JP3352776B2 - Benzopyran and benzoxazine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel benzopyran and benzoxazine derivatives which are compounds useful as medicines.

[0002]

2. Description of the Related Art Benzopyran derivatives having various pharmacological actions have been known. For example, JP-A-60-
No. 97974, No. 61-47416, No. 63-165
No. 317, No. 63-196581, No. 63-2011
No. 82, No. 63-303977, No. 64-26578
No. 64-38087, JP-A-2-129184 and Journal of Medical.
Chemistry vol. 33, no. 6, p
p1529-1541, 1990, etc., disclose various benzopyran derivatives in which the carbon atom at the 4-position of the benzopyran ring is directly bonded to a nitrogen atom, and these compounds have an antihypertensive effect, and are used for the treatment of heart diseases and the like. It is described that it can be used.

[0003] Among the benzopyran derivatives disclosed in the above-mentioned documents, cromakalim represented by the following formula, together with nicorandil and pinacidil, has recently attracted attention as a new kind of antihypertensive drug acting on the K ⁺ channel.

[0004]

Embedded image Benzopyran derivatives in which the carbon atom at the 4-position of the benzopyran ring is not directly bonded to a nitrogen atom are also described in JP-A-63-303977, JP-A-64-38087, and WO9
No. 0/14346, Journal of Het
erocyclic Chemistry vol. 1
1 (5), pp. 797-802, 1974 and Jo
urnal of Medicinal Chemis
tryvol. 33, no. 6, pp. 1529-
1541, 1990 and the like. Above all,
WO 90/14346 discloses that a benzopyran ring having 4
Disclosed are compounds analogous to the compounds of the present invention having an amide or thioamide group at the 1-position.

[0005]

The present inventors have found that these compounds have a K ⁺ channel action activity equal to or higher than that of these similar compounds and cromakalim, and that the carbon atom at the 4-position of the benzopyran ring is directly bonded to the nitrogen atom. As a result of intensive studies on the synthesis of benzopyran derivatives having no benzopyran derivative and K ⁺ channel activity, it was discovered that novel benzopyran and benzoxazine derivatives which have not been described in the literature have such pharmacological activities. Was completed.

[0006]

The compound of the present invention is a novel compound represented by the following formula (I) and has an excellent K
⁺ Has channel action activity.

General formula

Embedded image Wherein R ₁ and R ₂ are the same or different and represent a lower haloalkyl group; R ₃ represents a hydrogen atom, or X
R ₄ represents a substituted or unsubstituted amino group, a saturated or unsaturated heterocyclic group, or A-
O- (A is a saturated or unsaturated carbocyclic group or a saturated or unsaturated heterocyclic group); R ₅ and R ₆ are the same or different and are a hydrogen atom, a halogen, a lower alkyl group, a lower haloalkyl group, a nitro group or a cyano group; X is = N-, N ⁺ -O ^- or

Embedded image Wherein R ₇ and R ₈ are the same or different and each represent a hydrogen atom, a hydroxyl group or a lower acyloxy group, or R ₇ is directly bonded to R ₃ to form a single bond). Benzopyran or benzoxazine derivatives.

In the definition of the compound represented by the formula (I), the alkyl group portion of the lower alkyl group or lower haloalkyl means an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms. It is. Examples of such lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and the like. . Further, the halogen atom of the lower haloalkyl means chlorine, fluorine, bromine and iodine, preferably chlorine and fluorine. The lower haloalkyl group includes, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a difluoroethyl group, a trifluoroethyl group, a pentafluoroethyl group and the like.

Examples of the substituent of the substituted amino group include a lower alkyl group, a lower alkanoyl group, a lower alkoxy group, an optionally protected hydroxyl group and the like.

Examples of the saturated or unsaturated heterocyclic groups include pyrrolidinyl, piperidinyl, pyridyl, pyridazinyl, isoindolyl, 2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl, 2-oxo. Examples include a pyridyl group, a 2-thioxo-1-pyridyl group, a 2-cyanoimino-1,2-dihydro-1-pyridyl group.

Examples of the lower acyloxy group include an acetyloxy group, a propionyloxy group, a butyryloxy group and a valeryloxy group.

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

General formula (II)

Embedded image (Wherein R ₁ , R ₂ , R ₅ and R ₆ have the same meanings as described above), and a compound represented by the general formula (II)
I) It can be obtained by reacting a compound represented by R ₄ H (III) (wherein R ₄ has the same meaning as described above) in the presence of a base in an inert solvent.

The base used herein includes, for example, sodium hydride, sodium alkoxide, potassium alkoxide, alkyl lithium, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, pyridine and triethylamine.

The compound of the general formula (I) is a compound of the general formula (IV)

Embedded image (Wherein R ₁ , R ₂ , R ₅ and R ₆ have the same meanings as described above), and the compound represented by the general formula (V)

Embedded image (In the formula, Y represents a lower alkylene group, an arylalkylene group, an alkylene group having a saturated or unsaturated heterocyclic ring, and Z represents a leaving group such as chlorine or bromine); And cyclization in an inert solvent.

The compound of the general formula (I) is a compound of the general formula (VI)

Embedded image (Where W is chlorine, bromine, a methanesulfonyloxy group,
A leaving group such as a trifluoromethanesulfonyloxy group) is represented by the general formula (VII):

Embedded image (Wherein R ₉ represents a methyl, ethyl, n-butyl, phenyl group or the like) by reacting the compound represented by the formula (1) in the presence of a palladium (0) complex in an inert solvent.

The palladium (0) complex used here includes a palladium (0) -phosphine complex, a palladium (0) -alkene complex and a palladium (0) -diene complex.

The compound of the general formula (I) is a compound of the general formula (VIII)

Embedded image (Wherein, R ₁ , R ₂ , R ₄ , R ₅ and R ₆ have the same meanings as described above).

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

The compound of the general formula (I) is a compound of the general formula (IX)

Embedded image (Wherein R ₁ , R ₅ , R ₆ and Z have the same meaning as described above), and the above-mentioned general formula (III) R ₄ H (III) (wherein R ₄ represents the same meaning as described above) in the presence of a base in an inert solvent.

Examples of the base used herein include sodium hydride, sodium alkoxide, potassium alkoxide, alkyl lithium, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, pyridine and triethylamine.

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

Hereinafter, the production of the compound of the present invention will be described in more detail with reference to Examples. Of course, the invention is not limited by these examples.

[0024]

【Example】

[0025]

Embodiment 16-pentafluoroethyl-2,2-bisfluoromethyl
4- (2-oxo-1-pyrrolidinyl) -2H-1
-Benzopyran (Compound 1-1),Trans-6-P
N-fluoroethyl-2,2-bisfluoromethyl-
3,4-dihydro-4- (2-oxo-1-pyrrolidini
Ru) -2H-1-benzopyran-3-ol(Compound 1
-2) 3,4-epoxy-6-pentafluoroethyl-2,2
-Bisfluoromethyl-3,4-dihydro-2H-1-
Benzopyran 0.41 g, 2-pyrrolidinone 0.18 g
And a mixture of 8 ml of tetrahydrofuran under ice-cooling and stirring.
0.22 g of potassium tert-butoxide was added and stirred for 3.5 hours
Then, the mixture was stirred at room temperature for 4 days. Add water and methylene
Extract with chloride. After washing the organic layer with water and drying, the solvent is distilled off.
Silica gel column chromatography
(Developing solution: MeOH: CH_TwoCl_Two= 1:99)
As a result, the melting point 104-1
6-pentafluoroethyl represented by the following formula at 05 ° C:
2,2-bisfluoromethyl-4- (2-oxo-1-
0.08 g of (pyrrolidinyl) -2H-1-benzopyran
Obtained.

[0026]

Embedded image Then, from the distilling fraction, the melting point is 196-197.
Trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4- (2-oxo-1-pyrrolidinyl) -2H-1- represented by the following formula:
0.25 g of benzopyran-3-ol was obtained.

[0027]

Embedded image

[0028]

Example 2 6-cyano-2,2-bisfluoromethyl-4- (2-
Oxo-1-pyrrolidinyl) -2H-1-benzopyran (compound 2-1), trans-6-cyano-2,2-
Bisfluoromethyl-3,4-dihydro-4- (2-o
(Oxo-1-pyrrolidinyl) -2H-1-benzopyran-
3-ol (Compound 2-2) In the same manner as in Example 1, a low-polar component having a melting point of 1
6-cyano-2,2 represented by the following formula at 40-141 ° C.
-Bisfluoromethyl-4- (2-oxo-1-pyrrolidinyl) -2H-1-benzopyran was obtained.

[0029]

Embedded image Next, trans-6-cyano-2,2-bisfluoromethyl-3,4-dihydro-4- (2-oxo-1-pyrrolidinyl) represented by the following formula having a melting point of 216-218 ° C. as a highly polar component. -2H-1-benzopyran-3-
Got an oar.

[0030]

Embedded image

[0031]

Example 3 2,2-bisfluoromethyl-6-nitro-4- (2-
Oxo-1-pyrrolidinyl) -2H-1-benzopyran (compound 3-1), trans-2,2-bisfluoro
Methyl-3,4-dihydro-6-nitro-4- (2-o
(Oxo-1-pyrrolidinyl) -2H-1-benzopyran-
3-ol (Compound 3-2) In the same manner as in Example 1, a low-polar component having a melting point of 1
There was obtained 2,2-bisfluoromethyl-6-nitro-4- (2-oxo-1-pyrrolidinyl) -2H-1-benzopyran represented by the following formula at 47-148 ° C.

[0032]

Embedded image Next, as a highly polar component, trans-2,2-bisfluoromethyl-3,4-dihydro-6-nitro-4- (2-oxo-) represented by the following formula and having a melting point of 256-258 ° C.
1-Pyrrolidinyl) -2H-1-benzopyran-3-ol was obtained.

[0033]

Embedded image

[0034]

Embodiment 46-pentafluoroethyl-2,2-bisfluoromethyl
4- (2-oxo-1-piperidinyl) -2H-1
-Benzopyran (Compound 4-1),Trans-6-P
N-fluoroethyl-2,2-bisfluoromethyl-
3,4-dihydro-4- (2-oxo-1-piperidini
Ru) -2H-1-benzopyran-3-ol(Compound 4
-2) 3,4-epoxy-6-pentafluoroethyl-2,2
-Bisfluoromethyl-3,4-dihydro-2H-1-
Benzopyran 0.54 g, 2-piperidinone 0.24 g
And a mixture of 10 ml of tetrahydrofuran and ice-cooled
Below, 0.27 g of potassium tert-butoxide is added and stirred for 6 hours
Then, the mixture was stirred at room temperature for 16 hours. Add ice water and add
Extract with len chloride. After washing the organic layer with water and drying, the solvent
The residue obtained by distilling off the residue was purified by silica gel column chromatography.
(Developing solution: MeOH: CH_TwoCl_Two= 1:99)
When produced, the first distilling fraction has a melting point of 149
6-pentafluoroethyl represented by the following formula at −150 ° C.
Ru-2,2-bisfluoromethyl-4- (2-oxo-
1-piperidinyl) -2H-1-benzopyran 0.02
g was obtained.

[0035]

Embedded image Subsequently, the melting point of 199-200
Trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4- (2-oxo-1-piperidinyl) -2H-1- represented by the following formula:
0.44 g of benzopyran-3-ol was obtained.

[0036]

Embedded image

[0037]

Example 5 6-cyano-2,2-bisfluoromethyl-4- (2-
Oxo-1-piperidinyl) -2H-1-benzopyran (compound 5-1), trans-6-cyano-2,2-
Bisfluoromethyl-3,4-dihydro-4- (2-o
(Oxo-1-piperidinyl) -2H-1-benzopyran-
3-ol (Compound 5-2) In the same manner as in Example 4, a compound having a melting point of 1 having a low polarity was used.
6-cyano-2,2 represented by the following formula at 74-176 ° C:
-Bisfluoromethyl-4- (2-oxo-1-piperidinyl) -2H-1-benzopyran was obtained.

[0038]

Embedded image Next, trans-6-cyano-2,2-bisfluoromethyl-3,4-dihydro-4- (2-oxo-1-piperidinyl) represented by the following formula having a melting point of 201 to 203 ° C. as a highly polar component. -2H-1-benzopyran-3-
Got an oar.

[0039]

Embedded image

[0040]

Example 6 2,2-bisfluoromethyl-6-nitro-4- (2-
Oxo-1-piperidinyl) -2H-1-benzopyran (compound 6-1), trans-2,2-bisfluoro
Methyl-3,4-dihydro-6-nitro-4- (2-o
(Oxo-1-piperidinyl) -2H-1-benzopyran-
3-ol (Compound 6-2) In the same manner as in Example 4, the compound having a melting point of 1
There was obtained 2,2-bisfluoromethyl-6-nitro-4- (2-oxo-1-piperidinyl) -2H-1-benzopyran represented by the following formula at 61-162 ° C.

[0041]

Embedded image Next, trans-2,2-bisfluoromethyl-3,4-dihydro-6-nitro-4- (2-oxo-1-piperidinyl) represented by the following formula having a melting point of 231-233 ° C. as a highly polar component. -2H-1-benzopyran-3-
Got an oar.

[0042]

Embedded image

[0043]

Example 7 trans-6-pentafluoroethyl-2,2-bisph
Fluoromethyl-3,4-dihydro-4- (2-pyridyl
Oxy) -2H-1-benzopyran-3-ol (compound 7-1), trans-6-pentafluoroethyl-
2,2-bisfluoromethyl-3,4-dihydro-4-
(1,2-dihydro-2-oxo-1-pyridyl) -2
H-1-benzopyran-3-ol (compound 7-2) 3,4-epoxy-6-pentafluoroethyl-2,2
-Bisfluoromethyl-3,4-dihydro-2H-1-
Benzopyran 0.42 g, 2-hydroxypyridine 0.
A mixture of 21 g, 0.11 g of pyridine and 4 ml of ethanol was refluxed for 3 hours. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (developing solution: MeOH:
(CH ₂ Cl ₂ = 1: 99), oily trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydrochloride represented by the following formula was obtained from the first distilled fraction. -4- (2-pyridyloxy)
0.11 g of -2H-1-benzopyran-3-ol was obtained.

[0044]

Embedded image Then, the melting point 162-164 was obtained from the distilling fraction.
Trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4- (1,2-dihydro-2-oxo-1-pyridyl) -2H- 0.29 g of 1-benzopyran-3-ol
I got

[0045]

Embedded image

[0046]

Example 8 6-pentafluoroethyl-2,2-bisfluoromethyl
4- (1,2-dihydro-2-oxo-1-pyridi
L) -2H-1-benzopyran (compound 8) trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4- (1,2-dihydro-2-oxo-1-pyridyl ) A mixture of 0.15 g of 2H-1-benzopyran-3-ol, 0.07 g of methanesulfonyl chloride, 0.08 g of triethylamine and 10 ml of tetrahydrofuran was stirred at room temperature for 8 hours. The solvent is distilled off, water is added, and the mixture is extracted with methylene chloride. The organic layer was washed with water and dried, and the residue obtained by evaporating the solvent was dissolved in 4 ml of tetrahydrofuran.
0.06 g of sodium hydride (60%) was added, and the mixture was stirred at room temperature for 66 hours. Add ice water and extract with methylene chloride. After the organic layer is washed with water and dried, the residue obtained by evaporating the solvent is subjected to silica gel column chromatography (developing solution: M
(MeOH: CH ₂ Cl ₂ = 1: 99).
6-pentafluoroethyl-2,2-bisfluoromethyl-4- (1,2-dihydro-2-oxo-1-pyridyl) -2H-1-benzopyran represented by the following formula at 7-138 ° C. 09 g were obtained.

[0047]

Embedded image

[0048]

Example 9 trans-6-cyano-2,2-bisfluoromethyl-
3,4-dihydro-4- (1,2-dihydro-2-oxo
So-1-pyridyl) -2H-1-benzopyran-3-o
In Lumpur similar to (Compound 9) Example 7 method, trans-6-cyano-2,2-bis-fluoro-3,4-dihydro-4 represented by the following formula having a melting point of 213-214 ° C. ( 1,2-Dihydro-2-oxo-1-pyridyl) -2H-1-benzopyran-3-ol was obtained.

[0049]

Embedded image

[0050]

Example 10 6-cyano-2,2-bisfluoromethyl-4- (1,
2-dihydro-2-oxo-1-pyridyl) -2H-1
-Benzopyran (compound 10) trans-6-cyano-2,2-bisfluoromethyl-
A mixture of 0.13 g of 3,4-dihydro-4- (1,2-dihydro-2-oxo-1-pyridyl) -2H-1-benzopyran-3-ol, 0.13 g of soda talc and 2 ml of dioxane was refluxed for 45 minutes. did. Add water and extract with ethyl acetate. The organic layer was washed with water and dried, and the residue obtained by evaporating the solvent was recrystallized from ethyl acetate to give 6-cyano-melting point having a melting point of 174 to 175 ° C.
2,2-Bisfluoromethyl-4- (1,2-dihydro-2-oxo-1-pyridyl) -2H-1-benzopyran was obtained.

[0051]

Embedded image

[0052]

Example 11 trans-2,2-bisfluoromethyl-3,4-dihi
Dro-6-nitro-4- (1,2-dihydro-2-oxo
So-1-pyridyl) -2H-1-benzopyran-3-o
Lumpur in the same manner as (Compound 11) Example 7 method, trans-2,2-bis fluoromethyl represented by the following formula having a melting point of 226-228 ° C. -
3,4-Dihydro-6-nitro-4- (1,2-dihydro-2-oxo-1-pyridyl) -2H-1-benzopyran-3-ol was obtained.

[0053]

Embedded image

[0054]

Example 12 2,2-Bisfluoromethyl-6-nitro-4- (1,1
2-dihydro-2-oxo-1-pyridyl) -2H-1
-Benzopyran (Compound 12) In the same manner as in Example 10, 2,2-bisfluoromethyl-6-nitro-4- (1,2-dihydro-2- having a melting point of 171-173 ° C and represented by the following formula: Oxo-1-pyridyl) -2H-1-benzopyran was obtained.

[0055]

Embedded image

[0056]

Example 13 2,2-bisfluoromethyl-6-nitro-4- (1,1
2-dihydro-2-thioxo-1-pyridyl) -2H-
1-benzopyran (compound 13) 2,2-bisfluoromethyl-6-nitro-4- (1,1
2-dihydro-2-oxo-1-pyridyl) -2H-1
A mixture of 0.13 g of benzopyran, 83 mg of Lawesson's reagent, 1 ml of benzene and 1 ml of 1,2-dichloroethane was refluxed for 3 hours. After the solvent was distilled off, the residue was purified by silica gel column chromatography (developing solution: CH ₂ Cl ₂ ), and then recrystallized from a mixture of ethyl acetate and hexane. 2
-Bisfluoromethyl-6-nitro-4- (1,2-dihydro-2-thioxo-1-pyridyl) -2H-1-benzopyran 0.05 g was obtained.

[0057]

Embedded image

[0058]

Example 14 4- (2-cyanoimino-1,2-dihydro-1-pyri )
(Jill) -2,2-bisfluoromethyl-6-nitro-2
H-1-benzopyran (compound 14) 2,2-bisfluoromethyl-6-nitro-4- (1,
2-dihydro-2-thioxo-1-pyridyl) -2H-
1-benzopyran 0.09 g, methyl iodide 0.20 g
And a mixture of 5 ml of tetrahydrofuran were refluxed for 50 minutes, and then 57 mg of cyanamide and sodium hydride (60 ml) were added.
%) And refluxed for 1.5 hours. Methylene chloride was added, the insolubles were filtered off, the mother liquor was distilled off, and the residue obtained was purified by silica gel column chromatography (developing solution:
Purification by AcOEt: hexane = 1: 1) gives 4- (2-cyanoimino-1,2-dihydro-1-pyridyl) -2,2- represented by the following formula having a melting point of 238-240 ° C.
There was obtained 0.05 g of bisfluoromethyl-6-nitro-2H-1-benzopyran.

[0059]

Embedded image

[0060]

Example 15 trans-3-acetoxy-4- (N-acetyl-N-
Benzyloxy) amino-6-pentafluoroethyl-
2,2-bisfluoromethyl-3,4-dihydro-2H
-1-benzopyran (compound 15-1), trans-
4- (N-acetyl-N-benzyloxy) amino-6
-Pentafluoroethyl-2,2-bisfluoromethyl
-3,4-dihydro-2H-1-benzopyran-3-o
Lumpur (Compound 15-2) 3,4-epoxy-6-pentafluoroethyl-2,2
-Bisfluoromethyl-3,4-dihydro-2H-1-
A mixture of 0.45 g of benzopyran, 0.25 g of benzyloxyamine hydrochloride, 0.28 g of triethylamine and 4 ml of ethanol was refluxed for 10 hours. The solvent is distilled off, water is added, and the mixture is extracted with a mixed solvent of ethyl acetate and ether. The organic layer was washed with brine, dried, evaporated, and purified by silica gel column chromatography (developing solution: MeOH: CH ₂ Cl ₂ = 1: 99) to give trans-4- (N-benzyloxy). Amino-6-pentafluoroethyl-2,2-bisfluoromethyl-
0.43 g of 3,4-dihydro-2H-1-benzopyran-3-ol was obtained. 0.40 ml of this pyridine
And 4 ml of chloroform, and 0.10 ml of acetyl chloride was added under ice-cooling and stirring, followed by stirring for 30 minutes and then at room temperature for 1 hour. Add diluted hydrochloric acid and extract with methylene chloride. After the organic layer was washed with water and dried, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (developing solution: MeOH: CH ₂ Cl ₂ = 1: 99).
Melting point 107-108 ° C from the first distilling fraction
Trans-3-acetoxy-4- represented by the following formula:
(N-acetyl-N-benzyloxy) amino-6-pentafluoroethyl-2,2-bisfluoromethyl-
0.15 g of 3,4-dihydro-2H-1-benzopyran
I got

[0061]

Embedded image Next, the melting point is 98-100 ° C. from the distilling fraction.
Trans-4- (N-acetyl-N represented by the following formula:
-Benzyloxy) amino-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2
0.20 g of H-1-benzopyran-3-ol was obtained.

[0062]

Embedded image

[0063]

Example 16 trans-4- (N-acetyl-N-hydroxy) amido
No-6-pentafluoroethyl-2,2-bisfluoro
Methyl-3,4-dihydro-2H-1-benzopyran-
3-ol (Compound 16) trans-4- (N-acetyl-N-benzyloxy) amino-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran-3 -All 0.10
g, 10% palladium on carbon 90mg and ethanol 8m
The mixture was catalytically reduced at room temperature under a stream of hydrogen. The insolubles were removed by suction filtration, and the residue obtained by evaporating the mother liquor was subjected to silica gel column chromatography (developing solution: MeOH: C
(H ₂ Cl ₂ = 1: 99), melting point 67-70 ° C.
Trans-4- (N-acetyl-N represented by the following formula:
-Hydroxy) amino-6-pentafluoroethyl-
2,2-bisfluoromethyl-3,4-dihydro-2H
0.06 g of -1-benzopyran-3-ol was obtained.

[0064]

Embedded image

[0065]

Embodiment 17Trans-4- (N-acetyl-N-benzyloxy)
Amino-6-cyano-2,2-bisfluoromethyl-
3,4-dihydro-2H-1-benzopyran-3-o
Le (Compound 17) In the same manner as in Example 15, with a melting point of 210-212 ° C.
The trans-4- (N-acetyl-N-beta) represented by the above formula
Ndyloxy) amino-6-cyano-2,2-bisfur
Oromethyl-3,4-dihydro-2H-1-benzopyra
-3-ol was obtained.

[0066]

Embedded image

[0067]

Example 18 trans-4- (N-acetyl-N-H
Droxy) amino-6-cyano-2,2-bisfluoro
Methyl-3,4-dihydro-2H-1-benzopyran-
3-ol (Compound 18) In the same manner as in Example 16, trans-4- (N-acetyl-N-hydroxy) amino-6-cyano-2,2 having a melting point of 230-232 ° C. and represented by the following formula: -Bisfluoromethyl-3,4-dihydro-2H-1-benzopyran-
3-ol was obtained.

[0068]

Embedded image

[0069]

Example 19 trans-4- (N-acetyl-N-benzyloxy)
Amino-2,2-bisfluoromethyl-3,4-dihydride
B-6-Nitro-2H-1-benzopyran-3-ol (Compound 19) In the same manner as in Example 15, trans-4- (N-acetyl-N having a melting point of 207-210 ° C and represented by the following formula: -Benzyloxy) amino-2,2-bisfluoromethyl-
3,4-Dihydro-6-nitro-2H-1-benzopyran-3-ol was obtained.

[0070]

Embedded image

[0071]

Example 20 trans-6-pentafluoroethyl-
2,2-bisfluoromethyl-3,4-dihydro-4-
(3-oxo-1-cyclopent-1-enyloxy)
-2H-1-benzopyran-3-ol (compound 20) Dissolve 0.36 g of cyclopentane-1,3-dione in 40 ml of tetrahydrofuran, and cool at −20 ° C. under a nitrogen stream while cooling at −20 ° C. (60%) After adding 0.13 g and stirring at room temperature for 15 minutes, 0.72 g of a copper (I) bromide / dimethylsulfide complex was added. To this reaction solution,
0.92 g of 4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran was dissolved in 10 ml of tetrahydrofuran, and the mixture was stirred for 6 days. Add water, add a small amount of concentrated sulfuric acid, and extract with methylene chloride. The organic layer was washed with water and dried, and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography (developing solution: MeOH: CH ₂ Cl ₂ = 1: 1).
99), followed by silica gel column chromatography (developing solution: AcOEt: hexane = 1: 1).
When purified in 1), trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4- (3-oxo-1-cyclopent- having a melting point of 165 to 167 ° C and represented by the following formula: 1-enyloxy) -2H-1
0.04 g of -benzopyran-3-ol was obtained.

[0072]

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[0073]

Example 21 trans-6-cyano-2,2-bisph
Fluoromethyl-3,4-dihydro-4- (3-oxo-
1-cyclopent-1-enyloxy) -2H-1-be
Nzopyran-3-ol (Compound 21) In the same manner as in Example 20, trans-6-cyano-2,2-bisfluoromethyl-3,4-dihydro- having a melting point of 200-201 ° C and represented by the following formula: 4- (3-oxo-
1-Cyclopent-1-enyloxy) -2H-1-benzopyran-3-ol was obtained.

[0074]

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[0075]

Example 22 trans-2,2-bisfluoromethyl
-3,4-dihydro-6-nitro-4- (3-oxo-
1-cyclopent-1-enyloxy) -2H-1-be
Nzopyran-3-ol (Compound 22) In the same manner as in Example 20, trans-2,2- bisfluoromethyl- 3,4-dihydro-6-nitro- having a melting point of 206-208 ° C and represented by the following formula: 4- (3-oxo-
1-Cyclopent-1-enyloxy) -2H-1-benzopyran-3-ol was obtained.

[0076]

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[0077]

Example 23 trans-6-pentafluoroethyl-2,2-bisph
Fluoromethyl-3,4-dihydro-4-[(1,6-di
Hydro-1-methyl-6-oxo-3-pyridazinyl)
Oxy] -2H-1-benzopyran-3-ol (compound 23) 3,4-epoxy-6-pentafluoroethyl-2,2
-Bisfluoromethyl-3,4-dihydro-2H-1-
Benzopyran 0.58 g, 3-hydroxy-1-methyl-1,6-dihydropyridazin-6-one 0.22 g,
A mixture of 0.16 g of pyridine and 5 ml of ethanol was added to 5
Refluxed for hours. The residue obtained by evaporating the solvent is subjected to silica gel column chromatography (developing solution: MeOH: CH ₂ C).
l ₂ = 1: 99), melting point 189-191 ° C.
Trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro- represented by the following formula:
4-[(1,6-dihydro-1-methyl-6-oxo-
0.60 g of [3-pyridazinyl) oxy] -2H-1-benzopyran-3-ol was obtained.

[0078]

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[0079]

Example 24 trans-6-cyano-2,2-bisfluoromethyl-
3,4-dihydro-4-[(1,6-dihydro-1-me
Tyl-6-oxo-3-pyridazinyl) oxy] -2H
-1-benzopyran-3-ol (compound 24) In the same manner as in Example 23, trans-6-cyano-2,2-bisfluoromethyl-3,4 having a melting point of 215 to 217 ° C. and represented by the following formula: -Dihydro-4-[(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)
Oxy] -2H-1-benzopyran-3-ol was obtained.

[0080]

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[0081]

Example 25 trans-2,2-bisfluoromethyl-3,4-dihi
Dro-4-[(1,6-dihydro-1-methyl-6-o
Oxo-3-pyridazinyl) oxy] -6-nitro-2H
-1-benzopyran-3-ol (compound 25) In the same manner as in Example 23, trans-2,2-bisfluoromethyl-3,4-dihydro-4 represented by the following formula and having a melting point of 226-228 ° C. -[(1,6-dihydro-1-
Methyl-6-oxo-3-pyridazinyl) oxy] -6
-Nitro-2H-1-benzopyran-3-ol was obtained.

[0082]

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[0083]

Example 26 6-pentafluoroethyl-2,2-bisfluoromethyl
Ru-4-[(1,6-dihydro-1-methyl-6-oxo
So-3-pyridazinyl) oxy] -2H-1-benzopy
Run (Compound 26) In the same manner as in Example 8, melting point 150-152 ° C, 6-pentafluoroethyl-2,2-bisfluoromethyl-4-[(1,6-dihydro- 1-methyl-6-oxo-3-pyridazinyl) oxy] -2H-
1-benzopyran was obtained.

[0084]

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[0085]

Example 27 trans-2,2-bisfluoromethyl-3,4-dihi
Dro-4- (2,3-dihydro-1-oxo-1H-i
Soindol-2-yl) -6-nitro-2H-1-be
Nzopyran-3-ol (Compound 27) (1) 0.53 g of 3,4-epoxy-2,2- bisfluoromethyl- 3,4-dihydro-6-nitro-2H-1-benzopyran, 15 ml of concentrated aqueous ammonia and A mixture of 15 ml of ethanol was stirred at room temperature for 42 hours. The solvent is distilled off, methylene chloride is added, and the mixture is extracted with 1N aqueous hydrochloric acid. The aqueous layer is made alkaline with 2N sodium hydroxide and extracted with methylene chloride. After the organic layer was washed with water and dried, the residue obtained by evaporating the solvent was recrystallized with a mixed solvent of ethyl acetate and hexane to give a melting point of 1
4-amino-2,2-bisfluoromethyl-3,4-dihydro-6 represented by the following formula at 74-177 ° C (decomposition).
-Nitro-2H-1-benzopyran-3-ol 0.3
2 g are obtained.

[0086]

Embedded image (2) 4-amino-2,2-bisfluoromethyl-3,
4-dihydro-6-nitro-2H-1-benzopyran-
A mixture of 0.25 g of 3-ol, 0.22 g of methyl 2-bromomethylbenzoate, 0.40 g of potassium carbonate, 0.09 g of potassium iodide and 5 ml of acetonitrile was stirred at 75-85 ° C. for 6 hours. Add water and extract with a mixed solvent of ethyl acetate and ether. The organic layer was washed with 1N aqueous hydrochloric acid, dried, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (developing solution: Ac
OEt: hexane = 1: 1) and recrystallized with a mixed solvent of ethyl acetate-hexane.
Trans-2,2- represented by the following formula at 85-288 ° C.
Bisfluoromethyl-3,4-dihydro-4- (2,3
-Dihydro-1-oxo-1H-isoind-2-yl) -6-nitro-2H-1-benzopyran-3-ol 0.15 g was obtained.

[0087]

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[0088]

Example 28 2- (6-cyano-2,2-bisfluoromethyl-2H
-1-benzopyran-4-yl) pyridine N-oxy
De (Compound 28) (1) 6-cyano-2,2-bisfluoromethyl -3,
4-dihydro-2H-1-benzopyran-4-one
A mixture of 20 g, 3.09 g of dimethylaminopyridine and 12 ml of dry methylene chloride was added dropwise with stirring under ice-cooling to 0.35 ml of trifluoromethanesulfonic anhydride.
Stir for a minute. Then, the mixture was stirred at room temperature for 1 hour. Add water,
Extract with methylene chloride. After washing the organic layer with water and drying,
The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (developing solution: CH ₂ Cl ₂ : hexane = 1: 1).
Purification in 1) gives an oily 6-cyano-4-trifluoromethanesulfonyloxy-2 represented by the following formula:
2-bisfluoromethyl-2H-1-benzopyran
12 g were obtained.

[0089]

Embedded image (2) 6-cyano-4-trifluoromethanesulfonyloxy-2,2-bisfluoromethyl-2H-1-benzopyran 120 mg, 2-trimethylstannylpyridine 87 mg, trisdibenzylideneacetone chloroformdipalladium (0) 25.4 mg , 12.8 mg of triphenylphosphine, 110 mg of lithium chloride and 6 ml of dry tetrahydrofuran were refluxed for 6.5 hours. After cooling, add ether and filter through a Celite membrane. The organic layer of the mother liquor 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 C).
l ₂ ), the oily product of 6- represented by the following formula:
80 mg of cyano-2,2-bisfluoromethyl-4- (2-pyridyl) -2H-1-benzopyran were obtained.

[0090]

Embedded image (3) 6-cyano-2,2-bisfluoromethyl-4-
Dissolve 80 mg of (2-pyridyl) -2H-1-benzopyran in 3 ml of methylene chloride, and add
75.7 mg of chloroperbenzoic acid (70%) was added, and the mixture was stirred at room temperature for 15 hours. m-chloroperbenzoic acid (70%) 2
8 mg was added, and the mixture was stirred again for 19 hours. Add aqueous sodium bicarbonate,
Extract with methylene chloride. After washing the organic layer with water and drying,
The residue obtained by distilling off the solvent is subjected to silica gel column chromatography (developing solution: MeOH: CH ₂ Cl ₂ = 1: 99).
2- (6-cyano-2,2-bisfluoromethyl-2H having a melting point of 204-207 ° C.
30 mg of -1-benzopyran-4-yl) pyridine N-oxide were obtained.

[0091]

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[0092]

Example 29 2- (2,2-Bisfluoromethyl-6-nitro-2H
-1-benzopyran-4-yl) pyridine N-oxy
De (Compound 29) (1) 2,2-bis-fluoro-3,4-dihydro-6-nitro-2H-1-benzopyran-4-one as a starting material, in the same manner as in Example 28 method, oil 4-trifluoromethanesulfonyloxy-2,2-bisfluoromethyl-6-nitro-2H represented by the following formula:
-1-benzopyran was obtained.

[0093]

Embedded image (2) In the same manner as in Example 28, an oil-like 2,2-bisfluoromethyl-6-nitro-4 represented by the following formula:
-(2-Pyridyl) -2H-1-benzopyran was obtained.

[0094]

Embedded image (3) In the same manner as in Example 28, melting point 183-184
2- (2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl) represented by the following formula at ° C.
Pyridine N-oxide was obtained.

[0095]

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[0096]

Example 30 2,2-Bisfluoromethyl-6-nitro-4- (2-
Oxo-1-pyrrolidinyl) -2H-1,3-benzoo
Xazine (compound 30) (1) 2,2- bisfluoromethyl -3,4-dihydro-6-nitro-2H-1,3-benzoxazine-4-
A mixture of 0.09 g of ON, 0.18 g of phosphorus pentachloride and 1 ml of phosphorus oxychloride was stirred at room temperature for 20 minutes.
Stirred at 60 ° C. for 3 hours. The residue obtained by evaporating the solvent is subjected to silica gel column chromatography (developing solution: CH ₂ C).
Purification by l _2), to give 4-chloro-2,2-bisfluoromethyl-6-nitro-2H-1,3-benzoxazine 0.10g represented by the following formula having a melting point of 75-77 ° C..

[0097]

Embedded image (2) 62 mg of 2-pyrrolidinone was dissolved in 1 ml of N, N-dimethylformamide, 35 mg of sodium hydride (60%) was added under a stream of nitrogen, and the mixture was stirred at room temperature for 20 minutes. 90 mg of fluoromethyl-6-nitro-2H-1,3-benzoxazine was added to N,
A solution dissolved in 2 ml of N-dimethylformamide was added, and the mixture was stirred at 45 to 55 ° C for 5 hours. Add saturated saline and extract with ethyl acetate. The organic layer was washed with saturated saline, dried, and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography (developing solution: MeOH: CH).
₍ Cl ₂ = 1: 99).
2,2-bisfluoromethyl-6 represented by the following formula
-Nitro-4- (2-oxo-1-pyrrolidinyl) -2
50 mg of H-1,3-benzoxazine were obtained.

[0098]

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[0099]

Example 31 trans-6-cyano-2,2-bisfluoromethyl-
4- (1,2-dihydro-2-oxo-4-pyridylo
Xy) -2H-1-benzopyran-3-ol (Compound 31) 6-cyano-3,4-epoxy-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran 2
50 mg, 2,4-dihydroxypyridine 116 mg,
A mixture of 4 ml of ethyl alcohol and 0.084 ml of pyridine was heated under reflux for 4 hours. The residue obtained by removing the solvent is subjected to silica gel column chromatography (developing solution: MeO
H: CH ₂ Cl ₂ = 1: 99).
Trans-6-cyano represented by the following formula at −250 ° C.
71 mg of 2,2-bisfluoromethyl-4- (1,2-dihydro-2-oxo-4-pyridyloxy) -2H-1-benzopyran-3-ol was obtained.

[0100]

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[0101]

Example 32 trans-2,2-bisfluoromethyl-6-heptaph
Fluoropropyl-3,4-dihydro-4- (2-oxo
-1-pyrrolidinyl) -2H-1-benzopyran-3-
All (compound 32) (1) 2,2-bisfluoromethyl-6-iodo-2H
-1-benzopyran 4.4 g, potassium heptafluorobutyrate 34.3 g, cuprous iodide 26.2 g, toluene 4
0 ml and N, N-dimethylformamide 100 ml
The mixture was heated and stirred at 110 ° C. for 1 hour and further stirred for 150 hours.
The mixture was heated and stirred at 300C for 3 hours while distilling off toluene. A mixture of 2N hydrochloric acid and ethyl acetate was added to the reaction mixture, and insolubles were removed by filtration through Celite. The filtrate was further extracted with ethyl acetate, washed with a 10% aqueous solution of sodium sulfite and saturated saline, dried over sodium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (developing solution: hexane: CH _2). Purification with Cl ₂ = 5: 1) gave 2.5 g of an oily 2,2-bisfluoromethyl-6-heptafluoropropyl-2H-1-benzopyran represented by the following formula.

Embedded image (2) A mixture of 3.1 g of 2,2-bisfluoromethyl-6-heptafluoropropyl-2H-1-benzopyran, 4.20 g of m-chloroperbenzoic acid (70%) and 50 ml of methylene chloride was allowed to stand at room temperature for 27 hours. And stirred. After the precipitated crystals were separated by filtration, the filtrate was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (developing solution: hexane). : C
_{H 2 Cl 2 = 5: 1} ) to furnish the following formula oily 3,4-epoxy-2,2-bisfluoromethyl -6
-Heptafluoropropyl-3,4-dihydro-2H-
1.44 g of 1-benzopyran were obtained.

[0102]

Embedded image (3) 3,4-epoxy-2,2-bisfluoromethyl-6-heptafluoropropyl-3,4-dihydro-2
In the same manner as in Example 1 using H-1-benzopyran,
Trans- having a melting point of 174-175 ° C. and represented by the following formula:
2,2-Bisfluoromethyl-6-heptafluoropropyl-3,4-dihydro-4- (2-oxo-1-pyrrolidinyl) -2H-1-benzopyran-3-ol was obtained.

[0103]

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[0104]

Example 33 2,2-Bisfluoromethyl-6-heptafluoropro
Pyr-4- (2-oxo-1-pyrrolidinyl) -2H-
1-benzopyran (compound 33) trans-2,2-bisfluoromethyl-6-heptafluoropropyl-3,4-dihydro-4- (2-oxo-1-pyrrolidinyl) -2H-1-benzopyran-3-
In the same manner as in Example 10 using all as a starting material, an oily 2,2-bisfluoromethyl-6 represented by the following formula was used.
-Heptafluoropropyl-4- (2-oxo-1-pyrrolidinyl) -2H-1-benzopyran was obtained.

[0105]

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[0106]

Example 34 trans-2,2-bisfluoromethyl-6-trifur
Oromethyl-3,4-dihydro-4- (2-oxo-1
-Pyrrolidinyl) -2H-1-benzopyran-3-o
Le (Compound 34) (1) 2,2-bis fluoromethyl-6-iodo -2H
Using benzopyran and potassium trifluoroacetate,
In the same manner as in Example 32 (1), oily 2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran represented by the following formula was obtained.

[0107]

Embedded image (2) Example 32 using 2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran
In the same manner as in (2), an oily compound represented by the following formula
-Epoxy-2,2-bisfluoromethyl-6-trifluoromethyl-3,4-dihydro-2H-1-benzopyran was obtained.

[0108]

Embedded image (3) 3,4-epoxy-2,2-bisfluoromethyl-6-trifluoromethyl-3,4-dihydro-2H-
In the same manner as in Example 1 using 1-benzopyran, trans-2,2 having a melting point of 186-187 ° C. and represented by the following formula:
-Bisfluoromethyl-6-trifluoromethyl-3,
4-dihydro-4- (2-oxo-1-pyrrolidinyl)
2H-1-benzopyran-3-ol was obtained.

[0109]

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[0110]

Example 35 2,2-bisfluoromethyl-6-trifluoromethyl
-4- (2-oxo-1-pyrrolidinyl) -2H-1
Nzopyran (Compound 35) trans-2,2- bisfluoromethyl -6-trifluoromethyl-3,4-dihydro-4- (2-oxo-1
-Pyrrolidinyl) -2H-1-benzopyran-3-ol as a starting material in the same manner as in Example 10;
2,2-bisfluoromethyl-6-trifluoromethyl-4- (2-oxo-1-pyrrolidinyl) -2H-1benzopyran represented by the following formula at 25 to 127 ° C. was obtained.

[0111]

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[0112]

Example 36 trans-2,2-bisfluoromethyl-6-heptaph
Fluoropropyl-3,4-dihydro-4- (2-oxo
-1-piperidinyl) -2H-1-benzopyran-3-
All (compound 36) 3,4-epoxy-2,2-bisfluoromethyl-6-
Heptafluoropropyl-3,4-dihydro-2H-1
-Trans having a melting point of 156 to 157 ° C and represented by the following formula using benzopyran as a starting material in the same manner as in Example 4-
2,2-Bisfluoromethyl-6-heptafluoropropyl-3,4-dihydro-4- (2-oxo-1-piperidinyl) -2H-1-benzopyran-3-ol was obtained.

[0113]

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[0114]

Example 37 2,2-Bisfluoromethyl-6-heptafluoropro
Pyr-4- (2-oxo-1-piperidinyl) -2H-
1 Benzopyran (Compound 37) trans-2,2-bisfluoromethyl-6-heptafluoropropyl-3,4-dihydro-4- (2-oxo-1-piperidinyl) -2H-1-benzopyran-3-
In the same manner as in Example 10 using all as a starting material, an oily 2,2-bisfluoromethyl-6- represented by the following formula was used.
Heptafluoropropyl-4- (2-oxo-1-piperidinyl) -2H-1-benzopyran was obtained.

[0115]

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[0116]

Example 38 trans-2,2-bisfluoromethyl-6-trifur
Oromethyl-3,4-dihydro-4- (2-oxo-1
-Piperidinyl) -2H-1-benzopyran-3-o
Le (Compound 38) 3,4-epoxy-2,2-bis trifluoromethyl-6-
Using trifluoromethyl-3,4-dihydro-2H-1-benzopyran as a starting material, trans-2 represented by the following formula and having a melting point of 184-187 ° C. in the same manner as in Example 4.
2-bisfluoromethyl-6-trifluoromethyl-
3,4-Dihydro-4- (2-oxo-1-piperidinyl) -2H-1-benzopyran-3-ol was obtained.

[0117]

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[0118]

Example 39 2,2-Bisfluoromethyl-6-trifluoromethyl
-4- (2-oxo-1-piperidinyl) -2H-1-
Benzopyran (compound 39) trans-2,2-bisfluoromethyl-6-trifluoromethyl-3,4-dihydro-4- (2-oxo-1
-Piperidinyl) -2H-1-benzopyran-3-ol as a starting material, melting point 16 in the same manner as in Example 10.
2,2-bisfluoromethyl-6-trifluoromethyl-4- (2-oxo-) represented by the following formula at 6-168 ° C:
1-piperidinyl) -2H-1-benzopyran was obtained.

[0119]

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[0120]

Example 40 trans-2,2-bisfluoromethyl-6-heptaph
Fluoropropyl-3,4-dihydro-4- (1,2-di
(Hydro-2-oxo-1-pyridyl) -2H-1-ben
Zopyran-3-ol (compound 40) 3,4-epoxy-2,2- bisfluoromethyl- 6
Heptafluoropropyl-3,4-dihydro-2H-1
-Transformant represented by the following formula and having a melting point of 111-113 ° C in the same manner as in Example 7 using benzopyran as a starting material-
2,2-bisfluoromethyl-6-heptafluoropropyl-3,4-dihydro-4- (1,2-dihydro-2
-Oxo-1-pyridyl) -2H-1-benzopyran-
3-ol was obtained.

[0121]

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[0122]

Example 41 2,2-Bisfluoromethyl-6-heptafluoropro
Pyr-4- (1,2-dihydro-2-oxo-1-pyri
Jil) -2H-1-benzopyran (compound 41) trans-2,2-bisfluoromethyl-6-heptafluoropropyl-3,4-dihydro-4- (1,2-dihydro-2-oxo-1-pyridyl ) Using 2-H-1-benzopyran-3-ol as a starting material, 2,2-bisfluoromethyl-6-heptafluoropropyl-4 represented by the following formula and having a melting point of 101-104 ° C in the same manner as in Example 10. -(1,2-Dihydro-2-oxo-1-pyridyl) -2H-1-benzopyran was obtained.

[0123]

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[0124]

Example 42 trans-2,2-bisfluoromethyl-6-trifluoro
Oromethyl-3,4-dihydro-4- (1,2-dihydrido
B-2-oxo-1-pyridyl) -2H-1-benzopy
Lan-3-ol (compound 42) 3,4-epoxy-2,2-bisfluoromethyl-6-
Using trifluoromethyl-3,4-dihydro-2H-1-benzopyran as a starting material, trans-2 represented by the following formula and having a melting point of 210-212 ° C. in the same manner as in Example 7.
2-bisfluoromethyl-6-trifluoromethyl-
3,4-Dihydro-4- (1,2-dihydro-2-oxo-1-pyridyl) -2H-1-benzopyran-3-ol was obtained.

[0125]

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[0126]

Embodiment 432,2-bisfluoromethyl-6-trifluoromethyl
-4- (1,2-dihydro-2-oxo-1-pyridi
Ru) -2H-1-benzopyran (Compound 43) trans-2,2-bisfluoromethyl-6-trifluoro
Oromethyl-3,4-dihydro-4- (1,2-dihydrido
B-2-oxo-1-pyridyl) -2H-1-benzopy
As in Example 10, using lan-3-ol as a starting material
2,2 represented by the following formula having a melting point of 139-140 ° C.
-Bisfluoromethyl-6-trifluoromethyl-4-
(1,2-dihydro-2-oxo-1-pyridyl) -2
H-1-benzopyran was obtained.

[0127]

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[0128]

Example 44: 4- (2-cyanoimino-1-pyrrolidinyl) -6-pe
N-fluoroethyl-2,2-bisfluoromethyl-2
H-1-benzopyran (compound 44) (1) 6-pentafluoroethyl-2,2-bisfluoromethyl-4- (2-oxo-1-pyrrolidinyl) -2
Using H-1-benzopyran as a starting material and having the melting point of 110-112 ° C. in the same manner as in Example 13, represented by the following formula 6
-Pentafluoroethyl-2,2-bisfluoromethyl-4- (2-thioxo-1-pyrrolidinyl) -2H-1
-Benzopyran was obtained.

[0129]

Embedded image (2) 6-pentafluoroethyl-2,2-bisfluoromethyl-4- (2-thioxo-1-pyrrolidinyl)-
0.05 g of 2H-1-benzopyran, 0.1 g of iodomethane.
In a mixture of 20 g, 0.05 g of cyanamide and 3 ml of tetrahydrofuran, 0.06 g of sodium hydride (60%) was added under ice-cooling and stirring, followed by stirring for 30 minutes and then for 17 hours at room temperature. Add ice water and extract with methylene chloride. 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:
(MeOH: CH ₂ Cl ₂ = 1: 99).
49 mg of 4- (2-cyanoimino-1-pyrrolidinyl) -6-pentafluoroethyl-2,2-bisfluoromethyl-2H-1-benzopyran represented by the following formula at 07-210 ° C. was obtained.

[0130]

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[0131]

Example 45 6-pentafluoroethyl-2,2-bisfluoromethyl
4- (2-nitromethylene-1-pyrrolidinyl)-
2H-1-benzopyran (compound 45) (1) 6-pentafluoroethyl-2,2-bisfluoromethyl-4- (2-thioxo-1-pyrrolidinyl)-
0.16 g of 2H-1-benzopyran, 0.1 ml of iodomethane.
0.10 g of sodium hydride (60%) was added to a mixture of 78 g, 0.41 g of nitromethane and 6 ml of tetrahydrofuran with stirring at room temperature, and the mixture was refluxed for 2 hours. Add ice water and extract with methylene chloride. The organic layer was washed with water and dried, and the solvent was distilled off. The residue obtained was subjected to silica gel column chromatography (developing solution: MeOH: CH ₂ Cl ₂ =
1:99), and has a melting point of 195-197 ° C and is represented by the following formula: 6-pentafluoroethyl-2,2-bisfluoromethyl-4- (2-nitromethylene-1-pyrrolidinyl) -2H-1- 0.02 g of benzopyran was obtained.

[0132]

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[0133]

Working Example 46 4- (2-cyanoimino-1-piperidinyl) -6-pe
N-fluoroethyl-2,2-bisfluoromethyl-2
H-1-benzopyran (compound 46) (1) 6-pentafluoroethyl-2,2-bisfluoromethyl-4- (2-oxo-1-pyrrolidinyl) -2
Using H-1-benzopyran as a starting material and having a melting point of 118-120 ° C. represented by the following formula 6 in the same manner as in Example 13:
-Pentafluoroethyl-2,2-bisfluoromethyl-4- (2-thioxo-1-piperidinyl) -2H-1
-Benzopyran was obtained.

[0134]

Embedded image (2) 6-pentafluoroethyl-2,2-bisfluoromethyl-4- (2-thioxo-1-piperidinyl)-
Using 2H-1-benzopyran as a starting material, 4- (2-cyanoimino-1-piperidinyl) -6-pentafluoroethyl-2,2 represented by the following formula having a melting point of 196-197 ° C. in the same manner as in Example 44. -Bisfluoromethyl-2
H-1-benzopyran was obtained.

[0135]

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[0136]

Example 47 4- (2-cyanoimino-1,2-dihydro-1-pyri )
Jil) -6-pentafluoroethyl-2,2-bisfur
Oromethyl-2H-1-benzopyran (Compound 47) (1) 6-pentafluoroethyl-2,2 -bisfluoromethyl -4- (1,2-dihydro-2-oxo-1-
Using pyridyl) -2H-1-benzopyran as a starting material, 6-pentafluoroethyl-2,2-bisfluoromethyl-4- (1) having a melting point of 122 to 123 ° C. and represented by the following formula, in the same manner as in Example 13. , 2-dihydro-2-thioxo-1-pyridyl) -2H-1-benzopyran.

[0137]

Embedded image (2) 6-pentafluoroethyl-2,2-bisfluoromethyl-4- (1,2-dihydro-2-thioxo-1
4- (2-cyanoimino-1,2-dihydro-1-pyridyl) represented by the following formula and having a melting point of 196-198 ° C. in the same manner as in Example 44 using -pyridyl) -2H-1-benzopyran as a starting material. -6-pentafluoroethyl-
2,2-Bisfluoromethyl-2H-1-benzopyran was obtained.

[0138]

Embedded image

[0139]

Working Example 48 2- (6-Pentafluoroethyl-2,2-bisfluoro)
Romethyl-2H-1-benzopyran-4-yl) pyridi
N-oxide (compound 48) (1) 2,2-bisfluoromethyl-6-nitro-4-
(2-pyridyl) -2H-1-benzopyran 6.2 g,
A mixture of 11.7 g of stannous chloride and 80 ml of ethanol was heated to reflux for 3 hours. The solvent is distilled off, the mixture is made strongly alkaline with an aqueous sodium hydroxide solution, and then extracted with methylene chloride. The organic layer is extracted with 2N hydrochloric acid. The aqueous layer is made strongly alkaline by adding 2N sodium hydroxide, and then extracted with methylene chloride. After the organic layer is washed with water and dried, the solvent is distilled off to obtain 4.8 g of 6-amino-2,2-bisfluoromethyl-4- (2-pyridyl) -2H-1-benzopyran. 4.8 g of this 6-amino-2,2-bisfluoromethyl-4- (2-pyridyl) -2H-1-benzopyran, 1.0 ml of concentrated sulfuric acid and 80 ml of water
1.20 g of sodium nitrite in a mixture of
Was dissolved in 10 ml of water, and the mixture was stirred for 20 minutes.
A solution prepared by dissolving 3.31 g of potassium iodide in 10 ml of water was added, and 100 ml of methylene chloride was added.
Stirred for hours. Add water and extract with methylene chloride. The organic layer is washed with an aqueous sodium hydroxide solution, dried,
The residue obtained by distilling off the solvent is subjected to silica gel column chromatography (developing solution: MeOH: CH ₂ Cl ₂ = 1: 99).
2,2-bisfluoromethyl-6-iodo-4- (2-pyridyl) -2H represented by the following formula as an oil
4.50 g of -1-benzopyran was obtained.

[0140]

Embedded image (2) 2,2-bisfluoromethyl-6-iodo-4-
(2-pyridyl) -2H-1-benzopyran 1.11
g, potassium pentafluoropropionate 1.17 g,
A mixture of 1.18 g of cuprous iodide, 20 ml of N, N-dimethylformamide and 7 ml of toluene was heated and stirred at 160 ° C. for 3 hours in a nitrogen gas atmosphere while removing toluene. Add ether, add water and filter through a Celite membrane. The mother liquor is extracted with ether. After washing the organic layer with water and drying,
The residue obtained by distilling off the solvent is subjected to silica gel column chromatography (developing solution: MeOH: CH ₂ Cl ₂ = 1: 99).
Then, 0.86 g of an oily 6-pentafluoroethyl-2,2-bisfluoromethyl-4- (2-pyridyl) -2H-1-benzopyran represented by the following formula was obtained.

Embedded image (3) m-chloroperoxide was added to a mixture of 0.50 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4- (2-pyridyl) -2H-1-benzopyran and 15 ml of methylene chloride under ice-cooling and stirring. Benzoic acid (70%)
0.70 g was added, and the mixture was stirred for 1 hour, and then stirred at room temperature for 16 hours. An aqueous potassium carbonate solution is added, and the mixture is extracted with methylene chloride. The organic layer is washed with water and dried, and the solvent is distilled off. The residue obtained is purified by silica gel column chromatography (developing solution: MeOH: CH ₂ Cl ₂ = 1: 99). 2- (3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4 represented by the following formula:
-Dihydro-2H-1 benzopyran-4-yl) pyridine N-oxide 0.50 g.

[0141]

Embedded image Subsequently, the melting point of 105-107
0.04 g of 2- (6-pentafluoroethyl-2,2-bisfluoromethyl-2H-1-benzopyran-4-yl) pyridine N-oxide represented by the following formula at <0> C was obtained.

[0142]

Embedded image (4) 0.50 g of 2- (3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran-4-yl) pyridine N-oxide, A mixture of 0.10 g of 10% palladium carbon and 15 ml of methanol is stirred at room temperature under a hydrogen stream. The reaction solution was subjected to suction filtration to remove the catalyst, and the residue obtained by evaporating the mother liquor was dissolved in 10 ml of dioxane, 0.82 g of soda talc was added, and the mixture was heated under reflux for 1 hour. The reaction solution is subjected to suction filtration to remove insolubles, water is added to the mother liquor, and the mixture is extracted with methylene chloride. After the organic layer was washed with water and dried, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (developing solution: MeOH: CH ₂ Cl ₂ = 1: 99) to give 2- (6-pentafluoroethyl-2, 0.18 g of 2-bisfluoromethyl-2H-1-benzopyran-4-yl) pyridine N-oxide was obtained.

[0143]

Working Example 49 2- (6-Pentafluoroethyl-2,2-bisfluoro)
Romethyl-2H-1-benzopyran-4-yl) pyridi
N-oxide (compound 49) (1) 2,2-bisfluoromethyl-6-iodo-4-
1.04 g of (2-pyridyl) -2H-1-benzopyran
And methylene chloroperbenzoic acid (70%) 0.78 g was added to a mixture of
The mixture was stirred for an hour and then at room temperature for 25 hours. An aqueous solution of potassium carbonate is added, and the mixture is extracted with methylene chloride. 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: MeOH: CH).
₂ Cl ₂ = 1: 99) to furnish the following formula oily 2- (2,2-bisfluoromethyl-6-iodo -2
H-1-benzopyran-4-yl) pyridine N-oxide 0.25 g was obtained.

[0144]

Embedded image (2) 2- (2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-yl) pyridine N-
2- (6-pentafluoroethyl-) shown in Example 48 (3) in the same manner as in Example 48 (2) using the oxide
2,2-Bisfluoromethyl-2H-1-benzopyran-4-yl) pyridine N-oxide was obtained.

[0145]

Working Example 50 2- (2,2-Bisfluoromethyl-6-trifluoro)
Methyl-2H-1-benzopyran-4-yl) pyridine
N-oxide (compound 50) (1) 2,2-bisfluoromethyl-6-iodo-4-
Using (2-pyridyl) -2H-1-benzopyran and potassium trifluoroacetate, an oily 2,2-bisfluoromethyl-6-triol represented by the following formula was prepared in the same manner as in Example 48 (2). Fluoromethyl-4- (2-pyridyl) -2H-1-benzopyran was obtained.

[0146]

Embedded image (2) Using 2,2-bisfluoromethyl-6-trifluoromethyl-4- (2-pyridyl) -2H-1-benzopyran in the same manner as in Example 48 (3), the oil was represented by the following formula. 2- (3,4-epoxy-2,2-bisfluoromethyl-6-trifluoromethyl-3,4-dihydro-2H-1-benzopyran-4-yl) pyridine
N-oxide was obtained.

[0147]

Embedded image (3) 2- (3,4-epoxy-2,2-bisfluoromethyl-6-trifluoromethyl-3,4-dihydro-
Using 2H-1-benzopyran-4-yl) pyridine N-oxide, in the same manner as in Example 48 (4), melting point 16
2- (2,2-Bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-yl) pyridine N-oxide represented by the following formula at 9 to 170 ° C. was obtained.

[0148]

Embedded image

[0149]

Example 51 2- (2,2-bisfluoromethyl-6-heptafluo
Propyl-2H-1-benzopyran-4-yl) pyri
Zin N-oxide (compound 51) (1) 2,2-bisfluoromethyl-6-iodo-4-
Using (2-pyridyl) -2H-1-benzopyran and potassium heptafluorobutyrate, an oily 2,2-bisfluoromethyl-6-hepta represented by the following formula was prepared in the same manner as in Example 48 (2). Fluoropropyl-4- (2-pyridyl) -2H-1-benzopyran was obtained.

[0150]

Embedded image (2) Using 2,2-bisfluoromethyl-6-heptafluoropropyl-4- (2-pyridyl) -2H-1-benzopyran in the same manner as in Example 28 (3), the oil was represented by the following formula. 2- (2,2-bisfluoromethyl-
6-Heptafluoropropyl-2H-1-benzopyran-4-yl) pyridine N-oxide was obtained.

[0151]

Embedded image

[0152]

Working Example 52 2- (2,2-Bisfluoromethyl-6-nitro-2H)
-1-benzopyran-4-yl) pyridine N-cyano
Imine (compound 52) 2,2-bisfluoromethyl-6-nitro-4- (2-
To a mixture of 200 mg of pyridyl) -2H-1-benzopyran and 2 ml of methylene chloride was added (O-
Mesitylenesulfonyl) hydroxylamine 135m
g and 3 ml of methylene chloride were added dropwise, and the mixture was stirred for 1 hour. Ether was added to the reaction mixture, and the precipitated crystals were collected by filtration to give N-amino-2- (2,2
-Bisfluoromethyl 6-nitro-2H-1-benzopyran-4-yl) pyridinium mesitylenesulfonate (240 mg) was obtained. The resulting N-amino-2-
(2,2-bisfluoromethyl-6-nitro-2H-1
-Benzopyran-4-yl) pyridinium mesitylenesulfonate 60 mg and dimethylformamide 1 m
To this mixture were added sodium hydride (5 mg) and cyanogen bromide (36 mg) under ice-cooling and stirring, and the mixture was stirred for 1 hour under water-cooling. Add water and extract with ether. After the organic layer was washed with water and dried, the residue obtained by evaporating the solvent was purified by silica gel column chromatography (developing solution: MeOH: CH ₂ Cl ₂ = 5: 95), and expressed by the following formula having a melting point of 212-214 ° C. 2
-(2,2-bisfluoromethyl-6-nitro-2H-
1-benzopyran-4-yl) pyridine 11 mg of N-cyanoimine was obtained.

[0153]

Embedded image

[0154]

Example 53 2- (6-cyano-2,2-bisfluoromethyl-2H
-1-benzopyran-4-yl) pyridine N-cyano
Imine (compound 53) 6-cyano-2,2-bisfluoromethyl-4- (2-
Using pyridyl) -2H-1-benzopyran as a starting material, 2- (6-cyano-2,2-bisfluoromethyl-2H- represented by the following formula having a melting point of 251 to 253 ° C. in the same manner as in Example 52. 1-benzopyran-4-yl) pyridine N-cyanoimine was obtained.

[0155]

Embedded image

[0156]

Working Example 54 2- (2,2-Bisfluoromethyl-6-trifluoro)
Methyl-2H-1-benzopyran-4-yl) pyridine
N-cyanoimine (compound 54) 2,2 -bisfluoromethyl -6-trifluoromethyl-4- (2-pyridyl) -2H-1-benzopyran as a starting material, in the same manner as in Example 52, melting point 228-
2- (2,2-Bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-yl) pyridine N-cyanoimine represented by the following formula at 230 ° C. was obtained.

[0157]

Embedded image

[0158]

Working Example 55 2- (6-Pentafluoroethyl-2,2-bisfluoro)
Romethyl-2H-1-benzopyran-4-yl) pyridi
N-cyanoimine (compound 55) 6-pentafluoroethyl-2,2 -bisfluoromethyl -4- (2-pyridyl) -2H-1-benzopyran as a starting material and a melting point of 190
There was obtained 2- (6-pentafluoroethyl-2,2-bisfluoromethyl-2H-1-benzopyran-4-yl) pyridine N-cyanoimine represented by the following formula at -191 ° C.

[0159]

Embedded image

[0160]

Example 56 2- (2,2-bisfluoromethyl-6-heptafluo
Propyl-2H-1-benzopyran-4-yl) pyri
Gin N-cyanoimine (compound 56) Starting from 2,2 -bisfluoromethyl -6-heptafluoropropyl-4- (2-pyridyl) -2H-1-benzopyran as a starting material, the melting point was 16
2- (2,2-bisfluoromethyl-6-heptafluoropropyl-2H-1 represented by the following formula at 2-163 ° C.
-Benzopyran-4-yl) pyridine N-cyanoimine was obtained.

[0161]

Embedded image

[0162]

Example 57 2- (2,2-bisfluoromethyl-6-nitro-2H
-1-benzopyran-4-yl) thiazole N-cia
Neumine (compound 57) (1) 4-cyano-2,2- bisfluoromethyl -6
Nitro-2H-1-benzopyran 3g and sulfuric acid 20ml
Was stirred for 36 hours. The reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration. The obtained crystals are diluted with ethyl acetate, and the organic layer is washed with water and dried, and the solvent is distilled off. Then, 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carbamide represented by the following formula is obtained. 3 g were obtained.

[0163]

Embedded image (2) 2,2-bisfluoromethyl-6-nitro-2H
Using 2-benzopyran-4-carbamide as a starting material, 2,2-
Bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carbothioamide was obtained.

[0164]

Embedded image (3) 2,2-bisfluoromethyl-6-nitro-2H
-1-benzopyran-4-carbothioamide 600m
g, bromoacetaldehyde dimethyl acetal 1.2
A mixture of 11 ml of potassium hydroxide, 11 mg of potassium hydroxide and 3 ml of benzene was heated under reflux for 1 hour. Add water and extract 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 (developing solution: hexane: ethyl acetate = 2: 1) to give 2- (2,2) represented by the following formula. -Bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl)
380 mg of thiazole were obtained.

[0165]

Embedded image (4) Using 2- (2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl) thiazole as a starting material, changing the sodium hydride of the base in Example 52 to potassium carbonate, and so forth Melting point 193-19
4- (2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl) thiazole N-cyanoimine represented by the following formula at 4 ° C. was obtained.

[0166]

Embedded image

[0167]

Working Example 58 2,2-Bisfluoromethyl-6-nitro-4- (1-
(Oxide-2-pyridyl) -2H-1,3-benzooxy
Sagin 3-oxide (compound 58) (1) 2,2-bisfluoromethyl-6-nitro-3,
4-dihydro-2H-1,3-benzoxazine-4-
To 1.0 g of ON was added 50 ml of dichloromethane, 0.98 ml of trifluoromethanesulfonic anhydride and 0.98 ml of 2,6-lutidine were added under ice cooling, and the mixture was stirred for 23 hours. The solvent is distilled off, and the residue is purified by silica gel column chromatography (developing solution: CH ₂ Cl ₂ ) to give oily 4-trifluoromethanesulfonyloxy-2,2-bisfluoromethyl- represented by the following formula. 1.48 g of 6-nitro-2H-1,3-benzoxazine was obtained.

[0168]

Embedded image (2) 1.38M n-butyllithium hexane solution 1.38 in -78 ° C under a nitrogen atmosphere in 3ml of anhydrous tetrahydrofuran solution of 0.21ml of 2-bromopyridine.
ml was added dropwise. 30 minutes later, 4.26 ml of a 0.5 M zinc chloride solution in anhydrous tetrahydrofuran was added, and the mixture was added at -78 ° C.
For 15 minutes and with ice cooling for 15 minutes. Then, under ice cooling,
65 mg of tetrakis (triphenylphosphine) palladium (0) and 4-trifluoromethanesulfonyloxy-2,2-bisfluoromethyl-6-nitro-2H
330 mg of -1,3-benzoxazine were added. The temperature was raised to room temperature, and the mixture was further stirred for 36 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried, and the solvent was distilled off. The resulting residue was subjected to column chromatography (developing solution: AcO 2
Et: hexane = 1: 5) to give an oily 2,2-bisfluoromethyl-6 represented by the following formula.
110 mg of -nitro-4- (2-pyridyl) -2H-1,3-benzoxazine were obtained.

[0169]

Embedded image (3) 2,2-bisfluoromethyl-6-nitro-4-
(2-pyridyl) -2H-1,3-benzoxazine 1
10 mg was dissolved in methylene chloride and stirred under ice-cooling.
116 mg of m-chloroperbenzoic acid (67%) was added, and the mixture was stirred at room temperature for 16 hours. Aqueous sodium bicarbonate was added, extracted with methylene chloride, dried, and the solvent was distilled off. The obtained residue was subjected to column chromatography (developing solution: MeOH: CH ₂ Cl _2).
= 1: 99) and recrystallized with a mixed solvent of ethyl acetate-hexane to give a melting point of 197-2.
2,2-bisfluoromethyl-6-nitro-4- (1-oxide-2-pyridyl)-represented by the following formula at 00C.
9 mg of 2H-1,3-benzoxazine 3-oxide
I got

[0170]

Embedded image

[0171]

Example 59 N-acetylimino-2- (2,2-bisfluoromethyl
Ru-6-nitro-2H-1-benzopyran-4-yl)
Pyridine (Compound 59) N-amino-2- (2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl) pyridinium mesitylenesulfonate 200 mg obtained in Example 52, acetic anhydride A mixture of 2 ml and 1 ml of acetyl chloride was stirred at 40 ° C. for 10 hours. After concentration under reduced pressure, the residue was diluted with methylene chloride, washed with a 10% aqueous sodium hydroxide solution, dried, and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography (developing solution: aq, NH ₃ : M).
MeOH: CHCl ₃ = 1: 10: 100) to give N-acetylimino-2- (2,2-bisfluoromethyl-6-nitro-2H represented by the following formula having a melting point of 202-204 ° C. -1-benzopyran-4-yl)
96 mg of pyridine were obtained.

[0172]

Embedded image

[0173]

Example 60 N-methanesulfonylimino-2- (2,2-bisfur
Oromethyl-6-nitro-2H-1-benzopyran-4
-Yl) pyridine (compound 60) 100 mg of N-amino-2- (2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl) pyridinium mesitylenesulfonate obtained in Example 52 And 2 ml of methanesulfonyl chloride were stirred at 40 ° C. for 3 hours. The mixture was poured into ice water, diluted with methylene chloride, washed with a 20% aqueous sodium hydroxide solution, dried, and the residue obtained by distilling off the solvent was subjected to silica gel column chromatography (developing solution: MeOH: CH _2).
(Cl ₂ = 3: 97) to give a melting point of 19
N-methanesulfonylimino-2- (2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl) pyridine 20 represented by the following formula at 7-198 ° C.
mg was obtained.

[0174]

Embedded image

[0175]

Embodiment 61N-benzoylimino-2- (2,2-bisfluorome
Tyl-6-nitro-2H-1-benzopyran-4-i
Le) pyridine (Compound 61) N-amino-2- (2,2-bis) obtained in Example 52
Fluoromethyl-6-nitro-2H-1-benzopyran
-4-yl) pyridinium mesitylenesulfonate
350 mg and 1 ml of 20% aqueous sodium hydroxide solution
0.2 ml of benzoyl chloride was added to the mixture under ice cooling,
For 48 hours. After filtering the obtained product, silica
Gel column chromatography (Developing solution: MeOH: C
H_TwoCl_Two= 5: 95) to give a melting point of 1
89-190 ° C N-benzoylimid represented by the following formula
No-2- (2,2-bisfluoromethyl-6-nitro-
2H-1-benzopyran-4-yl) pyridine 40 mg
I got

[0176]

Embedded image

[0177]

Example 62 N-nitroimino-2- (2,2-bisfluoromethyl
-6-nitro-2H-1-benzopyran-4-yl) pi
Lysine (Compound 62) N-amino-2- (2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl) pyridinium mesitylenesulfonate 200 mg obtained in Example 52, acetic anhydride A mixture of 0.09 ml of nitric acid and 1 ml of acetic anhydride was added to a mixture of 1 ml and 0.5 ml of acetic acid under ice cooling, followed by stirring at the same temperature for 2 hours. After concentration under reduced pressure, the residue was diluted with methylene chloride, washed with a 10% aqueous sodium hydroxide solution, dried, and the residue obtained by evaporating the solvent was purified by recrystallization (recrystallization solvent: EtOH) to give a melting point of 262-264. C. N-nitroimino-2- (2,2-bisfluoromethyl-6-nitro-2 represented by the following formula:
H-1-benzopyran-4-yl) pyridine 14 mg was obtained.

[0178]

Embedded image

[0179]

Example 63 N-phenylcarbamoylimino-2- (2,2-bis
Fluoromethyl-6-nitro-2H-1-benzopyran
-4-yl) pyridine (compound 63) N-amino-2- (2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl) pyridinium mesitylene sulfo obtained in Example 52 Phenylisocyanate (0.03 ml) was added to a mixture of 100 mg of catenate and 4 ml of methylene chloride while stirring at room temperature.
Stirred for hours. Water was added and extracted with methylene chloride. After the organic layer is washed with water and dried, the residue obtained by evaporating the solvent is subjected to silica gel column chromatography (developing solution: MeO
H: CH ₂ Cl ₂ = 5: 95)
N-phenylcarbamoylimino-2- (2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-yl) represented by the following formula having a melting point of 103-105 ° C.
40 mg of pyridine were obtained.

[0180]

Embedded image

[0181]

Example 64 6-Bromo-7-chloro-2,2-bis
Fluoromethyl-4- (1-oxide-2-pyridyl)
-2H-1,3-benzoxazine 3-oxide (compound 64) (1) 6-bromo-7-chloro-2,2-bisfluoromethyl-3,4-dihydro-2H-1,3-benzoxazine- 1.60 g of 4-one, methylene chloride 60
ml, 1.61 m of trifluoromethanesulfonic anhydride
Example 58 using 1.72 ml of l, 2,6-lutidine
6-bromo- represented by the following formula in the same manner as in (1).
1.16 g of 7-chloro-4-trifluoromethanesulfonyloxy-2,2-bisfluoromethyl-2H-1,3-benzoxazine was obtained.

[0182]

Embedded image (2) 9 ml of a solution of 0.63 ml of 2-bromopyridine in anhydrous tetrahydrofuran, 4.32 ml of a 1.61 M solution of n-butyllithium in hexane, 12.8 ml of a 0.5 M solution of zinc chloride in anhydrous tetrahydrofuran, tetrakis (triphenylphosphine) palladium ( 0) 193 mg and 6-bromo-7-chloro-4-trifluoromethanesulfonyloxy-2,2-bisfluoromethyl-2H-
Example 5 using 1.16 g of 1,3-benzoxazine
6-Bromo-7-chloro-2,2-bisfluoromethyl-4- (2
-Pyridyl) -2H-1,3-benzoxazine 230
mg was obtained.

[0183]

Embedded image (3) 6-bromo-7-chloro-2,2-bisfluoromethyl-4- (2-pyridyl) -2H-1,3-benzoxazine 50 mg, m-chloroperbenzoic acid (67%)
6-Bromo-7 represented by the following formula having a melting point of 146-148 ° C in the same manner as in Example 58 (3) using 32 mg.
5 mg of -chloro-2,2-bisfluoromethyl-4- (1-oxide-2-pyridyl) -2H-1,3-benzoxazine 3-oxide was obtained.

[0184]

Embedded image

[0185]

Example 65 2- (2,2-Bistrifluoromethyl-6-nitro-
2H-1-benzopyran-4-yl) pyridine N-O
Oxide (Compound 65) (1) A method similar to that of Example 28 (1) using 2,2-bistrifluoromethyl-3,4-dihydro-6-nitro-2H-1-benzopyran-4-one as a starting material. so,
4-trifluoromethanesulfonyloxy-2,2-bistrifluoromethyl-6-nitro-2H-1-benzopyran represented by the following formula and having a melting point of 60-61 ° C. was obtained.

[0186]

Embedded image (2) To a solution of 0.16 ml of 2-bromopyridine in 5 ml of anhydrous tetrahydrofuran, under nitrogen atmosphere, at -78 ° C, a 1.6 m solution of n-butyllithium in hexane at 1.0 m.
1 was added dropwise. After 30 minutes, 3.2 ml of a 0.5 M zinc chloride solution in anhydrous tetrahydrofuran was added, and the mixture was added at -78 ° C for 1 hour.
The mixture was stirred for 5 minutes and ice-cooled for 15 minutes. Then, under ice cooling, tetrakis (triphenylphosphine) palladium (0) 5
0 mg and 4-trifluoromethanesulfonyloxy-
2,2-bistrifluoromethyl-6-nitro-2H-
A solution of 300 mg of 1-benzopyran in 5 ml of anhydrous tetrahydrofuran was added. The temperature was raised to room temperature, and the mixture was further stirred for 15 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The residue obtained by evaporating the solvent after washing and drying the organic layer with water is purified by silica gel column chromatography (developing solution; CH ₂ Cl ₂ : hexane = 1: 1) to give the following compound having a melting point of 105-107 ° C. 2,2-bistrifluoromethyl-6-nitro-4- represented by
(2-pyridyl) -2H-1-benzopyran 200 mg
I got

[0187]

Embedded image (3) 2,2-bistrifluoromethyl-6-nitro-
4- (2-pyridyl) -2H-1-benzopyran 200
mg was dissolved in 4 ml of methylene chloride, 210 mg of m-chloroperbenzoic acid (67%) was added under ice cooling and stirring, and the mixture was stirred at room temperature for 14 hours. An aqueous solution of potassium carbonate was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried, and the residue obtained by evaporating the solvent was subjected to silica gel column chromatography (developing solution; MeOH: CH ₂ Cl ₂ = 1: 9).
By purifying in 9), 140 mg of 2- (2,2-bistrifluoromethyl-6-nitro-2H-1-benzopyran-4-yl) pyridine N-oxide represented by the following formula having a melting point of 208 to 210 ° C. is obtained. Obtained.

[0188]

Embedded image

[0189]

Example 66 2- (6-trifluoromethyl-2,2-bistrifur
Oromethyl-2H-1-benzopyran-4-yl) pyri
Zin N-oxide (Compound 66) (1) 2,2-bistrifluoromethyl-6-nitro-
Using 4- (2-pyridyl) -2H-1-benzopyran in the same manner as in Example 48 (1), an oily 2,2-bistrifluoromethyl-6-iodo- represented by the following formula:
4- (2-Pyridyl) -2H-1-benzopyran was obtained.

[0190]

Embedded image (2) 2,2-bistrifluoromethyl-6-iodo-
Using 4- (2-pyridyl) -2H-1-benzopyran and potassium trifluoroacetate, an oily 6-trifluoromethyl-2,2- represented by the following formula was prepared in the same manner as in Example 48 (2). Bistrifluoromethyl-4- (2
-Pyridyl) -2H-1-benzopyran was obtained.

[0191]

Embedded image (3) Using 6-trifluoromethyl-2,2-bistrifluoromethyl-4- (2-pyridyl) -2H-1-benzopyran, in the same manner as in Example 65 (3), using the following oily formula. The represented 2- (6-trifluoromethyl-
2,2-Bistrifluoromethyl-2H-1-benzopyran-4-yl) pyridine N-oxide was obtained.

[0192]

Embedded image

[0193]

Working Example 67 2- (6-Pentafluoroethyl-2,2-bistrif)
Fluoromethyl-2H-1-benzopyran-4-yl) pi
Lysine N-oxide (compound 67) (1) 2,2-bistrifluoromethyl-6-iodo-
Example 48 was prepared using 4- (2-pyridyl) -2H-1-benzopyran and potassium pentafluoropropionate.
In the same manner as in (2), 6-pentafluoroethyl-2,2-bistrifluoromethyl-4- (2-pyridyl) -2H-1-benzopyran represented by the following formula and having a melting point of 92-93 ° C. was obtained. .

[0194]

Embedded image (2) Using 6-pentafluoroethyl-2,2-bistrifluoromethyl-4- (2-pyridyl) -2H-1-benzopyran, in the same manner as in Example 65 (3), using the following formula as an oil. The indicated 2- (6-pentafluoroethyl-2,2-bistrifluoromethyl-2H-1-benzopyran-4-yl) pyridine N-oxide was obtained.

[0195]

Embedded image Next, the excellent activity of the compound of the present invention on the K ⁺ channel will be described with reference to Test Examples.

[0196]

[Test Example 1] Test male Sprague Dawley rat (450-6) using an isolated rat aorta
00g), the thoracic aorta was taken out and used as a 2 mm-width annular specimen. Krebs-Henseleit
Solution (NaCl: 119, KCl: 4.8, CaCl _{2
· 2H 2 O: 2.53, KH} 2 PO 4: 1.2, MgSO 4
Suspension under 2 g tension in a 10 ml organ bath containing 7H ₂ O: 1.2, NaHCO ₃ : 24.8, glucose: 10 (mM), 37 ° C) and 95% O _2.5 % CO ₂ gas was ventilated. The contractile response of the specimen was recorded isometrically with an FD pickup.
After equilibration for 1-1.5 hours, 3
0 mM KCl was added and the 50% inhibitory concentration (I
_C50 ) was evaluated.

The test compound used was the compound of the present invention obtained in the above example and chroma potassium as a control compound. The results are shown in Table 1 below.

[0198]

[Test Example 2] Test using guinea pig tracheal muscle Male Hartley guinea pig (450-550 g)
The trachea was removed from the sample and used as a chain specimen. Specimen 95% O
_The above Krebs-Hen through which _2.5 % CO ₂ gas is passed.
suspended in a bath containing a select solution (37 ° C.)
The contractile response of the specimen was recorded isometric under 1 g tension. The relaxation effect of aminophylline 1 mM on spontaneous tension was 10
The concentration (IC ₅₀ ) showing 50% relaxation activity of the test compound when it was set to 0% was determined and evaluated.

The test compound was used in the same manner as in Test Example 1. Table 1 shows the results.

[0200]

[Table 1]  Compound number Rat aorta Guinea pig tracheal muscleIC ₅₀ (M) IC ₅₀ (M) 2-2 7.4 × 10^-8 3.9 × 10^-7 6-2 2.6 × 10^-9 6.8 × 10^-9 4-2 2.8 × 10^-Ten 6.9 × 10^-9 12 2.5 × 10^-9 5.9 × 10^-9 48 1.6 × 10^-9 3.9 × 10^-9 50 5.1 × 10^-9 1.8 × 10^-8 52 2.0 × 10^-9 1.2 × 10^-8 55 8.2 × 10^-Ten 6.3 × 10^-9 Cromakalim 1.7 × 10 ^-7 8.6 × 10 ^-7  As mentioned above, the compounds of the invention have excellent K⁺Channel
Has an activating effect. Therefore, the present invention⁺Cha
Pharmaceutical compositions (eg, anti-asthma)
In technical fields such as respiratory and epilepsy treatments)
It is expected to make a contribution.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/4035 A61K 31/4035 31/4178 31/4178 31/4433 31/4433 31/453 31/453 31/501 31/501 31/5355 31/5355 A61P 9/00 A61P 9/00 9/12 9/12 11/06 11/06 25/08 25/08 C07D 311/68 C07D 311/68 405/04 405/04 405/12 405 / 12 413/04 413/04 417/04 417/04 493/04 106 493/04 106A (72) Inventor Hiroyuki Nabata 1-135 Komamon, Gotemba-shi, Shizuoka Chugai Pharmaceutical Co., Ltd. (56) References JP-A-62-246570 (JP, A) JP-A-54-62320 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 311/22 A61K 31/35 A61K 31/352 A61K 31/353 A61K 31/4025 A61K 31/4035 A61K 31/4178 A61K 31/4433 A61K 31/453 A61K 31/501 A61K 31/5355 A61P 9/00 A61P 9/12 A61P 11/06 A61P 25/08 C07D 311 / 68 C07D 405/04 C07D 405/12 C07D 413/04 C07D 417/04 C07D 493/04 106 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula Wherein R ₁ and R ₂ are the same or different and represent a lower haloalkyl group; R ₃ represents a hydrogen atom, or X
R ₄ represents a substituted or unsubstituted amino group, a saturated or unsaturated heterocyclic group, or A-
O- (A is a saturated or unsaturated carbocyclic group or a saturated or unsaturated heterocyclic group); R ₅ and R ₆ are the same or different and are a hydrogen atom, a halogen, a lower alkyl group, a lower haloalkyl group, a nitro group or a cyano group; X is = N-, N ⁺ -O ^- or ## STR2 ## Wherein R ₇ and R ₈ are the same or different and each represent a hydrogen atom, a hydroxyl group or a lower acyloxy group, or R ₇ is directly bonded to R ₃ to form a single bond). Benzopyran or benzoxazine derivatives.