxamide, 14.2 g of methyl iodide and 50 m of tetrahydrofuran with stirring, and the mixture was heated under reflux for 3 hours. Water was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. 4.26 g of Lawesson's reagent and 20 m of toluene were added to the residue, and the mixture was heated under reflux for 1.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (developing solution, methylene chloride), and further recrystallized from a mixture of ethyl acetate and n-hexane to give a melting point of 139-141 ° C.
N, N-dimethyl-6-nitro-2,2-dimethyl-2H-1
4.86 g of -benzopyran-4-carbothioamide were obtained.

NMR (CDCl ₃ ): 1.5 (6H, s), 3.2 (3H, s), 3.6 (3H, s),
5.65 (1H, s), 6.85 (1H, d), 7.85 (1H, d), 8.05 (1H, d
d) (2) N, N-dimethyl-6-nitro-2,2-dimethyl-2H
A mixture of 2.93 g of -1-benzopyran-4-carbothioamide, 4.11 g of methyl iodide and 30 m of tetrahydrofuran was heated under reflux for 1 hour. When the internal temperature drops to room temperature,
Add 1.34 g of cyanamide and 0.44 g of sodium hydride,
The mixture was refluxed for 1 hour. The reaction solution was concentrated under reduced pressure, methylene chloride was added, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (developing solution, a mixed solution of n-hexane and ethyl acetate), and further recrystallized from a mixed solution of ethyl acetate and n-hexane to give a melting point of 209-211 ° C.
N ² - cyano -N ^1, N ¹ - dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine 2.
57 g were obtained.

NMR (CDCl ₃ ): 1.6 (6H, s), 3.0 (3H, s), 3.25 (3H, s),
5.95 (1H, s), 6.95 (1H, d), 7.7 (1H, d), 8.1 (1H, dd) MS: 300 (M ⁺ ) IR (KBr): 2172cm ^-1 (C≡N) Production Example 12 N-Cyano-N'-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamidine (1) N-methyl-6 obtained according to Production Example 10 (3)
-Nitro-2,2-dimethyl-2H-1-benzopyran-4
-A mixture of 5.26 g of carboxamide, 4.26 g of Lawesson's reagent and 20 m of benzene was heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (developing solution, methylene chloride), and further recrystallized from a mixed solution of ethyl acetate and n-hexane to give N-methyl-6-p. 4.84 g of nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide were obtained.

(2) N-methyl-6-nitro-2,2-dimethyl-2H-
1-benzopyran-4-carbothioamide 0.56 g, p-toluenesulfonyl chloride 0.39 g, triethylamine 0.21 g
And a mixture of 3 m of acetonitrile were heated to reflux for 30 minutes. The solvent was distilled off, and to the residue, 0.27 g of cyanamide, 0.17 g of sodium hydride and 4 m of ethanol were added, and the mixture was heated under reflux for 30 minutes. Concentrated hydrochloric acid and water were added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a 2N aqueous solution of potassium carbonate and a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 1: 1).
Further, the product was recrystallized and purified with a mixture of ethyl acetate and diethyl ether to obtain 50 mg of the desired compound having a melting point of 240-243 ° C.

_{NMR (CDCl 3): 1.6 (} 6H, s), 3.1 (3H, d), 5.9-6.2 (1H,
bs), 6.1 (1H, s), 6.9 (1H, d), 7.85 (1H, d), 8.1 (1H,
dd) MS: 286 (M ⁺ ) IR (KBr): 2180 cm ^-1 (C≡N) Production Example 13 N- (2 ', 2', 2'-trifluoroethyl) -6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbamide 6-nitro-2,2-dimethyl-2H -1-benzopyran-4-carboxylic acid 1.00 g, 2,2,2-trifluoroethylamine 0.44 g, 2,2'-dipyridyl disulfide 0.97 g, triphenylphosphine 1.16 g and dichloromethane 20 m
Was stirred at room temperature for 3 hours. After the solvent was distilled off, the residue was subjected to silica gel chromatography (developing solution AcOEt: n-Hex).
ane = 1: 1), recrystallized with a mixed solution of n-hexane and ethyl acetate, and having a melting point of 178-180 ° C. and N- (2 ′, 2 ′, 2′-trifluoro) represented by the following formula: Ethyl) -6
-Nitro-2,2-dimethyl-2H-1-benzopyran-4
0.93 g of carboxamide was obtained.

_{NMR (CDCl 3): 1.5 (} 6H, s), 3.7-4.4 (2H, m), 6.1 (1H,
s), 6.85 (1H, d), 8.05 (1H, dd), 8.4 (1H, d). MS: 330 (M ⁺ ) Production Example 14 N- (N'-cyano-6-nitro-2,2-dimethyl-2H
-1-benzopyran-4-yliminoyl) -pyrrolidin-3-ol N- (N'-cyano-6-nitro-2,2-dimethyl-2
H-1-benzopyran-4-yliminoyl) -3-t
-Butyldimethylsilyloxypyrrolidine 0.11 g, tetra-n-butylammonium fluoride (1 mol / 1 TH
F solution) A mixture of 0.5 m and 5 m of tetrahydrofuran was stirred for 1 hour under ice cooling. After evaporation of the solvent, the residue was subjected to silica gel column chromatography (AcOEt: n-Hexane = 1: 5).
And then recrystallized with a mixture of n-hexane and ethyl acetate, and having a melting point of 199-200 ° C.
-(N'-cyano-6-nitro-2,2-dimethyl-2H-
28 mg of 1-benzopyran-4-yliminoyl) -pyrrolidin-3-ol were obtained.

_{NMR (CDCl 3): 1.6 (} 6H, s), 1.7-4.8 (8H, m), 6.0 (1H,
s), 6.9 (1H, d), 7.55-7.8 (1H, m), 8.05 (1H, dd). MS: 342 (M ⁺ ) Production Example 15 N-ethyl-6-trifluoromethyl-2,2-dimethyl-2H-1-benzopyran-4-carbamide N-methyl-3,4-dihydro-3-hydroxy-6
A mixture of 0.17 g of trifluoromethyl-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.21 g of p-toluenesulfonyl chloride and 10 m of pyridine was added to 4
After heating under reflux for 2 hours, 2N hydrochloric acid was added, the mixture was extracted with dichloromethane, dried over magnesium sulfate, purified by silica gel column chromatography (CH ₂ Cl ₂ : Methanol = 100: 1), and re-used with a mixture of diethyl ether and n-hexane. N-methyl- having a melting point of 146-150 ° C. and having the following formula
44 mg of 6-trifluoromethyl-2,2-dimethyl-2H-1-benzopyran-4-carbamide were obtained.

_{NMR (CDCl 3): 1.4 (} 6H, s), 2.85 (3H, d), 5.95 (1H,
s), 6.1-6.7 (1H, m), 6.8 (1H, d), 6.35 (1H, dd), 7.7
5 (1H, d). MS: 285 (M ⁺ ) Production Example 16 N-methyl-6-cyano-2-ethyl-2-methyl-2H
-1-benzopyran-4-carbamide N-methyl-6-cyano-2-ethyl-2-methyl-
After heating a mixture of 70 mg of 2H-1-benzopyran-4-carbothioamide, 55 mg of p-toluenesulfonyl chloride and 5 m of pyridine under reflux for 6 hours, adding 2N hydrochloric acid, extracting with dichloromethane, drying over magnesium sulfate, and silica gel column chromatography (AcOEt chromatography). : n-Hexane = 1: 1), and further recrystallized with a mixture of ethyl acetate and n-hexane to give N-methyl-6-cyano-2- having a melting point of 152-154 ° C and represented by the following formula. 41 mg of ethyl-2-methyl-2H-1-benzopyran-4-carbamide were obtained.

NMR (CDCl ₃ ): 0.95 (3H, t), 1.4 (3H, s), 1.8 (2H, q),
2.9 (3H, d), 6.0 (1H, s), 6.2-6.7 (1H, m), 6.8 (1H,
d), 7.4 (1H, dd), 7.85 (1H, d). MS: 256 (M ⁺ ) Production Example 17 N-ethyl-N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbamide N-methyl-6-nitro-2,2-dimethyl-2H-1-
Benzopyran-4-carbamide 0.53 g, ethyl iodide
A mixture of 1.60 g, 0.09 g of sodium hydride and 10 m of tetrahydrofuran was heated under reflux for 30 minutes, dichloromethane was added, and insolubles were filtered off. The mixture was recrystallized with a mixed solution of diethyl ether and n-hexane, and N-ethyl-N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran represented by the following formula having a melting point of 121-124 ° C. 0.45 g of -4-carbamide was obtained.

_{NMR (CDCl 3): 0.9-1.5 (} 3H, m), 1.5 (6H, s), 2.8-3.8
(5H, m), 5.7 (1H, s), 6.95 (1H, d), 7.9 (1H, d), 8.1
(1H, dd). MS: 290 (M ⁺ ) Production Examples 18-20 Ethyl N-cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-imidate N-cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran- 4-amidine 6-nitro-2,2-dimethyl-2H-1-benzopyran-
Ethyl 4-carboxylate 4-cyano-6-nitro-2,2-dimethyl-2H-1-
Hydrochloric acid gas was added to a mixture of 1.04 g of benzopyran and 20 m of ethyl alcohol under ice cooling and stirring until the mixture became supersaturated, and the mixture was stirred at 5 ° C. for 6 days. After concentration of the reaction solution, a 1: 1 mixture of diethyl ether and ethyl alcohol was added to the residue, and the mixture was triturated. The crystals were collected by filtration, washed with a mixture of ethyl alcohol and diethyl ether and dried to give 6-nitro-2, 1.13 g of ethyl 2-dimethyl-2H-1-benzopyran-4-imidate hydrochloride were obtained. Next, a mixture of the obtained present compound (0.94 g), triethylamine (0.31 g), cyanamide (0.13 g) and ethyl alcohol (7 m) was stirred at room temperature for 6 hours. After concentration of the reaction solution, water was added, extracted with dichloromethane, washed with 2N hydrochloric acid, and dried over magnesium sulfate. Furthermore, silica gel column chromatography (AcOEt: n-Hex
ane = 1: 1) to isolate components of different polarities. The least polar component is further recrystallized with a mixture of diethyl ether and n-hexane to give 6-nitro-2,2-dimethyl-2H-1-benzopyran- 0.15 g of ethyl 4-carboxylate was obtained.

NMR (CDCl ₃ ): 1.4 (3H, t), 1.5 (6H, s), 4.35 (2H, q),
6.8 (1H, s), 6.85 (1H, d), 8.05 (1H, dd), 9.0 (1H,
d). MS: 277 (M ⁺ ) The next less polar component is further ethyl acetate and n-
N-cyano-6-nitro-2,2-dimethyl-2 represented by the following formula having a melting point of 91-93 ° C.
0.14 g of ethyl H-1-benzopyran-4-imidate was obtained.

NMR (CDCl ₃ ): 1.5 (3H, t), 1.6 (6H, s), 4.6 (2H, q),
6.5 (1H, s), 6.85-7.1 (1H, m), 8.0-8.3 (2H, m). MS: 301 (M ⁺ ) The most polar components are additionally ethyl acetate and n-
The mixture was recrystallized from a mixed solution of hexane to obtain 0.08 g of N-cyano-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-amidine represented by the following formula and having a melting point of 205-207 ° C.

_{NMR (CDCl 3): 1.5 (} 6H, s), 5.6-6.5 (2H, m), 6.2 (1H,
s), 6.9 (1H, d), 8.05 (1H, dd), 8.55 (1H, d). MS: 272 (M ⁺ ) Production Example 21 N-cyano-N'-cyclopropyl-6-nitro-2,2
-Dimethyl-2H-1-benzopyran-4-amidine N-cyano-6-nitro-2,2-dimethyl-2H-1-
A mixture of 98 mg of ethyl benzopyran-4-imidate, cyclopropylamine and 1 m of dichloromethane was added at room temperature,
After stirring for 1.5 hours, the mixture was purified by silica gel column chromatography (AcOEt: n-Hexane = 1: 1), and further recrystallized with a mixture of acetone and n-hexane to give a melting point of 206-207.
There was obtained 30 mg of N-cyano-N'-cyclopropyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-amidine represented by the following formula.

_{NMR (CDCl 3): 0.5-1.0 (} 4H, m), 1.5 (6H, s), 2.7-3.2
(1H, m), 5.9 (1H, s), 6.8 (1H, d), 6.9-7.4 (1H, m),
7.7 (1H, d), 8.0 (1H, dd). MS: 312 (M ⁺ ) Production Example 22 N-methyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbamide N-methyl-6-nitro-2,2-dimethyl-2H-1-
A mixture of 0.53 g of benzopyran-4-carbamide, 0.38 g of sodium borohydride, 5 m of tetrahydrofuran and 5 m of methyl alcohol was stirred at room temperature for 20 minutes, 2N hydrochloric acid was added, extracted with dichloromethane, dried over magnesium sulfate, further ethyl acetate and Recrystallized from n-hexane and having a melting point of 161-162 ° C, N-methyl-3,4- represented by the following formula:
0.42 g of dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbamide was obtained.

_{NMR (CDCl 3): 1.3 (} 3H, s), 1.4 (3H, s), 1.9-2.4 (2H,
m), 2.85 (3H, d), 3.7 (1H, dd), 5.7-6.3 (1H, m), 6.8
5 (1H, d), 7.85-8.2 (2H, m). MS: 264 (M ⁺ ) Production Example 23 N, N-dimethyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbamide N-methyl-6-nitro-2,2-dimethyl-2H- 1-
A mixture of 2.63 g of benzopyran-4-carbamide, 1.90 g of sodium borohydride, 25 m of tetrahydrofuran and 25 m of methyl alcohol was stirred at room temperature for 20 minutes, 2N hydrochloric acid was added, and the mixture was extracted with dichloromethane and dried over magnesium sulfate. After evaporating the solvent, 7.1 g of methane iodide, 0.44 g of sodium hydride and 50 m of tetrahydrofuran were added to the residue, and the mixture was heated under reflux for 30 minutes, 2N hydrochloric acid was added, and the mixture was extracted with dichloromethane, washed with saturated saline, and dried over magnesium sulfate. did. In addition, silica gel column chromatography (CH ₂ C
N represented by the following formula recrystallized mp 162-164 ° C. with a mixture of purified ethyl acetate and n- hexane l _2), N-dimethyl-3,4-dihydro-6-nitro-2,2 Dimethyl-2H
0.49 g of -1-benzopyran-4-carbamide was obtained.

_{NMR (CDCl 3): 1.35 (} 3H, s), 1.5 (3H, s), 1.75-2.5 (2
H, m), 2.1 (3H, s), 2.25 (3H, s), 4.2 (1H, dd), 6.85
(1H, d), 7.8-8.2 (2H, m). MS: 278 (M ⁺ ) Production Example 24 N, N-dimethyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide N, N-dimethyl-3,4-dihydro-6-nitro −2,2−
Dimethyl-2H-1-benzopyran-4-carbamide 0.
43 g, a mixture of Lawson's reagent 0.33 g and benzene 2 m
After heating and refluxing for 30 minutes, the mixture was purified by silica gel column chromatography (CH ₂ CH ₂ ), and further recrystallized from a mixture of ethyl acetate and n-hexane to give N, N-dimethyl represented by the following formula having a melting point of 158-160 ° C. -3,4-dihydro-6-nitro-2,2
-Dimethyl-2H-1-benzopyran-4-carbothioamide 0.33 g was obtained.

_{NMR (CDCl 3): 1.3 (} 3H, s), 1.5 (3H, s), 1.8-2.7 (2H,
m), 3.3 (3H, s), 3.6 (3H, s), 4.6 (1H, dd), 6.8 (1H,
d), 7.75-8.2 (2H, m). MS: 294 (M ⁺ ) Production Example 25 N-cyano-N ', N'-dimethyl-3,4-dihydro-6
-Nitro-2,2-dimethyl-2H-1-benzopyran-4
-Amidine N, N-dimethyl-3,4-dihydro-6-nitro-2,2-
Dimethyl-2H-1-benzopyran-4-carbothioamide 0.27 g, methyl iodide 0.66 g and tetrahydrofuran
After heating and refluxing the 2 m mixture for 1 hour, 40 mg of sodium hydride and 44 mg of cyanamide were further added, and the mixture was heated and refluxed for 2 hours. Dichloromethane was added, insolubles were removed by filtration, and the residue was subjected to silica gel column chromatography (AcOEt: n-Hexane = 1: 1).
Purified in 1), recrystallized from a mixture of ethyl acetate and n-hexane, and having a melting point of 222-224 ° C, N-cyano-N ', N'-dimethyl-3,4-dihydro-6-nitro −
2,2-dimethyl-2H-1-benzopyran-4-amidine 9
0 mg was obtained.

_{NMR (CDCl 3): 1.35 (} 3H, s), 1.6 (3H, s), 1.8-5.5 (9
H, m), 6.95 (1H, d), 7.8-8.3 (2H, m). MS: 302 (M ⁺ ) Production Example 26 N-hydroxy-N ', N'-dimethyl-6-nitro-2,
2-dimethyl-2H-1-benzopyran-4-amidine N, N-dimethyl-6-nitro-2,2-dimethyl-2H-1
A mixture of 0.30 g of benzopyran-4-carbothioamide, 2.5 g of methyl iodide and 10 m of tetrahydrofuran
After heating and refluxing for 0 minutes, further 0.37 g of hydroxylamine hydrochloride
And 0.15 g of triethylamine, and the mixture was heated under reflux for 1.5 hours. An aqueous potassium carbonate solution was added, the mixture was extracted with dichloromethane, dried over magnesium sulfate, purified by silica gel column chromatography (AcOEt: n-Hexane = 1: 1), further recrystallized with a mixture of dichloromethane and n-hexane, and represented by the following formula. N-hydroxy-N ', N'-dimethyl-
6-nitro-2,2-dimethyl-2H-1-benzopyran-
72 mg of 4-amidine were obtained.

NMR (CDCl ₃ ): 1.55 (6H, s), 2.75 (6H, s), 5.8 (1H,
s), 6.9 (1H, d), 7.4-8.2 (3H, m). MS: 291 (M ⁺ ) Production Example 27 N-Sulfamoyl-N ', N'-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-amidine N, N-dimethyl-6-nitro-2,2-dimethyl- 2H-1
A mixture of 0.29 g of benzopyran-4-carbothioamide, 0.71 g of methyl iodide and 2 m of tetrahydrofuran
After heating under reflux for 0 minutes, 105 mg of sulfamide and 44 mg of sodium hydride were further added, and the mixture was heated under reflux for 5 hours. After adding 2N hydrochloric acid, the mixture is extracted with dichloromethane, washed with saturated saline, dried over magnesium sulfate, purified by silica gel column chromatography (AcOEt: n-Hexane = 1: 1), and re-used with a mixture of ethyl acetate and n-hexane. Crystallization gave 0.17 g of N-sulfamoyl-N ', N'-dimethyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-amidine represented by the following formula and having a melting point of 212-214 ° C.

NMR (CDCl ₃ ): 1.55 (3H, s), 1.6 (3H, s), 2.9 (3H, s),
3.2 (3H, s), 4.4−4.8 (2H, m), 5.95 (1H, s), 6.9 (1H,
d), 7.7 (1H, d), 8.1 (1H, dd). MS: 354 (M ⁺ ) Production Example 28 N-carbamoyl-N ', N'-dimethyl-6-nitro-
2,2-dimethyl-2H-1-benzopyran-4-amidine N-cyano-N ', N'-dimethyl-6-nitro-2,2
-Dimethyl-2H-1-benzopyran-4-amidine 300 m
g, a mixture of 10 m of ethyl alcohol and 10 m of chloroform was added under ice-cooling until hydrochloric acid gas was saturated.
Stirred at ° C. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added, extracted with dichloromethane, dried over sodium sulfate, and then subjected to silica gel column chromatography (AcOEt:
n-Hexane = 3: 1) and further purified with ethyl acetate and n
N-carbamoyl-N ', N'-dimethyl-6 represented by the following formula having a melting point of 157-159 ° C.
-Nitro-2,2-dimethyl-2H-1-benzopyran-4
-236 mg of amidine were obtained.

NMR (CDCl ₃ ): 1.5 (3H, s), 1.55 (3H, s), 2.9 (3H, s),
3.15 (3H, s), 4.6-5.4 (2H, m), 5.7 (1H, s), 6.85 (1
H, d), 7.8 (1H, d), 8.05 (1H, dd). MS: 318 (M ⁺ ) Production Example 29 3-hydroxy-2,2-dimethyl-6-nitro-2H-1
-Benzopyran-4-carbamide 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1
To a mixture of 41.5 g of -benzopyran-3-one and 500 m of dry N, N-dimethylformamide, 8.2 g of sodium hydride (60%) was gradually added while stirring under ice-cooling under a nitrogen stream, followed by stirring for 50 minutes. Carbonyldiimidazole
After adding 33.5 g and stirring for 1 hour, 11.2 g of ammonium chloride and 29 m of triethylamine were added, and the mixture was stirred at 5 ° C for 12 hours and then at room temperature for 14 hours. Ice water was added and washed with ether. The aqueous layer was acidified with hydrochloric acid and extracted with a mixed solvent of ethyl acetate and ether. The organic layer was washed with water and dried, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ : MeOH = 99: 1) to give a melting point of 189-191.
23.2 g of 3-hydroxy-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamide represented by the following formula at a temperature of ° C. was obtained.

_{NMR (CDCl 3 -CD 3 OD)} : 1.50 (6H, s), 7.00 (1H, d), 7.97
(1H, dd), 8.27 (1H, d). MS: 264 (M ⁺ ) Production Example 30 2,2-dimethyl-6-nitro-2H-1-benzopyran-
4-carboxylic acid 3-hydroxy-2,2-dimethyl-6-nitro-2H-
To a mixture of 13.2 g of 1-benzopyran-4-carbamide, 16.6 g of sodium cyanoborohydride and 200 m of tetrahydrofuran, 100 m of acetic acid was added under ice-cooling and stirring.
After stirring for 3 hours under ice-cooling and stirring for 18 hours at room temperature, 5.6 g of sodium cyanoborohydride and 50 m of methanol
Added and stirred at room temperature for 40 hours. The reaction solution was distilled off under reduced pressure,
Water was added, and the mixture was extracted with a mixed solvent of ethyl acetate and ether.
The organic layer was washed with water and dried, and the solvent was distilled off to obtain 24 g of 3,4-dihydro-3-hydroxy-2,2-dimethyl-6-nitro-2H.
-1-benzopyran-4-carbamide was obtained. Next, 51.5 g of paratoluenesulfonyl chloride and 400 m of pyridine were added thereto, and the mixture was heated under reflux for 3 hours, and the solvent was distilled off. Ice water was added to the residue, the mixture was acidified with hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried. The crystals were subjected to silica gel chromatography (developing solution: CH ₂ Cl ₂ : hexane = 7:
Purified in 3), having a melting point of 162-164 ° C, represented by the following formula 4-
17.9 g of cyano-2,2-dimethyl-6-nitro-2H-1-benzopyran were obtained.

NMR (CDCl ₃ ): 1.58 (6H, s), 6.51 (1H, s), 6.94 (1H,
d), 8.15 (1H, dd), 8.23 (1H, d) MS: 230 (M ⁺ ) 4-cyano-2,2-dimethyl-6-nitro-2H-1-
Benzopyran 13.0 g, acetic acid 400 m, water 200 m, concentrated sulfuric acid 100
After refluxing the mixture of 1.5 m for 1.5 hours, 100 m of concentrated sulfuric acid was added and the mixture was refluxed for 1 hour. When the reaction mixture was poured into ice water, crystals precipitated. The crystals are washed with water and dried, and then recrystallized with a mixed solvent of acetonitrile and water to give 2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxylic acid having a melting point of 203-204 ° C and represented by the following formula. 11.9 g of the acid were obtained.

_{NMR (CDCl 3 -CD 3 OD)} : 1.50 (6H, s), 6.80 (1H, s), 6.85
(1H, d), 8.03 (1H, dd), 8.99 (1H, d) MS: 249 (M ⁺ ) Production Example 31 6,6-dimethyl-6H-pyrano [2,3-f] benzo-2,1,3
-Oxadiazole-8-carbamide 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H
-Pyrano [2,3-f] benzo-2,1,3-oxadiazole
To a mixture of 3.9 g and toluene 80 m, under ice-cooling and stirring, 1.0
M diethylaluminum cyanide 90m (toluene solution)
Was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, 2N-NaOH was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solution: CH ₂ Cl ₂ ) to give 8-cyano-6 having a melting point of 136-138 ° C. and represented by the following formula.
6-dimethyl-6H-pyrano [2,3-f] benzo-2,1,3-
2.9 g of oxadiazole was obtained.

NMR (CDCl ₃ ): 1.55 (6H, s), 6.83 (1H, s), 7.03 (1H,
s), 7.83 (1H, s) MS: 227 (M ⁺ ) IR (KBr): 2232 cm ^-1 8-cyano-6,6-dimethyl-6H-pyrano [2,3-f]
Benzo-2,1,3-oxadiazole 0.66 g and concentrated sulfuric acid 15
m mixture was stirred at room temperature for 45 hours. The reaction mixture was poured into ice water and extracted with ether. The organic layer was washed with water and dried, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (developing solution: CH ₂ Cl ₂ : MeOH = 99: 1).
Recrystallization from a mixed solution of ethyl acetate and hexane gave a melting point of 16
6,6-Dimethyl-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole-8- represented by the following formula at 8-169 ° C.
0.35 g of carboxamide was obtained.

_{NMR (CDCl 3): 1.52 (} 6H, s), 6.30 (2H, br.s), 6.60 (1
H, s), 7.07 (1H, s), 8.18 (1H, s) MS: 245 (M ⁺ ) Production Example 32 6,6-Dimethyl-6H-pyrano [2,3-f] benzo-2,1,3
-Oxadiazole-8-carboxylic acid 8-cisano-6,6-dimethyl-6H-pyrano [2,3-f]
Using 1.74 g of benzo-2,1,3-oxadiazole, the reaction was carried out in the same manner as in Production Example 30, and the melting point was 246-248 ° C., and represented by the following formula, 6,6-dimethyl-6H-pyrano [2,3 -F] benzo-2,
1.76 g of 1,3-oxadiazole-8-carboxylic acid was obtained.

NMR (CD ₃ OD): 1.52 (6H, s), 7.07 (1H, s), 7.27 (1H,
s), 8.61 (1H, s) MS: 246 (M ⁺ ) Production Example 33 N, 2,2-trimethyl-6-acetylamido-2H-1-benzopyran-4-carbamide N, 2,2-trimethyl-6-nitro-2H-1-benzopyran-4-carbamide 1.55 g, chloride A mixture of 3.84 g of stannous and 30 m of dry ethanol was heated to reflux for 4 hours. After the solvent was distilled off, 15 m of acetic anhydride was added, and the mixture was added at room temperature for 1 hour.
Stir for 7 hours. The reaction solution was evaporated under reduced pressure, 2N-hydrochloric acid was added, and the mixture was extracted with a mixed solvent of ethyl acetate and ether. The organic layer is washed with water, dried and the solvent is distilled off. The residue obtained is purified by silica gel column chromatography (developing solution: CH ₂ Cl ₂ : MeOH = 99: 1), and expressed in the following formula with a melting point of 203-210 ° C. This gave 1.30 g of N, 2,2-trimethyl-6-acetylamido-2H-1-benzopyran-4-carbamide.

_{NMR (CDCl 3 -DMSO-d 6} ): 1.42 (6H, s), 2.06 (3H, s),
2.85 (3H, d), 5.99 (1H, s), 6.74 (1H, br.d), 7.50 (1
H, br.s), 7.52 (1H, s), 7.60 (1H, br.d), 9.43 (1H, br.
s) MS: 274 (M ⁺ ). Production Example 34 N, 2,2-trimethyl-6-acetylamido-7-nitro-2H-1-benzopyran-4-carbamide N, 2,2-trimethyl-6-acetylamido-2H-1-
Benzopyran-4-carbamide 1.16 g and acetic acid 15 m
To a mixture of the above, 0.50m of fuming nitric acid was added to 2m of acetic acid under ice-cooling and stirring.
Was added and stirred at room temperature for 1 hour. Ice water was added, and the mixture was extracted with a mixed solution of ethyl acetate and ether. The organic layer is washed with water and dried, and the residue obtained by evaporating the solvent is subjected to silica gel column chromatography (developing solution: CH ₂ Cl ₂ : MeOH = 9).
9: 1) and purified by melting point 213-215 ° C.
2,2-trimethyl-6-acetylamido-7-nitro-2
0.55 g of H-1-benzopyran-4-carbamide was obtained.

NMR (CDCl ₃ ): 1.45 (6H, s), 2.23 (3H, s), 2.96 (3H,
d), 6.25 (1H, br.s), 6.29 (1H, s), 7.59 (1H, s), 8.66
(1H, s), 9.92 (1H, br.s) MS: 319 (M ⁺ ) Production Example 35 N, 2,2-Trimethyl-6-amino-7-nitro-2H-1
-Benzopyran-4-carbamide N, 2,2-trimethyl-6-acetylamido-7-nitro-2H-1-benzopyran-4-carbamide 0.50 g,
A mixture of 15m of ethanol and 2N-sodium hydroxide was stirred at room temperature for 3 hours. Saturated saline was added and extracted with ether. The organic layer was washed with a saturated saline solution, dried, and the solvent was distilled off.N, 2,2 having a melting point of 202-205 ° C and represented by the following formula:
0.40 g of -trimethyl-6-amino-7-nitro-2H-1-benzopyran-4-carbamide were obtained.

_{NMR (CDCl 3): 1.43 (} 6H, s), 2.93 (3H, d), 5.91 (3H, b
rs), 6.20 (1H, s), 7.13 (1H, s), 7.52 (1H, s) MS: 277 (M ⁺ ) Production Example 36 N-cyano-N ', N'-dimethyl-6-nitrospiro [2H-1-benzopyran-2,1'-cyclobutane] -4
-Amidine N, N'-dimethyl-6-nitrospiro [2H-1-benzopyran-2,1'-cyclobutane] -4-carbothioamide 0.08 g, iodomethane 0.42 g, cyanamide 0.08 g and dry tetrahydrofuran 4m in a mixture of ice, Under cold stirring, 0.08 g of sodium hydride (60%) was added, and the mixture was stirred at room temperature for 12 hours and then at 40 ° C for 30 minutes. Ice water was added and extracted with methylene chloride. After washing the organic layer with water and drying,
The residue obtained by distilling off the solvent was purified by silica gel column chromatography (developing solution: CH ₂ Cl ₂ : MeOH = 99: 1), and recrystallized from a mixed solvent of ethyl acetate and hexane to give a melting point of 185-1.
At 87 ° C., N-cyano-N, N′-dimethyl-6-nitrospiro [2H-1-benzopyran-2,1′-
Cyclobutane] -4-amidine 0.06 g was obtained.

_{NMR (CDCl 3): 1.56-2.88 (} 6H, m), 3.00 (3H, s), 3.24
(3H, s), 6.25 (1H, s), 6.88 (1H, d), 7.56 (1H, d), 8.
01 (1H, dd). MS: 312 (M ⁺ ) Production Example 37 N-cyano-N'-methyl-6-nitrospiro [2H-1
-Benzopyran-2,1'-cyclohexane] -4-amidine N-methyl-6-nitro-spiro [2H-1-benzopyran-2,1'-cyclohexane] -4-carbothioamide 120 mg, iodoethane 150 μl and dry tetrahydrofuran 3 m To the mixture was added 23 mg of sodium hydride (60%) with stirring under ice-cooling, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, 80 mg of cyanamide and 17 mg of sodium hydride (60%) were added, and the mixture was heated under reflux for 4 hours. Ice water was added and extracted with ethyl acetate. The organic layer is washed with water and dried, and the residue obtained by evaporating the solvent is purified by silica gel column chromatography (developing solution: ethyl acetate: hexane = 2: 3) and recrystallized from a mixed solvent of ethyl acetate and hexane. As a result, 90 mg of N-cyano-N'-methyl-6-nitrospiro [2H-1-benzopyran-2,1'-cyclohexane] -4-amidine represented by the following formula and having a melting point of 244-245 ° C. was obtained.

_{NMR (CDCl 3 -CD 3 OD)} : 1.40-2.20 (10H, m), 2.95 (3H,
d), 5.95 (1H, s), 6.85 (1H, d), 7.75 (1H, d), 8.00 (1
H, dd) MS: 326 (M ⁺ ) Production Example 38 N- (2-cyanoethyl) -6-nitrospiro [2H-1
-Benzopyran-2,1'-cyclohexane] -4-carbamide 6-nitrospiro [2H-1-benzopyran-2,1'-
To a mixture of 500 mg of (cyclohexane) -4-carboxylic acid and 7 m of tetrahydrofuran, 365 mg of carbonyldiimidazole was added under ice-cooling and stirring, and the mixture was stirred for 1.5 hours, and then a solution of 0.37 m of 2-cyanoethylamine in 3.5 m of tetrahydrofuran was added.
Was added and the mixture was stirred under ice cooling for 45 minutes. An aqueous potassium carbonate solution was added, and the mixture was extracted with methylene chloride. The organic layer is washed with water and dried, and the residue obtained by evaporating the solvent is purified by silica gel column chromatography (developing solution: MeOH: CH ₂ Cl ₂ = 1: 99) and recrystallized from a mixed solvent of ethyl acetate and hexane. N- (2-cyanoethyl) -6-nitrospiro [2H-1-benzopyran-2, having a melting point of 122-124 ° C.
12.6 g of 1'-cyclohexane] -4-carbamide were obtained.

_{NMR (CDCl 3) δ: 0.89-2.32} (10H, m), 2.71 (2H, t), 3.
61 (2H, q), 6.11 (1H, s), 6.78 (1H, d), 7.26 (1H, t),
7.89 (1H, dd), 8.36 (1H, d). MS m / z: 341 (M ⁺ ) Production Example 39 2,2-Bisfluoromethyl-N-methyl-6-nitro-2
H-1-benzopyran-4-carbothioamide A mixture of 2,2-bisfluoromethyl-N-methyl-6-nitro-2H-1-benzopyran-4-carbamide 0.08 g, Lawesson's reagent 0.06 g, and benzene 2 m for 1 hour Heated to reflux. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (developing solution: CH ₂ Cl ₂ ), and further recrystallized with a mixed solvent of ethyl acetate and hexane to give a melting point.
2,2-bisfluoromethyl-N-methyl-6-nitro-2H-1-benzopyran- represented by the following formula at 134-135 ° C.
71 mg of 4-carbothioamide were obtained.

NMR (CDCl ₃ ) δ: 3.30 (3H, d), 4.60 (4H, d), 5.85 (1H,
d), 6.98 (1H, d), 7.97 (1H, brs), 8.07 (1H, dd), 8.37
(1H, d). MS m / z: 314 (M ⁺ ) Production Example 40 2,2-Bisfluoromethyl-N-methyl-6-nitro-2
H-1-benzopyran-4-carbamide (1) 2,2-bisfluoromethyl-3,4-dihydro-6
To a mixture of 4.05 g of nitro-2H-1-benzopyran-4-one and 10 m of dry benzene, while stirring under ice-cooling,
Add 2.52m of trimethylsilyl cyanide, add zinc iodide
0.82 g was added, and the mixture was stirred at room temperature for 12 hours. Further, 8 m of pyridine and 4.41 m of phosphorus oxychloride were added, and the mixture was heated under reflux for 6 hours. Ice water was added to the residue to make it hydrochloric acid and extracted with methylene chloride. The organic layer was washed with water and dried, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (eluent: CH ₂ Cl ₂ : hexane = 7: 3) to give a melting point of 136-137.
0.99 g of 4-cyano-2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran at <RTIgt;

NMR (CDCl ₃ ) δ: 4.57 (4H, d), 6.50 (1H, s), 6.97 (2H,
dd), 8.14 (2H, dd), 8.23 (1H, s) MS m / z: 266 (M ⁺ ) (2) 4-cyano-2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran 0.93g, acetic acid 20m, water 10m
And a mixture of concentrated sulfuric acid (10 m) was heated to reflux for 4.5 hours. When the reaction mixture was poured into ice water, crystals precipitated. The crystals were dissolved in aqueous sodium hydrogen carbonate and washed with methylene chloride. The aqueous layer was acidified with hydrochloric acid and extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off to obtain 0.83 g of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carboxylic acid having a melting point of 171-172 ° C.

IR (KBr) cm ^-1 : 1698 (C = 0). MS m / z: 285 (M ⁺ ) (3) 2,2-bisfluoromethyl-6-nitro-2H-1
A mixture of 0.78 g of -benzopyran-4-carboxylic acid and 5 m of tetrahydrofuran was added with 0.67 g of carbonyldiimidazole under ice cooling and stirring, followed by stirring for 1 hour. Thereafter, 6.3 m of 40% methylamine (methanol solution) was added, and the mixture was added under ice cooling for 1 hour.
And then stirred at room temperature for 14 hours. An aqueous potassium carbonate solution was added, and the mixture was extracted with ether. The organic layer is washed with water and dried, and the residue obtained by evaporating the solvent is purified by silica gel column chromatography (developing solution: MeOH: CH ₂ Cl ₂ = 1: 99 and expressed by the following formula having a melting point of 178-179 ° C. This gave 0.13 g of 2,2-bisfluoromethyl-N-methyl-6-nitro-2H-1-benzopyran-4-carbamide.

NMR (CDCl ₃ ) δ: 2.80 (3H, d), 4.68 (4H, d), 6.21 (1H,
s), 7.08 (1H, d), 8.10 (1H, dd), 8.46 (1H, brs), 8.48
(1H, d). MS m / z: 298 (M ⁺ ) Production Example 41 N- (2-cyanoethyl) -6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide N- (2-cyanoethyl) -6-nitro-2,2-dimethyl-2H -1-benzopyran-4-carbamide 0.40
g, Lawson's reagent 0.28g and benzene 2m
After heating and refluxing for 30 minutes, the mixture was purified by silica gel column chromatography (CH ₂ CH ₂ ), and further recrystallized from a mixture of diethyl ether and n-hexane to give N- (2 -Cyanoethyl) -6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide was obtained in an amount of 0.24 g.

NMR (CDCl ₃ ): 1.5 (6H, s), 2.9 (2H, t), 4.05 (2H, t),
5.9 (1H, s), 6.85 (1H, d), 8.0 (1H, dd), 8.3 (1H, d),
8.0-8.6 (1H, m). MS: 317 (M ^* ) Production Example 42 N- (2-cyanoethyl) -2,2-bisfluoromethyl-6-nitro-2H-benzopyran-4-carbamide 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4- To a mixture of 30 mg of carboxylic acid and 2 m of tetrahydrofuran, carbonylimidazole was added while stirring on ice.
28 mg was added and the mixture was stirred for 1 hour. Thereafter, 0.10 m of 2-cyanoethylamine was added, and the mixture was stirred under ice cooling for 1 hour, and then stirred at room temperature for 12 hours. An aqueous potassium carbonate solution was added, and the mixture was extracted with methylene chloride. The organic layer is washed with water and dried, and the residue obtained by evaporating the solvent is recrystallized with a mixed solvent of ethyl acetate and hexane to give N- (2) having a melting point of 173-174 ° C and represented by the following formula.
-Cyanoethyl) -2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carbamide 26.6 mg
I got

NMR (CDCl ₃ -CF ₃ COOD) δ: 2.89 (2H, t), 3.81 (2H, t),
4.61 (4H, d), 6.24 (1H, s), 7.05 (1H, d), 8.15 (1H,
d), 8.29 (1H, d) MS m / z: 337 (M ⁺ ). Production Examples 43 to 255 The compounds shown in the following table were synthesized using the methods described in the above Examples.

Next, the effects of the hair growth promoting agent of the present invention will be described with reference to examples, but the scope of the present invention is not significantly limited by the examples.

Example Hair growth promotion experiment using C3H mice Using C3H / HeN mice (male) whose hair cycle is in telogen,
Ogawa et al.'S method (“Normal and Abnormal Epidermal Diff
erentiation ", edited by M. Seiji and A. Bernstein, 159-170
Page, 1982, University of Tokyo Press).

That is, C3H / HeN mice (male) at the age of 7 weeks old were purchased and preliminarily reared for 2 weeks, and 10 mice were grouped as a group. The back was shaved. After one day, an ethanol solution (0.0003 to 1%) of the compound of the present invention is added for 1 day.
Once a day, 100 μ / animal was applied and administered with a pipette. Another group was applied with ethanol alone as a control, and another group was applied with an ethanol solution of minoxidil (0.1-1%) for comparison. The area of the hair growth portion was measured a predetermined number of days after application and administration, and the hair growth rate (%) was calculated assuming that the area of the hair removal portion on the back of the mouse was 100%. As the compound according to the present invention, compounds 3, 8, 10, 11, 14, 38, 39, 40, 41, 42,
87, 88, 89, 92, 94, 103, 108, 109, 131, 133, 135,
187, 190, 191, 195, 275, 282, 293, 302 were used. The results were as shown in FIGS. 2 and 4 show photographs of the mice 14 days after the application of Compound 3 and Compound 8, respectively.

INDUSTRIAL APPLICABILITY As is apparent from FIGS. 1 to 19, the hair growth promoter of the present invention containing a benzopyran derivative shows a considerably higher hair growth promoting effect than minoxidil. Therefore, the hair growth-promoting agent of the present invention is useful for treating and preventing alopecia areata, postpartum alopecia, and alopecia with anticancer agents, as well as male pattern baldness.

──────────────────────────────────────────────────続 き Continuation of front page (56) References JP-A-63-303977 (JP, A) JP-A-51-57838 (JP, A) JP-A-2-273610 (JP, A) JP-A-5-273 43432 (JP, A) JP-A-55-85582 (JP, A) Japanese Translation of PCT Application No. Hei 2-500272 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 7/06 C07D 311 / 58 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] (1) General formula (Wherein X represents OO,, S, ＮNZ or CHCHNO ₂ , wherein Z is a hydrogen atom, a lower alkyl group, an aryl group, a hydroxyl group, a lower alkoxy group, a cyano group, a carbamoyl group or a sulfamoyl group. Y represents -NR ₈ R ₉ , -OR ₁₀ or -SR ₁₁ , wherein R ₈ and R ₉ are the same or different and may be a lower alkoxy group optionally substituted by a hydrogen atom, a hydroxyl group or an ethynyl group; A cyano group, an amino group which may have a substituent, a lower alkyl group which may have a substituent, an unsaturated lower alkyl group which may have a substituent, May represent a cycloalkyl group, an aryl group optionally having a substituent, a heteroaryl group optionally having a substituent, or R ₈ and R ₉ together with a nitrogen atom, A heterocyclic ring which may have a substituent, such as an aziridinyl group, Group, a pyrrolidinyl group, a piperidinyl group, piperazyl group,
It represents a heterocyclic ring selected from a morpholino group and an imidazolyl group, and R ₁₀ and R ₁₁ represent a hydrogen atom, a lower alkyl group or an aryl group. Here, the substituent is a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, a nitro group,
Lower haloalkyl group, lower haloalkoxy group, cyano group, hydroxy group, lower alkoxycarbonylamino group, phenyl group, lower alkoxycarbonyl group, trialkylsilyl group, trialkylsilyloxy group, aminocarbonyl group, ethynyl group, lower alkylamino And represents one or more groups selected from a group, a lower alkylthio group and a lower alkylcarbonyl group. However, when R ₈ and R ₉ are a lower alkyl group, the lower alkyl group as the substituent is excluded. ; Or R ₁ represents a hydrogen atom, a lower alkyl group or an aryl group, or forms a single bond directly bonded to the R _2: R ₂ and R ₃ represents a hydrogen atom or a hydroxyl group the same or different, or Together to form = O, or
R ₂ is directly bonded to R ₁ to form a single bond; R ₄ and R ₅ are the same or different and represent a hydrogen atom, a lower alkyl group which may have a substituent, or taken together; Indicates a polymethylene group. Here, the substituent is a halogen atom,
And at least one group selected from a lower alkoxy group, an amino group, a nitro group, a lower haloalkyl group, a lower haloalkoxy group and a cyano group. R ₆ and R ₇ are the same or different and are a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a halogen atom, a lower alkoxy group, a lower haloalkoxy group, an amino group, an acylamino group, a nitro group, a cyano group, an ester group, A lower alkylsulfonyl group or an arylsulfonyl group, or together form = N-ON =), or one or more pharmaceutically acceptable salts thereof. A hair growth promoting agent comprising: 2. The hair growth promoting method according to claim 1, wherein R ₁ and R ₂ are directly bonded to form a single bond, and the benzopyran derivative or a pharmaceutically acceptable salt thereof wherein R ₃ is a hydrogen atom is contained. Agent. 3. R ₄ and R ₅ are the same or different and each represents one or more substituents selected from a halogen atom, a lower alkoxy group, an amino group, a nitro group, a lower haloalkyl group, a lower haloalkoxy group and a cyano group. The hair growth promoting agent according to claim 1, which contains a benzopyran derivative or a pharmaceutically acceptable salt thereof, which is a lower alkyl group which may be present or forms a polymethylene group together. 4. The hair growth-promoting agent according to claim 1, which comprises a benzopyran derivative wherein R ₆ is a 6-nitro group or a pharmaceutically acceptable salt thereof. 5. The hair growth-promoting agent according to claim 1, comprising a benzopyran derivative wherein Y is -NR ₈ R ₉ or a pharmaceutically acceptable salt thereof.