JPH0532655A - Benzopyran relative material - Google Patents

Abstract

PURPOSE:To obtain a new benzopyran relative material useful as a therapeutic agent for cardiovascular functional disorder, digestive system ulcer, cerebrovascular disease, etc., having strong and durable antihypertensive action, smooth muscle relaxing action and coronary vascular flow action. CONSTITUTION:A compound shown by the formula [A is OR1, NH-COR<2> (R<1> is H, alkyl, alkenyl, formyl, aralkyl, etc.; R<2> is H, alkyl, alkoxy, NH2, aryl, etc.); R<3> is H, alkyl, alkoxy, NH2, aryl, heteroaryl, etc., or R<2> and R<3> are mutually bonded to form 1-2C alkylene; R<4> and R<5> are H, alkyl or mutually bonded to form 2-5C alkylene; R<6> is H, OH, nitroxy, formyloxy, etc.; R<7> is H or R<7> and R<6> show bond; X is single bond, CH2, 0, S(O)g2 or NR (R is H, alkyl, etc.); ring B is benzene ring or 5- to 6-membered ring] such as 4-(2-acetyl-1- nitroxyacetylhydrazino)-6-cyano-3,4-dihydro-2, 2-dimethyl-2H-1-benzopyran.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel benzopyran analog having a remarkable and long lasting blood pressure lowering action and a relaxing action of vascular smooth muscle and other smooth muscles, or a pharmaceutically acceptable benzopyran analog thereof. Regarding Uru-salt.

[0002]

2. Description of the Related Art JP-A-58-67683 discloses 6-cyano-3,4-dihydro- which has antihypertensive activity.
2,2-Dimethyl-trans-4- (2-oxo-1-)
Pyrrolidinyl) -2H-1-benzopyran-3-ol (BRL-34915) is disclosed and further disclosed in JP-A-6-36
JP-A-3-170376, JP-A-63-303977 and JP-A-64-26578 disclose a group of benzopyran compounds having an improved anti-hypertensive effect, a smooth muscle relaxing effect and the like, which is substituted at the 4-position. Has been done. Also, WO8905808 and JP-A-2-152.
In 974, a nitroester form of benzopyran, for example, trans-6-cyano-3,4-dihydro-2,2-dimethyl-4- (2-oxopyrrolidinyl-
1-yl) -2H-1-benzopyran-3-ol nitrate or trans-6-cyano-3,4-dihydro-4-hydroxyacetylamino-2,2-dimethyl-2H-1-benzopyran-3-oldi It has been disclosed that nitrates have smooth muscle relaxing activity.

[0003]

DISCLOSURE OF THE INVENTION An object of the present invention is to develop a benzopyran compound exhibiting a sustained blood pressure lowering action or a coronary blood flow increasing action.

[0004]

[Means for Solving the Problems]
-A novel benzopyran analogue having an acyl-N-oxy-substituted amino group or a hydrazino group, and further having a nitroesterified hydroxyl group as a substituent at the 3-position or 4-position and a substituent of ring B is remarkable and is also durable. It has been found that it has a certain blood pressure lowering action, a coronary blood flow increasing action, and further has a relaxing action on vascular smooth muscle and other smooth muscles, and has completed the present invention. That is, the present invention has the general formula

[Chemical 2] [In formula, A is -OR < ¹ >, -NH-COR < ² > (Here, R
¹ is hydrogen, lower alkyl, lower alkoxy lower alkyl, alkenyl, formyl, alkanoyl, aroyl,
R ² represents hydrogen, lower alkyl, lower alkoxy, amino, mono- or di-lower alkylamino, amino lower alkyl, hydroxy lower alkyl, nitrooxy lower alkyl, halo lower alkyl, lower alkoxy lower alkyl, acyloxy. Lower alkyl, lower alkoxycarbonyl represents lower alkyl, aryl and heteroaryl. ), And R ³
Is hydrogen, lower alkyl, lower alkoxy, amino, mono- or di-lower alkylamino, amino lower alkyl, hydroxy lower alkyl, nitrooxy lower alkyl, halo lower alkyl, lower alkoxy lower alkyl, acyloxy lower alkyl, lower alkoxycarbonyl lower alkyl, aryl , Heteroaryl, or R ² and R ³ represent a group which is bonded to each other to form an alkylene having 1 to 2 carbon atoms, and R ⁴ and R ⁵ are the same or different and represent hydrogen or lower alkyl. Or R ⁴ and R ⁵ represent a group which is bonded to each other to form an alkylene having 2 to 5 carbon atoms, and R ⁶ is hydrogen, hydroxyl group, nitrooxy, formyloxy, alkanoyloxy, haloalkanoyloxy, lower alkoxycarbonyloxy. , Aroyloxy, heteroaroyl Shi, carbamoyloxy, shows a mono- or di-lower alkylcarbamoyloxy, R ⁷
Represents hydrogen, or R ⁶ and R ⁷ together represent a bond, and X represents a single bond, methylene, oxygen, —S (O) _n.
-(N represents an integer of 0, 1, 2), -NR- (R represents hydrogen, lower alkyl, alkanoyl),
Ring B is a benzene ring, a 5- or 6-membered heterocycle, or halogen, nitro, cyano, amino, hydroxyl group, nitrooxy,
Formyloxy, alkanoyloxy, haloalkanoyloxy, lower alkoxycarbonyloxy, aroyloxy, heteroaroyloxy, carbamoyloxy,
Mono or di lower alkylcarbamoyloxy, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, carboxy, lower alkoxycarbonyl,
Aralkyloxycarbonyl, formyl, alkanoyl, aroyl, haloalkanoyl, carbamoyl, mono- or di-lower alkylcarbamoyl, lower alkylthio, halo lower alkylthio, lower alkylsulfinyl, halo lower alkylsulfinyl, arylsulfinyl, lower alkylsulfonyl, halo lower alkylsulfonyl, A benzene ring having at least one substituent selected from arylsulfonyl, sulfamoyl and mono- or di-lower alkylsulfonamide, or 5
Indicates a 6-membered heterocycle. However, when R ⁶ represents a group other than nitrooxy, one of R ² and R ³ represents nitrooxy lower alkyl, or the substituent of ring B represents nitrooxy. ] The benzopyran analog represented by these, or its pharmaceutically acceptable salt.

In the definitions of the above symbols, halogen is chlorine,
Bromine, fluorine, and iodine are lower alkyls having 1 to 1 carbon atoms.
6 straight or branched chain alkyls, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, etc., and amino lower alkyl is a linear or branched aminated alkyl having 1 to 6 carbon atoms. Aminomethyl, 2-aminoethyl, 3-aminopropyl, 1
-Aminomethylethyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl and the like, and hydroxy lower alkyl means a straight or branched chain hydroxylated alkyl having 1 to 6 carbon atoms. Hydroxymethyl,
2-hydroxyethyl, 3-hydroxypropyl, 1-
Hydroxymethylethyl, 4-hydroxybutyl, 5-
Hydroxypentyl, 6-hydroxyhexyl, etc.
Nitrooxy lower alkyl is a linear or branched nitroesterified alkyl having 1 to 6 carbon atoms, and includes nitrooxymethyl, 2-nitrooxyethyl, 3
-Nitrooxypropyl, 1-nitrooxymethylethyl, 4-nitrooxybutyl, 5-nitrooxypentyl, 6-nitrooxyhexyl and the like, and halo lower alkyl is a straight or branched chain having 1 to 4 carbon atoms. A halogenated alkyl in the form of chloromethyl, bromomethyl, fluoromethyl, iodomethyl, dichloromethyl,
Dibromomethyl, difluoromethyl, diiodomethyl,
Trifluoromethyl, chloroethyl, bromoethyl, fluoroethyl, iodoethyl, difluoroethyl, trifluoroethyl, chloropropyl, bromopropyl, fluoropropyl, iodopropyl, difluoropropyl, trifluoropropyl, chlorobutyl, bromobutyl, fluorobutyl, iodobutyl, difluorobutyl , Trifluorobutyl, etc., lower alkoxy is a linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy,
Butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy and the like, halo lower alkoxy is chloromethoxy, bromomethoxy, fluoromethoxy,
Iodomethoxy, dichloromethoxy, dibromomethoxy, difluoromethoxy, diiodomethoxy, trifluoromethoxy, chloroethoxy, bromoethoxy, fluoroethoxy, iodoethoxy, difluoroethoxy,
Lower alkoxy lower alkyl is trifluoroethoxy, chloropropoxy, bromopropoxy, fluoropropoxy, iodopropoxy, difluoropropoxy, trifluoropropoxy, chlorobutoxy, bromobutoxy, fluorobutoxy, iodobutoxy, difluorobutoxy, trifluorobutoxy, etc. The alkoxy part and the alkyl part have an alkoxy and alkyl having 1 to 4 carbon atoms, and include methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, ethoxymethyl, propoxymethyl, butoxymethyl and the like. , Lower alkoxycarbonyl lower alkyl is one in which the alkoxy part and the alkyl part have alkoxy and alkyl having 1 to 4 carbon atoms, and is methoxycarbonylmethyl, - methoxycarbonylethyl, 3
Methoxycarbonylpropyl, 4-methoxycarbonylbutyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, butoxycarbonylmethyl, etc., and acyloxy lower alkyl are acetyloxymethyl, acetyloxyethyl, acetyloxypropyl, acetyloxybutyl, propionyloxymethyl, Butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl and the like, and the aralkyl has an alkyl part having 1 to 1 carbon atoms.
Aralkyl having 4 alkyls, benzyl,
α-phenylbenzyl, α-2-pyridylbenzyl, 2
-Phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylethyl, 3-
Naphthylpropyl, 4-naphthylbutyl or benzyl having at least one substituent selected from halogen, lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and sulfamoyl on the aromatic ring, α -Phenylbenzyl, α-2-
Pyridylbenzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-
Naphthylethyl, 3-naphthylpropyl, 4-naphthylbutyl and the like, and lower alkoxycarbonyl means that the alkoxy part has an alkoxy having 1 to 4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl. And aralkyloxycarbonyl are those having an aralkyl in which the alkyl part has an alkyl having 1 to 4 carbon atoms, and are benzyloxycarbonyl, α-phenylbenzyloxycarbonyl, α-2-pyridylbenzyloxycarbonyl,
2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, naphthylmethoxycarbonyl, 2-naphthylethoxycarbonyl, 3-naphthylpropoxycarbonyl, 4-naphthylbutoxycarbonyl or halogen on an aromatic ring,
Benzyloxycarbonyl, α-phenylbenzyloxycarbonyl, α-2-pyridylbenzyloxy having at least one substituent selected from lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and sulfamoyl. Carbonyl,
2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, naphthylmethoxycarbonyl, 2-naphthylethoxycarbonyl, 3-naphthylpropoxycarbonyl, 4-naphthylbutoxycarbonyl and the like, and aryl is phenyl, naphthyl or aromatic. Halogen (chlorine, bromine, iodine, fluorine), lower alkyl, lower alkoxy (straight or branched alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy on the group ring. , Butoxy, isobutoxy, tertiary butoxy), hydroxyl group, trifluoromethyl, cyano, nitro, amino and phenyl having at least one substituent selected from sulfamoyl, naphthyl and the like,
Heteroaryl is furyl (2-furyl, 3-furyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), thienyl (2-thienyl, 3-thienyl) or halogen, lower alkyl, lower on the ring. Alkoxy,
Furyl, pyridyl, thienyl and the like having at least one substituent selected from hydroxyl group, trifluoromethyl, cyano, nitro, amino and sulfamoyl can be used as 5
A ~ 6 membered heterocycle is thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, etc., and a heteroarylalkyl is an alkyl moiety having 1 carbon atom.
~ 4 alkyls having furylmethyl, furylethyl, furylpropyl, furylbutyl, pyridylmethyl, pyridylethyl, pyridylpropyl, pyridylbutyl, thienylmethyl, thienylethyl, thienylpropyl, thienylbutyl or on the ring halogen,
Furylmethyl, furylethyl, furylpropyl, furylbutyl, pyridylmethyl, pyridylethyl, pyridyl having at least one substituent selected from lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino and sulfamoyl. Propyl, pyridylbutyl, thienylmethyl, thienylethyl, thienylpropyl, thienylbutyl and the like, alkanoyl is an alkanoyl having 2 to 5 carbon atoms, which may be substituted by phenyl, acetyl, propionyl, butyryl, valeryl. , Pivaloyl, phenylacetyl, phenylpropionyl, phenylbutyryl, etc., and haloalkanoyl means chloroacetyl, bromoacetyl, fluoroacetyl, iodoacetyl, dichloroacetyl, dibromoacryl. Chill, difluoroacetyl, di iodoacetyl, trifluoroacetyl, chloropropionyl, bromopropionyl, fluoro propionyl,
Iodopropionyl, difluoropropionyl, trifluoropropionyl, chlorobutyryl, bromobutyryl, fluorobutyryl, iodobutyryl, difluorobutyryl, trifluorobutyryl, fluorovaleryl, fluorohexanoyl, etc., aroyl is benzoyl,
As for naphthoyl and the like, mono- or di-lower alkylamino means that the alkyl part has an alkyl having 1 to 4 carbon atoms, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, Butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, ditertiary butylamino, dipentylamino, dihexylamino, etc. with mono- or di-lower alkylcarbamoyl Is methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl. Le, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoylphosphine, ditertiary butylcarbamoyl, di-pentylcarbamoyl, Hye alkoxy carbamoyl, N-
Methyl-N-ethylcarbamoyl, N-methyl-N-propylcarbamoyl, N-methyl-N-butylcarbamoyl, N-methyl-N-tertiarybutylcarbamoyl, N
-Methyl-N-pentylcarbamoyl, N-methyl-N
-Hexylcarbamoyl and the like, alkenyl is vinyl, allyl, butenyl, pentenyl, hexenyl and the like, alkylene having 1 to 2 carbon atoms is methylene, ethylene and the like, alkylene having 2 to 5 carbon atoms is ethylene,
Trimethylene, propylene, tetramethylene, pentamethylene and the like, and alkanoyloxy means that the alkanoyl moiety has an alkanoyl having 2 to 5 carbon atoms, which may be substituted by phenyl, and is acetyloxy, propionyloxy, butyryloxy. , Valeryloxy, pivaloyloxy, phenylacetyloxy, phenylpropionyloxy, phenylbutyryloxy, etc., and haloalkanoyloxy is chloroacetyloxy in which the alkanoyl part has a halogenated alkanoyl having 2 to 5 carbon atoms, Bromoacetyloxy, fluoroacetyloxy, iodoacetyloxy, dichloroacetyloxy, dibromoacetyloxy, difluoroacetyloxy, diiodoacetyloxy, trifluoroacetic acid Tyloxy, chloropropionyloxy, bromopropionyloxy, fluoropropionyloxy, iodopropionyloxy, difluoropropionyloxy, trifluoropropionyloxy, chlorobutyryloxy, bromobutyryloxy, fluorobutyryloxy, iodobutyryloxy, difluorobutyryl Oxy, trifluorobutyryloxy, fluorovaleryloxy, fluoropivaloyloxy, etc., and lower alkoxycarbonyloxy means that the alkoxy part has an alkoxy having 1 to 6 carbon atoms, such as methoxycarbonyloxy and ethoxycarbonyl. Oxy,
Propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, tertiary butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy, etc., aroyloxy means benzoyloxy, naphthoyloxy, etc. Aroyloxy is 2-furoyloxy, 3-furoyloxy, nicotinoyloxy, isonicotinoyloxy, 4-pyridylcarbonyloxy, 2-thenoyloxy, 3-thenoyloxy and the like, and mono- or di-lower alkylcarbamoyloxy is an alkyl part. Having an alkyl having 1 to 6 carbon atoms, which is methylcarbamoyloxy, ethylcarbamoyloxy, propylcarbamoyloxy, isopropylcarbamo Yloxy, butylcarbamoyl oxy, iso-butylcarbamoyl oxy, tertiary butylcarbamoyl oxy, pentylcarbamoyl oxy, hexylcarbamoyl oxy, dimethylcarbamoyloxy,
Diethylcarbamoyloxy, dipropylcarbamoyloxy, diisopropylcarbamoyloxy, dibutylcarbamoyloxy, diisobutylcarbamoyloxy, ditertiarybutylcarbamoyloxy, dipentylcarbamoyloxy, dihexylcarbamoyloxy, etc., and lower alkylthio is methylthio, ethylthio, propylthio, isopropyl. Thio, butylthio, isobutylthio, tertiary butylthio, pentylthio, hexylthio, etc., and halo lower alkylthio are chloromethylthio, bromomethylthio, fluoromethylthio, iodomethylthio, dichloromethylthio, dibromomethylthio,
Difluoromethylthio, diiodomethylthio, trifluoromethylthio, chloroethylthio, bromoethylthio, fluoroethylthio, iodoethylthio, difluoroethylthio, trifluoroethylthio, chloropropylthio, bromopropylthio, fluoropropylthio,
Iodopropylthio, difluoropropylthio, trifluoropropylthio, chlorobutylthio, bromobutylthio, fluorobutylthio, iodobutylthio, difluorobutylthio, trifluorobutylthio, etc., and lower alkylsulfinyl have an alkyl part with carbon number Methylsulfinyl having 1 to 6 alkyls,
Ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, tertiary butylsulfinyl, pentylsulfinyl, hexylsulfinyl and the like, arylsulfinyl is phenylsulfinyl, naphthylsulfinyl or halogen (chlorine, bromine, Iodine, fluorine), lower alkyl, lower alkoxy, hydroxyl group, phenylsulfinyl having at least one substituent selected from trifluoromethyl, cyano, nitro, amino and sulfamoyl, naphthylsulfinyl, etc. Is chloromethylsulfinyl, bromomethylsulfinyl, fluoromethylsulfinyl, iodomethylsulfinyl, dichloromethylsulfinyl. Le, dibromo methylsulfinyl, difluoromethyl methylsulfinyl, di-iodo methylsulfinyl, trifluoromethylsulfinyl, chloro ethylsulfinyl, bromo ethylsulfinyl, fluoro ethylsulfinyl, iodo ethylsulfinyl,
Difluoroethylsulfinyl, trifluoroethylsulfinyl, chloropropylsulfinyl, bromopropylsulfinyl, fluoropropylsulfinyl, iodopropylsulfinyl, difluoropropylsulfinyl, trifluoropropylsulfinyl, chlorobutylsulfinyl, bromobutylsulfinyl, fluorobutylsulfinyl, iodobutylsulfinyl, Difluorobutylsulfinyl, trifluorobutylsulfinyl and the like, lower alkylsulfonyl is one in which the alkyl part has alkyl having 1 to 6 carbon atoms,
Methyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, isobutyl sulfonyl, tertiary butyl sulfonyl, pentyl sulfonyl, hexyl sulfonyl and the like, and aryl sulfonyl is phenyl sulfonyl, naphthyl sulfonyl or halogen (chlorine on the aromatic ring). , Bromine, iodine, fluorine), lower alkyl, lower alkoxy, hydroxyl group, trifluoromethyl, cyano, nitro, amino, and phenylsulfonyl having at least one substituent selected from sulfamoyl, naphthylsulfonyl, etc. Alkylsulfonyl means chloromethylsulfonyl, bromomethylsulfonyl, fluoromethylsulfonyl, iodomethylsulfonyl, dichloromethylsulfonyl, dibromomethyl. Rufonyl, difluoromethylsulfonyl, diiodomethylsulfonyl, trifluoromethylsulfonyl, chloroethylsulfonyl, bromoethylsulfonyl, fluoroethylsulfonyl, iodoethylsulfonyl, difluoroethylsulfonyl, trifluoroethylsulfonyl, chloropropylsulfonyl, bromopropylsulfonyl, fluoro Propylsulfonyl,
Iodopropylsulfonyl, difluoropropylsulfonyl, trifluoropropylsulfonyl, chlorobutylsulfonyl, bromobutylsulfonyl, fluorobutylsulfonyl, iodobutylsulfonyl, difluorobutylsulfonyl, trifluorobutylsulfonyl, etc.,
The mono- or di-lower alkylsulfonamide has an alkyl part having an alkyl having 1 to 6 carbon atoms, and includes methylsulfonamide, ethylsulfonamide, propylsulfonamide, isopropylsulfonamide, butylsulfonamide, isobutylsulfonamide, Tertiary butyl sulfonamide, pentyl sulfonamide, hexyl sulfonamide, dimethyl sulfonamide, diethyl sulfonamide, dipropyl sulfonamide, diisopropyl sulfonamide, dibutyl sulfonamide, diisobutyl sulfonamide, ditertiary butyl sulfonamide, dipentyl sulfone Amide, dihexylsulfonamide and the like are shown respectively.

Since the compounds of the present invention have at least one or more asymmetric carbon atoms, optical isomers and stereoisomers based on them are present, but these isomers and mixtures thereof are all included in the present invention. It is a thing. Also,
The configuration of R ⁶ and -N (A) -COR ³ in the compound of the present invention is trans, but the optical isomers based on the chiral carbon atom at the 3,4 position are (+)-form and (-)-form. And (±)-
Including the body. Further, inorganic acid salts of the compounds of the present invention with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid,
The present invention also includes organic acid salts with tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc., and hydrates and / or various solvates. .. The compound of the present invention can be synthesized, for example, by a method known per se. In the compound of [Chemical formula 2], R ⁶ is a hydroxyl group,
^{When 6} represents a group other than a hydroxyl group, either R ² or R ³ is hydroxy lower alkyl, or the substituent of ring B is a hydroxyl group, the starting compound of the present invention is disclosed in Japanese Patent Application No.
-106454, Japanese Patent Application No. 3-45980 and Japanese Patent Application No. 3-72434 can be used for the synthesis. Among the compounds of [Chemical Formula 2] of the present invention, the compound having a nitrooxy group can be obtained by synthesizing the compound having a hydroxyl group obtained by the method described above by a nitroesterification method known per se. The nitroesterification method generally uses concentrated nitric acid or fuming nitric acid as an acid, and sulfuric acid, fuming sulfuric acid, acetic acid, acetic anhydride, phosphoric acid, phosphorus pentoxide, etc. as a dehydrating agent, and acetonitrile, chloroform, dichloromethane, 1 as a solvent. , 2-dichloroethane, carbon tetrachloride and the like can be used under ice cooling or at room temperature. Preferably, a mixture of acetic anhydride-fuming nitric acid is used.

Thus obtained [Chemical formula 2] of the present invention
The compound (1) can be separated and purified from the reaction mixture by a method known per se such as recrystallization or chromatography. In addition, the compound of [Chemical Formula 2] of the present invention is prepared by a conventional method such as inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) Malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc.) to give a pharmaceutically acceptable salt, and a hydrate. Alternatively, various solvates can be used. When the compound of the present invention has a chiral carbon atom as described above,
Usually obtained as a racemate. The racemate can be resolved into optical isomers by a conventional method. Such optical isomers can also be produced by using an optically active starting compound. Individual diastereomers can be purified by fractional recrystallization or chromatography.

When the compound of the present invention and a pharmaceutically acceptable salt thereof is used as a medicine, it is usually a carrier, an excipient,
Mixing with pharmaceutically acceptable additives such as diluents, solubilizers, tablets (including sugar-coated tablets and film-coated tablets), capsules, powders, granules, injections, drip suppositories, suppositories, etc. It can be safely administered orally or parenterally in the form. The dose may vary depending on the patient's sex, age, body weight or symptoms, but it is usually about 1 for oral administration per day for adults.
The dose is in the range of up to 500 mg, and is administered once or several times a day.

[0009]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto.

Example 1- (1) trans-4- (N-acetyl-N-benzyloxyamino) -6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3- Suspend 1.0 g of all in 5 ml of chloroform and 1.03 ml of acetic anhydride,
Fuming nitric acid (specific gravity 1.50) 0.46 while stirring at 0 ° C
Add ml dropwise. After further stirring at 0 ° C. for 30 minutes, ice water and chloroform are added and the solution is separated with a separating funnel. The chloroform layer is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residual oily substance was mixed with 10 m of hexane.
When recrystallized from a mixed solvent of 1 and 4 ml of ethanol, the desired trans-4- (N-acetyl-N) was obtained as white crystals.
-Benzyloxyamino) -6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3
760 mg of all nitrates are obtained. Melting point 134.
5-136.5 ° C

Similarly, the following compound is obtained from the compound having a hydroxyl group at the 3-position. 1- (2): trans-4- (N-acetyl-N-benzyloxyamino) -3,4-dihydro-2,2-dimethyl-6-methylsulfonyl-2H-1-benzopyran-3-ol nitrate , Melting point 169.5-170
C. (decomposition) (recrystallized from ethanol: ethyl acetate = 3: 2) 1- (3): trans-6-cyano-4- (1,2-diacetylhydrazino) -3,4-dihydro-2,2 -Dimethyl-2H-1-benzopyran-3-ol nitrate, melting point 185.5-186 ° C (decomposition) (hexane:
Recrystallized from ethyl acetate = 1: 1) 1- (4): trans-4- (1,2-diacetylhydrazino) -3,4-dihydro-2,2-dimethyl-6-
Methylsulfonyl-2H-1-benzopyran-3-ol nitrate, melting point 197.5-198 ° C (decomposition)
(Recrystallized from ethanol: ethyl acetate = 1: 1) 1- (5): trans-4- (1,2-diacetylhydrazino) -3,4-dihydro-2,2-dimethyl-7-
Trifluoromethyl-2H-pyrano [2,3-b] pyridin-3-ol nitrate, melting point 199-200 ° C
(Decomposition) (Recrystallization from hexane: ethyl acetate = 1: 1)

Example 2 700 mg of 4- (2-acetyl-1-hydroxyacetylhydrazino) -6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran was added to 9.5 ml of chloroform and anhydrous. It was dissolved in 0.84 ml of acetic acid, and 0.37 ml of fuming nitric acid (specific gravity 1.50) was added dropwise under stirring with ice cooling.
Stir for 35 minutes under ice cooling. Chloroform and ice cooling were added to the mixture and shaken, and the chloroform layer was washed with saline,
Dry with sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (eluted with chloroform: ethyl acetate = 1: 2) and recrystallized with hexane-ethanol (3: 1) to give 4- (2-acetyl-1).
-Nitrooxyacetylhydrazino) -6-cyano-3,
260 mg of 4-dihydro-2,2-dimethyl-2H-1-benzopyran is obtained as white crystals. Melting point 179-
181.5 ° C (decomposition)

Example 3 4- (1-acetylhydrazino) -6-cyano-3,4
4- (1-acetyl-2-hydroxyacetylhydrazino) was prepared by reacting 590 mg of dihydro-2,2-dimethyl-2H-1-benzopyran with acetoxyacetyl chloride in the same manner as in Example 2 and treating with alkali. ) -6-Cyano-3,4-dihydro-2,2-
Dimethyl-2H-1-benzopyran is obtained. This amorphous crude product was treated with fuming nitric acid (specific gravity 1.50) and acetic anhydride in the same manner as above to obtain a crude nitrooxy compound 620 m.
get g. This was purified by silica gel chromatography (elution; chloroform: ethyl acetate = 1: 2) and recrystallized from hexane-ethanol (4: 1) to give 4- (1-acetyl-2-nitrooxyacetylhydrazino). -6-Cyano-3,4-dihydro-2,2-
250 mg of dimethyl-2H-1-benzopyran are obtained.
Melting point 155-158 ° C (decomposition)

According to the above method, the following compounds are obtained. ◎ trans-4- (1,2-diacetylhydrazino)
-3,4-Dihydro-2,2-dimethyl-2H-pyrano [3,2-c] pyridin-3-ol nitrate ester trans-4- (N-acetyl-N-benzyloxyamino) -3,4 -Dihydro-2,2-dimethyl-2
H-pyrano [3,2-c] pyridin-3-ol nitrate ester trans-4- (1,2-diacetylhydrazino)
-3,4-Dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-1-benzopyran-3-ol nitrate ◎ trans-4- (N-acetyl-N-benzyloxyamino) -3,4- Dihydro-2,2-dimethyl-6
-Nitro-2H-1-benzopyran-3-ol nitrate ester ◎ trans-4- (1,2-diacetylhydrazino)
-3,4-dihydro-2,2-dimethyl-6-nitro-
2H-1-benzopyran-3-ol nitrate

[0015]

INDUSTRIAL APPLICABILITY The nitroesterified benzofuran analog of the present invention and a pharmaceutically acceptable salt thereof exhibit a markedly long-lasting blood pressure lowering action and a peripheral vasorelaxing action, and are therefore therapeutic agents for hypertension. Is useful as Further, it exhibits a selective coronary blood flow increasing action, and since the action is also extremely persistent, it is useful as a therapeutic drug for cardiovascular disorders such as angina and heart failure. Further, by showing the relaxing action of vascular smooth muscle and other smooth muscle by the above action, digestive ulcer, irritable bowel syndrome and diverticulopathy, reversible tracheal obstruction and asthma, preterm birth, urinary incontinence and cerebrovascular disease, It is also useful as a remedy for hair loss or baldness.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical display location A61K 31/35 ACL 7252-4C 31/44 ACJ 7252-4C ACV 7252-4C C07D 311/70 6701- 4C 491/052 7019-4C (72) Inventor Toru Nakajima Address 955, Otomi, Yoshitomi-cho, Tsukigami-gun, Fukuoka Prefecture Central Research Laboratory, Yoshitomi Pharmaceutical Co., Ltd. (72) Osamu Yaoka, Otomi-cho, Yoshitomi-cho, Chikage-gun, Fukuoka 955 Yoshitomi Pharmaceutical Co., Ltd. Central Research Laboratory

Claims (1)

What is claimed is: 1. A general formula: [In formula, A is -OR < ¹ >, -NH-COR < ² > (Here, R
¹ is hydrogen, lower alkyl, lower alkoxy lower alkyl, alkenyl, formyl, alkanoyl, aroyl,
R ² represents hydrogen, lower alkyl, lower alkoxy, amino, mono- or di-lower alkylamino, amino lower alkyl, hydroxy lower alkyl, nitrooxy lower alkyl, halo lower alkyl, lower alkoxy lower alkyl, acyloxy. Lower alkyl, lower alkoxycarbonyl represents lower alkyl, aryl and heteroaryl. ), And R ³
Is hydrogen, lower alkyl, lower alkoxy, amino, mono- or di-lower alkylamino, amino lower alkyl, hydroxy lower alkyl, nitrooxy lower alkyl, halo lower alkyl, lower alkoxy lower alkyl, acyloxy lower alkyl, lower alkoxycarbonyl lower alkyl, aryl , Heteroaryl, or R ² and R ³ represent a group which is bonded to each other to form an alkylene having 1 to 2 carbon atoms, and R ⁴ and R ⁵ are the same or different and represent hydrogen or lower alkyl. Or R ⁴ and R ⁵ represent a group which is bonded to each other to form an alkylene having 2 to 5 carbon atoms, and R ⁶ is hydrogen, hydroxyl group, nitrooxy, formyloxy, alkanoyloxy, haloalkanoyloxy, lower alkoxycarbonyloxy. , Aroyloxy, heteroaroyl Shi, carbamoyloxy, shows a mono- or di-lower alkylcarbamoyloxy, R ⁷
Represents hydrogen, or R ⁶ and R ⁷ together represent a bond, and X represents a single bond, methylene, oxygen, —S (O) _n.
-(N represents an integer of 0, 1, 2), -NR- (R represents hydrogen, lower alkyl, alkanoyl),
Ring B is a benzene ring, a 5- or 6-membered heterocycle, or halogen, nitro, cyano, amino, hydroxyl group, nitrooxy,
Formyloxy, alkanoyloxy, haloalkanoyloxy, lower alkoxycarbonyloxy, aroyloxy, heteroaroyloxy, carbamoyloxy,
Mono or di lower alkylcarbamoyloxy, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, carboxy, lower alkoxycarbonyl,
Aralkyloxycarbonyl, formyl, alkanoyl, aroyl, haloalkanoyl, carbamoyl, mono- or di-lower alkylcarbamoyl, lower alkylthio, halo lower alkylthio, lower alkylsulfinyl, halo lower alkylsulfinyl, arylsulfinyl, lower alkylsulfonyl, halo lower alkylsulfonyl, A benzene ring having at least one substituent selected from arylsulfonyl, sulfamoyl and mono- or di-lower alkylsulfonamide, or 5
Indicates a 6-membered heterocycle. However, when R ⁶ represents a group other than nitrooxy, one of R ² and R ³ represents nitrooxy lower alkyl, or the substituent of ring B represents nitrooxy. ] The benzopyran analog represented by these, or its pharmaceutically acceptable salt.