JP2612971B2 - Benzopyran compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel benzopyran compound or a pharmaceutically acceptable salt thereof which exhibits a slow and sustained hypotensive action and a smooth muscle relaxing action.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication No. Hei.
A novel benzopyran compound having an N-acyl-N-oxy-substituted amino group or a hydrazino group at the position has a remarkable and long-lasting blood pressure lowering action, coronary blood flow increasing action,
Further, it is disclosed that the vascular smooth muscle and other smooth muscles have a relaxing action. Also, JP-A-2-403
No. 75 and JP-A-2-145584 disclose that 3-chromene or chroman derivatives have an effect on the cardiovascular system.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to develop a benzopyran compound having a remarkable and sustained blood pressure lowering action or smooth muscle relaxing action.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies with the aim of finding a more useful drug, and as a result, the N-acyl-N-oxy-substituted amino group or hydrazino group at the 4-position was found. A novel benzopyran compound in which the 3-position is unsubstituted has a potent and persistent blood pressure lowering effect,
The present inventors have found that the present invention has a smooth muscle relaxing action, and have completed the present invention.

That is, the present invention relates to the general formula

Embedded image [Wherein A is -OR ¹ , -NH-COR ² (where R is
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, halo lower alkyl, lower alkoxy lower alkyl, acyloxy lower alkyl, lower And alkoxycarbonyl-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, halo lower alkyl, lower alkoxy lower alkyl, acyloxy lower alkyl, lower alkoxycarbonyl lower alkyl , Aryl, heteroaryl, or a group in which R ² and R ³ are 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 each represents hydrogen or lower alkyl. Or a group in which R ⁴ and R ⁵ are bonded to each other to form an alkylene having 2 to 5 carbon atoms, and X and Y are the same or different and are hydrogen, halogen, nitro, cyano, amino, hydroxyl, lower Alkyl,
Halo lower alkyl, lower alkoxy, halo lower alkoxy, carboxy, formyl, alkanoyl, aroyl,
Haloalkanoyl, carbamoyl, lower alkylcarbamoyl, lower alkylcarbamoyl, lower alkylthio, lower haloalkylthio, lower alkylsulfinyl, halolower alkylsulfinyl, arylsulfinyl, lower alkylsulfonyl, halolower alkylsulfonyl, arylsulfonyl, sulfamoyl, mono or di 3 shows a lower alkylsulfonamide. Or a pharmaceutically acceptable salt thereof.

In the definitions of the above symbols, halogen is chlorine,
Bromine, fluorine, and iodine
6 straight or branched alkyl, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl and the like are referred to as amino lower alkyl, which 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; hydroxy-lower alkyl is a straight-chain or branched hydroxy-alkyl having 1 to 6 carbon atoms; Hydroxymethyl,
2-hydroxyethyl, 3-hydroxypropyl, 1-hydroxymethylethyl, 4-hydroxybutyl, 5-
Hydroxypentyl, 6-hydroxyhexyl and the like,
Halo-lower alkyl is a straight-chain or branched-chain halogenated alkyl having 1 to 4 carbon atoms, which is chloromethyl, bromomethyl, fluoromethyl, iodomethyl, dichloromethyl, dibromomethyl, difluoromethyl, diiodomethyl, triiodomethyl, Fluoromethyl, chloroethyl, bromoethyl, fluoroethyl, iodoethyl, difluoroethyl, trifluoroethyl, chloropropyl, bromopropyl, fluoropropyl, iodopropyl, difluoropropyl, trifluoropropyl, chlorobutyl, bromobutyl, fluorobutyl, iodobutyl, difluorobutyl, Trifluorobutyl and the like; lower alkoxy is a straight 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 means chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, dichloromethoxy, dibromomethoxy, difluoromethoxy, diiodomethoxy, trifluoromethoxy, chloro Ethoxy, bromoethoxy, fluoroethoxy, iodoethoxy, difluoroethoxy, trifluoroethoxy, chloropropoxy, bromopropoxy, fluoropropoxy, iodopropoxy, difluoropropoxy, trifluoropropoxy, chlorobutoxy, bromobutoxy, fluorobutoxy, iodobutoxy, difluoro Butoxy, trifluorobutoxy and the like, a lower alkoxy lower alkyl is an alkoxy part and an alkyl part having 1 to 1 carbon atoms. Methoxymethyl be one having a number of alkoxy and alkyl, 2-methoxyethyl, 3-methoxypropyl, 4
-Methoxybutyl, ethoxymethyl, propoxymethyl, butoxymethyl and the like, lower alkoxycarbonyl-lower alkyl means that the alkoxy part and the alkyl part have alkoxy and alkyl having 1 to 4 carbon atoms, and methoxycarbonylmethyl, Methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4-methoxycarbonylbutyl, ethoxycarbonylmethyl,
Propoxycarbonylmethyl, butoxycarbonylmethyl and the like, acyloxy lower alkyl and acetyloxymethyl, acetyloxyethyl, acetyloxypropyl, acetyloxybutyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl,
Pivaloyloxymethyl and the like; aralkyl is an aralkyl having an alkyl portion having 1 to 4 carbon atoms, such as benzyl, α-phenylbenzyl, α-2-pyridylbenzyl, 2-phenylethyl, 3-phenylpropy , 4-phenylbutyl, naphthylmethyl, 2-naphthylethyl, 3-naphthylpropyl, 4-naphthylbutyl or halogen, lower alkyl, lower alkoxy, hydroxyl, trifluoromethyl, cyano, nitro, amino and Benzyl having at least one substituent selected from sulfamoyl, α-phenylbenzyl, α-2-pyridylbenzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylethyl , 3-naphthylpropyl, 4-naphthylbuty Etc., phenyl and aryl, halogen onto naphthyl or an aromatic ring (chlorine, bromine,
Iodine, fluorine), lower alkyl, lower alkoxy (linear or branched alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, etc.) ), Hydroxyl, trifluoromethyl, cyano, nitro,
Heteroaryl refers to furyl (2-furyl, 3-furyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), for example, phenyl or naphthyl having at least one substituent selected from amino and sulfamoyl. ), Thienyl (2-thienyl, 3-thienyl) or at least one substituent selected from halogen, lower alkyl, lower alkoxy, hydroxyl, trifluoromethyl, cyano, nitro, amino and sulfamoyl on the ring Heteroarylalkyl refers to furyl, pyridyl, thienyl, etc., in which the alkyl portion has alkyl having 1 to 4 carbon atoms, and includes furylmethyl, furylethyl, furylpropyl, furylbutyl, pyridylmethyl, pyridylethyl, pyridylpropyl. , Pyridylbutyl, thienylmethyl, thi Nylethyl, thienylpropyl, thienylbutyl or furylmethyl, furylethyl having at least one substituent selected from halogen, lower alkyl, lower alkoxy, hydroxyl, trifluoromethyl, cyano, nitro, amino and sulfamoyl on the ring , Furylpropyl, furylbutyl, pyridylmethyl, pyridylethyl, pyridylpropyl, pyridylbutyl, thienylmethyl, thienylethyl, thienylpropyl, thienylbutyl, etc., where alkanoyl is alkanoyl having 2 to 5 carbon atoms and is substituted by phenyl Acetyl, propionyl, butyryl, valeryl, pivaloyl, phenylacetyl, phenylpropionyl, phenylbutyryl and the like; haloalkanoyl is chloroacetyl, bromoacetate, etc. , Fluoroacetyl, iodoacetyl, dichloroacetyl, dibromoacetyl, difluoroacetyl, diiodoacetyl, trifluoroacetyl, chloropropionyl, bromopropionyl, fluoropropionyl, iodopropionyl, difluoropropionyl, trifluoropropionyl, chlorobutyryl, bromobutyryl, fluorobutyl Ryl, iodobutyryl, difluorobutyryl, trifluorobutyryl, fluorovaleryl, fluorohexanoyl, etc., aroyl is benzoyl, naphthoyl, etc., and mono or di-lower alkylamino is alkyl having 1 to 4 carbon atoms. Having alkyl, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tertiary butylamino No, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, ditertiary butylamino, dipentylamino, dihexylamino, etc .; lower alkylcarbamoyl is methylcarbamoyl, ethyl Carbamoyl, propyl carbamoyl, isopropyl carbamoyl, butyl carbamoyl, isobutyl carbamoyl, tertiary butyl carbamoyl, pentyl carbamoyl, hexyl carbamoyl, etc .; Diisobutylcarbamoyl, ditertiarybutylcarbamoyl, dipentylcarbamoy , Dihexylcarbamoyl, N-methyl-N-ethylcarbamoyl, N-methyl-N-propylcarbamoyl, N-methyl-N-butylcarbamoyl, N-methyl-N-tertiary butylcarbamoyl, N-methyl-N-penty Rucarbamoyl, 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; ethylene, trimethylene, propylene, tetramethylene, pentamethylene and the like; lower alkylthio means methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tertiary butylthio , Pentylthio, hexylthio and the like; halo-lower alkylthio is 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 and the like; lower alkylsulfinyl means an alkyl moiety having alkyl having 1 to 6 carbon atoms, and methylsulfinyl, ethylsulfinyl Propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, tertiary butylsulfinyl, pentylsulfinyl, hexylsulfinyl, etc. Phenylsulfinyl and sulfonyl,
Naphthylsulfinyl or phenyl having at least one substituent selected from halogen (chlorine, bromine, iodine, fluorine), lower alkyl, lower alkoxy, hydroxyl, trifluoromethyl, cyano, nitro and amino on an aromatic ring Halo-lower alkylsulfinyl such as chloromethylsulfinyl, bromomethylsulfinyl, fluoromethylsulfinyl, iodomethylsulfinyl, dichloromethylsulfinyl, dibromomethylsulfinyl, difluoromethylsulfinyl, diiodomethylsulfinyl, trifluoromethylsulfinyl , Chloroethylsulfinyl, bromoethylsulfinyl, fluoroethylsulfinyl, iodoethylsulfinyl, difluoroethylsulfinyl , Trifluoroethylsulfinyl, chloropropylsulfinyl, bromopropylsulfinyl, fluoropropylsulfinyl, iodopropylsulfinyl, difluoropropylsulfinyl, trifluoropropylsulfinyl, chlorobutylsulfinyl, bromobutylsulfinyl, fluorobutylsulfinyl, iodobutylsulfinyl, difluorobutyl Sulfinyl, trifluorobutylsulfinyl and the like, a lower alkylsulfonyl in which the alkyl portion has alkyl having 1 to 6 carbon atoms, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, Tertiary butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like, Reel sulfonyl means at least a substituent selected from phenylsulfonyl, naphthylsulfonyl or an aromatic ring having halogen (chlorine, bromine, iodine, fluorine), lower alkyl, lower alkoxy, hydroxyl, trifluoromethyl, cyano, nitro, amino. Phenylsulfonyl having one,
Naphthylsulfonyl and the like; halo-lower alkylsulfonyl are chloromethylsulfonyl, bromomethylsulfonyl, fluoromethylsulfonyl, iodomethylsulfonyl, dichloromethylsulfonyl, dibromomethylsulfonyl, difluoromethylsulfonyl, diiodomethylsulfonyl, trifluoromethylsulfonyl, Ethylsulfonyl, bromoethylsulfonyl, fluoroethylsulfonyl, iodoethylsulfonyl, difluoroethylsulfonyl, trifluoroethylsulfonyl, chloropropylsulfonyl, bromopropylsulfonyl, fluoropropylsulfonyl, iodopropylsulfonyl, difluoropropylsulfonyl, trifluoropropylsulfonyl, chloro Butylsulfonyl, bromobutylsulfonyl, full Mono- or di-lower alkylsulfonamides such as robutylsulfonyl, iodobutylsulfonyl, difluorobutylsulfonyl, trifluorobutylsulfonyl, etc., in which the alkyl moiety has alkyl having 1 to 6 carbon atoms, and methylsulfonamide, ethyl Sulfonamide, propylsulfonamide, isopropylsulfonamide, butylsulfonamide, isobutylsulfonamide, tertiary butylsulfonamide, pentylsulfonamide, hexylsulfonamide, dimethylsulfonamide, diethylsulfonamide, dipropylsulfonamide, diisopropylsulfonamide ,
Dibutylsulfonamide, diisobutylsulfonamide, ditertiarybutylsulfonamide, dipentylsulfonamide, dihexylsulfonamide and the like are respectively shown.

Since the compound of the present invention has at least one or more asymmetric carbons, there exist optical isomers and stereoisomers based thereon, and these isomers and mixtures thereof are all included in the present invention. Things.

Further, the compound of the present invention may be used in the form of an inorganic acid salt with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc., acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid,
Organic acid salts with tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc., as well as hydrates and / or various solvates, are also included in the present invention. .

The compound of the present invention can be synthesized, for example, by a method known per se. For example, the compound of the general formula (I) can be synthesized by the following method.

Method 1

Embedded image [In the above step, Z represents a hydroxyl group or a reactive derivative of a carboxylic acid, and other symbols are as defined above. ]

The reaction of step 1 is usually carried out at 10 to 100 ° C. in a solvent such as a lower alcohol, especially methanol, ethanol or propanol. The reaction proceeds particularly smoothly when carried out under reflux. The resulting compound (III) can be purified by a conventional method, or can be subjected to the reaction in Step 2 without purification.

The reaction of step 2 includes various reducing agents such as sodium borohydride, diborane, triethylsilane,
The compound (IV) is led by reduction with sodium cyanoborohydride or the like, and it is particularly preferable to use sodium cyanoborohydride as a reducing agent.

In the reaction of the step 3, when Z of the compound (VI) is a compound having a hydroxyl group, that is, a free carboxylic acid,
The reaction is carried out by various known dehydration condensing agents, for example, dicyclohexylcarbodiimide (N-hydroxybenzotriazole may be used in combination), titanium tetrachloride, phosphorus halide (phosphorus trichloride, phosphorous oxychloride, etc.), diethylchlorophosphite, o -Phenylene chlorophosphite,
Ethyldichlorophosphite, dimethylformamide-
Thionyl chloride, carbonyldiimidazole, diphenylphosphoryl azide, 1-ethoxycarbonyl-2
-Ethoxy-1,2-dihydroxyquinoline (EED
The reaction is carried out in an inert solvent, under cooling, at room temperature or under heating in the presence of Q). Incidentally, after reacting the compound (IV) with phosphorus halide in an inert solvent in advance, the compound
It can also be condensed with (VI). For example, when the phosphorus halide is phosphorus trichloride, about モ ル mol of phosphorus trichloride is added to the compound (IV) in advance in an inert solvent with a tertiary amine such as triethylamine, pyridine or N, N-dimethylaniline. After acting under cooling or at room temperature in the presence of a base, the compound (VI) is reacted with the compound (VI) in an inert solvent at room temperature or under heating, preferably under reflux with heating.

When an acid halide such as acid chloride or acid bromide is used as a reactive derivative of the carboxylic acid of the general formula (VI), the reaction is carried out in an inert solvent such as triethylamine, pyridine, N, N-dimethylaniline and the like. Under cooling or at room temperature in the presence of a tertiary base deoxidizing agent, or under cooling or at room temperature in water in the presence of an alkali such as sodium hydroxide or potassium hydroxide.

As the reactive derivative of the compound (VI), acid anhydride or mixed acid anhydride such as mixed acid anhydride of alkyl carbonic acid, mixed acid anhydride of alkyl phosphoric acid, mixed acid anhydride of alkyl phosphorous acid, mixed acid anhydride of sulfuric acid, etc. When a compound is used, compound (VI) can be converted to a mixed acid anhydride using, for example, isobutyl chloroformate and pivalic acid chloride. The reaction is carried out in an inert solvent in triethylamine, pyridine, N,
The reaction is carried out in the presence of a tertiary base such as N-dimethylaniline under cooling, at room temperature or under heating.

When an active amide such as acid imidazolide, acid pyrrolidide or 2,4-dimethylpyrazolide is used as a reactive derivative of compound (VI), the reaction is carried out in an inert solvent at room temperature or under heating.

When an active ester such as methyl ester, ethyl ester, p-nitrophenyl ester or p-chlorophenyl ester is used as a reactive derivative of compound (VI), the reaction is carried out in an inert solvent at room temperature or under heating. The reaction is preferably carried out under reflux.

As the inert solvent used in each of the above condensation reactions, benzene, toluene, xylene, methanol, ethanol, isopropyl alcohol, ethyl ether, dioxane, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, hexamethylphosphoric triamide , Diethylene glycol, dimethylformamide and the like, or a mixed solvent thereof, and when the compound (VI) is a reactive derivative, it is appropriately selected depending on its type.

Method 2

Embedded image [In the above reaction formula, R ⁶ represents an amino protecting group (benzyloxycarbonyl, tertiary butoxycarbonyl, formyl, trityl, tosyl, etc.), and other symbols are as defined above. ]

The present method comprises the step of preparing a compound of the formula (I) wherein R ² and R ³ are the same (excluding the group in which R ² and R ³ are bonded to each other to form an alkylene having 1 to 2 carbon atoms). Can be used to obtain The reaction in step 4 can be performed under the same conditions as in step 1 above, the reaction in step 5 can be performed under step 2 above, and the reaction in step 7 can be performed under the same conditions as in step 3 above.

When R ⁶ is benzyloxycarbonyl, the deprotection reaction in step 6 is carried out by hydrogenolysis under normal pressure using palladium carbon in ethanol or methanol.
When R ⁶ is tertiary butoxycarbonyl, the reaction can be carried out by the action of trifluoroacetic acid, hydrochloric acid-ethyl acetate or the like.

Method 3

Embedded image [In the above reaction formula, each symbol is as defined above. ]

The present method can be used to obtain a compound other than a group in which R ² and R ³ of the general formula (I) are bonded to each other to form an alkylene having 1 to 2 carbon atoms. Steps 8 and 1
The reaction of 0 can be carried out under the same conditions as in Step 1 and Step 9 described above, and in Step 6 described above.

Method 4

Embedded image [In the above reaction formula, each symbol is as defined above. ]

In the dehydration reaction in step 11, a base (sodium hydride, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, etc.) or an acid (thionyl chloride,
Phosphorus oxychloride, phosphorus pentoxide, etc.). In that case, when using a base as a dehydrating agent, it is preferable to use dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and the like as a solvent, and when using an acid, chloroform, 1,2-dichloroethane, toluene, benzene and the like are used as a solvent. used. The reduction reaction in step 12 can be performed with a reducing agent such as hydrogen-palladium, sodium-alcohol, zinc-acetic acid, or the like.

Method 5

Embedded image [In the above reaction formula, B represents a leaving group such as halogen, arylsulfonyloxy, lower sulfonyloxy, and the other symbols are as defined above. ]

The substitution reaction in step 13 uses a water-soluble solvent such as water, methanol, ethanol or dioxane in the presence of sodium hydroxide, potassium hydroxide or potassium carbonate or a solvent such as benzene, toluene, dimethylformamide or dimethylsulfoxide. The reaction is carried out in the presence of an organic base such as triethylamine or pyridine or potassium carbonate, and the reaction can be carried out from room temperature to heating under reflux. The reaction in step 14 can be performed under the same conditions as in step 1 above.

Method 6

Embedded image [In the above reaction formula, R ⁷ represents lower alkyl, n represents 1 or 2, and other symbols are as defined above. ]

The present method can be used to obtain a compound of the general formula (I) in which R ² and R ³ are bonded to each other to form an alkylene having 1 to 2 carbon atoms. The reaction in step 15 can be carried out under the same conditions as in step 3, and the reaction in step 16 can be carried out under the same conditions as in step 9 above. In addition, the cyclization reaction in Step 17 is performed at a pH higher than neutrality and, if necessary, in the presence of an organic base such as pyridine and triethylamine, with ethanol,
Toluene, benzene, in xylene, can be carried out by by heating to reflux for 1 to 30 hours to remove the alcohol (R ⁷ OH).

The compound of the formula (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization, chromatography and the like.

The compound of the formula (I) can be prepared by a conventional method using inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, apple Acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc.) to obtain a pharmaceutically acceptable salt. Various solvates can also be used.

The compound of the present invention has a chiral carbon atom as described above and is usually obtained as a racemic form. The racemate can be separated into optical isomers by a conventional method. Such an optical isomer can also be produced by using an optically active starting compound, and it is particularly useful to use an optically active epoxide compound (general formula II) as a raw material.

The compound of the present invention and a pharmaceutically acceptable salt thereof exhibit a slow and sustained blood pressure lowering action and a peripheral vasorelaxation action, and thus are useful as therapeutic agents for hypertension.

When the compound of the present invention or a pharmaceutically acceptable salt thereof is used as a medicament, it is usually used as a carrier, excipient,
Mix with pharmaceutically acceptable additives such as diluents and solubilizers, and prepare tablets (including sugar-coated tablets and film-coated tablets), capsules, powders, granules, injections, drops, suppositories, haptics, suspensions It can be safely administered orally or parenterally in the form of a suspension, aerosol or the like. The dose may vary depending on the sex, age, weight or condition of the patient, but is usually in the range of about 1 to 500 mg orally per adult daily.
It is administered once or several times a day.

[0035]

EXAMPLES Hereinafter, the present invention will be described in detail with reference to Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 a) 6 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-one was dissolved in 25 ml of ethanol, and 6.9 g of acetohydrazide was added. Heat to reflux for 96 hours. The solvent is distilled off under reduced pressure, ice water is added to the residue, and the solid to be separated is collected by filtration and dried under reduced pressure. This was recrystallized from ethyl acetate-hexane (1: 1) to give 2.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-one 2-acetylhydrazone. Can be Melting point 226-22
7.5 ° C b) 2.48 g of the above compound was added to 35 ml of ethanol and 1 part of acetic acid.
Dissolved in 0 ml, sodium cyanoborohydride 1.7 g
And heated to reflux. Further, the mixture is heated and refluxed for a total of 8 hours while a total of 3.0 g of the reducing agent is added sequentially in three portions. Ethanol is distilled off under reduced pressure, water is added to the residue, the pH is adjusted to 10 with potassium carbonate, and ethyl acetate is added for extraction. The organic layer was washed with saline, and the concentrated residue was subjected to silica gel column chromatography (elution solvent: chloroform:
Purification by methanol = 8: 1) gave 4- (2-acetyl) hydrazino-6-cyano-3,4-dihydro-.
1.7 g of 2,2-dimethyl-2H-1-benzopyran are obtained as an oil.

Reference Example 2 a) 7.1 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-one and 8.3 g of t-butylcarbazate in 30 ml of ethanol. And reflux under heating for 134 hours. Further, 30 ml of ethanol is added to the mixture, the mixture is cooled to room temperature, and insolubles are filtered off. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from hexane-ethanol (3: 1) to give 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran.
5.3 g of 2-t-butyloxycarbonylhydrazone are obtained. Melting point: 200.5-201.5 ° C (decomposition) b) 3.12 g of the above compound was dissolved in 50 ml of ethanol and 1 part of acetic acid.
0 ml, and sodium cyanoborohydride 6.0 total
g, and reduced and treated in the same manner as in Reference Example 1b).
Purification by silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 8: 1), concentration and concentration of the desired 4- (2-t-butyloxycarbonyl) hydrazino-6-cyano-3,4-dihydro-2, 3.0 g of 2-dimethyl-2H-1-benzopyran are obtained as a glassy solid.

Example 1 860 mg of the compound of Reference Example 1b) was dissolved in 2.0 ml of pyridine, and 0.47 ml of acetyl chloride was added with stirring under ice-cooling, followed by stirring at 0 ° C. for 5 minutes. Return to room temperature and keep stirring for 30 minutes. Ice water is added to the mixture, extracted with ethyl acetate, washed with brine, filtered and concentrated. The residue was recrystallized from hexane-ethanol (5: 3) to give 4
-(1,2-diacetyl) hydrazino-6-cyano-
535 mg of 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran are obtained. 193.5-195
° C

Example 2 The reaction was carried out in the same manner as in Example 1 except that benzoyl chloride was used instead of acetyl chloride, and recrystallized from ethanol to give 4- (2-acetyl-1-benzoyl) hydrazino-6-cyano-3,4. -Dihydro-2,2-dimethyl-2H-1-benzopyran is obtained. Melting point 244-
245 ° C

Example 3 The reaction was carried out in the same manner as in Example 1 by using trifluoroacetic anhydride instead of acetyl chloride, and recrystallized from hexane-ethyl acetate (1: 1) to give 4- (2-acetyl-1-methyl).
Trifluoroacetyl) hydrazino-6-cyano-3,
4-Dihydro-2,2-dimethyl-2H-1-benzopyran is obtained. 197.5-199 ° C

Example 4 600 mg of the compound of Reference Example 1b) is dissolved in 3.6 ml of 99% formic acid, and 0.90 ml of acetic anhydride is added. After standing at room temperature for 35 minutes, the mixture is further stirred on a water bath at 40 to 50 ° C for 45 minutes. The mixture was concentrated under reduced pressure, and the residue was recrystallized from hexane-ethyl acetate (1: 3) to give 4- (2-acetyl-1-).
370 mg of ethyl formyl) hydrazino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran 1/2 acetate are obtained. Melting point 175-17
6.5 ° C

Example 5 700 mg of the compound of Reference Example 1b) was added to 4.5 ml of chloroform.
And 0.80 ml of pyridine is added. While stirring under ice-cooling, 0.52 ml of acetoxyacetyl chloride is added. After reacting for 2 minutes at 0 ° C, return to room temperature and
Stir for 0 minutes. The solvent is distilled off under reduced pressure, and the residue is dissolved in 5 ml of methanol. At room temperature, 3.0 ml of a 10% sodium hydroxide solution was added, and the mixture was stirred at the same temperature for 45 minutes. The reaction product is concentrated under reduced pressure, ice water is added to the residue, and the mixture is stirred to separate a solid. The solid was collected by filtration, dried, and recrystallized from ethyl acetate-ethanol (1: 1) to give 4- (2-acetyl-
1-hydroxyacetyl) hydrazino-6-cyano-
330 mg of 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran are obtained. 234-235 ° C

Example 6 1.85 g of the compound of Reference Example 2b) was dissolved in 4.8 ml of pyridine, and 0.83 g of acetyl chloride was added dropwise with stirring under ice cooling. After 5 minutes, transfer to a water bath at 40 ° C. and stir for 10 minutes. Ice water is added, extracted with ethyl acetate, and the organic layer is washed with brine. After filtration, the filtrate was concentrated, and the residue was recrystallized from ethanol-hexane (1: 1) to give 4- (1
1.1 g of -acetyl-2-t-butyloxycarbonyl) hydrazino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran are obtained as a white solid. Melting point: 191 ° -192 ° C. (decomposition) 1,000 mg of the obtained compound is suspended in 10 ml of ethanol, 4 ml of concentrated hydrochloric acid is added, and the mixture is stirred on a water bath at 40 ° to 50 ° C. for 100 minutes. The solvent is distilled off under reduced pressure, a diluted aqueous solution of potassium carbonate and common salt are added to the residue, and the mixture is extracted with ethyl acetate. The organic layer was washed with brine and concentrated under reduced pressure to give 4- (1-acetyl)
Hydrazino-6-cyano-3,4-dihydro-2,2-
680 mg of dimethyl-2H-1-benzopyran are obtained as a white solid. The obtained compound was used for the following reaction without purification. The total amount of the above compound was dissolved in 5.0 ml of 99% formic acid, and stirred at room temperature while stirring for 1.2 ml of acetic anhydride.
Add. After standing overnight at room temperature, the solvent was completely distilled off under reduced pressure, and the residue was recrystallized from hexane-ethanol (1: 1) to give 4- (1-acetyl-2-formyl) hydrazino-6-cyano-3, 470 mg of 4-dihydro-2,2-dimethyl-2H-1-benzopyran are obtained. Melting point 1
88.5-191.5 ° C

Example 7 4- (1-acetyl) hydrazino-6-cyano-3,4
-Dihydro-2,2-dimethyl-2H-1-benzopyran and trifluoroacetic anhydride were reacted in the same manner as in the above example and recrystallized from hexane-ethanol (5: 1) to give 4- (1-acetyl- 2-trifluoroacetyl)
Hydrazino-6-cyano-3,4-dihydro-2,2-
Dimethyl-2H-1-benzopyran is obtained. Melting point 1
94.5-195.5 ° C

Example 8 4- (1-acetyl) hydrazino-6-cyano-3,4
-Dihydro-2,2-dimethyl-2H-1-benzopyran and acetoxyacetyl chloride were reacted in the same manner as in the above example, and then saponified in the same manner as in Example 5 to obtain 4- (1- Acetyl-2-hydroxyacetyl) hydrazino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran is obtained. NMR (DMSO-d ₆ , ppm) δ: 1.26 (3H, s), 1.42
(3H, s), 2.01 (3H, s), 1.60-2.30 (2H, m), 3.95
(2H, d), 5.58 (1H, t), 5.50 to 5.90 (1H, m), 6.84 (1
H, d), 7.30 to 7.90 (2H, m), 10.07 (1H, s)

Example 9 4- (1-acetyl) hydrazino-6-cyano-3,4
-Dihydro-2,2-dimethyl-2H-1-benzopyran and 4-chloro-3-sulfamoylbenzoyl chloride were reacted and treated in the same manner as in the above example to give
The amorphous solid 4- (1-acetyl-2- (4-chloro-
3-sulfamoylbenzoyl)) hydrazino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1
-Benzopyran is obtained. NMR (DMSO-d ₆ , ppm)
δ: 1.29 (3H, s), 1.41 (3H, s), 1.92 (3H, s), 1.62
~ 2.40 (4H, m), 5.76 (1H, m), 6.86 (1H, d), 7.40 ~
8.10 (4H, m), 8.44 (1H, s), 10.92 (1H, s)

Example 10 4- (1-acetyl) hydrazino-6-cyano-3,4
-Dihydro-2,2-dimethyl-2H-1-benzopyran and benzoyl chloride were reacted in the same manner as in the above example, and recrystallized from hexane-ethyl acetate (2: 1) to give 4- (1-acetyl-2-yl). Benzoyl) hydrazino-6-cyano-3,4-dihydro-2,2-dimethyl-
2H-1-benzopyran 1/2 ethyl acetate hydrate monohydrate is obtained. 121-135 ° C

Example 11 4- (1-acetyl) hydrazino-6-cyano-3,4
-Dihydro-2,2-dimethyl-2H-1-benzopyran and ethyl chlorocarbonate were reacted in the same manner as in the above example, and recrystallized from hexane-ethyl acetate (5: 1) to give 4- (1-acetyl). -2-Ethoxycarbonyl) hydrazino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran is obtained. Melting point 14
1.5-144 ° C

Example 12 5.0 g of the compound of Reference Example 2b) was dissolved in 30 ml of ethanol, and 15 ml of concentrated hydrochloric acid was added with stirring under ice-cooling. Further, after stirring on a water bath at 40 ° C. for 150 minutes, the solvent is distilled off under reduced pressure. An aqueous potassium carbonate solution is added to the residue, and the mixture is extracted with chloroform. After drying over magnesium sulfate, the mixture was concentrated to give an amorphous glass as 6-cyano-3,4-dihydro-2,2-dimethyl-4-hydrazino-2H-1-.
3.5 g of benzopyran are obtained. The obtained compound is dissolved in 30 ml of 99% formic acid without purification, 7.0 ml of acetic anhydride is added, and the mixture is stirred for 30 minutes. After overnight standing at room temperature, the solvent was completely distilled off under reduced pressure, and the residue was recrystallized from hexane-ethanol (1: 1) to give 6-cyano-
3,4-dihydro-2,2-dimethyl-4- (1,2-
Diformyl) hydrazino-2H-1-benzopyran
58 g are obtained. 168-170 ° C

Example 13 1.95 g of the compound of Reference Example 2b) was dissolved in 5.0 ml of pyridine and benzoyl chloride 1.
Add 4 ml. After further stirring on a water bath at 40 to 50 ° C. for 120 minutes, ice water and potassium carbonate were added to the mixture and stirred,
The insoluble matter is collected by filtration. After drying , recrystallization from ethanol-hexane (2: 1) gave 4- (1-benzoyl-
2-tert-butyloxycarbonyl) hydrazino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1
1.75 g of benzopyran are obtained. Melting point 217.5
C. (Decomposition) 1.38 g of the above compound were suspended in 20 ml of ethanol, 6.0 ml of concentrated hydrochloric acid was added, and the mixture was stirred on a water bath at 65 to 70.degree. C. for 40 minutes. The solvent is distilled off under reduced pressure, and ice water and potassium carbonate are added to the residue, followed by stirring. The separated crystals are collected by filtration and dried to give 4- (1-benzoyl) hydrazino-6.
-Cyano-3,4-dihydro-2,2-dimethyl-2H
960 mg of -1-benzopyran are obtained. The obtained compound was formylated without purification, in the same manner as in Example 4, and the obtained crude product was treated with hexane-ethanol (1: 1).
Recrystallization from 4- (1-benzoyl-2-formyl) hydrazino-6-cyano-3,4-dihydro-2,
800 mg of 2-dimethyl-2H-1-benzopyran / 1/3 ethanolate are obtained. 179-180 ° C

Example 14 The reaction was carried out in the same manner as in Example 13 using propionyl chloride instead of benzoyl chloride, and recrystallized from hexane-ethanol (1: 1) to give 6-cyano-3,
4-Dihydro-2,2-dimethyl-4- (2-formyl-1-propionyl) hydrazino-2H-1-benzopyran is obtained. 180-181 ° C

Example 15 4- (N-acetyl-N-benzyloxyamino) -6
-Cyano-3,4-dihydro-2,2-dimethyl-2H
-1-benzopyran

Example 16 4- (N-acetyl-N-hydroxyamino) -6-cyano-3,4-dihydro-2,2-dimethyl-2H-1
-Benzopyran

Example 17 6-cyano-4- (N-hydroxy-N-nicotinoylamino) -3,4-dihydro-2,2-dimethyl-2H
-1-benzopyran

Example 18 4- (N-acetyl-N-methoxyamino) -6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-
Benzopyran

[0056]

The blood pressure lowering effect of the compound of the present invention will be described with reference to the following experimental examples.

EXPERIMENTAL EXAMPLE 1 Two groups of male spontaneously hypertensive rats (SHR: 24-
Using a 30-week-old, 320-410 g body weight), a polyethylene catheter filled with saline was inserted into the left common carotid artery and vein of the SHR anesthetized with ether, and the other end was passed subcutaneously from the back neck. Derived. SH after awakening
In a box where R can move freely, it is connected to a pressure measurement transducer (blood pressure monitoring kit, manufactured by Spectrand Medical Products) inserted into the left common carotid artery, and the average blood pressure and heart rate are polygraphed by NEC Saneisha Was measured invasively. The drug was dissolved in dimethylsulfoxide, diluted with physiological saline, and administered intravenously via a catheter inserted into the left common jugular vein. Table 1 shows the results.

[0058]

Table 1 Table 1 Compound dose (mg / kg, iv ) Maximum pressure drop (mmHg) 化合物 Compound of Example 1 0.1 − 20 0.3-60 Compound of Example 6 0.01-45 ° ─

As is clear from the above experimental examples and various pharmacological experiments, the compound of the present invention and a pharmaceutically acceptable salt thereof show a potent and sustained blood pressure lowering action and a peripheral vasorelaxant action, and It is useful as a remedy for diseases. In addition, it exhibits a selective coronary blood flow increasing action and its action is extremely persistent, and thus is useful as a therapeutic drug for cardiovascular disorders such as angina pectoris and heart failure. Furthermore, since the above-mentioned action shows a relaxing action of vascular smooth muscle and other smooth muscle, gastrointestinal ulcer, irritable bowel group and diverticulum disease, reversible tracheal obstruction and asthma, preterm birth, urinary incontinence and cerebrovascular disease It is also useful as a treatment for hair loss or baldness.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 31/35 ACL A61K 31/35 ACL 31/44 ACF 31/44 ACF C07D 405/12 C07D 405 / 12

Claims (1)

(57) [Claims] 1. A compound of the general formula [Wherein A is -OR ¹ , -NH-COR ² (where R is
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, halo lower alkyl, lower alkoxy lower alkyl, acyloxy lower alkyl, lower And alkoxycarbonyl-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, halo lower alkyl, lower alkoxy lower alkyl, acyloxy lower alkyl, lower alkoxycarbonyl lower alkyl , Aryl, heteroaryl, or a group in which R ² and R ³ are 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 each represents hydrogen or lower alkyl. Or a group in which R ⁴ and R ⁵ are bonded to each other to form an alkylene having 2 to 5 carbon atoms, and X and Y are the same or different and are hydrogen, halogen, nitro, cyano, amino, hydroxyl, lower Alkyl,
Halo lower alkyl, lower alkoxy, halo lower alkoxy, carboxy, formyl, alkanoyl, aroyl,
Haloalkanoyl, carbamoyl, lower alkylcarbamoyl, lower alkylcarbamoyl, lower alkylthio, lower haloalkylthio, lower alkylsulfinyl, halolower alkylsulfinyl, arylsulfinyl, lower alkylsulfonyl, halolower alkylsulfonyl, arylsulfonyl, sulfamoyl, mono or di 3 shows a lower alkylsulfonamide. Or a pharmaceutically acceptable salt thereof.