WO1992012973A1

WO1992012973A1 - Chroman derivative

Info

Publication number: WO1992012973A1
Application number: PCT/JP1992/000046
Authority: WO
Inventors: Akira Shiozawa; Yukihiro Sagawa; Makoto Hosono; Atsuro Inubushi; Kazuhisa Narita; Masashi Iida
Original assignee: Nippon Kayaku Kabushiki Kaisha
Priority date: 1991-01-23
Filing date: 1992-01-22
Publication date: 1992-08-06

Abstract

A chroman derivative, e.g., represented by formula (I). It has a potent potassium channel opener activity and hence is prospective as a tracheal smooth muscle relaxant or the like.

Description

Chromane derivative

〔Technical field〕

The present invention relates to antihypertensive agents, therapeutic agents for angina pectoris, circulatory agents such as cerebral circulation improving agents, antiasthmatic agents, therapeutic agents for disorders associated with smooth muscle contraction of the uterus or urinary tract, and anticonvulsants for epilepsy. New chromane derivatives that are expected to grow.

(Background technology)

As a compound expected as an antihypertensive drug by the K ion channel opener action, the following formula (a)

[Y]

Are known (JP-A-58-67683; Br. J. Pharmac. (19986)), 88, 103-ll; Br. J. Pharmac. (19986), 89, 395-405).

However, this compound is not necessarily sufficient in terms of efficacy, sustainability, side effects, etc., and improvement is required. To

[Disclosure of the Invention]

The present invention has the general formula (1):

[Where R ¹ is — C (= X) — (0) _n — R ⁴ (where = 0, = N-CN, = N-C 0 R,

= C 0 NHR ⁵ , = NCSNHR ⁵ , = NCSR ⁵ , = NS 02 CF 3, = NNHR ⁵ , 2 NOR ⁵ , = CH-02 (where R ⁵ is a hydrogen atom, a lower alkyl group, 1 to 10 A lower alkyl group, a phenyl group, a substituted phenyl group, a pyridyl group, or a pyrimidinyl group substituted with one halogen), n is an integer of 0 or 1, and R ⁴ is a lower alkyl group, a cycloalkyl group having 1 to 10 carbon atoms, a phenyl group, a substituted phenyl group, a furyl group, a phenyl group, a pyridyl group, a pyrimidyl group, Lower alkyl groups substituted with 1 to 10 halogen groups, lower alkyl groups substituted with 1 to 10 halogen atoms, amino groups, lower alkyl groups, 1 to 3 nitroxyl groups Or a lower alkylamino group substituted with: or S〇 ₂ — R ⁴ (here, R ⁴ is the same as described above), and R ² is substituted with a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with 1 to 3 dihydroxy groups, and 1 to 10 halogen atoms Lower alkyl group phenyl group, substituted phenyl group, phenyl lower alkyl group, substituted phenyl lower alkyl group, pyridyl group, pyrimidyl group, R ³ is a hydrogen atom, lower alkyl group, Lower alkyl group substituted with 1 to 3 2-hydroxy groups, lower alkyl group substituted with 1 to 10 halogen atoms, phenyl group, substituted phenyl group, phenylalkyl group , Substitution

10 alkyl group, pin lysyl group, Pi Li Mi Jill group, was until one I Do to R ² your good beauty R ³ Guarding緖(CH ₂₎ _m one (this Kodewa m is 1 - 5 Is an integer), — CH = CH— CH = CH— or — CH = CH— N = CH— A is a hydrogen atom, a nitro group, a lower alkyl group, one to three nitroxy groups Replaced by

A lower alkyl group, —C (= X) 1 (〇) „1 R (where X, n, and R ⁴ are the same as above) or a protecting group]. And a physiologically acceptable acid addition salt thereof.

In R ¹ to R ⁵ and A in the general formula (I),

20 A lower alkyl group is a straight-chain or branched alkyl group having 1 to 5 carbon atoms, and a substituted phenyl group is, for example, each independently a lower alkyl group having 1 to 3 carbon atoms such as a methyl group. , Halogens such as chloro, methoxy, etc., alkoxy substituted with 1 to 3 carbon atoms, amino, or mono-substituted with nitro, etc .; Di-, tri-substituted phenyl groups, and -A phenyl group and a phenyl lower alkyl group substituted by 0CH2CH (0N02) are a lower alkyl group having 1 to 5 carbon atoms substituted by a phenyl group. The substituted phenyl lower alkyl group means a lower alkyl group having 1 to 5 carbon atoms, which is substituted with the substituted phenyl group. The lower alkylamino group refers to an amino group substituted with a lower alkyl having 15 to 15 carbon atoms. Examples of the protecting group include general protecting groups such as an alkoxybenzyl group such as a tetrahydropyranyl group, a benzyl group, and a methoxybenzyl group; a benzyl group; Kid

10 phenylsilyl group, t-butynoresylmethylsilyl group, isopeptylpyrumethysilyl group, lower alkoxycarbonyl group, aryloxycarbonyl group and the like.

Examples of the compound of the present invention include the following compounds.

15 1. Trans-one 6-(N-2-Two troch

1,3,4—Dihydro-1,2,2—Dityl——4-Acetamine 2H—Venzo [b] pyran-13-All

2. Trans. 6 — (1 — Cyan Immino 4 — Nitroki

20 Cibutyl.) 1,3,4-Dihydro-1,2,2-Dimethyl-14, Acetylamino-1,2H-Benzo [b] pyran-1,3-O-1) 1

3. Trans 1-6 — [N ² — Cyan 1 N ¹ — (2—2 mouth mouth shechyl) amidino] 1 3, 4 — Dihydro 2, 2, or J: — Dimethyl 4-acetylamino 2 H-benzo [b] Pilane 1 3 — All

4. Trans. 1-6! ; (N-2-nitrohexyl) aminos-nore-fonyl] 1-3, 4-dihydro2, 2-dimethyl-14-acetylamino-2H- Benzo [b] piran-1 3-all

5-Trans 1-6-(2-2-Troxisheti Loxy Carbonil)-1, 3-4-Dihydro 1-2,2-Dimethyl-4-1

(N — methyl acetate) 1 2 H — benzo [b] pyran 1 3 — all

6. Trans 1-6 — [((4-Nitro 1-1-(Trifluorometansulfoniiminino))] Butyl) 1-3, 4- Rows 2 and 2 — Dimethyl 4 — (N — Methyl acetate) 1 2 H — Benzo [b] pyran 13 — All

7 Trans 1-6 — CN ² — Acetyl N ¹ — (2 — Nichiguchi) Amidino] 1-3, 4 — Dihydro 2

2 — Dimethylamine 1-4-acetylamino 2 H — Benzo [b] pyran 1 3 — All

8. Trans 1-6—CN- (2—Nitroxyl) aminocarbyl) 13,4—Dihydro 1-2,2—Dimethyl 4— (2-oxo-1-pyrrolidinyl) -2H-benzo [b] pyran-3-all

9 Trans 1-6 — (2—2 troche sheroxy carbonil) 13, 4 —Dihydro 1, 2,2 — Dimethyl 1 4 — (2—o 1 1 1 1-pyrrolidine 1) 2 H-benzo [b] pyran 1 3-all 10. Trans 1-6 — (2,3 — dinitroxypropoxy xycanolebonyl) 1-3, 4 — Dihydro 2,2 — Dimethylol 4 1 (2 —oxo 1 1 —pyrrolidinyl 1) 2H—benzo [b] pyran 1 3— all

11. Transance — 6 — (4 — 2-hydroxybutyryl) — 3, 4-dihydroxy 2, 2 — dimethyl 4- 1 (2 — oxo 1 1 — pyrrolidinyl) 1 2 H-benzo [b] pyran 1 3

12. Trans 1-6 — (1 — cyanomino 4 — nitroxybutyl) 1, 3, 4 — dihydro 1, 2 — 2 — dimethyl 4

-(2-oxo-111-pyrrolidinyl) -1-2H-benzo [b] pyran-13-ol

13. Trans-I 6 — (1-Acetyl imino 4-12-Trooxybutyl) 1,3,4-Dihydro 2,2 —Dimethyl I 4 1 (2-Oxo 1 11 Pyrrolidinyl) 1 2 H—benzo C b 3 pyran 1 3 — all

14. Trans 1-6— (1—Trifluoroacetyl-4—nitroxybutyl) 1,3,4-Dihydro 1-2,2—Dimethyl 4-1-1 (2—Oxo 1 1 1-pyrrolidinyl) 1-2H-benzo [b] pyran-13-ol

15. Trans 1 6 — (1 — Trifluoromethylsulfoni lumino 4 — Nitroxybutyl) — 3,4-Dihydro 1-2, 2 — Dimethyl 4 — (2 — Oxo 1 1-pyrrolidinyl) 1 2 H-benzo [b] pyran 13-ol

16. Trans 1-6 — [N ² — cyano N ¹ — (2 — nit Mouth quichetyl) amidino] 1, 3, 4 — dihydro 2, 2 1 dimethyl 4 — (2 — oxo 1 1 — pyrrolidinyl) 1 2 H — benzo [b] pyran One 3 — oar

17. preparative lance one 6 - [N ² - Asechiru - N〗 one (2 - Two Bok opening key Shechiru) A Mi Gino] one 3, 4 "di heat mud-2,

2 — dimethyl 1 4 — (2 — oxo 1 1 — pyrrolidinyl) — 2 H — benzo [b] pyran 1 3 — all

18. Trans 1-6 — CN ² 1 Trifluoroacetyl

N ¹ i (2 - D DOO Rokishechiru) A Mi Gino] one 3, 4 one di heat mud - 2, 2 - di main Chiru 4 _ (2 - O Kiso one 1 one pyro Li Jiniru) Single 2 H - Zo [b] piran-1 3-all

19. Trans 1-6 — CN ² — Trifluoromethyl sulfone 2 N ¹ — (2—2 trochecil) amidino] 1 3: 4 — Dihydro 2, 2 — Dime Cyl 1 4 — (2 — Oxo 1 1 — Pyrrolidinyl) 1 2 H — Benzo [b] pyran 1 3 — All

20. Trans 1-6! N— (2-Nitroxicetyl) aminosulfonyl] 13,4—Dihydro2,2—Dimethylone-4— (2—Oxo-11-Pyrrolidinyl) 1 2 H — benzo [b] pyran 1 3 — all

21. Trans 1-6 — (3—2-Tropoxypropylpyrusulfo 2) -3,4-Dihydro 2,2 —Dimethyl 1 4 — (2—Oxo 1 1 1 Pyrrolidinyl ) 1 2 H — benzo [b] pyran 1 3 — all 22. Trans 1-6— [3— (2—Nitroxitytil) aminobution pionyl) 1 3,4—Dihydro 2,2—Dimethyl 4— (2—Oxo— 1-pyrrolidinyl) 1 2 H-benzo [b] pyran 1 3-all

23. Trans 1-6! : N— (2-Troxitytyl) amino carbonyl] 1, 3,4—Dihydro2,2—Dimethyl 4 1 (2—Oxo 1 1—Piveridinyl) 1 2H— Benzo [b] pyran-1 3-all

24. Trans 1-6 — (2—Troxicetyloxycarbonyl) 1-3, 4 — Dihydro 2,2 — Dimethyl 4 —

(2 —oxo 1-piperidinyl) 1 2 H-benzo [b] pyran 1 3 —ol

25. Trans 1-6— (2,3—Dinitrooxypyroxycarbonyl) 1-3,4—Dihydro-1,2,2—Dimethylol 4-1-1 (2—Oxo-1-1-piperidinyl ) 1 2H-benzo (b) pyran 1-3-all-

26. Transform — 6 — (4 — nitroxybutyryl)) 1,3,4-dihydro-2, 2 — Dimethicone 4 — (2 — Oxo-1-1-piperidinyl) ) 1 2H—Venzo [b] pyran 1 3—Fall

27. Trans 1-6— (1—Cyanomino 4—Nitroxybutyl) 1,3,4-Dihydro-1,2,2—Dimethylyl 4-1-1 (2—Oxo 1 1— Piveridinyl) 1 2H—benzo

[B] Pyran-1 3-all

28. Trans. 1 6 — (1 — Acetylmino 4 — Nitro 1,3,4—Dihydro-2,2—Dimethylyl 4- (2—oxo-11-piperidinyl) -12H—Benzo [b] pyran-13—All

29. Trans 1-6— (1—Trifluoroacetyl-41-nitroxybutyl) 1-3,4—Dihydro 2,2—Dimethyl 4-41 (2—Oxo 1 1-pipe Lysinyl) 1 2H — benzo [b] pyran 1 3 — all

30. Trans 1-6— (1—Trifluoromethylsulfoni luminino 1-4—Nitroxybutyl) 1 3,4—Dihydro—2,2—Dimethyl 4— (2—o 1-Pyveridinyl) 1 22Η-Benzo [b] pyran-1 3-All

31. Trans 1-6 — CN ² -cyano N ¹ — (2 — 2 mouth quichetyl) amidino) 1 3, 4 — Dihydro 2, 2-Dimethyl 1 4 1 (2 —Oxo 1-piperidinyl) — 2 H —benzo [b] pyran-1 3 —ol

32. Trans 1-6 — [N ² —acetyl-N ¹ — (2—2-troxitytyl) amidino] 1-3,4-oji Hydro 2,

2 — dimethyl 1 4 — (2 — oxo 1 1 -piperidinyl) — 2 H — benzo [b] pyran 1 3 — ol

33. Trans 1-6 — [N ² — Trifluoroacetizole N ¹ 1 (2—2 troxicetil) amidino] 1-3,4—Dihydro 1-2,2—Dimethinolate 4 1 (2—oxo 1—pyrrolidinyl) 1 2 H—benzo [b] pyran 1 3—one

34. Trans 1-6 — [N ² — Trifluoromethylsulfo Nil—N ^1- (2—Nitroxitytyl) amidino] 1, 3,4—Dihydro ¹ , 2,2—Dimethyl ¹ 4— (2—Oxo ^{1 1—} Pyrrolidinyl) ¹ 2H —Benzo! : B] piran one 3 — oar

35. Trans 6-! : N— (2-Nitroxitytyl) aminosulfonyl] 1,3,4—Dihydro-1,2,2-Dimethyl-1 41 (2-Oxo-1-1-piperidinyl) 1-2 H-Venzo [b] 1-pyran

36. Trans- 1 6 — (3—2 T-hydroxypyrropylsulfonyl) 1, 3, 4 — Dihydro2, 2 — dimethylyl 4— 1 (2,1oxo1—11, 1-pyrrolidinyl) 1-2H —Venzo [b] Pyrane 1 3 —All

37. Trans 1-6 — [3— (2-Troxicetilamino) propionyl] 1-3,4—Dihydro-1,2,2—Dimethylyl 4-1-1 (2—Oxo 1 1— Piberidinyl) 1 2 H-benzo [b] pyran 1 3 — ol

38. Trans 1-6 — (1 — cyanomino 4-1 2 oxybutyl) 1 3, 4 — dihydro 2, 2 — dimethyl 4 1 (2 — oxo 1 1 — pyriyl Gin) 1 2 1 Benzo [b] Pyran 1 3 — All

39. Trans 1-6 — CN- (2—Nitroxityl) amino Sulfonyl] 1-3, 4 — Dihydro 1 2, 2 — Dimethyl 4 — (2 — Oxo 1 1 — P Resin) 1 2H—Venzo

[B] Pyran 1-all

40. Transform — 6 — [3 — (2 — Nitroxchecilami No.) Propionyl] 1,3,4-Dihydro 2,2—Dimethyl_4-1 (2—Oxo-1 1—Pyridine) 1 2H—Venzo [b] Pilane 1 3 — Oar

41. Trans 1-6— (2—Nitroxypropionyl) —3,4-Dihydro-1,2,2—Dimethyl 4— (2—Oxo 1—Pyridine) 1 2 H-benzo [b] pyridine 1 3 — all

42. Trans 3-1, 4—Dihydro 2, 2—Dimethyl 1 6— (1—Methyl 1 2—2 Troxicetilokisikarubonil) 1-41 (2—Oxo 1 1-pyrrolidinyl) 1-2H-benzo [b] pyran-13-ol

43. Trans 1, 3, 4 — dihydroxy 2, 2 — dimethyl 6 — (2 — 2 oxypropiroxy carbonyl) 1 4-1 (2 — oxo 1 1 — pyrrolidinyl) 1 2 H—benzo [b] pyran 1 3 — all

44. Trans-1,3-dihydro-2,2-Dimethyl-6- (412-Troxyl 1-oxobutyl) —4-1- (2,1oxo-111-pyrrolidinyl) 1) 2H—benzo [b] pyran 1— 3—

The compound of the present invention has an asymmetric carbon atom at the 3- and 4-positions of the chroman ring (and, in some cases, in the substituents of the chroman ring), The body exists. The target compound of the present invention includes each of the purely isolated optically active substances and their racemic substances. It also includes cis or trans isomers based on the 3rd and 4th configuration, but preferred coordination Is a trans isomer.

The compound of the present invention can be produced by the following production method.

Manufacturing method 1.

N A

Cll] [III]

CIV]

[V]

C I]

twenty five The compound [I] of the present invention or a salt thereof is a 6-cyano form

C II) to produce 6-amide [III], 6-ester [IV], 6-carboxyl [V], and then convert them [Root 11-1] or [II] Can also be produced directly from [IV] [root.11] by converting to [V] [root.11]. The following partial structural formulas (a) of the compounds [I] to CV)

R

-X (a)

The group represented by f is CH ₃ CO NH group, CF ₃ CO NH group CH 3 NC 0 CH 3 group, C s H ₅ CONH group,

C 6 H 5 C 0 NCH 3 group, 2-oxo-11-pyrrolidinyl group, 2-oxo-11-piperidinyl group, 1,2—dihydro-2-oxo-1-1-pyridyl A is a hydrogen atom, a nitro group, a lower alkyl group, a lower alkyl group substituted with 1 to 3 nitroxyl groups,

— Suitable for synthesizing a compound having C (= X)-(0) „-R ⁴ or a general protecting group.

The details of the method will be described below.

[Root. 1 1 1]

6 — Convert Cyan field [体 I] to 6 – Amide field [[I 〖] There are three methods (a) to (c).

(1) 6-Conversion of Cyan form [II] to 6-Amide form [III]

(I). BF ₃ with respect to (II), T i C l 0 Louis scan acids such as _4, 5-1 0 times moles, and preferred rather about 1-3 fold molar is used. The reaction is usually performed in a mixed solvent of water and an acid. Examples of the acid include acetic acid and propionic acid. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature, or under heating. Specifically, the reaction is carried out for 1 to 48 hours from room temperature to around the boiling point of the solvent, but a reaction around the boiling point of the solvent gives good results.

(Mouth). An acid such as H ₂ SO ₄ or HCl is used in an amount of about 0.5 to 10 times, preferably about 1 to 3 times, of [II]. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature, or under heating. Specifically, the reaction is carried out from room temperature to the boiling point of the solvent for 1 to 48 hours, but a reaction near the boiling point of the solvent gives good results.

(8) 0.5 to 31%, preferably 3 to 5% of hydrogen peroxide and sodium hydroxide or potassium hydroxide to [II] 0.5 to 20 times A molar amount, preferably about 1 to 10 times, is used. The reaction is usually carried out in an organic solvent or water, but a mixed solvent of alcohol and water gives good results. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature to around the boiling point of the solvent for 1 to 48 hours. The 6-amide form [ΠΙ] is isolated by a conventional isolation method such as extraction, recrystallization, or chromatography (2) 6-amide form [ΙΠ] To 6—ester [IV]

The amount of an acid such as HC 1 gas or a Lewis acid such as BF ₃ or Et 20 is about 0.5 to 10 moles, preferably about 1 to 3 moles relative to C III]. The reaction is usually performed in an alcohol solvent such as ethanol. Better results are obtained when the reaction temperature is near the boiling point of the solvent or when the temperature is higher than the boiling point of the solvent in a sealed tube. Depending on the alcohol solvent used, the corresponding 6-ester [IV] is formed. [IV] is isolated by a conventional isolation method such as extraction, recrystallization, or chromatography.

(3) Conversion of 6-ester [IV] to 6-carboxyl [V]

An acid such as hydrochloric acid or hydrogen bromide or a base such as sodium hydroxide or potassium hydroxide is used in a large excess, preferably about 1 to 3 moles, based on the catalyst amount with respect to [IV]. Is done. The reaction is usually carried out in an alcohol solvent such as ethanol or diethyl glycol or in water. The reaction temperature is not particularly limited, and may range from room temperature to the vicinity of the boiling point of the solvent for 1 to 48 hours; (depends. [V] is used for the conventional isolation method such as extraction, recrystallization, or chromatography, etc.) Thus, it is isolated.

(4) 6-carboxyl compound [V] is converted to the present compound [I] First, lead from [V] to the 6-cloth holmium body. That is, about 1 to 10 times mol, preferably about 1 to 3 times mol of oxazolychloride or thionyl chloride is used with respect to [V]. The reaction is usually performed in an organic solvent such as ether or benzene at room temperature to near the boiling point of the solvent for 10 minutes to 3 hours. After the completion of the reaction, the reaction solution is concentrated under reduced pressure to obtain 6-close formyl form.

When synthesizing an amide compound substituted with a nitroxyl group, for example, an amine such as nitroxylamin is added 1 to 10 times the obtained 6-chloroformyl compound. About 1 mole, preferably about 1 to 3 moles, is used. The reaction is carried out in an organic solvent such as methylene chloride or chloroform and the reaction temperature is not particularly limited.The reaction is carried out at a temperature from room temperature to the boiling point of the solvent for 0.1 to 48 hours.

[I] is isolated by a conventional isolation method such as extraction, recrystallization, or chromatography.

Next, when synthesizing an ester compound substituted with a nitroxyl group, for example, an alcohol such as ethoxyethyl alcohol is preferably used in an amount of about 1 to 10 times the molar amount of the 6-chloroformyl compound. and rather the _c reaction about 1-3 fold molar is used the reaction temperature around the boiling point of the chamber warm et solvent in an organic solvent menu Chi les emissions chloride, such as click throat Holm not particularly limited, at room temperature ~ 1 to 48 hours near the boiling point of the solvent. [I] can be isolated by a conventional isolation method such as extraction, recrystallization, or chromatography. [Root. 1 1 2]

As a method for converting 6-cyano form [II] directly to 6-ester form UV], use an acid such as sulfuric acid, P-toluene sulfonic acid, hydrochloric acid gas, hydrobromic acid, etc. About 0.5 to 10 times, preferably about 1 to 3 times, is used. The reaction is usually heated to reflux in an alcohol solvent such as ethanol to produce the 6-ester [IV]. [IV] is isolated by a conventional isolation method such as extraction, recrystallization, or chromatography.

[Root. 1 1 3]

The method for converting 6-cyano form [I I] directly to 6-carboxyl form [V] is to convert [II] to an acid such as sulfuric acid, concentrated hydrochloric acid, hydrobromic acid, or hydroxylated sodium. The base such as lithium and potassium hydroxide is used in an amount of about 0.5 to 10 moles, preferably about 1 to 3 moles. The reaction is usually carried out by heating and refluxing for 1 to 48 hours in a mixed solvent of an alcohol such as ethanol and diethyl glycol and water to produce a 6-carboxyl compound [IV]. [V] is isolated by a conventional isolation method such as extraction, recrystallization, or chromatography.

Examples of the compound obtained by the production method 1 include compounds No. 1, 5, 8, 9, 23, 24 and the like. Manufacturing method 2.

This method utilizes the Grignard reaction, for example, the R ¹ force in the compound [I] in the following scheme. One CO (CH 2) a 0 N 02, etc., wherein the group represented by the above-mentioned partial structural formula (a) is 2-oxo-111-pyrrolidinyl group, ₂ -oxo- 1 —piperidinyl group, 1 , 2 — Jihiro

Suitable for the synthesis of compounds such as 2-oxo-pyridine ο

This method includes the following methods.

(I)

[I]

6—The Grignard reagent can react with the cyano form [II]. The imino body is immediately hydrolyzed with an acid.

The details of this method will be described below. That is, for compound [〔], R ⁶ MgBr (here, R ⁶ ) represents a lower alkyl group, a cycloalkyl group having 11 to 10 carbon atoms, a phenyl group, a substituted phenyl group, or a substituted phenyl group. It is a aryl group, a phenyl group, a pyridyl group, a pyrimidyl group, or a lower alkyl group substituted with one to three protected hydroxyl groups. )

The Grignard reagent represented by the formula (1) is used in an amount of about 0.5 to 5 times, preferably about 1 to 3 times by mole. The reaction is carried out in an organic solvent such as anhydrous ether, anhydrous tetrahydrofuran, or anhydrous benzene or anhydrous toluene at room temperature to near the boiling point of the solvent for 1 to 48 hours. A ketone form is obtained by hydrolyzing an imine form obtained as a reaction intermediate with an acid such as hydrochloric acid by an ordinary method. For example, as R ⁶ M g B r

_{_{M g B r CH z CH 2}} CH 2 0 P and the like. Here, P is a suitable protecting group, for example, a tetrahydrovinylyl group, a methoxybenzyl group, a t-butyldimethylsilyl group or the like. These protecting groups are deprotected by a conventional method, and the resulting alcohol is ditoxylated by a conventional method to obtain the compound [I] of the present invention.

Production Method 1. The Grignard reagent may be reacted with the 6-chloroformyl form obtained in (4) in the presence of cuprous chloride in the same manner as in (a) above.

Examples of the compound obtained by the production method 2 include the compounds N 0.11, 26, and 41.

Manufacturing method 3.

The compound [I] of the present invention or a salt thereof can also be produced by the following two methods.

(Y :)

L r

J

[VI]

This method involves acylating an amidine derivative [] obtained by reacting, for example, nitroxyshetilamine with an imidite [VIII] derived from the 6-cyano derivative [II]. For example, in the compound [I] in the above scheme,

R ^{1 is} C (= NCN) NHCH 2 CH ₂ 0 N 0 ₂ ,

-C (= NC 0 CH a) NHCH 2 CH ₂ 0 N 0 ₂ ,

— C (two NC〇 CF ₃ ) NHCH ₂ CH ₂ 0 N 0 ₂ , - C (= NS 02 CF 3 ) NHCH Ri 2 CH ₂ 0 N 0 _2, etc. der, the partial structural formula (a) groups represented by the 2 - Okiso one 1 - pyrosulfite Li Jiniru group, 2 - Okiso one 1 -Suitable for the synthesis of compounds such as piperidinyl group, 1,2-dihydro-2-oxo-pyridinine.

The details of this method are shown below. That is, compound (II) is dissolved in anhydrous alcohol such as anhydrous methanol or anhydrous ethanol, hydrochloric acid gas is introduced under ice-cooling, and left in a refrigerator for 1 hour to 1 week. The corresponding alcohol hydrochloride [VIII] used as a solvent is obtained. This product is neutralized with sodium hydrogencarbonate, ammonia water, etc., and then the imidite [VIII] is reacted with, for example, 2-2-troxicetilamine. The resulting amidine [IX] is converted to a normal acylation reaction condition, for example, with acetyl chloride or the like, in the presence of triethylamine, in an inert solvent such as black form. By doing so, the desired compound [I] of the present invention is obtained.

(σ)

CI]

[门

This method is based on N-cyanoimidate [Χί] obtained by reacting an orthoester [X] derived from 6-cyano isomer [II] with cyanamide or the like. A method of reacting thiamine, for example, in the above scheme R ¹ in compound [I]

-C (= NCN) NHCH 2 CH ₂ 0 N 0 _2, etc., wherein the group represented by the aforementioned partial structural formula (a) is 2—oxo-1 1—piperidinyl group, 2—oxo—1 -Suitable for the synthesis of compounds such as piperidinyl group, 1,2-dihydro-2--2-oxo-pyridine.

The details of this method are shown below. That is, compound (II) is dissolved in anhydrous alcohol such as anhydrous methanol or anhydrous ethanol, hydrochloric acid gas is introduced under ice-cooling, and left in a refrigerator for 1 hour to 1 week. The corresponding alcoholic hydrochloride used as the solvent is obtained. This product is neutralized with sodium bicarbonate, ammonia water, etc., and then this imidite [VIII] is dissolved in anhydrous alcohol such as anhydrous methanol under ice cooling to a solvent. To the corresponding orthoester [X]. This product is reacted with cyanamide in the presence of about 1 to 5.0 moles of acetic anhydride at about 0.1 to 5.0 moles at 130 to 140 ° C to give N-cyanoimide. (XI) with good yield. By reacting this [XI] with, for example, about 0.1 to 5.0 moles of nitroxyshetilamine, the desired compound [I] of the present invention can be obtained at a high yield.

Next, the action of the compound of the present invention will be described.

Experimental example 1

The thoracic aorta of a male SD rat was excised and a 3 mm wide ring specimen was prepared. The sample is filled with Krebs-Henseleit solution The suspension was suspended in a 10 ml Organ bath with a static tension of 1.0 g. Nutrient solution was maintained at 3 7, 9 5% 0 ₂ - aerated with 5 ¾ C 02. Muscle isometric tension was measured with an FD pick-up and recorded with a recorder.

After an equilibration time of about 1 hour, the test drug was cumulatively administered to the sustained contraction induced by 20 mM or 80 mM KC1, and its contraction-releasing effect was examined. . The test compound's contraction-relaxation effect was determined by setting the maximum relaxation obtained with papaverine hydrochloride 10 — ⁴ M to 100% and the IC ₅₀ value ( ₅₀ 'relaxation concentration) of the test drug at the inhibition rate. The efficacy was expressed as one log IC ₅₀ value determined from the curve.

Results>

Compound 20 mM KCl 20 mM KC1 Compound No. 9 6.83 ± 0.10 4.81 Sat 0.03 (Compound of Example 5 described later) (n = 3) (n = 3 Compound No. 42 6.35 ± 0.01 5.39

(Compound of Example 6 described later) (n = 2) (n = 2) Compound No. 44 6.45 ± 0.14 4.54 ± 0.03 (Compound of Example 8 described later) (n = 3) (n = 3) Result As is clear from the above, the compound of the present invention has a potent vasoconstrictor ameliorating effect and is expected as a vasodilator.

Experimental example 2

Detects the extended action on the guinea pig Bok isolated tracheal smooth muscle, the relaxing action on the contraction caused by B A co-door Li E down D ₄ to index Discussed.

After killing Hartley male guinea pigs (Nissei Lab.), The trachea was removed. Carefully, 2ϋ tracheal pieces were carefully attached so as not to damage the tracheal smooth muscle, and 5 pieces were connected alternately with a thread to prepare a tracheal chain specimen. Specimens, Lee emissions domain data Thin - pendent over ^{(5 x 1 0 6 Μ)} modif ied Krebs-Henseleit 0 in organ bath nutrient solution was less than the 1 5 m 1 containing 5 g heavy tension. . Nutrient solution was maintained at 3 7 ° C, 9 5% 〇 ₂ Ten 5%

10 C 02 gas was vented. The experiment was performed after 1 hour equilibrium. The reaction is made isotonic with a multi-pen recorder (Rikadenki Kogyo, Nihon Kohden, JD-112S) and an input box (Nihon Kohden, JD-112S). R — 64 VL).

15 each specimen to a maximum contraction Ri by the carbachol (3 X 1 0 one ⁶ and 1 0 one ⁵ M), this and was Tsu name to cleaning after equilibration Roda Mi Roh Bae putida Ichize inhibitor L one Shisuti down (3 X 10 — ³ M). 30 minutes later, Leukotrien D ₄ (3 X

1 0 - ⁹ M) to elicit by Ri contraction reaction, the contraction is a constant state

In this filtration that Tsu Na to 20, test drug (1 0 one ^{8 ~ 3 X 1 0 - M} ) were applied cumulatively in bus common ratio 3. Each specimen was finally confirmed for maximum relaxation by papaverine.

Analyzing the results

Relaxation at each concentration of test drug is maximal relaxation by papaverine n

0 Relaxation is converted to a relaxation rate of 100%, and the maximum ED ₃ is the dose that gives a relaxation rate of 30%, determined by linear regression from the relaxation value (? Ό) and the relaxation rate of the two doses. (L) -log value is displayed in the result.

Results>

Table 1 shows the results. Relaxing action on the contraction caused by the drug leuco M E emissions D ₄

l o g [ED 3 o (M)) J Maximum relaxation (%) Compound No. 9 5.69 97.4 (Compound of Example 5 described later)

Compound No. 44 5.79 95.3

(Compound of Example 8 described later)

Chroma limb 5.78 52. 0

As is evident from Table 1, Compound No. 9 and Compound No. 44 exhibited complete relaxation, unlike cromakalim, which exhibited inadequate relaxation even at high doses. It has a stronger action of dilating tracheal smooth muscle than chromamaclim.

As is clear from the above, the compound of the present invention strongly relaxes tracheal smooth muscle. Therefore, it is expected to be a new type of tracheal smooth muscle relaxant that is effective not only for mild to moderate attacks but also for severe attacks. Similarly, not only bronchial asthma but also difficult breathing based on bronchial obstructive disorders such as asthma-like bronchitis, acute bronchitis, chronic bronchitis, emphysema, silicosis, pneumoconiosis, pulmonary tuberculosis, etc. Effective for remission of various symptoms It is also expected as a new drug.

When the compound of general formula (I) is used as a pharmaceutical, it may be used alone, or as a mixture with an excipient or carrier, for injection, granules, fine granules, powder, capsules, suppositories, eye drops, patches. It is orally or parenterally administered as a preparation such as a patch, ointment, spray or the like, or as an inhalant. Pharmaceutically acceptable excipients and carriers are selected, and their types and compositions are determined by the administration route and administration method.

The content of the compound of the present invention in the preparation varies depending on the preparation, but is usually 0.1 to 100% by weight. For example, in the case of a liquid preparation, it is usually preferable to contain 0.1 to 5% by weight of the compound of the present invention. The dose is determined according to the age, weight, condition, purpose of treatment, etc. of the patient, but the therapeutic dose is generally 0.000 ~; 0.003 mg / day, 0.003 to 3000 mg / day by oral administration.

[Best mode for carrying out the invention]

Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1

Trans 1-3 — (4—Methoxy benzene) 1 6—Hydroxy carb 2 3,4—Hydroxy 1,2—2—Jistyl 1 4-1 (2—Oxo Production of 1 1 1 pyrrolidinyl) 1 2 H-benzo [b] pyran

Trans 1-6—Methoxy carbonyl 3_, 4—Dihydro 2,2—Dimethy 4— (2—Oxo 1 1—Pyrrol Dissolve 36.6 mg of 2H-benzo [b] pyran in 11.5 ml of anhydrous dimethylformamide, and cool the solution with ice water. To this solution was added 57.6 mg of 60% oil-based sodium hydrogen hydride. After the addition, the temperature was returned to room temperature, and the mixture was stirred until hydrogen evolution ceased. Next, the mixture is cooled again with ice, and 25.3 mg of 2-dimethylbenzene anhydrous 2 ml of anhydrous dimethylformamide is added dropwise, and the mixture is added dropwise and stirred at room temperature for 1.5 hours. The reaction solution is transferred to ethyl acetate, a phosphate buffer is added, ethyl acetate extraction is performed, and then the organic layer is washed with a saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel chromatography (developing solvent: ethyl acetate: n-hexane = 1: 1), and trans- 3 — (4- 6-methoxycarbonyl-1,6-dihydroxy-2,2-dimethyl 2- (2-oxo-111-pyrrolidinyl) -12H-benzo [ b] Obtain 267.1 mg of pyridine.

On the other hand, the phosphate buffer solution and the aqueous layer of saturated saline are combined, concentrated under reduced pressure, and methylene chloride is added to the concentrated residue for extraction.

The trans one obtained above is 3-(4-methoxybenzyloxy) 1-6-methoxycarbonyl 3,4 dihydro 2,2-dimethyl 4- 1 (2 -oxo 1 Dissolve 267.1 mg of 1-pyrrolidinyl) 1-2H-benzo [b] pyran in 4.2 ml of methanol, and add a 25% aqueous solution of potassium hydroxide in 0.2 ml. Add 0 g. Heat this solution under reflux for 2 Allow the reaction to proceed for an hour, then cool, and adjust the pH to around 5 using 2N hydrochloric acid. This is concentrated under reduced pressure, and methylene chloride is added to the concentrated residue for extraction. This methylene chloride solution is mixed with the methylene chloride layer obtained from the above-mentioned aqueous layer, the solvent is concentrated under reduced pressure, and the residue is purified by silica gel chromatography (developing solvent ethyl acetate). Gelatin: Methanol: = 5: 1), purified by trans-one 3 — (4—methoxybensiloxy) 1 6—hydroxica ruboni 1, 3—4—dihydro 2,2—Dimethyl 4- (2-oxo-111-pyrrolidinyl) -12H-benzo [b] pyran was obtained in an amount of 372.3 mg.

Trans- 1 3 — (4 — methoxybenzene) 1- 6-methoxynorrebonil 1, 4-dihydro 2, 2 — dimethyl 4 — (2 — oxo 1 1-Pyrrolidinyl) -1H-Benzo [b] pyran

¹ H-NMR (200 MHz, DMS 0-d ₆ ) δ; 1.20 (s, 3Η), 54 (s, 3H), 1.85 (m, 2Η), 2.35 (m, 2Η), 2.85 (m, 1Η), 3.21 (m, 1Η), 3.76 (s, 3Η), 3.80 (s) , 3rd), 3.86 (d, 1st), 4.59 (q, 2nd), 5.19 (d, 1st) 6.92

(brd, 3rd, 7.24 (d, 2nd)), 7.46 (m, 1st), 7.78 (dd, 1st)

Trans 1-3 — (4—methoxybenzene) 1-6-Hydroxica carbonyl 3, 4 — Dihydro2,2-dimethylyl 4- 1 (2—oxo1 1 — pyrrolidinyl) one 2 H-benzo [b] pyridine

^{1 H - NMR (2 0 0} MHz, CD 3 0 D) δ;

1.28 (s, 3H), 1.58 (s, 3H), 1, 78 (m, 1H), 1.93 (m, 1H), 2.20 to

2.64 (m, 2 H), 2.86 to 3.18 (m,

2H), 3.78 (d, 1H), 3.80 (s, 3H), 4.55 (d,! H), 4.73 (d, lH), 5. 3 1 (d, 1 H), 6.8 3 to 6.96 (m, 3 H), 7.27 (aparentd, 1 H), 7.58 (m, .1 H), 7. 8 4 (aparentdd, 1 H)

IR (KBr) cm "¹;

3 4 5 0, 1 6 7 0, 1 1 1 0

Example 2.

Trans- 1 3 — (4-methoxybensiloxy) 1 6 1 N— (2-2 troxy shechil) amino carbone

4—Dihydro-1,2,2-Dimethyl-4— (2—oxo-1—pyrrolidinyl) 1-2H—Benzo [b] Production of pyran 1,6-Hydroxycasoleone 2,3—Dihydro2,2—Dimethyl-1 4— (2—Oxo-1-1-pi π-Lidinyl) 1-2H—Venoxy Dissolve 22.5 mg of zo [b] pyran in 3 ml of anhydrous benzene, then add 82.5 mg of oxalyl chloride, and stir at 50 for 30 minutes. Next, the reaction solution is concentrated under reduced pressure, and 2.5 ml of anhydrous methylene chloride is added to the concentrated residue, followed by 61.6 mg of pyridine. Cool the solution on ice. After that, add a solution of 6-l-nitroshethylamine 66.1 mg in 0.5 ml of pyridin and stir at room temperature for 1 hour. Dilute the reaction solution with methylene chloride, add water, extract with methylene chloride, dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The concentrated residue was purified by silica gel chromatography (developing solvent, ethyl acetate), and trans- 1 3 — (4 — methoxybenziloxy) 16 — N — (2-12)卜口キシェ口口 b チ 4 b b b b 口 [b] 91.6 mg of pyran was obtained.

^{1 H - NMR (2 0 0} MHz, CDC 1 3) δ;

1.13 (s, 3 layers), 1.54 (s, 3 layers), 1.6

2 to 2.10 (m, 3H), 2.26 to 2.70 (m, 2H), 2.92 (m, 2H), 3.38 to 3.85 ( m, 2H), 3.57 (d, 1H), 4.50 (m, 3H), 4.68 (d, 1H), 5.27 (d, 1H), 6.82 (d, 1H), 6.90 (aparentd, 2H), 7.23 (aparentd, 2H),

7.50 (m, 1H), 7.73 (dd, 1H)

IR (KBr) cm "¹;

3 3 0 0, 1 6 7 0, 1 6 3 0, 1 2 7 0, 10 8 0 Example 3.

Trans 1-6—N— (2—Nitroki Shechil) Aminocarbon 3,4—Dihydro 2,2—Dimethyl 4 -(2-Oxo-111-Pyrrolidinyl) -1-2H-Benzo [b] pyran-1-ol

Trans-one 3 — (4-Methoxybenziloxy) 1 6 — N— (2-Troxicetil) amino carboneru 3 4-Dihydro 1-2,2—Dimethyl 4— (2— Dissolve 81.7 mg of oxo-1- (pyrrolidinyl) -12H-benzo [b] pyran in 1.8 ml of methylene chloride and add 0.1 ml of water. Next, 2, 3 — dichlor 5 and 6 — di cyano. Add lavenzoquinone 45,2 rag and stir at room temperature for 6,5 hours. Dilute the reaction solution with methylene chloride, add saturated aqueous sodium bicarbonate, extract with methylene chloride, then wash with saturated saline and dry over anhydrous sodium sulfate. . After filtration, the filtrate is concentrated under reduced pressure, and the concentrated residue is purified by silica gel chromatography to obtain a 6-N- (2-nitroxitytyl) aminocarbo-transformer. 2,3—Dihydro 2,2—Dimethyl 4—1 (2—Oxo 1—11 Pyrrolidinyl) —1 2H—Venzo (b) Pyran 13—All is 49 Obtained at 5 mg.

1 H - NMR (2 0 0 MHz, CD 3 0 D) o;

l, 26 (s, 3H), 1.50 (s, 3H), 2.10 (m, 2H), 2.59 (m, 2H), 3.08 (m , 1 H), 3.41 (m, 1 H), 3.69 (m, 2 H), 3.78 (d, 1 H), 4.66 (t, 2 H), 5 19 (d, 1 H), 6.86 (d, 1 H), 7.46 (m, 1 H), 7.67 (aparentdd, 1 H), 8.6 1 (m, 1H)

IR (KBr) cm- ¹ ;

3 3 5 0, 1 6 4 0, 1 2 7 0, 1 0 7 0

Example 4.

Trans 1-3-(4-methoxybenzene) 1-6-(2-2 troxicetyloxycarbonyl) 1, 3-4-Dihydro-1, 2-2-Dimethyl-4-1 (2-Oxo-111-Pyrrolidinyl) -12H-Venzo [b] Preparation of pyran Trans- 13- (4-Methoxyxyl-ziroxy) -16-Hydro Kishoka norevonyl-3,4-dihydro-1,2,2-dimethyl-14- (2-oxo-11-pyrrolidinyl) -12H-benzo [b] pyran 532 To a solution of 4 mg (1.25 mmol) in benzene (10.2 ml) was added oxalyl chloride (198.9 mg, 1.57 mmol), and the solution was added at 50 ° C. Stir for 0 minutes. Next, the solvent is distilled off under reduced pressure, and the residue is diluted with methylene chloride (6.3 ml). To this solution, add pyridine (148.6 mg, 1.88 mmo 1), and add 2 — nitroxyethanol (201.1 mg, 1.8 8 mmol) in methylene chloride (2.0 ml) was added, and the reaction solution was cooled to room temperature and stirred for 30 minutes. Next, dilute with methylene chloride (appropriate amount), add water and wash. After the organic layer was dried over sodium sulfate anhydride, the solvent was distilled off under reduced pressure, and the concentrated residue was purified by silica gel chromatography (developing solvent, ethyl acetate: hexane = 3: 1). ) To give a trans- 1 3 — (4 — methoxybenziloxy) 1 6 — (2 — 2 (Troxetylcarbonyl) 1, 3 — 4

2-Dimethyl 1-4 (2-oxo-1-pyrrolidinyl)-1 H-benzo [b] pyran (252.2 mg) is obtained. 1 H-NMR (200 MHz, CDC ") δ;

1.56 (s, 3rds), 1.69 (s, 3rds), 1.63 to 2.09 (m, 2nds), 2.23 to 2.63 (m, 2), 2.9 1 (t, 2), 3.64 (d, 1),

3.81 (s, 3rd), 4.47 to 4.64 (m, 3rd), 4.69 (d, 1st), 4.78 (t, 2nd), 5 40 (d, 1 1), 6.8 1 to 6.96 (m, 3Η), 7.22 to 7.30 (m, 2Η), 7.59 to

7.6 3 (m, 1 Η), 7.80 to 7.88 (m, 1 Η)

IR (neat) cm "¹;

3 4 5 0, 1 7 2 0, 1 6 8 0, 1 6 4 0, 1 2 8 0, 1 2 6 0

Embodiment 5.

Trans 1, 3 — 4 — Hydro 2, 2 — Dimethyl 6 — (2 — 2 troxicetyloxycarbonyl) — 4 1

Preparation of (2-oxo-111-pyrrolidinyl) -12H-benzo [b] pyran-13-ol

Trans 1-3— (4-methoxybenzyloxy) obtained in Example 4—6— (2—2-Troxicetyloxycarbonyl) 1,3,4—Dihydro-2,2—Dimethylinole One four one

(2 — oxo 1 1 — pyrrolidinyl) 1 2 H—benzo [B] A mixture of pyran (240 mg, 0.47 mmol) in methylene chloride (5.3 ml) and water (0.3 ml) was added to the mixture, followed by 2,3-diamine. To the mixture was added chlorono-5,6-diisano-4-benzoquinone (16.6 mg, 0.51 mmol), and the mixture was stirred at room temperature for 3.5 hours. When the progress of the reaction has slowed down, add a small amount of 2,3-dichloro-5,6-dicyan-4benzoquinone. Dilute the reaction solution with methylene chloride, add dilute sodium hydrogencarbonate aqueous solution (appropriate amount), and perform methylene chloride extraction. Next, the methylene chloride layer is washed with water, dried over anhydrous sodium sulfate, and then the solvent is concentrated under reduced pressure. The concentrated residue is purified by silica gel chromatography (developing solvent, ethyl acetate), and the trans-1,3—4—dihydro-1,2,2—dimethyl 6— (2— (2)-(2-oxo-111-pyrrolidinyl) -12-H-benzo [b] pyran-13-ol (134.3 mg, yield) Rate of 73%).

1 H - NMR (2 0 0 MHz, CD 3 0 D) o;

1.28 (s, 3H), 1.51 (s, 3H), 2.00 to 2.20 (m, 2H), 2.59 (t, 2Η), 2 9.9 to 3.15 (m, 1st), 3.33 to 3.52 (m, 1st), 3.78 (d, 1st), 4.51 to

4. G 1 (m, 2 H), 4.80 to 4.9 1 (Over lapped with 0 H signal of Me H, 2 H), 5.2 1 (d, 1 H). 6 8 8 (d, 1H), 7.57 to 7.64 (m, 1H), 7.80 to 7.89 (m, 1 H)

IR (KBr) cm- ¹

3 5 0 0, 1 7 2 0: 1 6 6 0, 1 6 3 0, 1 2 9 0, 1 2 7 0

Embodiment 6.

Trans 1, 3,4-Dihydro 1, 2,2-Dimethyl 6 1 (1 -methyl 2 -nitroxyloxycarbonyl) 1 4-(2 -oxo 1 1 -pyro Production of lysinyl) 1 2H-benzo [b] pyran-3-3-ol

(Process 1)

Trans-One 3 — (4-Methoxybenziloxy) -1 6-Hydroxycasolevo-Niru 3,4-Dihydroxy-2,2-Dimethylyl 4-1-1 (2-Oxo-11-Pyrrolidinyl) -1 2H-benzo [b] pyran (1.00 mg, 2.35 mmol) .oxalyl chloride (373.5 mg, 2.94 mmol), pyridin (372.2 mg, 4.71 mmo I) and 1-methyl-2-nitroethoxyethanol (427 mg, 3.533 mmol) were reacted in the same manner as in Example 4. Then, after post-treatment and purification with silica gel chromatography (developing solvent, ethyl acetate: hexane = 3: 2), trans 3 — (4— 6- (1-Methyl-1-2-methoxyloxycarbonyl) -14- (2-oxo-111-pyrrolidinyl) -1-2H— This gives benzo [b] pyran (465.6 mg).

(Step 2 Transform obtained in step 1 3 — (4 — methoxybenziloxy) 1 6 — (1 — methinole 2 — nitroxy shecilo kisica rubonil) 1 4 — (2 — oxy So — 1 — pyrrolidinyl) 2H-benzo [b] pyran (449.5 mg, 0.85 mmo 1), 2, 3-dichloromethane 5, 6- Di-cyanone 4-benzoquinone (289.9 rag, 1.28 mmol) was reacted in the same manner as in Example 5 and worked up, followed by silica gel chromatography (development). Solvent, ethyl acetate), which gives a trans-1,3-dihydro-1,2,2-dimethyl-6- (1—methyl-2--2-nitroxyshetyl oxica Rubonyl) — 4 — (2-oxo-111-pyrrolidinyl) -12H-benzo [b] pyran-13-ol (238.5 mg, 69% yield) obtain.

1 H-NMR (200 MHz, CDC ") δ;

1.30 (s, 3rds), 1.42 (d, 3rds), 1.5

4 (s, 3H), 2.00 to 2.20 (m, 2Η),

2.53 to 2668 (m, 2Η), 3.03 to 3.18 (m, 1H) 3.20 to 3.36 (m, 2Η),

3.71 to 383 (m, 1st), 4.50 to 4.75 (m, 2H) 5.32 (d, 1st), 5.32 to

5.48 (m1Η), 6.8 3 to 6.9911 ((mm, 1H), 7.58-7.67 (m, 1H, 7.79)

7.90 (m, 1H)

IR (KBr) cm- ¹ ;

3 4 5 0, 1 7 1 0, 1 6 6 0, 1 6 4 0, 1 2 7 5, 1 2 6 5

Example 7.

Trans 3, 4 — Dihydro 2, 2 — Dimethyl 6-1 (2-2-Tropoxypropyroxycanolebonyl) 1 4 1-(2-Oxo 1 1-Pyrrolidinyl) 1 Production of 2H-benzo [b] pyran-1-ol

(Process 1)

Trans 3-(4-Hydroxybensiloxy) 1-6-Hydroxykarubonilou 3, 4-Dihydro-1, 2, 2-Dimethyl-4-(2-Oxo 1-pylori 1H-benzo (b) pyran (100 g, 2.35 ramol), oxalyl chloride (37335 mg, 2.94 mmo1), pyrinyl Reaction of benzene (372.2 mg, 471 mmol) and 2-methyl-12-dioxetanol (427 mg, 3.533 mmol) was carried out in the same manner as in Example 4. , Post-treatment and purification with silica gel chromatography (developing solvent, ethyl acetate: hexane = 2: 1). Methoxybenziloxy) 1 6 — (2 — nitroxypropyroxy zolevonyl) 1 4 1 (2 — oxo 1 1 — pyrrolidinyl) 1 2 H—benzo [b] pyra (718.9 mg).

(Process 2)

Transformed 1- 3-(4-methoxybenziloxy) 1 6-(2-2-hydroxypropyloxycarbonyl) obtained in step 1-1-2 H-2 -oxo 1-1 -pyrrolidinyl — Benzo [b] pyran (700.0 mg, 1.33 mmol), 2,3-dichloro-1,5,6—dicyan-4 monobenzoquinone (451.4 mg, 1.99 mmol) was reacted in the same manner as in Example 5, worked up, purified by silica gel chromatography (developing solvent, ethyl acetate), and Lance 1,3,4—Dihydro 2,2—Dimethylinole 6— (2,2-Propoxypropyloxycarbonyl) 1 4 1 (2—Oxo 1 1 1-Pyrrolidinyl) 1 2H —Benzo [b] pyran—3—ol (451.4 fflg, yield 69%) is obtained.

1 H-NMR (200 MHz, CDC ") δ; 1.30 (s, 3rd), 1.44 (d, 3rd), 1.5

4 (s, 3H), 2.01 to 2.19 (m, 2 2),

2.46 to 2.76 (m, 1Η), 3.02 to 3.16 (m, 1H), 3.21 to 3.36 (m, 1Η),

3.43 to 3.51 (m, 1Η), 4.17 to 65 (m, 2H), 5.31 (d, 1Η), 5.39 to

5.60 (m, 1st), 6.875 (d, 1st), 7.58 to 7.62 (m, 1st), 7.80 to 7.88 (m , 1 H)

I R (K B r) cm-]

3 4 5 0, 1 7 2 0 1 6 7 0, 1 6 3 0, 1 9 0, 1 2 7 5, 1 2 6 5

Example 8

Trans 1, 3 4 Hydro 2, 2 — Dimethyl 1- (412-Trooxy-1-oxo-butyl) —4— (2-O-oxo-111-pyrrolidinyl) 1-2H-Venzo [b] Vylan-3—All

(Process 1)

The trans obtained in Example 1—3— (4—Methoxybenzyldioxy) -1 6—Hydroxycarbonyl 3,4-dihydro1-2,2—Dimethylyl 4-1-1 (2—Oxo-1 1—Pyro Lysinyl) 1-2H-benzo [b] pyran (1.58 g, 3.72 mmol) was dissolved in anhydrous benzene (30.0 ml), and then oxalinolechloride (0.59 g, 4.65 mmol) and stir at 50 for 30 minutes. Next, the reaction solution is concentrated under reduced pressure, anhydrous tetrahydrofuran (5 ml) is added to the concentrated residue, and cuprous chloride (7.5 nig, 0.08 mmol) is added. The solution was cooled on ice, and a solution of 3-methoxybenziloxypropirma gnecimubutate in tetrahydrofuran (3-methoxybenziloxypropizolebromide 0.96 g, magne 99.4 rag. (Prepared with 7.5 ml of anhydrous tetrahydrofuran) and stirred under ice-cooling for 1 hour. The reaction is stopped with water, and the reaction mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated residue is purified by silica gel chromatography (developing solvent, ethyl acetate: hexane = 2: 1), and trans- 3 — (4-methoxybenziloxy) 1 6 — {4- (4-methoxybenziloxy) 1-1-oxobutyl} 1-4-1 (2-oxobutyl) Sodium 1-pyrrolidinyl) 1-2H-benzo [b] pyran (536.7 mg) was obtained.

(Process 2)

Trans 1-3 — (4 — methoxybenziloxy) 1 6 — {4 — (4 — methoxybenziloxy) 1 1-oxobutyl} — 4 — (2 — oxo1 1 1 (Pyrrolidinyl) 1 2 H—benzo! B) pyran (1.382 g, 2.35 mmol) was dissolved in ethanol (12.0 ml), and then lithium borohydride (51.3 mg, 2. Add 35 mmo 1) and stir at 50 for 1 hour. The reaction solution is cooled on ice, and a phosphate buffer is added to stop the reaction. The precipitate is removed by filtration, ethanol of the filtrate is distilled off under reduced pressure, and then ethyl acetate extraction is performed. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated residue is purified by silica gel chromatography (developing solvent, ethyl acetate :), and trans- ance is reduced to 3-(4-methoxybenzene). {1-Hydroxy (4-methoxybenzyl) butyl} 1-4 (2-oxo-1-pyrrolidinyl)-1H-benzo [b] pyran (1. 0 26 g).

(Process 3)

Trans-One 3 — (4 — Methoxybenziloxy) 1 6 1 {1-Hydroxy (4 — Methoxybenzil) Butinole) 1 4 — (2 — Oxo 1; 1 H-pyrrolidinyl) 1 H-benzo [b] pyran (989.3 rag, 1.68 mmol) It was dissolved in anhydrous methylene chloride (12 ml), and then pyridin (664.1 mg, 8.40 mmo1) and acetic anhydride (324.

9 mg, 3.36 mmol) and 4-dimethylaminopyridine (20.5 mg, 0.17 mmol) are sequentially added, and the mixture is stirred at room temperature for 1 hour. Dilute the reaction solution with methylene chloride, then add 2N hydrochloric acid (4.2 ml) and water, and extract with methylene chloride. The organic layer is washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated residue was purified by silica gel chromatography (developing solvent, ethyl acetate: hexane 2: 1), and trans- 3 — (4-methoxybenziloxy) — 6 — {1-ase 1- (4-methoxybenzyl) butyl} 1- (2-oxo-111-pyrrolidinyl) -12H-benzo [b] pyran (962.4 mg) Get.

(Step 4)

Trans 3-1 (4-Methoxybenzyloxy) 1 6 1 {1-Acetoxy 1- (4-methoxybenzyl) butyl} 1 4 1 (2—Oxo 1 1 1 Pyrrolidinyl ) One 2H—Benzo! B) pyran (938.8 mg, 1.49 mmol) was added to a mixed solvent of methylene chloride (18.0 ml) and water (1.0 ml), followed by addition of 2%. , 3-Dichloronole 5, 6-Dicyano-14-benzoquinone (743.0 mg, 3.27 mmol) was added and the mixture was stirred at room temperature for 2 hours and 20 minutes. Dilute the reaction solution with methylene chloride, add water, and perform methylene chloride extraction. Organic layer Dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The concentrated residue is purified by silica gel chromatography (developing solvent, ethyl acetate: methanol = 10: 1), and the trans-1,3-dihydrogen is purified. 2,2—dimethyl 6— (1-acetoxy 4-hydroxybutyl) 1-41- (2-oxo-11-pyrrolidinyl) 1-2H—benzo [b] pyran-1 3— Obtain all (4.67.2 mg).

(Process 5)

Trans-1,3-dihydroxy-1,2,2-dimethyl-2- (1-acetoxy-4-hydroxybutyl) —4— (2—oxo-11-pyrrolidinyl) 1 2H-benzo [b] pyran-13-ol (450.4 mg, 1.15 mraol) was dissolved in anhydrous methylene chloride (8 ml), followed by pyridin. (274.1 mg, 3.47 mmo I), methansulfonyl chloride (158.7 mg, 1.38 ramo 1), 4-dimethylaminopyridine (14 mg, 0.11 mmol) are added sequentially, and the mixture is stirred overnight at room temperature. Dilute the reaction solution with methylene chloride, then add 2N aqueous hydrochloric acid (1.7 ml) and water, and perform methylene chloride extraction. The organic layer is washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by silica gel chromatography (developing solvent, ethyl acetate: methanol = 20: 1), and the trans-1,3-dihydro-2, 2-dimethyl-6-(1-acetoxyl 4-methansulfonyloxyl butyl) 1-41 (2 '-oxo-1-pyrrolidinyl)-2 H-benzo [b] pyran-3-ol (314, 4 mg) is obtained. As a by-product, trans-3- (meth-sulfonyloxy) -6- (1-acetoxy-41-methansulfonyloxybutyl) -141 (2-oxo--11-pyrrolidinyl) -12 This gives H-benzo [b] pyran (16.1 mg).

(Step 6)

Trans-1,3,4-dihydro obtained in step 5 —2,2—dimethyl 6— (1—acetoxy 4—1 methansulfonyloxybutyl) 1 4— (2—oxo—1—1 (Pyrrolidinyl) -12H-benzo [b] pyran-13-ol (30.7 mg, 0.66 rnniol) was dissolved in anhydrous toluene (3.0 ml), and then dissolved. Add tetranitro-n-butylammonium nitrate (660.4 mg, 1.99 mmol) and add 85. In C

Stir for 3.5 hours. Dilute the reaction solution with toluene, add water, and perform toluene extraction. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated residue was purified by silica gel chromatography (developing solvent, ethyl acetate: methanol = 20: 1), and the trans-1,3-dihydro-2,2— Dimethyl 6— (1—acetoxy 4—nitroxybutyl) —41- (2-oxo-111-pyrrolidinyl) 1-2H-benzo [b] pyran-1 3— To obtain all (18.6 mg).

(Step 7)

Trans 1, 4 — dihydro 2, 2 — dimethyl 1 6 ― (1 — acetoxie 4 — nitroxy cybutinole) 1 4 1 (2 — oxo 1 1 -1 pyrrolidine) 1 2 H-benzo [b] pyran 1 3 ォ 1 No. (185.6 mg, 0.43 mmol) was dissolved in methanol (67.0 ml), and 0.1N aqueous sodium hydroxide solution (5 ml, 0.1 ml) was added. Add 50 mmo 1) and stir at room temperature for 8.5 hours. The reaction mixture is cooled on ice, 0.1 N hydrochloric acid (5 ml) is added, and the methanol of the reaction mixture is distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer is washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated residue was purified by silica gel chromatography (developing solvent, ethyl acetate: methanol = 15: 1), and the trans-1,3,4-dihydro-1,2,2 — Dimethyl 1 6 — (1-hydroxy 412 butyl butyl) — 4 — (2 — oxo 1 1 — pyrrolidinyl) — 2 H—benzo [b] pyran One 3 — Ole (155.7 mg)

¾ ： Adherence Q o

(Process 8)

Trans 1, 3, 4 — Dihydro 2, 2 — Dimethyl 6 ′-(1 ドロ Hydroxy 14 ト 1 2 二キチチ) 1 4 — (2 — Oxo 1 1 1 1 Pyrrolidinyl) 12-benzo [b] pyran-13-vinyl (142.2 mg, 0.36 mmol) was dissolved in anhydrous dioxane (2 ml). Add 3-dichlor--5,6-dicyano 4-benzoquinone (164.0 mg, 0.72 mmol) and stir at 50 ° C for 16 hours. . Dilute the reaction solution with methylene chloride, add water and chlorinate Perform methylene extraction. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrated residue was purified with silica gel chromatography (developing solvent, ethyl acetate), and the trans-1,3-dihydro-2,2-dimethyl-6- ( 4 12-Troxy-1-oxobutizole) 1-4- (2-oxo-1- 1-pyrrolidinyl) -12H-benzo [b] pyran-13-ol (14.9 mg, A yield of 81 °) is obtained.

^{.... 1 Η - NMR} (2 0 0 MHz, CDC 1 s) δ; 1 3 0 (s, 3 Η), 1 5 5 ", 3 Η), 1 6 5~ 1 9 5 (m, 1 )), 2.00 to 2.25 (m, 4 Η), 2.53 to 2.67 (m, 2 Η), 2.95 to 3.16 (m, 3 Η) , 3.22 to 3.37 (m, 1Η), 3.77 (d, 1Η), 4.57 (t, 2Η), 5.33 (d, 1Η), 6.89 (d, 1st), 7.57 to 7.62 (m, 1st), 7.75 to 7.85 (m, 1st)

IR (Κ Β r) cm- ¹ ;

3450, 1670, 1640, 1610, 1280, 1260.

Claims

Claims General formula [1]

[Where R ¹ is one C (= X) — (〇) _n —R ⁴ (where X is = 0, = N—CN, = N−C 0 R ⁵ ,

= NC 0 NHR ⁵ , = NCSNHR ⁵ , = NCSR ⁵ , = NS 0 2 CF 3, = NNHR ⁵ , = N 0 R ⁵ , = CH-N 02 (where R ⁵ is a hydrogen atom, a lower alkyl group, A lower alkyl group, a phenyl group, a substituted phenyl group, a pyridyl group, a pyrimidinyl group substituted with 1 to 10 halogen atoms), and n is 0 or Wherein R ⁴ is a lower alkyl group, a cycloalkyl group having 1 to 10 carbon atoms, a phenyl group, a substituted phenyl group, a furyl group, a phenyl group, a phenyl group, A pyrimidyl group, a lower alkyl group substituted with 1 to 3 nitroxyl groups, a lower alkyl group substituted with 1 to 10 halogen atoms, an amino group, alkylamine Mi amino group, 1-Ru three two preparative Loki sill group lower alkyl儿§ Mi substituted by Bruno Motodea) or one _{^{S 0 2 - R 4 (R}} 4 in here is The same as), R ² represents a hydrogen atom, a lower alkyl group, one to three of the two-Bok proxy substituted lower alkyl group group, 1 to 0 lower alkyl group substituted with a halogen, full E group, a substituted phenylalanine group, phenylalanine lower alkyl group, location換Fu enyl lower alkyl group, Pi lysyl group, Pi Li succinimidyl group R ³ is a hydrogen atom, a lower alkyl group, one to three double A lower alkyl group substituted with a troxyl group, a lower alkyl group substituted with 1 to 10 halogens, a phenyl group, a substituted phenyl group, a phenylalkyl group, a substituted phenylalkyl group, A jyl group, a pyrimidyl group, or R ² and R ³ together— (CH ₂ ) _m- one (where m is an integer from 1 to 5), one CH = CH—CH = CH— or one CH = CH— N = CH—, A is hydrogen atom, nitro group, lower alkyl Group, 1-3 two bets proxy substituted lower alkyl group group, - C (= X) one (0) "- R ⁴ (in here X, n, R ⁴ is the same as the above), or And a physiologically acceptable acid addition salt thereof.

X

II

2. R ¹ is —C— (〇) _n —R ^4, R ² and R ³ are united to be 1 (CH ₂ ) _m 1, and A is a hydrogen atom. 2. The chromane derivative and the physiologically acceptable salt thereof according to item 1.

3. X is 0, n is 0 or 1, R ⁴ is a lower alkyl group substituted by a di-toxyl group, and m is 3. The chromane derivative and the physiologically acceptable salt thereof according to claim 2, which is 3.

4. Trans 1-6— (2—Trosh Shechilokishka Carbonil) 1,3,4—Dihydro 1,2,2—Dimethinole 4—1 (2—Oxo 1—Pylori Dinyl) 1 2 H—benzo

[B] Pyran 1-3 — all.

5. Trans 1, 3 — Dihydro 2, 2 — Dimethyl 6 — (1 — methyl 1 2 — Nitroxshecilokoxyl ponion) 1 4 — (2 — Oxo 1 1 1 Pyrrolidinyl) -U2H-benzo [b] pyran-13-ol.

6. Trans- 1, 3-Dihydro 1, 2-Dimethyl 6-(4-2-Toxi-1-year-old butyl) 1 4-

(2-oxo-111-pyrrolidinyl) -12H-benzo [b] pyran-13-ol.

7. General formula [I]

[Where R ¹ is one C (= X) — (0) _n —R ⁴ (where X is = 〇, = N—CN, = N−C 0 R ⁵ ,

= NCONHR ⁵ , = NCSNHR ⁵ , = NCSR ⁵ , _{= NS 02 CF 3, = NNHR} 5, = N 0 R 5, = CH - 02 ( here R ⁵ is a hydrogen atom, a lower alkyl group, 1 to 0 lower alkyl group substituted with a halogen, full An aryl group, a substituted phenyl group, a pyridyl group, or a pyrimidinyl group), n is an integer of 0 or 1, and R ⁴ is a lower alkyl group, having 1 to 1 carbon atoms. 0 cycloalkyl groups, phenyl groups, substituted phenyl groups, furyl groups, phenyl groups, pyridyl groups, pyrimidyl groups, and lower alkyl groups substituted with 1 to 3 nitroxyl groups A lower alkyl group substituted with 1 to 10 halogens, an amino group, an alkylamino group, or a lower alkylamino group substituted with 1 to 3 nitroxyl groups) or S 0 ₂ —R ⁴ (where R ⁴ is the same as above), R ² is a hydrogen atom, a lower alkyl group, one to three A lower alkyl group substituted with a hydroxy group, a lower alkyl group substituted with 1 to 10 halogens, a phenyl group, a substituted phenyl group, a phenyl lower alkyl group, a substituted phenyl lower alkyl group, Pyridyl group, pyrimidyl group,

R ³ is a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with 1 to 3 nitroxyl groups, a lower alkyl group substituted with 1 to 10 halogen atoms, a phenyl group, A phenyl group, a phenylalkyl group, a substituted phenylalkyl group, a pyridyl group, a pyrimidyl group, or R ² and R ³ together form one (CH ₂ ) _m (where m is 1 — 5), — CH = CH— CH = CH— or one CH = CH— N2 CH—, A is a hydrogen atom, a nitro group, Lower alkyl group, lower alkyl group substituted with 1 to 3 nitroxy groups, one C (= X) — (〇) _n one R ⁴ (where X, n, and R ⁴ are the same as above) Or a protecting group). A tracheal smooth muscle relaxant comprising, as an active ingredient, a chromane derivative represented by the formula: or a physiologically acceptable acid addition salt thereof.

Scope of amended course

[June 9, 1992 (09.06.92) accepted by the International Bureau; claims 1 and 7 as originally filed have been amended; other claims 2-6 remain unchanged. Is a page)]

(After correction) General formula [1]

Ten

[Where R ¹ is one C (= X) — (〇) _n — R ⁴ (where, = 0, = N-C. = N-C 0 R ⁵ ,

= NC 0 NHR, = NCSNHR ⁵ , = NCSR ⁵ , = NS 02 CF 3, = NNHR ⁵ , = N 0 R ⁵ , = CH

15 - N 0 ₂ (here R ⁵ is a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with I ~ 1 0 halogens, full et alkenyl group, a substituted off Weniru group, Pi lysyl group, Pi N is an integer of 0 or 1, and R ⁴ is a cycloalkyl group having 1 to 10 carbon atoms, a phenyl group, or a substituent.

20 substituted phenyl, furyl, chenyl, pyridyl, pyrimidyl, lower alkyl substituted with 1 to 3 nitroxyl, 1 to 10 A lower alkyl group, an amino group, an alkylamino group, or a lower alkylamino group substituted with 1 to 3 nitroxyl groups.

! 5 or or S 0 ₂ — R ⁴ (where R ⁴ is the same as above), R ² is a hydrogen atom, a lower alkyl group, a lower alkyl group substituted with 1 to 3 nitroxy groups, 1 to! Lower alkyl group, phenyl group, substituted phenyl group, phenyl lower alkyl group, substituted phenyl lower alkyl group, pyridyl group, pyrimidyl substituted with 0 halogens Group, R ³ is a hydrogen atom, a lower alkyl group, a lower alkyl group substituted by 1 to 3 nitroxyl groups, a lower alkyl group substituted by 1 to 10 halogen atoms a alkyl group, full Weniru group, a substituted off We group, full Enirua alkyl group, a substituted phenylalanine alkyl group, Pi Li di group, Pi Li succinimidyl groups, were or, in R ² and R ³ gar緖Nate — (CH ₂ ) _m- (where m is an integer from 1 to 5), one CH = CH — CH = CH —, or

One CH = CH — N = CH-, A is a hydrogen atom, a nitro group, a lower alkyl group, a lower alkyl group substituted with 1 to 3 dioxy groups, — C (= X) — (0) _π —R ⁴ (where X, n, and R ⁴ are the same as above) or a protecting group], and a physiologically acceptable acid thereof. Addition salt.

X

II

2. R ^{1 is} -C 1 (0) _π -R ^4, R ² and R ³ together are 1 (C Η ₂ ) _m- , and A is a hydrogen atom. 2. The chromane derivative and the physiologically acceptable salt thereof according to Item 1.

3. X is 0, n is 0 or 1, R ⁴ is a lower alkyl group substituted with a dioxyl group, m 3. The chromane derivative according to claim 2 and a physiologically acceptable salt thereof.

4. Trans 1-6 — (2—Nitroxinyloxylka norrebonyl) 1-3, 4 — Dihydro 1 2, 2 — Dimethyl 1 4 — (2—Oxo 1 1 — Pylori Dinyl) 1 2H-benzo [b] pyran 13-ol.

5. Trans- 1, 3-4-Hydroxy 2, 2-Dimethyl 6-(1-methyl 2-2 troxicetyloxy carbonyl) 1 4 1 (2-oxo 1 1 1-pyrrolidinyl) 1-2H-benzo [b] pyran-13-ol.

6. Trans 1, 3 — 4 — Dihydro 2, 2 — Dimethyl 6 — (412 1-oxobutyl) — 4 —

(2-oxo-111-pyrrolidinyl) -12H-benzo [b] pyran-13-ol.

7. (After correction) General formula [I]

= NC 0 NHR ⁵ , = -NCSNHR, = NCSR ⁵ , = NS 02 CF 3, = NNHR 5, = N 0 R 5, = CH - N 02 ( here R ⁵ is a hydrogen atom, a lower alkyl group, a lower substituted with 1 to 0 halo gain down An alkyl group, a phenyl group, a substituted phenyl group, a pyridyl group, or a pyrimidinyl group), n is an integer of 0 or 1, and R ⁴ is a carbon atom. ~ 10 cycloalkyl groups, phenyl groups, substituted phenyl groups, furyl groups, chenyl groups, pyridyl groups, pyrimidyl groups, 1 to 3 nitro groups A lower alkyl group substituted with a xyl group, a lower alkyl group substituted with 1 to 10 halogen atoms, an amino group, an alkylamino group, and 1 to 3 double-mouthed xyl groups lower Arukirua Mi substituted with group Roh Motodea Ru) or one _{^{S 0 2 - R 4 (R}} 4 in here is the same as the above), R ² represents a hydrogen atom, a lower alkyl group, one to three A lower alkyl group substituted with 1 to 10 halogen atoms, a lower alkyl group substituted with 1 to 10 halogen atoms, a phenyl group, a substituted phenyl group, a phenyl lower alkyl group , A substituted phenyl-lower alkyl group, a pyridyl group, a pyrimidyl group, and R ³ are a hydrogen atom, a lower alkyl group, or a lower alkyl group substituted with 1 to 3 nitroxyl groups. , A lower alkyl group, a phenyl group, a substituted phenyl group, a phenylalkyl group, a substituted phenylalkyl group, a pyridyl group, a pyridyl group substituted with 1 to 10 halogens. A midyl group, or R ² and R ³ together — (CH ₂ ) _m- (where m is an integer from 1 to 5), one CH = CH—CH = CH — Or one CH = CH one N = CH-, A is a hydrogen atom, a nitro group, a lower alkyl Group, a lower alkyl group substituted by i to 3 nitrokidi groups, one c (= x) — (〇)-— ^{R 4} (where x, ⁿ ,

R ⁴ is the same as defined above) or represents a protecting group]. An agent for relaxing tracheal smooth muscle, comprising a norman derivative or a physiologically acceptable acid addition salt thereof as an active ingredient.