WO1994018195A1

WO1994018195A1 - Novel benzoxazine derivative, medicine containing the same, and intermediate therefor

Info

Publication number: WO1994018195A1
Application number: PCT/JP1994/000174
Authority: WO
Inventors: Yuzo Matsumoto; Wataru Uchida; Isao Yanagisawa
Original assignee: Yamanouchi Pharmaceutical Co., Ltd.
Priority date: 1993-02-05
Filing date: 1994-02-04
Publication date: 1994-08-18
Also published as: AU5979494A

Abstract

A benzoxazine derivative useful as a potassium channel activator and represented by general formula (I), a pharmaceutically acceptable salt thereof, a stereo-chemical isomer thereof, a medicinal composition containing the same, another benzoxazine derivative useful as an intermediate for the production thereof and represented by general formula (II), and a salt thereof. In formula (I), R1 represents hydrogen, lower alkyl, lower alkanoyl, carbamoyl, mono- or di(lower alkyl)carbamoyl or nitro; R2 represents lower alkyl; R3 represents nitro; m represents an integer of 1 to 4; and n represents 0 or 1. In formula (II), R?1, R2, R3¿ and m are each as defined above.

Description

Ming New gin derivatives and their pharmaceuticals and intermediates

The present invention relates to a novel benzoxazine derivative useful as a medicament, particularly a potassium channel (K; channel) activator, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a medicament containing these as an active ingredient. The intermediates for the production of these compounds are described below. Background art

Smooth muscle relaxants that act on the contractile system such as various excitatory chemical mediator receptor blockers and calcium antagonists, or inhibitory chemical mediator receptor stimulants and nitrates (nitrates) Act on the relaxation system. In addition, there is a type that exerts a smooth muscle relaxing action by activating the K + channel.

Unlike large excitable tissues, K + channels are activated early and strongly in large arteries (especially coronary and cerebral arteries) and in the tracheal smooth muscle, and function to prevent these tissues from being unnecessarily excited. However, when the physiology of the κ ⁺ channel is damaged, electrical excitation occurs as in general excitable tissue, and a strong contractile force, ie, a spasm (spasticity) is locally generated. Spam in the coronary arteries, cerebral arteries, and bronchial smooth muscle is said to cause diseases such as angina pectoris, cerebrovascular disorders, and asthma, and Κ channel activators are considered to be useful in treating and preventing them. You.

Conventionally, compounds having a κ ⁺ channel activating effect are disclosed in There is known a 6-cyano 4- (2-oxo-1-pyrrolidinyl) -12H-1-benzopyran-13-yl derivative as disclosed in No. 58-86783. In addition, the present inventors have previously found that a 2H-1,4-benzoxazine derivative having a structure different from that of the above compound has a strong K + channel activating effect, and a patent application has already been filed. (Japanese Unexamined Patent Publication No. 4-1787375). Among them, 2- (3,4-dihydro-1,2,2-dimethyl-6-nitro-1H, 1,4-benzoxazine-14-yl) pyridine N-oxide (hereinafter abbreviated as 2,2-dimethyl form) Is attracting attention as an excellent compound. Research and development of compounds that are comparable to the above compounds is still active, and there is still a demand for the development of excellent K + channel activators.

The present inventors have further studied 2H-1,4-benzoxazine derivatives, and surprisingly found that the main metabolite, 2- (3, 4-Dihydroxy-2-hydroxymethyl 1-2-methyl-6-nitro-2H-1, 4-benzoxazine-14-yl) Pyridine-1-oxide is comparable to the 2,2-dimethyl form of K + They found that they exhibited channel activating action and had characteristics of a favorable pharmacological profile as a K ⁺ channel activator, and that derivatives with this as the core were also excellent Κ + channel activators. They have found and completed the present invention.

That is, the present invention relates to a benzoxazine derivative represented by the following general formula (I), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof.

(The symbols in the formula represent the following meanings.

R ^{1 is a} hydrogen atom, a lower alkyl group, a lower alkanoyl group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group, or a nitro group;

R ² : lower alkyl group,

R ³ : nitro group,

m: an integer from 1 to 4,

n: 0 or 1. )

Pharmaceuticals are generally metabolized in vivo by oxidation, reduction, hydrolysis, conjugation, etc., and are inactivated (detoxified), but the methyl at the 2-position of the 2,2-dimethyl form It was completely unexpected that the compound of the present invention exhibited a K + channel activating effect comparable to that of the 2,2-dimethyl form, despite the fact that the metabolite was converted to a hydroxymethyl group or a derivative thereof. Was.

Therefore, the compound of the present invention has the following partial structure _

CH 0 Conventionally, the 2H-1,4-benzoxadi derivative has a hydroxymethyl group, a lower alkoxymethyl group, a lower alkanoyloxymethyl group, a hydroxylamine methyl group, There is no known compound having a mono- or di-lower alkyl group rubamate methyl group or a nitratomethyl group. The pharmacological characteristics of the compound of the present invention are that it has a ^{τ τ} channel activating action comparable to the known 2,2-dimethyl form, and has a pharmacologically characteristic profile of its activity. .

The present invention also provides a benzoxazine derivative represented by the following general formula (II) or a salt thereof, which is useful as a production intermediate of the compound (I) and the like found in the above metabolite synthesis research and derivative research. _C included

(In the formula, R ¹ , R ² , R ³ and m have the above-mentioned meanings.) The feature of the intermediate of the present invention is that R ¹ -0-CH ₂ — is located at the 2-position of 2H-1,4-benzoxazine. And that the 4-position is unsubstituted. These compounds are also novel compounds that have not been published in the literature.

The present invention further provides a pharmaceutical composition comprising a benzoxazine derivative represented by the above general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a pharmaceutically acceptable carrier. included.

An object of the present invention is to provide a novel benzoxazine derivative (I) useful as a channel activator, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Another object of the present invention is to provide a pharmaceutical composition comprising a benzoxazine derivative (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof and a pharmaceutically acceptable carrier, particularly a κ ⁺ channel. In providing activators

A further object of the present invention is to provide a benzoxazine derivative (II) or a salt thereof, which is useful as an intermediate for producing the compound (II).

Hereinafter, the compound of the present invention will be described in detail.

In the definition of the general formula in this specification, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.

Accordingly, as the “lower alkyl group”, specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group , Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3- Methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl Group, 1-ethylbutyl group, 0.2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl A pill group and a 1-ethyl-2-methylpropyl group. Among them, a C ₄ alkyl group, particularly a C 1, —C ₂ alkyl group, is preferred.

The “lower alkanoyl group” includes formyl group, acetyl group, pentionyl group, butyryl group, isoptyryl group, valeryl group, isobaric group Reriru group, Viva yl group, etc. Kisanoiru group and the like to a preference given d one C ₄ Arukanoiru group, the optimum d - a c ₃ alkanol I le group.

The term "mono- or di-lower alkyl rubamoyl group" means a group in which the lower alkyl group is mono- or di-substituted on the nitrogen atom of rubamoyl, specifically, for example, a methylcarbamoyl group, an ethylcarbamoyl group, or a propyl-powerrubamoyl group. Mono-lower alkyl group substituted with d-C ₆ alkyl group, such as a carbamoyl group, isopropyl carbamoyl group, butyl carbamoyl group, isoptyl carbamoyl group, pentyl carbamoyl group, isopentyl carbamoyl group, hexyl carbamoyl group; Symmetric type di-substituted with C, -C alkyl groups such as dimethylcarbamoyl group, getylcarbamoyl group, dipropyl-lubamoyl group, diisopropyl-lrubamoyl group, dibutylcarbamoyl group, dipentylcarbamoyl group, and dihexylcarbamoyl group Different C, -Cs such as di-lower alkyl rubamoyl, ethylmethylcarbamoyl, methylpropyl rubamoyl, ethylpropyl rubamoyl, butyl methylcarbamoyl, butylethylcarbamoyl, butylpropyl carbamoyl, etc. Examples include asymmetric dialkyl rubamoyl groups di-substituted with alkyl groups, among which mono-substituted with C, alkyl groups or di-lower alkyl rubamoyl groups, particularly mono-substituted with C, -C alkyl groups. — Or a di-lower alkyl group rubamoyl group is preferred.

The compounds (I) and (II) of the present invention may form an acid addition salt. The present invention also includes pharmaceutically acceptable salts of compound (I) and salts of compound (III), such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Inorganic acids such as acids (especially mineral acids) Formic acid, acetic acid, Propionic acid, butyric acid, valeric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, lingic acid, tartaric acid, carbonic acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamate, etc. Acid addition salts with organic acids can be mentioned.

Further, the compounds (I) and (II) of the present invention contain an asymmetric carbon atom, and there are optical isomers (optically active, racemic, diastereomers, etc.) based on the presence of the asymmetric carbon atom. The present invention includes isolated isomers such as optical isomers and mixtures thereof.

Further, the compounds (I) and (II) of the present invention may be isolated as hydrates, various solvates or polymorphic substances, and the present invention also includes these substances.

Among the compounds of the present invention, a compound particularly useful as a K + channel activator is represented by the following general formula (ΠΙ) or (IV)

(Wherein, R ¹ , R ² , R ³ and m have the above-mentioned meanings, and R ⁴ is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a carbamoyl group, or a mono- or di-lower alkyl group. Lubamoyl means tomb.)

₂ 0— NO (In the formula, R ² , R ³ and m have the above-mentioned meanings.)

Or a pharmaceutically acceptable salt thereof, or a stereoisomer compound group thereof.

In particular, as the compound (m), a compound in which R ⁴ is a hydrogen atom, a lower alkyl group or a lower alkanoyl group, and m is 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, As the compound (W), a compound in which m is 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof is preferable, and particularly preferable compounds include the following.

(1) 2 — (3,4 —dihydro-1 2 —hydroxymethyl-1 2 —methyl-1 6 —nitro-1 2H—1,4 —benzoxazine-1 4-yl) pyridin — 1-oxide A pharmaceutically acceptable salt or a stereoisomer thereof.

(2) 2 — (3,4 dihidro 2 — methoxymethyl 1 2 — methyl — 6 — nitro 2 H — 1, 4 1 benzoxazine 1 4 — yl) pyridine 1 1 oxide, its pharmaceutical manufacturing Or a stereoisomer thereof.

(3) 2 — (3,4 dihidro 2 —acetoxymethyl 1 2 —methyl 1 6 —ditro 2 H—1,4 1-benzoxazine 1 4 1-) pyridin 1 1-oxide, its pharmaceutical A physiologically acceptable salt or a stereoisomer thereof.

(4) 2 — (3, 4 — dihydro 1 2 — 2-trimethyl 1 2 — methyl 1 6 — nitro 1 2 H— 1, 4 — benzoxazine 1 4 — yl) pyridin — 1 monooxide Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

Among the compounds of the present invention, compounds particularly useful as intermediates include those described above. Particularly useful compounds each having a substituent corresponding to the target compound group, that is, a compound in which R ¹ is a hydrogen atom, a lower alkyl group, a lower alkanol group, or a nitro group, and the 1-position is unsubstituted (Π) Or a salt thereof. In particular, 3,4-dihydroxy-12-hydroxymethyl-2-methyl-6-nitro-12H-1,4-benzoxazine is a preferred compound.

(Manufacturing method)

The compound of the present invention can be produced by applying various synthetic methods utilizing characteristics based on the basic skeleton or the type of the substituent. The typical production method is shown below.

First production method (N-alkylated A)

(V) (VI)

(I)

(Wherein, R ¹ , R ² , R ³ , m and n have the above-mentioned meanings, and X represents a halogen atom or an organic sulfonic acid residue.)

The compound (I) of the present invention is an N-unsubstituted benzene represented by the general formula (V). The compound can be produced by a conventional N-alkylation method in which a dioxazine derivative is reacted with a pyridine represented by the general formula (VI) or a halide or sulfonate of the N-oxide thereof.

Here, the halogen atom represented by X includes an iodine atom, a bromine atom, a chlorine atom, a fluorine atom, and the like, and the organic sulfonic acid residue includes an alkyl sulfonyloxy group, an ethanesulfonyloxy group, and the like. Examples include arylsulfonyloxy groups such as a killsulfonyloxy group ゃ benzenesulfonyloxy group and toluene (particularly p-toluene) sulfonyloxy group.

Reactions using halide as the starting compound (VI) include N, N-dimethylformamide, dimethylsulfoxide, acetone, methylethylketone, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, chloroform, ether, tetrahydrofuran, In an organic solvent or water inert to the reaction such as dioxane, or water, or a mixed solvent thereof, use a compound (V) and (VI) in a substantially equimolar amount or in a slightly excess molar amount at room temperature or under heating. It is advantageous to carry out the process at a heating or reflux temperature.

For the reaction, secondary or tertiary bases such as pyridine, picoline, N, N-dimethylaniline, N-methylmorpholine, trimethylamine, triethylamine and dimethylamine, sodium hydride, sodium hydroxide, When it is advantageous to add an inorganic base such as potassium hydroxide, n-butyllithium, potassium, t-butoxide, carbonated lime, sodium carbonate, sodium hydrogencarbonate, etc. for the smooth progress of the reaction is there.

The reaction using sulfonate as the raw material compound (VI) may be carried out in a solvent inert to the same reaction as described above, in the same amount as described above, and under cooling. Is preferably carried out at room temperature. In any of the reactions, the reaction time is appropriately set in consideration of various reaction conditions.

In the raw material compound (V), the hydroxymethyl compound (Va) in which R ¹ is a hydrogen atom is obtained by reacting a 0-aminophenol derivative (W) and a halogenomalonate diester (H ) To reduce the 2-alkoxycarbonyl-2-oxobenzoxoxazine derivative obtained by cyclization. The substituted oxymethyl compound (Vb) in which R ¹ is another substituent may be prepared by introducing a hydroxymethyl compound (Va) as a raw material compound and, if necessary, introducing an amino-group-protecting group. It can be produced by treating in the same manner as described above and removing the protecting group as necessary.

(ΥΠ)

(K)

Vapour

(R

(Va) (Wherein, R ² , R ³ , and m have the above-mentioned meaning, Y is a halogen atom, and R ⁵ and R ⁶ are the same or different and represent an ester-forming group.) Examples of the halogen atom are the same as those described above. The ester-forming group represented by R ⁵ and R ⁶ may be any ester-forming group that does not inhibit the cyclization or reduction reaction. And ethyl groups are common.

The former reaction is usually performed with N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, ether, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform, benzene, toluene, xylene, etc. In an organic solvent which is inert to the reaction, a reaction-corresponding amount or one of them is used in a slight molar excess, preferably potassium fluoride, sodium amide, sodium hydroxide, barium oxide, silver oxide, trimethylamine, triethylamine, or the like. In the presence of an alkali metal such as sodium hydride, potassium hydride, potassium t-butoxide, a metal reagent such as a metal alcoholate, a base such as potassium carbonate or a copper catalyst such as copper, copper iodide, copper sulfate, etc. Perform under cooling, room temperature, or heating, depending on various reaction conditions. It is.

The latter reduction is preferably carried out using a reducing agent that selectively reduces the carbonyl group to a methylene group without reducing the nitro group. Such a reducing agent is preferably a borane reducing agent, Preferably, a borane-tetrahydrofuran complex is used. The reduction using the complex is advantageously performed by adding the compound (K) or the reaction solution of the preceding step to a tetradrofuran solution of the complex and heating and refluxing the mixture.

(Va)

(1) If necessary,

Introduction of protecting group to amino group

(2) Production methods 2 to 7 below (Vb)

Same treatment

(3) Removal of protecting group if necessary

(In the formula, R ² , R ³ and m have the above-mentioned meanings, and R ⁷ represents a lower alkyl group, a lower alkanoyl group, a rubamoyl group, a mono- or di-lower alkyl rubamoyl group.)

The amino-protecting groups used here include benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-methylbenzyloxycarbonyl, Nitrobenzyloxycarbonyl group, p-phenylazobenzyloxycarbonyl group, p-methoxyphenylazobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, 3,4,5- Urethane types such as trimethoxybenzyloxycarbonyl, tert-butoxycarbonyl, tert-amyloxycarbonyl, p-biphenylisopropyloxycarbonyl, and diisopropylpyrmethyloxycarbonyl Protecting groups, formyl group, acetyl group, trifluoroacetyl group, phthalyl group, , O-ditrophenylsulfenyl, P-methoxy-0--2-trophenylsulfenyl, benzoyl, chloroacetyl, and other acyl-type protecting groups, trityl, benzyl Alkyl-type protecting groups such as, 2-benzoyl-1-methylvinyl and trimethylsilyl groups, and arylidene-type protecting groups such as benzylidene and 2-hydroxylylidene. And a phthalimid group to be formed.

The reaction is carried out according to the method described later in the production method.

The elimination of the protecting group is carried out by applying a conventional method, and differs depending on the kind of the protecting group.

For example, when the protecting group of the amino group is a substituted or unsubstituted benzyloxycarbonyl group, catalytic reduction is suitable, and in some cases, hydrobromic acid Z acetic acid, hydrobromic acid Z trifluoroacetic acid, Acid treatment with hydrofluoric acid or the like is used. Other urethane-type protecting groups such as tert-butoxycarbonyl group are advantageous to acid treatment with hydrobromic acid / acetic acid, trifluoroacetic acid, hydrochloric acid, hydrochloric acid Z-acetic acid, hydrochloric acid / dioxane, or the like.

Second production method (etherification)

(R

(I a)

(Wherein, R ² , R ³ , m, n and X have the above-mentioned meanings, M represents a hydrogen atom or an alkali metal, and R ⁸ represents a lower alkyl group.) In the compound of the present invention, The alkoxymethyl compound represented by (lb) is obtained by reacting the corresponding hydroxymethyl compound (la) or its alkali metal-substituted product with a halide or a sulfonate (X) by a conventional method. Can be manufactured.

In addition, examples of the alkali metal include sodium and potassium.

This etherification reaction is almost the same as the N_alkylation in the first production method, and in the same solvent as in the first production method, in the presence of the same base when no alkali metal-substituted compound is used as the compound (la). The treatment is carried out in the same manner as in the first production method, if necessary, in the presence of a catalyst. Third production method (esterification) (R

(Ic) or its activated derivative or its activated derivative

(Id) (wherein, R ² , R ³ , m and n have the same meanings as described above, and R ⁹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.) Wherein the ester represented by the general formula (Id) is obtained by converting an alcohol of the general formula (Ic) or an activated derivative thereof with a carboxylic acid of the general formula (XI) or an activated derivative thereof by an ordinary method. Can be manufactured by

Here, as the activated derivative of compound (Ic), a salt or a halide or a sulfonate in which OH is X is used. As an activation inducer of compound (XI), its salt, acid chloride or acid bromide is used. Acid halides such as acid anhydrides; ordinary esters such as methyl esters and ethyl esters; and the like are preferably used. ''

When reacting the starting compound (XI) with free carboxylic acid It is advantageous to carry out the reaction in the presence of a condensing agent such as chlorohexylcarbodiimide.

The reaction is carried out by a conventional method, and although it differs depending on the starting compound, particularly the type of the activation derivative, usually, an organic solvent similar to that in the first production method is used in an amount corresponding to the reaction or an excess amount of one of them. In the presence of an acid catalyst such as a mineral acid such as hydrochloric acid, an organic acid such as aromatic sulfonic acid, or a Lewis acid such as boron fluoride ester, use a Dean-Stark azeotropic dehydrator if necessary, or use a desiccant. While the water generated by the addition of water is removed from the system, and while the hydrogen halide or the like generated by the reaction is trapped by adding the same base as in the first production method, the reaction is carried out at room temperature to under heating or at the boiling point of the solvent. It is advantageous to carry out the method below. _C Fourth manufacturing method (Carbamate)

(In the formula, R ² , R ³ , m, n and M have the above-mentioned meanings, and R ^IQ means a hydrogen atom or a lower alkyl group.) In the compound of the present invention, the ester ester of the formula (Ie) is converted to an alkali metal cyanate of the formula (ΧΠ) or an isocyanate of the formula (ΧΠΙ), It can be easily produced by adding the alcohol of (1).

The reaction is carried out in the same solvent as in the first production method, using the corresponding reaction amount or one of them in a slightly excessive molar amount.When using isocyanate, the base described in the first production method such as triethylamine or pyridine is used as a catalyst. When using an alkali metal cyanate, it is advantageous to add an acid such as trifluoroacetic acid and carry out the reaction under cooling to room temperature.

Method 5 (N-alkylation B)

(I e) (XIV)

(Wherein, R ² , R ³ , m, n, R ¹ ° and X have the above-mentioned meanings, R is a lower alkyl group, R ¹² is the same group as R ^1Q or the same group as R ¹¹ And -R ¹³ represents the same group as R ^11. ) In the compound of the present invention, the mono- or di-lower alkyl carbamic acid ester represented by the general formula (if), when the carbamic acid ester (Ie) obtained by the fourth production method is used as a raw material, It can also be produced by subjecting the halide or sulfonate of the general formula (XIV) to N-alkylation by a conventional method.

The reaction conditions and the like are the same as in the first production method. When producing a mono-lower alkylcarbamate ester (If) from a compound of a hydrogen atom (Ie) as a raw material, if necessary, a protecting group for suppressing tertiary conversion, for example, toluenesulfonyl Efficient production can be achieved by introducing and reacting an oxy group, a phenylsulfonyl group, a trifluoromethanesulfonyl group, a bisbenzenesulfonyl group, an acetyl group, and then removing the protecting group. .

Sixth production method (nitration A)

Nitrating agent

(I c)

(Wherein, R ² , R ³ , m and n have the meanings described above.) Among the compounds of the present invention, a compound having a methylatomethyl group at the 2-position (Ig) Can be produced by reacting a corresponding hydroxymethyl compound (Ic) with a nitrifying agent under controlled temperature to selectively dinitrogenate only at the 2-position.

As the nitrating agent, various conventional nitrating agents can be used. For example, concentrated nitric acid, fuming nitric acid, concentrated nitric acid + concentrated sulfuric acid, fuming nitric acid + acetic acid, nitronium tetrafluoroborane, and the like are preferable. Preferred examples thereof include nitrous oxide tetrafluoroborane.

The nitration reaction is usually carried out without solvent, but N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, hexamylphosphoramide, ether, dioxane, tetrahydrofuran, methylene chloride, dichloroethane, chloroform, benzene, The reaction may be carried out in an organic solvent inert to the reaction, such as toluene or xylene.

The reaction temperature is preferably between −40 ° C. and −35 ° C.

The seventh manufacturing method (Nitroi B)

Nitrifying agent

(XV)

N → (0) „

(R ³ )

(Wherein, R ¹ , R ² , R ³ and n have the above-mentioned meanings, R ¹⁴ is a hydrogen atom or a nitro group, ^ is 1 or 2, R ¹⁵ is a lower alkyl group, a lower Means an alkanoyl group, a carbamoyl group, a mono or dialkyl lower labamoyl group, or a nitro group.)

Among the compounds of the present invention, the compound (I h) having one or two ditoxyl groups on the aromatic ring of benzoxazine can be produced by reacting the compound (XV) with a ditrophy agent under control of the reaction temperature.

Preferable examples of the diluting agent and the reaction conditions other than the reaction temperature such as the reaction solvent are the same as those in the sixth production method, except that the reaction temperature of the aromatic ring diboration of benzoxazine is from −10 ° C. 0 ° C is preferred.

When a compound in which R ¹ is a hydrogen atom is used as a starting material, the 2-hydroxymethyl group is also nitrated and converted to a nitratomethyl group as in the sixth production method.

Other manufacturing methods

In the compound of the present invention, the pyridine N-hydroxy oxide compound can be easily produced by oxidizing the corresponding pyridine compound.

Oxidation is carried out by a conventional method in which an oxidizing agent is added in an organic solvent inert to the reaction, such as methylene chloride, dichloroethane, black form, carbon tetrachloride, or alcohol such as methanol, at room temperature or under heating. The oxidizing agent can be m-chloroperbenzoic acid, perbenzoic acid, formic acid, pertrifluoroacetic acid, perphthalic acid, permaleic acid, organic peracid such as peracetic acid, hydrogen peroxide, etc. Inorganic peracids such as perphosphoric acid, chromic anhydride, sulfuric acid peroxide, and sulfuric acid peroxide are used.

In the compound of the present invention, the carbamic acid ester compound is

'· R ^{1 6,} and the Production Process another, third production method similar to compound (I c)> NHC00H

R ¹ (R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom or a lower alkyl group) or its activated derivative such as an acid halide, or is reacted with the halogenoformate of the compound (Ic). , ammonia, or mono-mono- or di-lower Arukiruami down a reaction product obtained by _c above process can be prepared by applying conventional methods Kabame one Bok prepared by condensation reaction of the free compound It is isolated and purified as its salts, hydrates or various solvates. The salt can be produced by subjecting it to a usual salt formation reaction.

Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.

As described above, in the compound of the present invention, a racemic compound in which isomers such as a racemate, an optically active substance, and a diastereomer are present alone or as a mixture may be used by using an appropriate raw material compound or a general compound. By the racemic resolution method [for example, a diastereomer monosalt with a general optically active acid (tartaric acid, etc.) and a method of optical resolution] can be led to stereochemically pure isomers. The mixture of diastereomers can be separated by a conventional method, for example, fractional crystallization or chromatography. Industrial applicability

The compound of the present invention such as the compound (I) of the present invention, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof has a K + channel activating action comparable to that of the 2,2-dimethyl form. Circulatory system including ischemic heart disease such as angina pectoris and myocardial infarction, hypertension (arteriosclerosis, obesity and dyslipidemia), congestive heart failure, arrhythmia and peripheral vascular disorders (alopecia etc.) It is useful as an agent for preventing and treating diseases. In addition, the compounds of the present invention can be used for cerebrovascular disorders (cerebral vasospasm, migraine and dizziness, etc.), respiratory disorders (reversible airway obstruction, irritable airway obstruction, asthma, etc.), digestion, etc. Systemic disorders (ulcers, nervous gastrointestinal disorders, irritable bowel disorders and diverticulum disorders and bile duct obstruction, etc.)

(Inner ear modulation, auditory organ modulation, glaucoma, weak vision and intraocular hypertension, etc.), urinary disorders (renal failure, disorders associated with the passage of kidney stones, pollakiuria, dysuria, incontinence, etc.) and genital disorders ( It is also useful as a therapeutic agent for various disorders associated with smooth muscle contraction, such as premature birth and dysmenorrhea. Further, the compound of the present invention is also useful as a therapeutic agent for disorders based on abnormal blood sugar levels (hypoglycemia, diabetes, etc.) and abnormalities in the cardiac stimulation conduction system (arrhythmias, etc.). Further, the compound of the present invention has a pharmacologically characteristic profile for its K + channel activating action. For example, the compound of which R ¹ is hydrogen atom may also _c are particularly excellent in durability of the K + channel activating activity, the compounds R ¹ is a nitro group, in addition to K ⁺ channel activating effect, nitrates It has been confirmed that it also has the action of nitroglycerin (like nitroglycerin). Therefore, at present, there is a demand for a drug that imparts a new advantage to the Κ + channel activating action in the relevant region, and at present, the compound of the present invention is used as a characteristic preventive or therapeutic agent for the above-mentioned circulatory diseases and other diseases. It is useful as providing a more favorable effect.

On the other hand, the compound (II) of the present invention and a salt thereof are excellent compounds of the benzoxazine skeleton having a substituted or unsubstituted hydroxymethyl group at the 2-position such as the compound (I) useful as an excellent channel activator. Useful as an intermediate. The synthetic route from the compound (II) and its salt to the compound (I), its pharmaceutically acceptable salt and its stereoisomer is as described above.

The pharmacological effect of the compound of the present invention is confirmed by the following test methods. Test method (1) K ⁺ channel opening action

The experiments were performed by Uchida and Sugimoto et al. [Yasumi Uchida, Tsuneaki Sugimoto: 3,4-Diaminopyridine-induced cyclic contraction of coronary artery smooth muscle, vasculature, 24,

1 3 3-1 4 3, 1 9 8 4.] That is, male and female hybrid dogs were anesthetized by intravenous administration of 30 rag / kg of pentobarbital, and then bled to death, and the heart was isolated. 95 The circumflex branch or anterior descending branch of the left coronary artery was excised in Krebs-Henselit solution aerated with a mixed gas of 95% oxygen and 5% carbon dioxide, and a ring specimen about 2 IM1 in width was prepared. The specimen is

The suspension was suspended in a Magnus bath filled with Krebs-Henselit solution aerated with a mixture gas of 95% oxygen and 5% carbon dioxide, and kept at 37 ° C. Specimens were placed under 1 g of tension and allowed to stabilize for 30 minutes before cyclic contraction was induced by treatment with 3,4-diaminopyridine (1 OmM). Test compounds from the point of contraction height and contraction frequency of the periodic contraction is substantially stable cumulatively added to obtain the concentration first working curve of contraction frequency, 5 0% inhibition concentration (IC _5. Value) than the effect Was determined.

Representative examples are shown in Table 1.

Table 1 K + channel opening action

(The value is the average of 4 to 7 patients.) Test method (2) Effects on cardiovascular system and persistence

Male and female hybrid dogs were anesthetized by intravenous administration of pentobarbital 3 OmgZkg, and then the tracheal intubation was performed and the experiment was performed under artificial respiration. Under the thoracotomy, the heart The pulse, blood pressure, left ventricular pressure, left ventricular pressure maximum rise rate, pulmonary artery pressure, central venous pressure, cardiac output, and coronary artery blood flow were measured. The test compound was administered from a force neurator placed in the femoral vein, and the effect was determined.

Representative examples are shown in Table 2. The column (1) in Table 2 shows the dose (g / kg iv), mean blood pressure (MBP) lowering effect and coronary artery blood flow (CB F.) increasing effect from the pre-dose value (△%). However, column (2) shows the duration of action at that time. Table 2

(Values are average values of 4-5 cases.) Test method (3) Vasodilatory effect (evaluation of glycerin-like effect in human mouth) Male and female Japanese white rabbits (2-3 kg) were bled to death, and their chest was removed. The aorta was removed. After removing fat and connective tissue, a ring specimen with a width of about 3 mm was used. After removing the endothelium, it was suspended in a Magnus bath. The Magnus bath was filled with Krebs-Henselit solution aerated with a mixture of 95% oxygen and 5% carbon dioxide, and the temperature was maintained at 37 ° C. Tensioned 1 g of the sample, the experiment was started from so substantially constant shrinkage is obtained by Fuwenirefuri emissions (1 0- ⁷ M). After stable contraction was obtained by the addition of phenylephrine, the test compound was added cumulatively. In addition, antagonism with methylene blue is less likely to contract with phenylephrine. After was boss, administered methylene blue ^{(3 X 1 0- 6 g /} ml), contraction was added test compound after stable cumulatively. Relaxation calculates the relaxation by Papaberi switch (1 0 one ⁴ M) as 1 0 0% to determine the effect than the concentration that express a 50% relaxation operation (IC _5. Value).

Representative examples are shown in Table 3. Table 3

(The values are the average values of two cases.) The compound of Example 7 relaxed the above-mentioned funinirefrine contraction in a concentration-dependent manner. It is considered to have a nitroglycerin-like vasorelaxant effect as it undergoes significant suppression during treatment.

The compound of the present invention has an excellent K channel activating action comparable to that of the 2,2-dimethyl form, and also has an excellent pharmacological profile.

For example, as can be seen from the results in Tables 1 and 2, the compound of Example 1 exhibits the same Κ + channel opening action as the 2,2-dimethyl form, and has a greater effect than the 2,2-dimethyl form. And its remarkable duration of action.

In addition, for example, the compound of Example 7 has a channel opening action similar to that of the 2,2-dimethyl form, as is clear from the results in Tables 1 and 2, and has a ditroglycerin-like blood vessel. It is considered to have a relaxing effect. Pharmaceutical compositions containing one or more of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a commonly used carrier for pharmaceutical preparations and excipients. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches, etc., using tablets and powders, orally or parenterally. The clinical dose of the compound of the present invention administered to a human is appropriately determined in consideration of the symptoms, weight, age, sex, etc. of the patient to which the compound is applied. It is 0.01 to 10 Omg, which is administered once or in several divided doses. Since the dose varies under various conditions, a dose smaller than the above dose range may be sufficient.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances include at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, It is mixed with polyvinylpyrrolidone and magnesium aluminate metasilicate. In accordance with the usual methods, the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, glutamate. It may contain a solubilizing or solubilizing agent such as acid or aspartic acid. If necessary, tablets or pills may be coated with a film of an enteric substance, such as sucrose, gelatin, hydroxypropylcellulose, or hydroxypropylmethylcellulose phthalate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified water , Including ethanol. This group The composition may contain, in addition to the inert diluent, solubilizing or solubilizing agents, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of aqueous diluents and suspension diluents include distilled water for injection and physiological saline. As diluents for non-aqueous solutions and suspensions, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (products) Name). Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing aids. Good. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited at all by these examples. The starting compounds of the present invention also include novel compounds, and their production examples are shown as intermediate production examples.

Formulation example 1 (tablet)

Compound A of the present invention 0.1 rag

Lactose 6 3 mg

Cornstarch 1 6 rag

0.9 mg of magnesium stearate

80 mg After uniformly mixing the compound A of the present invention, lactose and corn starch, the mixture is wet-granulated with a corn starch binder. Furthermore, after mixing magnesium stearate, it is compressed into tablets.

Prescription example 2 (injection)

Fill the ampoule with the following ingredients, seal, and sterilize at 115 ° C for 30 minutes to prepare an injection.

Ingredient per lml

Compound B of the present invention 50 ng

Sodium chloride 9 rag

Make up to 1 ml with water for injection.

Example 1

2- (3,4-dihydro-2-hydroxymethyl-1-2-methyl-6-nitro-2H-1,4-benzoxazine_41-yl) pyridin-1-oxoxide

〇 ₂ N

3,4-dihydroxy 2—hydroxymethyl-1-2-methyl-6 To a mixture of 1.7 g of trolley 2 H—1,4-benzoxazine, 10 ml of dimethylformamide, and 1.6 g of 2-bromopyridine-11-oxide, was added sodium hydride under ice-cooling. After slowly adding 0.74 g, the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, concentrated under reduced pressure, and water and ether were added to the residue to precipitate crude crystals. The crude crystals were recrystallized from methanol / ethanol and then from methanol / chloroform to obtain 1.3 g of the desired compound.

(i) Melting point 189-19-11 ° C

(ϋ) Elemental analysis (CH ^ Ns 0 ₅ )

C (%) H (%) N (%) Calculated 56.7 8 47 6 1 3.2 4 Actual 56.5 5 4.7 2 13.0 5

(iii) ^ -NMR (DMS O-de)

δ p p m;

1.3.3 (3 H, s), 3.46 to 3.8 (4 Η, m),

6.94 (1 H, d, J = 3 H z),

7.03 (1 H, d, J = 9 Hz),

7.33 to 7.3.8 (1H, m), 7.45 to 7.49 (1H, m) 7.64 (1H, d, J = 7Hz),

7.7 1 (1 H, d d, J = 3, 8 H z), 8.39 (H, m) Example 2

2- (3,4-Dihydro-1--2-methyl-6-methyl-6-nitro-1,2-di-1,4-benzoxazine-1-41) Pyridine — 1-year-old oxide hydrochloride

2-(3, 4-Dihydro 2-Hydroxymethyl-2-Methyl-6-Nitroguchi _ 2H-1, 4-Benzoxazine 14 -yl) Pyridin-1-Oxide 0.2 g of dimethylforma The solution was dissolved in 2 ml of mid, and 0.05 g of sodium hydride (60% oil) was added, followed by 0.227 g of methyl iodide. After stirring at room temperature for 15 minutes, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to chromatography (eluent: ethyl acetate: methanol = 20: 1) to obtain a crude product of the target compound. This was dissolved in chloroform and treated with hydrogen chloride (ethyl acetate solution) to make the system acidic, followed by concentration under reduced pressure. The residue was crystallized from ethanol ether to obtain 0.22 g of the desired compound.

(i) melting point 140-143. C

(ii) Elemental analysis (C ₁₆ H ₁₈ N ₃ OBC 1) C (%) H (%) N (%) CI (%) Calculated 52.2 5 4.9 3 11.4 3 9.6 4 Actual 52.2 5 4.8 8 1 1.4 2 9.7 3

(iu) 'Η-NMR (DMS 0- d ₆ )

δ p p m no;

1.3 5 (3H, s), 3.24 (3H, s),

3.4 9 (2 H, A B q, J = 10 0 H z),

3.7 4 (2 H, A B q, J = 1 3 H z),

7.0 8 (1 H, d, J = 9 H z),

7.3 7 to 7.40 (1 H, m), 7.5 3 7.5 6 (1 H, m) 7.6 9 to 7.75 (2 H, m), 8.4 4 8.4 5 (1 H, m) Examples 3 to 4

The following compounds were obtained in the same manner as in Example 2.

Example 3

2- (3,4-dihydro-2-ethoxymethyl-2-methyl-6 12 Toro-2H-1 14 Benzoxazine 1 4-yl) Pyridin 1 11-year-old oxide

(i) Amorphous powder

(ϋ) Elemental analysis (C ₁₇ H ₁₉ N ₃ 0 ₅ 0.75 Η 20)

C (%) H (%) Ν (%) Calculated 56.9 0 5.7 6 1 1.7 1 Measured 56.9 0 5.8 3 1 1.7 1

δ (p p m);

1.0 5 (3 H, t, J = 7 H z) 1.4 3 (3 H, s), 3.3 2 to 4.10 (6 H, m),

6.9 8 (1 H, d, J = 9 Hz) 7.2 to 7.4 (3 H, m)

7.5 1 (1 H, d, J = 2 H z),

7.8 0 (1 H, d d, J = 2, 9 H z), 8.37 (1 H, m) Example 4

2- (3,4-dihydro-1-methyl-6-nitro-1-nitro-2-propoxymethyl-2H-1,4-benzoxazine-1-yl) pyridin-1-oxoxide

(i) Amorphous powder

(ii) elemental analysis _{_{(C, 8 Η 2 ιΝ3 0}} • 0.2 5 H 2 0)

C (%) H (%) N (%) Calculated 59.4 1 5.9 6 1 1.5 5 Actual 59.2 8 5.9 4 11.5 4

(iii) 'H-NMR (CDC 1 a)

δ (p p m);

0.7 8. (3 Η, t, J = 7 Hz), 1.5 to: L58 (5H, m), 3.2 to 3.6 (4H, m), 3.81 (2H, AB q, J = 14Hz),

6.96 (1 H, d, J = 9 H z),

7.1 2 to 7.36 (3 H, m),

7.45 (1 H, d, J = 3 H z),

7.79 (1H, dd, J = 3, 9Hz), 8.33 (1H, m)

2- (3,4-dihydro-2-acetylaceoxymethyl-2-methyl-6-2-nitro2H-1,4-benzoxazine-14-yl) pyridin-1-oxoxide.

2- (3,4-Dihydroxy-1-hydroxymethyl-2-methyl-6-nitro-2H-1,4-benzoxazine-4-yl) pyridin-1-oxide 0.5 g in dimethylformamide Dissolve in 5 ml, — At 10 ° to 15 °, 0.19 g of sodium hydride (60% oil) was added, followed by 0.32 g of acetyl chloride, which was slowly added dropwise. After 15 minutes, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (eluent; chloroform: methanol = 1100: 1) to obtain 0.3 g of the desired compound as an amorphous powder.

(I) Elemental analysis _{_{_{(C 17 H 17 N 3 0}}} 6 · H 2 0)

C (%) H (%) N (%) Calculated 54 1 1 5.0 8 11.1 4 Actual 54.0 2 4.7 2 10.9 7

(ϋ) Ή-NMR (CDC ")

δ p p m);

1.4 5 (3H, s), 2.03 (3H, s),

3.8 1 (2 H, AB q, J = 1 4 H z),

42 0 (2 H, AB q, J = 1 2 H z),

6.9 9 (1 H, d, J = 9 H z),

7.1 7 ~ 7 ・ 4 0 (3 H, m),

7.4 8 (1 H, d, J = 3 H z),

7.7 9 (1 H, d d, J = 3, 9 H z),

8 30 to 8.36 (1H, m)

Example 6

2- [3,4-dihydro-2- (N-methylcarbamoylmethyl) -1-methyl-6-nitro-1 2H-1,4-benzoxazine-14-yl] pyridine-1-oxoxide

〇 ₂ N

NHCHs

2- (3,4-dihydroxy-1-2-hydroxymethyl-12-methyl-6-dimethoxy-2H-1,4-benzoxazine-14-yl) pyridin-1-oxoxide 0.2 g, methylene chloride To a mixed solution of 4 ml and 0.19 g of triethylamine was added 0.11 g of methyl isocyanate, and the mixture was stirred at room temperature for 22 hours.The reaction solution was poured into ice water, extracted with chloroform, and extracted with an organic layer. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (eluent; chloroform: methanol = 50: 1) to convert the target compound into an amorphous powder. 0.14 g was obtained.

(I) Elemental analysis _{_{_{(C 17 H 18 N 4 0}}} 6 - 0.5 H 0)

C (%) H (%) N (%) Calculated value 53.2 6 5.0 0 14.6 1 Actual measured value 53.2 2 5.0 5 142 7 (ii) ^X H-NMR (CDC ")

δ (pm);

1.4 4 (3 H, s), 2.7 3 (1.5 H x 2, s),

3.6 9 ~ 41 8 (4 H, m),

7.0 0 (1 H, d, J = 9 H z),

7.2 0 ~ 7.4 9 (4 H, m),

7.8 1 (1H, d, J = 9Hz), 8.33 (1H, m) Example 7

2-[3,4-Dihydro-1-nitro-methyl-1-2-methyl-6-nitro-1H-2, 1,4-benzoxazine-1-4-yl) pyridin-1-oxide

0 ₂ N

2- (3,4-dihydro-2-hydroxymethyl-2-methyl-6-nitro-1H- 1,4-benzoxazine-14-yl) pyridin-11-oxide 2 g, acetonitrile 50 ml One in mixed solution 35 ° C to −40. After C, 1.26 g of ditronium tetrafluoroborane was slowly and carefully added over 30 minutes, and the reaction solution was poured into ice water. Saturated aqueous sodium hydrogen carbonate was added to make the system alkaline, and the solution was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (eluent, black form) to obtain a crude product of the desired compound. The crystal was recrystallized from getileru to give 0.74 g of the desired product.

(i) Melting point 156-158 ° C

(ii) Elemental analysis _{_{_{(C 15 H 14 N 4 Οτ}}} )

C (%) H (%) N (%) Calculated 49.7 3 3.8 9 15.4 6 Actual 49.6 1 3.8 3 15.3 1

(iii) ¹ H-NMR (CDC ")

δ (p p m);

1.5 2 (3 H, s), 3.8 3 (2 H, AB q, J = 13 H z),

4.6 7 (2 H, AB q, J = 1 2 H z),

7.0 1 (1 H, d, J = 9 H z),

7.2 4 to 7.27 (1H, m), 7.38 to 7.43 (3H, m), 7.79 (1H, dd, J = 3, 9Hz),

8.3 3 to 8.34 (1 H, m)

Example 8

2- [3,4-Dihydro-2-nitromethyl-6,7-dinitro2H-1,4-Benzoxazine-1-yl) Pyridine-1 1-year-old oxide. 0 ₂ N

2-(3,4-dihydroxy-1-hydroxymethyl_2-methyl-6-nitro2H-1,4-benzoxazine-4-yl) pyridin-1-oxoxide 0.4 g, acetonitrile 10 m 1 At 110 ° C. to 0 ° C., 0.45 g of nitronium tetrafluoroborane was added to the mixed solution over 30 minutes, and the reaction solution was poured into ice water. After adding saturated sodium bicarbonate water to make the system more viscous, the system was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude target product. Recrystallization from ethyl acetate-ethanol gave 0.16 g of the desired compound.

(i) Melting point 156-159 ° C

(ii) Elemental analysis (Ci ₅ H ₁₃ N ₅ 0 ₉ )

C (%) H (%) N (%) Calculated 44.2 3 3.2 2 17.1 9 .Measured 440 9 3.2 3 17.1 9

(iii) Ή-NMR (DMS 0- d ₆ ) δ (pp Li);

1.4 5 (3 H, s), 3.90 (2 H, AB q, J = 13 Hz), 4.77 to 4.87 (2 H, m), 6.93 (1 H, s),

7.4 1 to 7.5 2 (2 H, m), 7.7 1 to 7.74 (2 H, m),

8.4 0〜8.4 2 (1 H, m)

Intermediate production example

a) Ethyl 2- (3,4-dihydro-2-methyl-16-nitro-3-oxo-2H-1, 4-benzoxazine) carboxylate

A mixed solution of 6.0 g of potassium fluoride, 30 ml of dimethylformamide, 10 g of ethyl 2-bromo-2-methylmalonate, and 6.1 g of 4-nitroaminophenol was added at room temperature for 16 hours. After stirring, the reaction solution was poured into ice water. Ethyl acetate was added for extraction, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and ethanol was added to obtain 8.7 g of the desired product as crystals. (i) Melting point 170-172 ° C

(ii) Elemental analysis (C 12 H 12 N 2 0 6)

C (%) H (%) N (%) Calculated 51.4 3 4.3 2 10.0 0 Actual 51.4 1 4.3 9 10.0 4

δ (p p m);

1.2 1 (3 H, t, J = 7 Hz) 1.9 5 (3 H, s), 4.2 1 (2 H, q, J = 7 Hz),

7.17 (1 H, d, J = 9 H z),

7.8 5 (1 H, d, J = 3 H z),

7.9 6 (1 H, d d, J = 3, 8 H z),

9.6 6 (1 H, b r s)

b) 3,4-Dihydroxy 2-hydroxymethyl-1-methyl 6-dinitro 2 H-1,4-benzoxazine

A solution of the borane-tetrahydrofuran complex in tetrahydrofuran (1 M) was added to 0 ml of ethyl 2- (3,4-dihydro-2-methyl) under ice-cooling. After addition of 2.8 g of carboxylate, the solution was refluxed for 4 hours. After cooling, 24 ml of methanol was gradually added, and the mixture was heated under reflux for 30 minutes. After cooling, 24 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 30 minutes. After cooling, the mixture was concentrated under reduced pressure, and an aqueous sodium hydroxide solution was added to make the system more viscous. The target product was obtained as crude crystals. Recrystallization from ethanol gave 0.9 g of the above compound.

(i) Melting point 125-127 ° C

(ii) Elemental analysis _{_{(C 1 () H 12 N}} 2 0 4)

C (%) H (%) N (%) Calculated 53.5 7 5.3 9 12.4 9 Actual 53.4 5 5.3 4 12.4 2

(iii) 'H-NMR (C D C 1)

δ p p m;

1.3 7 (3H, s), 3.30 (2H, ABq, J = 12Hz), 3.70 (2H, ABq, J = 12Hz),

6.8 4 (1 H, d, J = 9 H z),

7.5 3 to 7.68 (2H, m)

Other compounds of the present invention of Examples B-1 to B-65 are shown below in the form of a table in addition to the exemplified compounds described above. These compounds can be synthesized using the synthetic routes and methods described in the above schemes and examples, and modifications thereof known to those of ordinary skill in the art and require special experimentation. It does not do.

Example B

Example Example

R ¹ R ² m R ³ n

5E.

杳

B-1 -CH (CH ₃ ) ₂ -CH ₃ 1 6-NO2 2 1

2 -H one 1 H I, ri 〃〃〃〃

3 -CH ₃ 〃 // 〃〃

4 — し H りし i 〃〃〃〃〃

5 one (Shi Ηί) 1 Η // 〃〃〃〃〃

6 -Η ― (LH then H ς 〃〃〃

7-CH ₃ // 〃〃〃

8-CH 2 CH 3 〃〃〃 // y し 2 2 2 Π 3 /, //

10 -C0CH ₂ CH ₃ -CH ₃ 〃〃〃

11 -C0 (CH ₂ ) ₂ CH ₃ 〃〃〃

12 -C0CH ₃ -CH 2CH3 〃〃〃〃

13 〃-(CH2) 2CH3 〃〃

14 -C0NHCH ₂ CH ₃ -CH ₃ 〃〃

15 -C0NH (CH ₂ ) ₂ CH ₃ 〃〃〃

16 -C0N (CH ₃ ) ₂ no / 〃〃〃

17 -C0N (CH ₂ ) (CH ₂ CH ₃ ) 〃〃〃〃〃

18 -C0N (CH ₂ CH ₃ ) ₂ 〃〃〃〃〃

19 -CONHCH3-CH sCH 〃 // 〃〃

20-(CH2) 2CH3 〃〃〃〃

21 -H -CH ₃ 〃 5-NO2-〃〃

22 〃〃〃 7-N0 ₂ 〃〃

23 〃〃 8-N0 ₂ 〃〃

24 〃〃 2 5, 6-NO2 〃

25 〃〃 6, 7-NO2 〃〃 26 -H-CH ₃ 2 2 1

27 〃〃〃 Uj O liU 2 〃〃

28 〃〃 3 fi U, 7 R 0-MI nu _ft 2 〃〃

29-CH2CI CH3) 2 〃 1 D 1 \ U2 〃〃

30-C (CH ₃ ) ₃ 〃〃 // 〃〃

31 -CH (CH ₃ ) CH ₂ CH ₃ 〃〃〃〃

32 -H 〃〃, z 3 〃

33 -CH ₃ 〃〃〃〃

34 -COCHs 〃〃 // 〃〃

35 -C0NH ₂ 〃〃 // 2 〃

36 -CONHCH 3 〃〃 // 3 〃

37 -H 〃〃 7-NO 2 〃〃

38-CH ₃ 〃〃〃〃

39 -COCH3 〃〃〃〃〃

40 -CONHCH 3 〃〃〃〃〃

41 -H 〃〃 6-NO ₂ 2 0

42 -CH ₃ 〃 // 〃〃〃

43 -COCH3 〃 // 〃〃〃

44 -CONHCH 3 〃〃 0 0 〃〃〃

45 -NO 2-CH2 CH3 〃〃 O 〃 1

46 〃-(CH ₂ ) ₂ CH ₃ 〃〃〃〃

47 〃 CH ₃ 5-NO2 〃

48 〃〃〃 7-NO 2 〃〃

49 〃〃〃 8-NO 2 〃〃

50 〃〃 25, 6-NO2 〃

51 〃〃 5, 7-NO 2 〃

52 〃〃〃 5, 8-NU ₂ 〃〃

53 〃〃〃 0 λΤΠ

D, O-INU2 〃〃

54 〃〃 1, 8-I U2 〃〃

55 〃〃 30, D, NU2 〃

56 〃〃〃〃〃

57 〃〃 1 6-N0 ₂ 3 〃

58 undefined undefined undefined 7-N02 undefined undefined undefined undefined Q? 5,6-N0 ₂

60 〃〃〃 6,7-N0 ₂ -〃〃

61 〃〃〃 6,8-N0 ₂ 〃

62 〃〃 1 6-NO2 2 0

63 〃〃〃 7-N02 〃〃

64 〃 26, 7-NO2 〃

65 〃〃〃 6, 8-N0 ₂ 〃〃

Claims

Sought

1. A benzoxazine derivative represented by the following general formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.ー blue

(The symbols in the formula represent the following meanings.

R ^{1 is a} hydrogen atom, a lower alkyl group, a lower alkanoyl group, a rubamoyl group, a mono- or di-lower alkyl rubamoyl group, or a ditoxyl group;

R ² : lower alkyl group,

R ³ : nitro group,

m: an integer from 1 to 4

n: 0 or 1. )

2. The compound according to claim 1, represented by the following general formula (m), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

N → (0)

CH 2-0-R (Wherein R ¹ , R ² , R ³ and m have the above-mentioned meanings, and R ⁴ is a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a carbamoyl group, or a mono- or di-lower-alkyl lower labamoyl group) 3. The compound according to claim 1, represented by the following general formula (IV), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

(Wherein, R ² , R ³ and m have the above-mentioned meanings.)

4. The compound according to claim 2, wherein R ¹ is a hydrogen atom, a lower alkyl group or a lower alkanoyl group, and m is 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

5. The compound according to claim ₄ , wherein R ¹ is a hydrogen atom, a C, —C ₄ alkyl group, or a —C ₄ alkanol group, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

6. The compound according to claim 3, wherein m is 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

7. 2— (3,4-Dihydroxy-1-hydroxymethyl-2-methyl-6-nitro-2H-1,4-benzoxazine-14-yl) piri ■ Gin-1-oxide, its pharmaceuticals A physiologically acceptable salt or a stereoisomer thereof.

8.2-(3,4-dihydro-2-methoxymethyl-2-methyl-1

6—2 trol 2H—1,4,4-benzoxazine—4-yl) 1-oxide, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

9. 2— (3,4-Dihydroxy 2-acetoxymethyl 1-2-methyl-6-nitro-2H—1,4-benzoxazine-4-yl) pyridin-1-oxide, its pharmaceutical properties An acceptable salt or a stereoisomer thereof.

1 0.2— (3,4-Dihydro-2-nitromethyl-2-methyl-6-Nitro2H-1,4 Benzoxazine-1 4-yl) Pyridin-1-oxoxide, A pharmaceutically acceptable salt thereof, or a stereoisomer thereof. .

1 1. A benzoxazine derivative represented by the following general formula (II) or a salt thereof.

(The symbols in the formula represent the following meanings.

R ^{1 is a} hydrogen atom, a lower alkyl group, a lower alkanoyl group, a carbamoyl group, a mono- or di-lower alkyl rubamoyl group, or a ditoxyl group;

R ² lower alkyl group,

R ³ nitro group,

m Integer from 1 to 4

n 0 or 1. )

1 2. R ¹ is a hydrogen atom, a lower alkyl group, a lower Arukanoiru group, or a compound of claim 1 1, wherein a nitro group, or a salt thereof _c

13.3,4-Dihydroxy-2-hydroxymethyl-2-methyl-16,2H-2,1,4-benzoxazine or a salt thereof.

1 4. A pharmaceutical composition comprising a benzoxazine derivative represented by the following general formula (I) (I) a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

(The symbols in the formula represent the following meanings.

R: lower alkyl group,

R: Nito α group

m: an integer from 1 to 4

n: 0 or 1. )

15. The pharmaceutical composition according to claim 14, which is a rheumatoid channel activator.

16. The pharmaceutical composition according to claim 15, which is a prophylactic and / or therapeutic agent for cardiovascular disease.

17. The pharmaceutical composition according to claim 16, which is an agent for preventing and / or treating ischemic heart disease.

1 8. The medicament according to claim 16, which is an agent for preventing and / or treating hypertension. Composition.

1 9. The pharmaceutical composition according to claim 15, which is a prophylactic and / or therapeutic agent for respiratory disorders.

20. The pharmaceutical composition according to claim 15, which is an agent for preventing and / or treating a urinary system disorder.