WO1994011355A1 - 3,4-dihydro-1-(2-hydroxyphenyl)-2(1h)-quinoxalinone derivative and related compound - Google Patents

Abstract

A 3,4-dihydro-1-(2-hydroxyphenyl)-2(1H)-quinoxalinone derivative represented by general formula (I) or alkali metal salts thereof, wherein A represents oxygen, carbonyl or NR1; B represents NR?2 or CR3R4; R3¿ represents hydrogen, etc., or is combined with R1 to form a double bond between A and B; W represents oxygen or sulfur; X?1 and X2¿ represent each trifluoromethyl, etc.; Y1 represents hydrogen, etc.; Y2 represents hydrogen, etc.; Y3 represents halogen, etc.; Y4 represents hydrogen, etc.; and Z represents hydrogen, lower alkyl, substituted lower alkyl, or a group eliminable in vivo to leave hydrogen behind; provided that when A represents oxygen or NR1, then B represents CR3R4, while when A represents carbonyl, then B represents NR2 and W represents oxygen. The compound (I) and salts thereof have vasodilatory and hypotensive effects based on the smooth muscle relaxant effect and hence are useful as a medicine for treating cardiovascular diseases and so forth.

Description

 Specification

3,4-dihydro-1-1 (2-hydroxyphenyl)

 2 (1H) Monoquinoxalinone derivatives and related compounds

 The present invention relates to a novel 3,4-dihydro-11- (2-hydroxyphenyl) -12 (1H) -quinoxalinone derivative represented by the following formula (I), which has a smooth muscle relaxing action, a related compound, and a compound thereof. Related to metal salts.

Background art

 To the inventors' knowledge, conventional 3,4-dihydroxy 1- (2-hydroxyphenyl) 1-2 (1H) -quinoxalinone and 1-1 (2-hydroxyphenyl) 1-2 (1H) -quinoxalinone derivatives Is not known.

 J. Chem. Reseach (S), 2-3 (1992) states that 11- (2,4-dimethoxyphenyl) -17-methoxy2 (1H) -quinoxalinone and its 3,4 —Although dihydro isomers are described, details of the synthesis method, physical properties such as melting point, and biological activities are not described.

Kh im. -Fa rm. Z h., 2 ^, 19-126 (1968) describes 1-ethoxyphenyl-3-propionylmethyl-2 (1H) -quinoxalinone. No biological activity of itself has been described. U.S. Pat. No. 4,296,114 discloses a 1-phenyl-2- (1H) -quinoxalinone derivative represented by the following formula [A] or pharmaceutically acceptable salts, esters and amides thereof. Are described as being useful as anti-inflammatory, skin disease treatment, central depressant, and appetite suppressant, but have a substituted phenyl group such as a hydroxyphenyl group or a 2-alkoxyphenyl group. There is no specific description about this compound.

[Wherein R! Is fuunyl substituted with halogen, alkyne, alkyl, carboxyalkyl, etc .;

R ₃ is hydrogen, alkyl, halogen, hydroxy. Cyano, carboxyl, trifluoromethyl, etc.

Ring A is a benzene or pyridine ring which may have up to 4 R ₃ . Te tr ahe dron, 4 _, 1837-1860 (1991), Tet ahe dr on Le tters, 1611-1614 (1979) and HETERO CYCLES, _20., 1481-1485 (1983) 2-Hydroxyphenyl) 17-Methoxy 2H-1,4 Benzoxazine 1 3 (4H) 1 On, 4 1 (2-Hydroxy 5 5-methylphenyl) 1 7-Methoxy 2H-1,4 Benzoxazine One 3 (4H) -one, 4- (2-hydroxy-4-methylphenyl) one 7-methoxy-2H-1,4-benzoxazine-1 3 (4H) One, four-one (2-hydroxy-6 —Methylphenyl) 1 7—Methoxy 2H— 1,4 Benzoxazine 1 3 (4H) —On, 4- (2-Hydroxy 5-Methoxyphenyl) 1 7—Methoxy 2H— '1,4 Benzoxazine-1 3 (4H) -one and 4- [2-hydroxy 5- (2-tert-butoxycarpamine lumino-2-ethoxycarbo) (Rethyl)] A method for synthesizing several compounds of 7-methoxy-2H-1,4,1-benzoxazine-13 (4H) -one is described, but the biological activity of these compounds is completely described. It has not been.

J. He tero cy clic C hem., 18, 287-291 (1 981) describes a method for synthesizing 1- (5-chloro-1--2-hydroxyphenyl) -1,2,4 (1H, 3H) -quinazolinedione, but the biological activity of this compound is completely unknown. Not listed.

West German Patent Application Publication No. 2652144 discloses that compounds represented by the following formula [B] and their physiologically acceptable acid addition salts and quaternary salts have anti-inflammatory, sedative and analgesic effects. However, there is no description about a compound having a hydroxyphenyl group or a 2-alkoxy-15-substituted phenyl group as R ¹ .

[Wherein, R ¹ represents C! -C ₆ alkyl, alkoxycarbonyl, hydroxy, etc., and when R ² is a hydrogen atom and R ³ is halogen, methoxyphenyl, ethoxyphenyl or 3,4-xylyl; When R ^{2 is} fuunyl substituted with benzyl or methyl, it may be a hydrogen atom.

R ² means benzyl, pyridyl or the like, and when R ^{1 is} methoxyphenyl, ethoxyphenyl or 3,4-xylyl and R ³ is halogen, it is a hydrogen atom.

R ³ represents a hydrogen atom or a halogen. However, when R ^{1 is} methoxyphenyl, ethoxyphenyl or 3,4-xylyl and R ² is a hydrogen atom, R ³ is halogen. ]

Ann. Pharma ceu ti que sfr an caises, 4 _6, 223-232 (1988) states that 7-chloro-1- (2-methoxyphenyl) 1-2,4 (1H, 3H) -quinazoline Zeon and 7-cloth 11- (2-ethoxyphenyl) -12,4 (1H, 3H) -quinazoline dione is described as having anti-inflammatory, antispasmodic and analgesic effects.

 Chil. Fr 0, (5—6, Pt. 2), 133 1—1338 (1975) shows that 7-chloro-1- (2-ethoxyethoxy) 1 2 , 4 (1H, 3H) -quinazolinedione is described, but its specific biological activity is not described.

Cu r r. S ci., 3 ^ 7, 529-539 (1968) describes a method for synthesizing 1- (2-methoxyphenyl) -1,2,4 (1H, 3H) -quinazolinedione. However, its biological activity is not described. The JP 49- one hundred ten thousand six hundred eighty-two JP, 2 represented by the following formula [C], 4 (1H, 3H) but over quinazoline dione derivatives have been perforated Then describes anti-inflammatory and analgesic effect, R ¹ There is no specific description of a compound having a hydroxyphenyl group or a 2-lower alkoxyphenyl group as a substituted phenyl group of the above.

[Wherein, R ¹ represents a phenyl group, a substituted phenyl group (where the substituent is 1 or 2 selected from halogen, lower alkyl, lower alkoxy and trifluoromethyl) or a cyclohexyl group; R ² represents an alkyl group, a substituted alkyl group or an unsaturated alkyl group. ]

Japanese Patent Application Publication No. 477819 discloses a 1- (2-hydroxy or mercaptophenyl) -1H-benzimidazol-2-one derivative represented by the following formula [D]: They are C a 2 ⁺ -dependent forces It is stated to have a channel opening effect. As is clear from the formula (I) described below, the compound of the present invention is different from the compound described in the above publication in that quinoxaline, benzoxazine or quinazoline is used as a basic skeleton. Are clearly different.

Five

Wherein R ¹ is hydrogen, d- ₆ alkyl, etc.

X is 0, S or NCN;

Y is 0 or S,

R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently hydrogen, halogen, trifluoromethyl, hydroxy, S 0 ₂ NR ¹ R ¹ ′ (where R ′ and R ^M are independently hydrogen or C — Is ₆ alkyl)

R ¹¹ is hydrogen, halogen, nitro, etc.

R ¹³ is hydrogen, halogen, etc.

R ¹² is hydrogen, or aromatic taken together with R ^13, or partially optionally saturated C ₄ - ₇ to form a carbocyclic ring,

R ¹⁴ is hydrogen, or R ¹³ together such connexion aromatic and, or partially form an optionally C _{4 7} carbon ring which may be saturated. ]

Compounds having a smooth muscle relaxing action are mainly used as therapeutic agents for cardiovascular, respiratory, digestive, urinary disorders and the like. For example, calcium channel antagonists Antidrugs and potassium channel openers are known. As compounds currently under development or clinical use, diphedipine, diltiazem, verabamil and the like are known as calcium channel antagonists [for example, Anne M. Keogh & John S. Schroeder: J.C. 6, s28-s35 (1990); Y. Ouchi & H. 0 rimo: J. Cardiovas c. Pharma col., 16 supp 1. 2, s 1—s 4 (1990)], and nicorandil, pinacidil, cromakalim and the like are known as potassium channel openers [for example, Buckingham, JC et al .: J. Cardiovas c. Pharma col., 8, 798-804 (1986); E scande D. & Cavero I .: Trends Ph. rma col. Sci., 1_3_, 269-272 (1992); Go od, MD et al. : Br. J. Pharmacol., 105_. 933-940 (1992)]. However, these drugs are not always satisfactory in terms of efficacy or side effects, and the development of new types of smooth muscle relaxants is desired.

Disclosure of the invention

 The present inventors have conducted intensive studies to obtain a compound having a new chemical structure and an excellent smooth muscle relaxing action. As a result, the present inventors have found that 3,4-dihydro 1- (2-hydroxyphenyl) 1 2 The present inventors have found that (1H) monoquinoxalinone derivatives and related compounds have a smooth muscle relaxing action, and have completed the present invention.

According to the invention, the general formula (I)

[Wherein, A represents an oxygen atom, a carbonyl group or NR ¹ , wherein R ¹ is a hydrogen atom, a lower alkyl group, a hydroxy-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, a lower alkyl group, Or B represents a NR ² or CR ³ R, wherein R ² is a hydrogen atom, a lower alkyl group, a hydroxy-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, or R ³ and R ⁴ are the same or different and are the same or different and represent a hydrogen atom, a lower alkyl group, a hydroxy-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, a nitroxy-substituted lower alkyl group, a phenyl-substituted group; Lower alkyl group, hydroxyphenyl-substituted lower alkyl group, lower alkoxyphenyl-substituted lower alkyl group, phenyl group, lower alkoxy Means a disubstituted phenyl group or a halogen-substituted phenyl group, or when A is NR] and B is CR ³ R, R ³ and R ¹ together form a bond between A and B (3,4-dihydro A double bond may be formed between the 3- and 4-positions of the quinoxaline ring), in which case R ^{4 also} represents a hydroxy group or a lower alkoxy group, W represents an oxygen atom or a sulfur atom,

X ¹ and X ² represent at least one atom or group other than a hydrogen atom, which is the same or different and is a hydrogen atom, a halogen atom, a trifluoromethyl group, a dinitro group, a cyano group, a lower alkoxycarbonyl group, carboxyl group, 5-tetrazolyl group, a force Rubamoiru group, hydroxy group, -C ₂ Furuoroa Alkoxy group, sulfamoyl group, lower alkylsulfamoyl group, di-lower alkylsulfamoyl group or benzoyl group,

Y ¹ represents a hydrogen atom, a halogen atom or a nitro group,

Y ² represents a hydrogen atom, or together with Y ³ together with the benzene ring to which they are attached to form a naphthalene ring;

Y ³ represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group or a phenyl group,

Y ⁴ represents a hydrogen atom or a lower alkyl group, or together with Y ³ together with the benzene ring to which they are attached, forms a naphthalene ring, and z represents a hydrogen atom, a lower alkyl group, a lower alkoxy substitution. It means a lower alkyl group, a hydroxy-substituted lower alkyl group, a nitroquine-substituted lower alkyl group, or a group that can be converted to a hydrogen atom in vivo.

However, (i) when A is an oxygen atom or NR ¹ , B is CR ³ R ⁴ , and (ii) when A is a carbonyl group, B is NR ² , W is an oxygen atom, and Y ³ Is a halogen atom, a trifluoromethyl group, a nitro group or a phenyl group. ]

Provided are 3,4-dihydroxy-1- (2-hydroxyphenyl) -12 (1H) -quinoxalinone derivatives and related compounds represented by the following formulas or metal salts thereof.

 Examples of the alkali metal salt of the compound represented by the formula (I) include a lithium salt, a sodium salt, and a potassium salt. Since the compounds of formula (I) and salts thereof may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention.

The group which can be converted into a hydrogen atom in a living body in the compound represented by the formula (I) is, for example, an acetyl group, a propionyl group, a benzoyl group, an ethoxycarbo group. And an acyl group such as an amino group and an amino acid residue. Hereinafter, a compound having such a group may be referred to as a prodrug.

 Since the compounds of formula (I) optionally have one or more asymmetric carbon atoms, it is possible that several stereoisomers may exist. These stereoisomers, their mixtures and racemates are included in the compounds of the present invention.

 The terms used in this specification are described below.

 The term "lower alkyl group" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms unless otherwise specified, and a lower alkyl group having 1 to 3 carbon atoms is preferable. “Lower alkanoyl group” means a saturated aliphatic carboxylic acid residue having 2 to 6 carbon atoms. The term "aroyl group" means an unsubstituted or substituted aromatic carboxylic acid residue, for example, a halogen atom, a lower alkyl group or a lower alkoxy group as a substituent such as benzoyl, chlorobenzoyl, methylbenzoyl or methoxybenzoyl. And a benzoic acid residue which may have the like.

 Among the compounds of the present invention, preferred are compounds of the general formula (Ia)

[Wherein, R ^la is a hydrogen atom, a C, to C ₃ alkyl group, a hydroxy-substituted d

~ C ₃ alkyl group, C! ~ (: ₃ alkoxy-substituted Ci ~ (: ₃ alkyl group,

Means C ₂ -C ₄ Arukanoiru group or Benzoiru group,

R ^3a and R ^4a are the same or different and each represent a hydrogen atom, a ~ C ₃ alkyl group, Human Dorokishi substituted d -C ₃ alkyl group, d -C ₃ alkoxy-substituted C, ~ c ₃ alkyl group, nitroxy substituted to c ₃ alkyl group, phenyl substituted

Ci -C ₃ alkyl group, human Dorokishifuweniru substituted D～c ₃ alkyl group, D～c ₃ alkoxy phenylalanine substituted c! To c ₃ alkyl group, phenyl group,

Means ci to c ₃ alkoxy substituent Fuweniru group or a halogen-substituted Fuweniru group, or R ^3a is optionally form a double bond between 3 and 4-position of the 3, 4 Jihi Dorokinokisarin ring together with R ^la In that case, R ^4a also means a hydroxy group or a d-C ₃ alkoxy group,

W represents an oxygen atom or a sulfur atom,

One of X ^la and X ^2a is a halogen atom, a trifluoromethyl group, a nitro group, a cyano group, a C! To C ₃ alkoxycarbonyl group, a carboxyl group, a 5-tetrazolyl group, a carbamoyl group or a Ci to C ₂ full group. A hydrogen atom or a halogen atom,

Y ^la represents a hydrogen atom, a halogen atom or a nitro group,

Y ^2a represents a hydrogen atom, or together with Y ^3a, together with the benzene ring to which they are attached, forms a naphthalene ring,

Y ^3a represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a fuunyl group,

Y ^a represents a hydrogen atom or a d-C ₃ alkyl group, or forms a naphthalene ring together with Y ^3a together with the benzene ring to which they are attached;

Z ^a represents a hydrogen atom, a C ₃ alkyl group, a C ₃ alkoxy substitution d a C ₃ alkyl group, a hydroxy substitution C! ~ C ₃ alkyl group, a nitroxy substitution ^ ~ (: a ₃ alkyl group or an acyl group Yes.]

3, 4-dihydroxy-1 1 (2—hydroxyphenyl) 1 2 (1 H) Monoquinoxalinone derivatives, their 3,4-dehydro bodies, and their salts.

 Another preferred compound of the present invention has the general formula (Ib)

[Wherein X ^la and X ^2a mean the same as above,

R ^3b is a hydrogen atom, Ci to C ₃ alkyl group, hydroxy substituted d to C ₃ alkyl group, d to C ₃ alkoxy substituted d to C ₃ alkyl group, nitroxy substituted d to (: ₃ alkyl group, phenyl substituted C ~ C ₃ alkyl group, hydroxyphenyl substituted C! ~ (: ₃ alkyl group or ~ C ₃ alkoxyphenyl substituted C〗 ~ (: ₃ alkyl group, R ^4b is a hydrogen atom, C! ~ C ₃ § alkyl group, human Dorokishi substituted d -C ₃ alkyl group, d -C ₃ alkoxy-substituted c! to c ₃ alkyl group, nitroxy substituted to c ₃ alkyl group, Hue-substituted Ci -C ₃ alkyl group, human Dorokishifuweniru substituted means d to c ₃ Al kills groups, c, to c ₃ alkoxy off We-substituted c! to c ₃ alkyl group, Hue group, a -C ₃ alkoxy substituent Fuweniru group or a halogen-substituted Fuweniru group,

w represents an oxygen atom or a sulfur atom,

One of which is a halogen atom, a trifluoromethyl group, a nitro group, a cyano group,

Ci to C ₃ alkoxyl radical, carbonyl group, 5-tetrazolyl group or rubamoyl group; the other means a hydrogen atom or a halogen atom; Y ^3a represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a phenyl group,

Y ^b represents a hydrogen atom or, together with Y ^3b , forms a naphthalene ring together with the benzene ring to which they are bound,

z ^b represents a hydrogen atom, a -c ₃ alkyl group or an acyl group. 4-Hydroxyphenyl) 2H-1,4-benzoxazin-13 (4H) -one derivatives and alkali metal salts thereof. Further preferred compounds of the present invention include compounds of the general formula (Ic)

^{Wherein, R 2a, Y la, Y} 2a, Y a, Z a denotes the same supra, one of X ^lb and X ^2b denotes a halogen atom, triflate Ruo Russia methyl group or a nitro group, the other is a hydrogen atom or a halogen atom, Upsilon ³ means halogen atom, triflate Ruo Russia methyl or Fuweniru group. ]

1- (2-hydroxyphenyl) -1,2,4 (1H, 3Η) -quinazolinedione derivatives and their metal salts.

 Specific examples of suitable compounds include the compounds in Tables 1 to 5 below and metal salts thereof.

The following abbreviations are used for simplification in Tables 1 to 5. Me: methyl group, Et: ethyl group, is 0—Pr: isopropyl group, Ph: phenyl group, Ac: acetyl group, Bz: benzoyl group. w X ^Ia Y 2a

Λ v I l ^a V 2 a 3 a V 4 a

 Ϊ V

 y Y

〇 6-CF ₃ HHHHHH

〇 6-CF ₃ HHHHH Me

〇 6-C F3 H H H CI H H

〇 6-CF ₃ HHH CI H Me

0 6-CN H H H CI H H

0 6-CN HHH CI HH

〇 6-CN H H H CI H ■ Me

0 6-0 CF ₃ HHH CI HH

0 6-OCF ₃ HHH CI H Me

0 6-S0 ₂ NMe ₂ HHH CI H Me

0 6-0 CF ₃ HHH Ph HH

0 H H H P h H Me

0 H H H C = C- C = C H

〇 6-CF3 HHH CF ₃ HH

s 6-Br 'HHH CI HH s 6-Br HHH CI H Me Two

 Η Η Η 0 Bz

Η Η Me 0 H

Η Η Me 0 Me

Η Η Me 0 Ac

Η Η Me 〇 Bz

Η Η Me 0 iso-Pr

Η Η Et 〇 H

Η Η Et 0 Me

Η Η iso-Pr 0 H

Η Η iso-Pr 〇 Me

Η Η Ph 0 H

Η Η Ph 〇 Me

Η Η Ph-2- Br 0 Me

Η Η CH2CH2OH 〇 H

〇F n

 (〇 CF T)

〇 〇

OH 0 CF ₃ HH

CH ₂ CH ₂ OH 〇 CF ₃ H Me

CH ₂ CH ₂ ONO2 〇 CF ₃ H Me

CH ₂ -Ph 0 CF ₃ H Me

CH ₂ -Ph -4-OMe 〇 CF ₃ H Me

CH ₂ -Ph -4-OH 0 CF ₃ H Me

H 0 Br H H

H 0 Br H Me

H 〇 C H H

H 0 CN H Me

H 〇 5-tetraso "ryl H Me

H 0 CONH ₂ H Me

H 0 C0 ₂ HHH

H 0 C0 ₂ HH Me

Ph 0 C〇 ₂ HHH

Ph 0 C0 ₂ HH Me

H 〇 C 0 ₂ Me HH

H 0 C0 ₂ Me H Me

HS CF ₃ HH

Me S CF ₃ HH

Me s CF ₃ H Me

Ph s. CF ₃ HH

Ph s CF ₃ H Me Four

w R ^3b R ^4b X ^la X ^2a Y 3a Y 4 b Z ^b

0 HH 7-CF ₃ H CI HH

0 H H 7-CFs H CI H Me

0 HH 7-CF ₃ H CI H Ac o HH 7-CI H CI HH

0 H H 7-C1 H CI H Me

〇 HHH 6-CF3 CI HH

 0 H H H 6-CI CI H H

0 H H H 6-CI CI H Me

0 H H H 6-CI CI H Bz

0 HHH 6-Br CI HH 0 HHH 6-Br CI H Me

0 H H H 6-CN CI H H

0 H H H 6-CN CI H Me

0 HHH 6-CN CI H Ac

0 HHH 6-CONH ₂ CI H Me

〇 HHH 6-C0 ₂ H CI HH

〇 H H H 6-CO2H CI H Me

0 HHH 6-C0 ₂ Me CI HH

〇 HHH 6-C0 ₂ Me CI H Me

〇 HHH 6-C0 ₂ Na CI HH

0 H H H 6- (5-tetraso, ril) CI H H

〇 H H H 6- (5-ϊ torazo, 'Ril) CI H Me

0 H H H 6-C1 c = c -C = C H

0 H H H 6-C1 c = c-C = C Me

0 H H 8- CI 6-C1 CI H H

0 H H 8-CI 6-C1 CI H Me

0 H H H 6-0Η CI H H

0 H H H 6-0Η c 1 H Me

0 HHH 6-OCF ₃ CI HH υ n. Ri 0 3 丄 rl M6

〇 HHH 6-Βζ CI HH

 0 H Me H 6-C1 CI H H

0 H Me H 6- CI c] H Me 0 H Ph H 6-C1 CI HH

0 H Ph H 6-C1 CI H Me

0 Me Me H 6- CI CI H H

0 Me Me H 6-C1 CI H Me

0 Me Me H 6-CN CI H H

0 Me Me H 6-C0 ₂ H CI H Me s HHH 6-Cl CI HH s HHH 6-CI CI H Me s HHH 6-CN CI HH s HHH 6-CN CI H Me s Me Me H 6-Cl CI HH s Me Me H 6-CI CI H Me

Five

E ^2a X ^lb X ^2b VI a γ2 a γ3 c γ4 a Z ^a

H 5- CI H H H CI H H

H 5-C1 HHH CI H Me

p r H

 u F1. 3 11 H ii H CI H Up

H 6-CFs H H H CI H Ac

H H 7-CFs H H CI H H

H H 7-CFs H H CI H Me

H 5-CI 7-CI H H CI H H

H 5-CI 7-C1 HH CI 'H Me

H 6-N0 ₂ HHH CI H Me

The compound of the present invention can be produced, for example, by the following method. Production method (a)

In the formula (I), a compound in which A is an oxygen atom or NR ¹ , B is CR ³¹ R ⁴¹ and W is an oxygen atom is represented by the general formula (II)

(Wherein Y ¹ , Y ² , Υ ³ , Y ⁴ and Z have the same meanings given above, A ¹ has an oxygen atom or NH, and R ³¹ has a hydrogen atom or a lower alkyl group. R ⁴¹ represents a hydrogen atom, a lower alkyl group, a phenyl group, a lower alkoxy-substituted phenyl group or a halogen-substituted phenyl group, and χη is the same or different and represents a hydrogen atom, a halogen atom, a trifluoromethyl group, Toromoto, human Dorokishi group means a C! -C ₂ full O b alkoxy group, Surufamoi group, a lower alkylsulfamoyl group, a di-lower alkylsulfamoyl group, or Benzoiru group, L ¹ is Amino group or a lower It means an alkoxy group.)

The compound represented by the general formula (I I I)

 (III)

(式中、 A¹ , R³¹ , R⁴¹ , X¹¹ , X²¹ , Υ¹ , Υ² , Υ³ , Υ⁴ 及 び Ζは前掲に同じものを意味する。 ）

(In the formula, A ¹ , R ³¹ , R ⁴¹ , X ¹¹ , X ²¹ , Υ ¹ , Υ ² , Υ ³ , Υ ⁴ and Ζ mean the same as described above.)

Can be produced by removing the protective group, if an ether-based protective group is present, and subjecting it to an alkylation reaction or an acylation reaction, if necessary.

 This ring closure reaction is performed without a solvent or in an appropriate solvent. Specific examples of the solvent include alcohols such as methanol and ethanol, ethers such as diisopropyl ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene, and dimethylformamide. Dimethyl sulfoxide, and acetonitrile. The reaction temperature is usually about 10 ° C to about 200 ° C, preferably about 60 ° C to about 150 ° C.

 This ring closure reaction is accelerated in the presence of an acid or a base. Specific examples of the acid used include hydrogen chloride, hydrogen bromide, sulfuric acid, p-toluenesulfonic acid, and camphorsulfonic acid. Specific examples of the base include sodium bicarbonate, bicarbonate lime, and the like. Alkali carbonates such as sodium bicarbonate, sodium carbonate and carbonated carbonate, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine Tertiary amines may be mentioned. The reaction temperature is usually about 0 ° C to about 200 ° C, preferably about 20 ° C to about 150 ° C.

The ring-closing reaction of the compound of the formula (II) wherein A ¹ is NH is preferably carried out in an inert atmosphere, for example, in a stream of nitrogen or argon.

To remove an ether-based protecting group such as methyl, ethyl, methoxymethyl, benzyl, etc. from the compound of the formula (III), the reaction is carried out in a suitable solvent in the presence of a reagent suitable for funolic ether cleavage, preferably inert. Under atmosphere (for example, (In a stream of nitrogen or argon). The combination of the reagent and the solvent should be appropriately selected according to the type of the compound (III). Specific examples thereof include trimethylsilane iodide chloroform, sodium ethanethiolate / dimethylformamide, and cyanide. Sodium dimethyl sulfoxide, lithium iodide Z collidine, aluminum bromide Z ethanethiol, boron tribromide methylene chloride, 48% hydrobromic acid acetic acid, boron trifluoride / ethyl ether complex / ethanethiol.

 The reaction temperature varies depending on the type of the compound (III) and / or the reagent. In the case of boron tribromide, it is usually about 180 ° C. to about 40 ° C., and aluminum bromide, boron trifluoride / getyl ether complex The temperature is usually about 5 ° C. to about 35 ° C. for trimethylsilane, usually about 5 ° C. to about 50 ° C. for trimethyl iodide, and usually the heating reflux temperature for other reagents.

When X ¹¹ and X ²¹ in the formula (III) are atoms or groups other than a nitro group, and the protecting group in Z is a benzyl group, they can also be eliminated by catalytic reduction. Examples of catalysts for catalytic reduction include palladium-carbon, palladium-barium sulfate, palladium-calcium carbonate, platinum oxide, and Raney nickel. Ethanol, acetic acid, etc. are used as solvents, and the reaction temperature is usually about 10 ° C to about 50 ° C.

In the formula (III), a compound in which Z is a lower alkoxy-substituted lower alkyl group, a hydroxy-substituted lower alkyl group or a nitroxy-substituted lower alkyl group is obtained by cleaving the ether bond of the compound in which Z is a lower alkyl group. Can be also produced by re-alkylating a phenolic hydroxyl group produced by converting a compound into a hydrogen atom with an alkylating agent having a target alkyl group by a conventional method. Similarly, a compound in which Z is a lower alkyl group may be converted to another compound in which Z is a lower alkyl group. This alkylation reaction is carried out in a suitable solvent in the presence of a base. Specific examples of the solvent include ethers such as tetrahydrofuran and dioxane, dimethylformamide, and dimethylsulfoxide. Specific examples of the base include alkali metal hydrides such as lithium hydride and sodium hydride, and alkali carbonates such as sodium carbonate and lithium carbonate.

 Examples of the alkylating agent include lower alkyl halides such as methyl iodide, halogenated ethers such as 2-iodoethyl methyl ether, benzyl halides such as benzyl bromide, and methyl methanesulfonate. Lower alkyl esters of lower alkyl sulfonic acids, and lower alkyl esters of aryl sulfonic acids such as methyl ρ-toluenesulfonic acid are exemplified. The reaction temperature is usually about 150 ° C to about 100 ° C, preferably about 120 ° C to about 50 ° C.

In the case of a compound in which A ¹ is NH in the formula (III), it is preferable that the compound is subjected to the present alkylation reaction with its amino group protected. Examples of the amino-protecting group include acyl groups such as trifluoroacetyl and trichloroacetyl.

The compound of the formula (III) wherein Z is a hydrogen atom can also be converted to a prodrug by reacting the compound with an acylating agent in a suitable solvent in the presence of a base. Specific examples of the solvent include ethers such as diisopropyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as methylene chloride, chloroform, and chlorinated ethylene, dimethylformamide, dimethyl sulfoxide, and acetonitrile. . Specific examples of the base include alkali bicarbonate such as sodium bicarbonate and potassium bicarbonate, and alkali carbonate such as sodium carbonate and lithium carbonate. Specific examples of the acylating agent include acetic anhydride, acetyl chloride, propionyl chloride, and benzoyl chloride. Can be The reaction temperature is generally about 45 ° C to about 100 ° C, preferably about 120 ° C to about 50 ° C.

The compound in which A ¹ is NH in the formula (II), which is a starting compound of the production method (a), can be produced, for example, by the method shown in the following scheme 1.

 Scheme 1

 (Ha)

(Wherein, R ³¹ , R ⁴¹ , X ¹¹ , X ²¹ , Y ¹ , Υ ² , Υ ³ , Y ⁴ , L ¹ and Z have the same meanings as described above, and L ² is a halogen atom, lower alkyl. It means the reactive ester residue of alcohol such as sulfonyloxy and arylsulfonyloxy.)

Compounds of formula (IV) are described, for example, in EP-A-477819. The compound can be produced according to the method described in JP-A No. 2000-223, or by a method known per se, and if necessary, used in a state in which a fininolic hydroxyl group is protected with an ether-based protecting group. The compound of the formula (V) is commercially available or can be produced by a method known per se.

 The reaction of the compound of the formula (IV) with the compound of the formula (V) is usually carried out in a solvent such as tetrahydrofuran in the presence of a base such as triethylamine. The reaction temperature is usually about 120 ° C to about 100 ° C. The compound (Δλ may be used in the form of an acid addition salt to form a free base in the reaction system.

The compound in which A ¹ is an oxygen atom in the formula (II), which is a starting compound of the production method (a), can be produced, for example, by the method shown in the following scheme 2. '

Scheme 2

 (lib)

(Wherein, R ³¹ , R ⁴¹ , X ¹¹ , X ²¹ , Υ ¹ , Υ ² , Υ ³ , Υ ⁴ , L ¹ and Ζ mean the same as described above, and L ³ means a halogen atom ) Each step of the scheme 2 will be described.

 (Process 1)

The compound of the formula (λ ^ I) can be produced by a method known per se, and the compound of the formula (VII) is commercially available or is produced by a method known per se. Can be The reaction of the compound of the formula (VI) with the compound of the formula (VI I) is usually carried out in the presence of copper powder or cuprous iodide and a base such as potassium carbonate, without solvent or in a solvent such as dimethylformamide. Done in The reaction temperature is usually about

20 ° C to about 250. C.

 (Process 2)

 This reaction is usually performed in a solvent such as methanol in the presence of a base such as sodium methoxide. The reaction temperature is usually about 0 ° C to about 150 ° C.

 (Process 3)

This step can be carried out in the same manner as in the method of Scheme 1, except that sodium hydride, potassium carbonate or the like can be further used as a base. The compound in which A ¹ is an oxygen atom in the formula (II), which is a starting compound of the production method (a), can also be produced, for example, by the method shown in Scheme 3 below.

Scheme 3

Process 1

 (X) (XI)

 (lib)

(Wherein, R ³¹ , R ⁴¹ , X ¹¹ , X ²¹ , Y ¹ , Y ² , Y ³ , Y ⁴ , L ¹ , L ³ and Z mean the same as described above, and R ⁵¹ is a lower alkyl group. Or a benzyl group.)

Each step of the scheme 3 will be described. (Process 1)

 The compound of the formula (X) can be produced by a method known per se, and the compound of the formula (XI) is commercially available or can be produced by a method known per se.

 The reaction of the compound of the formula (X) with the compound of the formula (XI) is usually carried out in the presence of copper powder or cuprous iodide and a base such as carbonated rim, without solvent or in a solvent such as dimethylformamide. Done. The reaction temperature is usually about 20 ° C to about 250 ° C. .

 (Process 2)

In this reaction, the protecting group R ⁵¹ is eliminated from the compound of the formula (XI I). In the same manner as in the above-mentioned method for removing the ether-based protecting group of the compound of the formula (III), fuanol Performed in the presence of a reagent suitable for cleavable ether cleavage (Step 3)

 This step can be performed in the same manner as in step 3 of scheme 2.

Production method (b)

In the formula (I), the compound wherein A is NR ¹ , B is CR ³¹ R ⁴¹ and W is an oxygen atom is also represented by the general formula (XIV)

(In the formula, R ³¹ , R ⁴¹ , X ¹¹ , X ²¹ YY ² , Y ³ , Y ⁴ , and Z mean the same as described above.) By ring-closing the compound represented by or a compound protected with an ether-based protecting group-

—General formula (XV)

(In the formula, R ³¹ , R ⁴¹ , X ¹¹ , X ²¹ , Υ ¹ , Y ² , Υ ³ , Y ⁴ and Z mean the same as described above.)

Can be produced by removing the protective group, if an ether-based protective group is present, and subjecting it to an alkylation reaction or an acylation reaction, if necessary.

The ring-closure reaction from the compound of the formula (XIV) to the compound of the formula (XV) is carried out under an inert atmosphere (for example, in a stream of nitrogen or argon) without a solvent or in a suitable solvent. As specific examples of the solvent, the solvent described in the production method (a) can be used as it is. This reaction is carried out in the presence of a base as necessary. Specific examples of the base include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, and water such as sodium hydroxide and potassium hydroxide. Alkali metal alkoxides such as alkali oxide and sodium methoxide, alkali carbonates such as sodium carbonate and potassium carbonate, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, triethylamine, diisopropylethylamine, pyridine, 2,4-dimethyl pyridine Organic bases. The reaction temperature is usually about -45 ° Ci to about 150 ° C, preferably about 0 ° C to about 100 ° C. The compound of the formula (XIV), which is the starting compound of the production method (b), can be produced, for example, by the method shown in Scheme 4 below.

 Scheme 4

Process 1

(Wherein, R ³¹ , R ", X ¹¹ , X ²¹ , Υ ¹ , Υ ² , Y ³ , Y ⁴ , L ² and Z have the same meanings given above, L ⁴ is a carboxylic acid halide, This refers to the residue obtained by removing the acyl group from the reactive derivative of sulfonic acid such as a symmetrical anhydride or a mixed anhydride.)

 Each step of the scheme 4 will be described.

 (Process 1)

The compound of the formula (XVI) can be produced, for example, according to the method described in EP-A-478197 or by a method known per se. It is used in a state where the functional hydroxyl group is protected with an ether-based protecting group, if necessary. Further, the compound of the formula (XVII) is commercially available or can be produced by a method known per se.

Reaction of a compound of formula (XVI) compounds with formula (XV II) is preferably in the presence of a base such as pyridine, _c reaction temperature is carried out in a solvent such as as tetrahydrofuran is about normal C~ about a 20 ° 100 ° C.

 (Process 2)

 This reduction step is carried out by reacting a compound of the formula (XVIII) ′ with a reducing agent in an appropriate solvent, or by catalytically reducing a compound of the formula (XVIII) in the presence of a catalyst.

 Examples of the reducing agent include a combination of a metal (eg, zinc powder, tin powder, tin samar gum) and an acid (eg, hydrochloric acid, acetic acid). Examples of the catalyst for catalytic reduction include palladium-carbon, palladium-barium sulfate, palladium-calcium carbonate, platinum oxide, and Raney nickel. The solvent used should be appropriately selected according to the type of the reducing agent or the reducing means, and includes, for example, ethanol and acetic acid. The reaction temperature varies depending on the type of the reducing agent or the reducing means. The reaction temperature is usually about -20 ° C to about 100 ° C, and in the case of catalytic reduction, preferably about 10 ° C to about 50 ° C.

Production method (c)

In the formula (I), a compound in which A is an oxygen atom or NR ¹ , B is CR ³ R, at least one of R ³ and R ⁴ is a hydrogen atom, and W is an oxygen atom, By subjecting the hydrogen atom to an alkylation reaction, the hydrogen atom is converted to a lower alkyl group, a hydroxy-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, a nitroxy-substituted lower alkyl group, a phenyl-substituted lower alkyl group, or a hydroxyphenyl-substituted lower alkyl group. Alkyl group or lower alcohol The compound of the present invention substituted with a xylixunyl-substituted lower alkyl group can be produced.

 This reaction is performed in a suitable solvent in the presence of a base. Specific examples of the solvent include ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane, and aromatic hydrocarbons such as toluene and xylene. Specific examples of the base include lithium diisopropylamide and lithium hexamethyldisilazide.

 Examples of the alkylating agent include lower alkyl halides such as methyl iodide, halogenated ethers such as 2-iodoethyl methyl ether, benzyl halides such as benzyl bromide, and methyl methanesulfonate. Lower alkyl esters of lower alkyl sulfonic acids, and lower alkyl esters of aryl sulfonic acids such as methyl ρ-toluenesulfonic acid are exemplified. The reaction temperature is generally about -150 ° C to about 100 ° C, preferably about 100 ° C to about 50 ° C.

The raw material compound used in the present alkylation reaction is the corresponding raw material compound. The compound in which A is an oxygen atom is prepared by the production method (a), and the compound in which A is NR ¹ is produced by the production method (a) or ( b). The starting compound was protected with an ether-based protecting group, if necessary, or when A was NH, protected with an amino-protecting group such as methoxymethyl, benzyloxymethyl, and trimethylsilylethoxymethyl. As such, it is subjected to an alkylation reaction.

The compound obtained by the present alkylation reaction is obtained by removing the protecting group, if any, in the compound and subjecting the compound to an alkylation reaction or an acylation reaction, if necessary, to obtain the compound of the present invention. Can be manufactured. The elimination of the protecting group for the amino group is carried out in a suitable solvent under acidic conditions. As the solvent, alcohols such as methanol, ethanol, propanol, and butanol, or a mixture of these with water is used.

 Specific examples of the acid include hydrogen chloride, hydrogen bromide, sulfuric acid, and camphorsulfonic acid. The reaction temperature is usually about -40 ° C to about 150 ° C, preferably about 0 ° C to about 100 ° C.

Production method (d)

In formula (I), A is NR ¹ , B is CR ³ R ⁴³ , and R ³ is linked to R ¹ to form a double bond between the 3- and 4-positions of the 3,4-dihydroquinoxaline ring. The compound in which W is an oxygen atom has the general formula (Id)

(Wherein, X ¹¹ , X ²¹ , Y ¹ , Y ² , Y ³ , Y ⁴ and Z have the same meanings as described above, and R ⁴³ is a hydrogen atom, a lower alkyl group, a hydroxy-substituted lower alkyl group, Lower alkoxy-substituted lower alkyl group, nitroxy-substituted lower alkyl group, fuunyl-substituted lower alkyl group, hydroxyphenyl-substituted lower alkyl group, lower alkoxyphenyl-substituted lower alkyl group, phenyl group, lower alkoxy-substituted phenyl group or halogen substitution A) A compound represented by) is oxidized under mild conditions, and then, if a protecting group is present, the protecting group is removed. If necessary, the compound is subjected to an alkylation reaction or an acylation reaction. It can be manufactured by attaching. This oxidation reaction is a method of treating with dichlorodisianoparabenzoquinone (DDQ) Z methanol at about 0 ° C to about 50 ° C, oxygen gas Z alcohol at about 0 ° C to about 50 ° C, and acidic conditions. (E.g., methanol, ethanol), and nitrobenzene at the reflux temperature.

 The compound of the formula (Id) can be produced by the production method (a), (b) or (c) using the corresponding starting compound.

Manufacturing method (e)

In the formula (I), a compound in which A is NR ¹ , B is CR ³ R ⁴ , and R ³ is connected to R ¹ to form a bond, and W is an oxygen atom is also represented by the general formula (I e)

(In the formula, X ¹¹ , X ²¹ , Υ ¹ , Υ ² , Υ ³ , Υ ⁴ and ζ mean the same as described above.)

After protecting the compound represented by with an ether-based protecting group, if necessary,

—General formula (ν ') people.

(In the formula, L ⁴ and R ⁴¹ mean the same as described above.)

Is condensed with a compound represented by the formula, and when protected, the protecting group is eliminated. Further, it can be produced by subjecting it to an alkylation reaction or an acylation reaction, if necessary.

 The compound of the formula (Ie) can be produced, for example, according to the method described in EP-A-477819 or by a method known per se. The compound of the formula (V ') is commercially available or can be produced by a method known per se.

The reaction of the compound of the formula (Ie) with the compound of the formula (V ') is usually carried out in the presence of an acid without solvent or in a suitable solvent. Specific examples of the solvent, Te Torahi Dorofuran, methylene chloride, ethanol, specific examples of the c acid methanol may be mentioned hydrochloric acid, sulfuric acid, _c reaction temperature include p- toluenesulfonic acid is usually about a 45 ° C To about 150 ° C, preferably from about 120 ° C to about 100 ° C. Compound (Ie) may be used in the form of an acid addition salt.

Production method (f)

In the formula (I), a compound in which A is NH, B is CR ³¹ R ⁴³ (except when R ³¹ is a hydrogen atom), and W is an oxygen atom is represented by the general formula (Iί)

()

(In the formula, R ⁴³ , X ¹¹ , X ²¹ , Y ¹ , Υ ² , Υ ³ , Y ⁴ and Z mean the same as described above.)

After protecting the compound represented by with an ether-based protecting group, if necessary, The product can be produced by adding a nucleophile thereto and, when protected, removing the protecting group and, if necessary, subjecting it to an alkylation reaction or an acylation reaction.

 This reaction is carried out in a suitable solvent in the presence of a nucleophile. Examples of the nucleophile include alkyl magnesium halides and lithium dialkyl copper (I) complexes. Specific examples include methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium bromide, and phenyl magnesium. Butyl amide, orthobromophenylmagnesium bromide ", paramethoxyphenylmagnesium bromide, dimethyl copper (I) lithium complex, and getyl copper (I) lithium complex.

Specific examples of the solvent include ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene. The reaction temperature is usually about a 100 ° Celsius to about 100 ° C, preferably about one 50 ^Q Celsius to about 50 ° C.

 The compound of the formula (If) can be produced by the production method (d) or (e) using the corresponding starting compound.

Production method (g)

In the formula (I), a compound in which A is NR ¹ or an oxygen atom, B is CR ³ R ⁴ and W is a sulfur atom is represented by the general formula (I g)

(式中、 A¹ , R³ ， R⁴ , Y¹ , Y² , Y³ ， Υ⁴ 及び Ζは前掲に同じ ものを意味し、 X¹³ 及び X²³ は同一又は異なって、 水素原子， ハロゲン 原子， トリフルォロメチル基， C! 〜C₂ フルォロアルコキシ基， ヒ ドロ キシ基又はスルファモイル基を意味する。 ただし、 X¹³ 及び X²³ が共に 水素原子の場合を除く。 ）

(Wherein, A ¹ , R ³ , R ⁴ , Y ¹ , Y ² , Y ³ , Υ ⁴ and を mean the same as described above, and X ¹³ and X ²³ are the same or different, and represent a hydrogen atom, a halogen atom, except atom, triflate Ruo Russia methyl, C! -C ₂ full O b alkoxy group, it means a hydroxycarboxylic group or a sulfamoyl group. However, in the case of X ¹³ and X ²³ are both hydrogen atoms.)

The compound represented by is protected with an ether-based protecting group, if necessary, and then reacted with phosphorus pentasulfide in a suitable solvent.If protected, the protecting group is eliminated, and if necessary, It can be produced by subjecting it to an alkylation reaction or an acylation reaction.

 Specific examples of the solvent include pyridine, lutidine, benzene, toluene, tetrahydrofuran, and dioxane. The reaction temperature is usually about 20 ° C to about 200 ° C, preferably about 20 ° C to about 150 ° C.

The reaction of the compound of the formula (I g) wherein A ¹ is NH is preferably carried out under an inert atmosphere, for example, in a stream of nitrogen or argon.

 The compound of the formula (Ig) can be produced by the production methods (a), (b), (c), (d), (e) and (f) using the corresponding starting compounds.

Production method (h)

In the formula (I), a compound wherein A is an oxygen atom, B is CR ³¹ R ⁴¹ and W is an oxygen atom is represented by the general formula (I h)

 1

(Where LR 31 RX 11 X 21 YY ² , Y ³ , Y ⁴ and And z mean the same as above. )

Can be produced by subjecting the compound represented by the formula to ring closure, removing an ether-based protecting group, if present, and subjecting it to an alkylation reaction or an acylation reaction, if necessary.

 This reaction is usually performed in the presence of a base, without a solvent, or in an appropriate solvent. Specific examples of the solvent include dioxane, diglyme, toluene, xylene, nitrobenzene, and dimethylformamide. Specific examples of the base include potassium acetate, potassium carbonate, potassium tert-butoxide, 4-dimethylaminopyridine, sodium hydride, and potassium hydride. The reaction temperature is usually about 0 ° C. to about 250 ° C., preferably about 50 ° C. to about 200 ° C.

The compound represented by the formula (Ih), which is a starting compound of the production method (h), can be produced, for example, by the method shown in the following scheme 5.

Scheme 5

Process 1

 (XIX) (V)

Compound '(XI)

 Process 2

 (XX)

 (Ih)

(In the formula, R ³¹ , R ⁴¹ , X ¹¹ , X ²¹ , Υ ¹ , Υ ² , Υ ³ , Υ ⁴ , L ¹ , L ² , L ³ and Ζ mean the same as described above.)

 Each step of the scheme 5 will be described.

 (Process 1)

 The compounds represented by the formulas (XIX) and (V) are commercially available, or can be produced by a method known per se. The compound of the formula (XIX) may be used in a protected state, if necessary. Is done.

The reaction of the compound of the formula (XIX) with the compound of the formula (V) is usually carried out in the presence of a base such as sodium hydride, in the absence of a solvent or in the presence of a solvent such as dimethylformamide. Performed in a medium. The reaction temperature is usually about 150 ° C to about 100 ° C.

 (Process 2)

 This step is performed in the presence of a base such as potassium tert-butoxide, without a solvent, or in a solvent such as dimethylformamide. The reaction temperature is usually about 150 ° C to about 150 ° C.

 In this reaction, under relatively strong conditions, the ring-closure reaction proceeds continuously, and a ring-closed compound (I h ′) can be obtained without being isolated as the compound (I h).

(In the formula, R ³¹ , R ⁴¹ , X ¹¹ , X ²¹ , Υ ¹ , Υ ² , Υ ³ , Y ⁴ and Z mean the same as described above.)

Production method (i)

In the formula (I), the compound in which A is a carbonyl group and B is NR ² is a compound represented by the general formula (XXI) protected with an ether-based protecting group, if necessary.

(Wherein, L ³ , X ¹¹ and X ²¹ have the same meanings as described above.) And a compound represented by the general formula (XX II) protected with a t-ether-based protecting group, if necessary.

(In the formula, Y ¹ , Y ² , Y ³ , Υ ⁴ and を mean the same as described above, and R ⁵ means a lower alkyl group.)

The compound can be produced by reacting with a compound represented by the formula (1) and, when protected, removing the protecting group and subjecting it to an alkylation reaction or an acylation reaction, if necessary.

 The compound of the formula (XXI) and the compound of the formula (XXII) are commercially available or can be produced by a method known per se.

 The reaction between compound (XXI) and compound (XXI I) is carried out without a solvent or in an appropriate solvent. Specific examples of the solvent include diisopropyl ether, tetrahydrofuran, dioxane, diglyme, benzene, toluene, xylene, dimethylformamide, and dimethylsulfoxide. This reaction is preferably performed in the presence of a base. Specific examples of the base include sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, and 4-diethylbenzene. Methylamino pyridine is mentioned. The reaction temperature is generally about 120 ° C to about 200 ° C, preferably about 50 ° C to about 150 ° C.

In the formula (I), A is an oxygen atom or NR ^1, B is a compound of CR ³ R ^4, or R ¹ is a hydrogen atom or a lower alkyl group, or R ³ and 3 become one cord, 4—Forms a double bond between the 3- and 4-positions of the dihydroquinoxaline ring. The compound in which X ¹ or X ² is a trifluoromethyl group can convert this trifluoromethyl group into a carboxyl group or a lower alkoxycarbonyl group by a conventional method.

In the formula (I), A is an oxygen atom or NR ^1, B is a compound of CR ³ R ^4, or R ¹ is a hydrogen atom or a lower alkyl group, or R ³ and 3 become one cord, A compound in which a double bond is formed between the 3- and 4-positions of the 4-dihydroquinoxaline ring and X ¹ or X ² is a bromine atom is converted to a cyano group or a carbamoyl group by a conventional method. , A carboxyl group, a lower alkoxycarbonyl group or a 5-tetrazolyl group.

In the formula (I), A is at NR ^1, B is CR ³ R, R ¹ and R ³ together 3, 4-dihydroquinoxaline sarin ring 3, 4 between the form a double bond By reducing the compound by a conventional method, a compound in which A is NH and B is CHR ⁴ in the formula (I) can be produced. In the formula (I), a compound in which A is NH and B is CH ₂ is an alkylating agent R ⁵ L ³ (R ⁵ is a lower alkyl group, and L ³ means a halogen atom) in an oxygen stream. Alkylation proceeds simultaneously with oxidation under the conditions of normal alkylation using, and in formula (I), A is NR ¹ , B is CR ³ R, and R ¹ and R ³ are taken together. Thus, a compound can be produced in which a double bond is formed between the 3,4-position of the 3,4-dihydroquinoxaline ring and R ⁴ is a lower alkoxy group. Further, a compound in which R ⁴ is a hydroxy group can be produced by cleaving the ether bond of R ⁴ by a conventional method. The product obtained by each of the above production methods can be isolated and purified by a conventional method such as chromatography, recrystallization, and reprecipitation.

The compound of the present invention represented by the formula (I) can be converted to an alkali metal salt by treating it with an alkali metal compound. A tool for metal compounds Examples include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, lithium methoxide, sodium methoxide and potassium tert. Metal alkoxides such as butoxide and sodium amide. The formation of salts is carried out according to a conventional method, for example, water, alcohols (eg, methanol, ethanol, isopropyl alcohol), ethers (eg, getyl ether, tetrahydrofuran, dioxane, diisopropyl ether), aromatic hydrocarbons (eg, The reaction is carried out by contacting the compound (I) with an appropriate alkali metal compound at about 120 ° C to about 50 ° C in benzene, toluene or a mixture thereof.

 The results of pharmacological tests on representative compounds of the present invention are shown below.

Test Example 11

 A spontaneously developing male hypertension rat (SHR) weighing about 300 g (16 weeks old) was subjected to a heparin-containing catheter (polyethylene tube; PE-50) for blood pressure measurement under inhalation anesthesia with getyl ether. Was placed in the left femoral artery, and the other end of the force neuron was guided out of the body through the posterior neck. After a stable period of 1 postoperatively, the test compound suspended in a tragacanth solution containing 30% polyethylene glycol was orally administered at a dose of 10 mg / kg, and blood pressure was measured. Blood pressure was measured using a real-time automatic measurement method by converting it into a digital electric signal via a pressure transducer, an amplifier and an AZD converter and taking it into a computer in order to remove noise and perform an accurate measurement.

The test results are shown in Table 6. 6 Test compound Delta MBP * ± S.E, the most decreased blood pressure after administration (represented by the example number) <, mmHg time (hr

 5 19 ± 2.9

 8 25 ± 3.3

 13 26 ± 6.7

 17 17 ± 3.4 4 10

 22 16 ± 2.1 1 10

 25 17 ± 3.5 10

 27 17 ± 3.9 9 10

 31 15 ± 3.5 5 5

 39 16 ± 2.2 9

 45 17 ± 5.9 9 9

 50 17 ± 3.8

 *: Lower blood pressure compared to the value before administration

Test Example 2

The thoracic aorta of a male Std-Wi star (body weight about 280 g) was excised, and a spiral specimen was prepared by a conventional method. After the specimen was peeled endothelial cells in cotton, modified Krebs solution (118mM N a C 1, 4. 7mM KC 1, 2. 5mM C a C 12, 1. 2mM KH 2 P0 4, 25mM NaHC0 3, 1. _{2 mM Mg S 0 4 · 7H} 2 0, 11 mM glucose) was suspended in a bus (1 OML) filled with. The resting tension 50 Omg loaded induced contractions in the winter two Refurin (10- ⁷ M). After the contraction was stabilized, the test compound was added cumulatively to examine the relaxation effect. The test compound was dissolved in a mixed solvent of polyethylene glycol: dimethyl sulfoxide (9: 1) or ethanol. It was appropriately diluted with purified water. Winter two Refurin (10- ⁷ M) due to shrinkage and high as 100%, Searching for the relaxation response as percent inhibition 50% inhibition concentration

(I Cso value) was calculated from the dose-response curve by the least squares method.

 The test results are shown in Table 7.

 Table 7

 Test compound Dissolution solvent I C 50

 2 PEG DMSO ^ 3x10- 6 M

 5 ethanol 3x10- 6 M

8 ethanol Ichiru 10- ⁶ M

 13 ethanol 3x10-6 M

 17 Ethano 3x10- 6 M

25 ethanol 2X 10— ⁶ M

 27 ethanol 3x10-6 M

 31 ethanol 3x10—6 M

 39 PEG: DMSO * 3x10-5 M

 50 PEG: DMSO * 3x10-6 M

 52 ethanol 3x10— 6 M

 58 ethanol 3x 10-6 M

 *: Polyethylene glycol: dimethyl sulfoxide (9: 1)

The compound of the formula (I) and an alkali metal salt thereof (hereinafter sometimes referred to as the compound of the present invention) have an excellent vasodilating action, hypotensive action, etc. based on a smooth muscle relaxing action, and therefore have high blood pressure. It is useful for the prevention and treatment of ischemic heart diseases such as arteriosclerosis, angina pectoris, myocardial infarction and congestive heart failure, arrhythmias, and alopecia. The compounds of the present invention may also be used in addition to cardiovascular diseases, such as cerebrovascular disorders (eg, cerebral vasospasm, migraine, dizziness), respiratory disorders. Harms (eg, reversible airway obstruction, irritable airway obstruction, bronchial asthma), gastrointestinal disorders (eg, neuro-gastrointestinal disorders, irritable bowel diseases), urinary disorders (eg, frequent urination, dysuria, incontinence) It is also useful as a treatment for various disorders associated with smooth muscle contraction.

 The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, but oral administration is preferred. The dose varies depending on the type of compound, the administration method, the patient's symptoms and age, etc., but is usually 0.1 to 50 mg Zg g Z, preferably 0.2 to: L O mg / k.

 The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As the pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, for example, lactose, glucose, mannitol, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum gaterate, crystalline cellulose, carboxymethylcellulose sodium, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin , Arabic rubber, Hydroxypropylpropylcellulose, Low-substituted hydroquinpropylcellulose, Hydroxypropylmethylcellulose, Polyvinylpyrrolidone, Polyvinyl alcohol, Light gay anhydride, Magnesium stearate, talc, Carboxy vinyl Nil polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, Cerro gelatin, - polysorbates, macrogol, vegetable oils, waxes, polyethylene glycol, propylene glycol, Echiruaruko Le, isopropyl alcohol, water and the like.

Dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, injections and the like. These preparations are prepared according to a conventional method. In the case of liquid preparations, they may be dissolved or suspended in water or other appropriate medium at the time of use. Tablets and granules may be coated by a well-known method. These preparations can contain the compound of the present invention in a proportion of 0.1% or more, preferably 0.5 to 70%. These formulations may also contain other therapeutically active ingredients.

BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described more specifically with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. The compounds were identified by elemental analysis, mass spectrum, IR spectrum, NMR spectrum, and the like. Reference example 1

 Preparation of 2- (5-chloro-2-methoxyphenyl) amino-5-trifluoromethylaniline hydrochloride:

 Dissolve 2.0 g (5.8 mmo 1) of N— (5-chloro-2-methoxyphenyl) 1-2-nitro-4-4-trifluoromethyladiline in ethanol 15τη 1, and add concentrated hydrochloric acid 0.5m1 and 5% 0.20 g of palladium on carbon was added, and the mixture was vigorously stirred at room temperature under a hydrogen stream. After absorption of the calculated amount of hydrogen gas was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.5 g (4.3 mmo 1) of the desired product.

Reference example 2

 [2- (5-Chloro-2-methoxyphenyl) amino-5-trifluoromethylarilino] Production of methyl acetate:

Dissolve 2.0 g (5.7 mmol) of 2- (5-chloro-2-methoxyfurinyl) amino-5-trifluoromethyldiamine hydrochloride obtained in Reference Example 1 in 20 ml of tetrahydrofuran Then, 3.0 ml (22 mmo 1) of triethylamine and 4.0 ml (42 mmo I) of methyl bromoacetate were added, The mixture was heated under reflux with stirring for 6 hours. After cooling, ethyl acetate was added to the reaction solution, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.5 g (3.9 mmo 1) of the desired product as a brown oil. .

Reference example 3

 [2- (5-Chloro-2-hydroxyphenyl) amino-5-trisoleolomethylarilino] Production of methyl acetate:

 Dissolve 5.0 g (15 mmo 1) 'of 2- (5-chloro-2-hydroxyphenyl) amino-5-trifluoromethyladiline hydrochloride in 3 Oml of tetrahydrofuran, 5.0 ml (36 mmo I) of triethylamine and bromoacetic acid 1.6 g (17 mmo 1) of methyl was added, and the mixture was heated under reflux with stirring for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the desired product.

Example 1

 Preparation of 1- (5-chloro-2-methoxyphenyl) -1,4-dihydro-6-trifluoromethyl-2 (1H) -quinoxalinone:

 1.5 g (3.9 mmoI) of methyl 2- [5- (5-chloro-2-methoxycarbonyl) amino-5-trifluoromethylarino] obtained in Reference Example 2 was added to toluene 5 Dissolved in Om 1 and d-camphorsulfonic acid 2.0 g

(9 mmo 1) was added and the mixture was heated under reflux with stirring for 30 minutes. After cooling, ethyl acetate was added to the reaction solution, washed with aqueous sodium bicarbonate and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with ethyl acetate hexane, and recrystallized from getyl ether / hexane to obtain 1.2 g (3.4 mm o 1) of the target product as colorless crystals. Obtained. Melting point 1.28-129 ° C

Example 2

1— (5-chloro-2-hydroxyphenyl) 1 3, 4-dihydro 6 Preparation of 1-trifluoromethyl-2 (1H) -quinoxalinone:

 0.11 g (0.28 mmo 1) of 1- (5-chloro-2-methoxyphenyl) -1,3,4-dihydro-6-trifluoromethyl-12 (1H) -quinoxalinone obtained in Example 1 was anhydrochlorinated. After dissolving in 5 ml of methylene and adding -85 ° C (0.85 mmol) of a 1 M solution of boron tribromide in methylene chloride at -78 ° C, the mixture was heated to room temperature and stirred overnight. Water was added to the reaction solution, the mixture was vigorously stirred for 30 minutes, extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from getyl ether hexane to give the desired product 0.05 g (0. Immo 1) as colorless crystals. 190-191 ° C

Example 3

Production of 1- (5-chloro-2-methoxyphenyl) 1-3,4-dihydro-13-methyl-6-trifluoromethyl-12 (1H) 1quinoxalinone: 2- (obtained in Reference Example 1 Dissolve 1.5 g (4.2 mmol) of 5-chloro-2-methoxyphenyl) amino-5-trifluoromethylaniline hydrochloride in 20 ml of tetrahydrofuran and 1.8 ml of triethylamine (13 mmo 1) And 1.4 ml (13 mmo 1) of methyl 2-bromopropionate were added, and the mixture was heated under reflux with stirring for 1 day. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a column form. Purified, and purified with 2- [2- (5-chloro-2-methoxyphenyl) amino-1-5-trifluoromethylanilino] propionate Chill was obtained as an oil. This was dissolved in toluene (50 ml), d-camphorsulfonic acid (1.0 g, 4.3 mmol) was added, and the mixture was heated under reflux with stirring for 30 minutes. After cooling, ethyl acetate was added to the reaction solution, and aqueous sodium bicarbonate was added. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from black-mouthed formnoethyl ether to give 0.82 g (2.2 mm 01) of the desired product as colorless crystals. Melting point 215 to 217 ° C Example 4

 Preparation of 1- (5-chloro-1-2-methoxyphenyl) -1-methyl-6-trifluoromethyl-2 (1H) -quinoxalinone:

 1,1- (5-Chloro-2-methoxyphenyl) -1,4-dihydroxy 3-methyl-6-trifluoromethyl-2 (1H) monoquinoxalinone obtained in Example 3. 3.18 g (8.57 mmo) 1) was dissolved in 50 ml of dioxane, 2.26 g (9.43 mmo 1) of 2,3-dichloro-5,6-dicyanol p-benzoquinone was added, and the mixture was stirred at 90 ° C. for 2 hours. After cooling, the reaction mixture was added with ethyl acetate, washed with aqueous sodium bicarbonate and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with ethyl ethyl acetate, and further recrystallized from chloroform / hexane to give 1.21 g (3.28 mmol) of the desired product. Obtained as colorless crystals. Melting point 165-166 ° C

Example 5

Preparation of 1- (5-chloro-1-2-hydroxyphenyl) -1,3-dihydro-3-methyl-6-trifluoromethyl-2 (1H) -quinoxalinone: Chloro-2-methoxy-1-unyl 3-, 4-dihydro 3-methyl-6-trifluoromethyl-2 (1H) -quinoxalinone was used as a starting material, and was treated in the same manner as in Example 2 to obtain 5- (chloro-2-unyl). (Droxyphenyl) 1-3,4-dihydro-3-methyl-6-trifluoromethyl-2 (1H) -quinoxalinone was obtained. Melting point 232 to 234 ° C Example 6 Preparation of 1- (5-chloro-2-methoxyphenyl) -1-6-trifluoromethyl-12 (1H) -quinoxalinone:

 In the same manner as in Example 4, 1- (5-chloro-2-methoxyphenyl) -13,4-dihydroxy 6-trifluoromethyl-2 (1H) -quinoxalinone obtained in Example 1 was used as a starting material. 1- (5-Chloro-2-methoxyphenyl) -1-6-trifluoromethyl-12 (1H) -quinoxalinone was obtained. 160-163 ° C

Example 7

 Preparation of 1- (5-chloro-2-methoxyphenyl) 1,3,4-dihydro 3-ethyl-6-trifluoromethyl-2 (1 H) 1-quinoxalinone: 1- (5-chloro-2) obtained in Example 6 —Methoxyphenyl) 1 6—Trifluoromethyl-2 (1H) —Quinoxalinone 1.0 g (2.8 mmo 1) was dissolved in tetrahydrofuran 2 Om I, and 1-78. At C, 3 ml of a tetrahydrofuran solution (2 M) of chlorinated ethyl magnesium was gradually added, and the mixture was stirred for 15 minutes. The temperature was raised to 150 ° C., and water was added to stop the reaction. Ethyl acetate was added to the reaction solution, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from getyl ether hexane to give 1.0 g (2.6 mmo 1) of the desired product as colorless crystals. Melting point 157-; 160. C

Example 8

Preparation of 1- (5-chloro-2-hydroxyphenyl) 1.3,4-dihydro-3-ethyl-6-trifluoromethyl-2 (1H) -quinoxalinone: Chloro-2-methoxyphenyl-1,3-dihydroxy 3-ethyl-6-trifluoromethyl-2 (1H) -quinoxalinone was used as a starting material in the same manner as in Example 2 to obtain a solution of 11- (5-chloro-1-phenyl) -quinoxalinone. Two —Hydroxyphenyl) -1,3,4-dihydro-1-ethyl-6-trifluoromethyl-2 (1H) —quinoxalinone was obtained. Melting point 168-169 ° C Example 9

 Preparation of 1- (5-chloro-2-hydroxyphenyl) -1-6-trifluoromethyl 2 (1H) -quinoxalinone:

 In the same manner as in Example 2, 11- (5-chloro-1--2-methoxyphenyl) -16-trifluoromethyl-2 (1H) -quinoxalinone obtained in Example 6 was used as a starting material. 5-Chloro-2-hydroxyphenyl-1-6-trifluoromethyl-12 (1H) -quinoxalinone was obtained. Melting point 220-2 22 ° C

Example 10

 Preparation of 1- (5-chloro-2-isopropoxyphenyl) -1,3,4-dihydro-6-trifluoromethyl-2 (1H) monoquinoxalinone:

1- (5-Chloro-2-hydroxyfunyl) -16-trifluoromethyl-12 (1H) -quinoxalinone obtained in Example 9 was converted to N, N-dimethylform with 0.80 g (2.4 mmol). The solution was dissolved in 5 ml of an amide, 2.0 ml (5. Ommo 1) of isopropyl bromide and 3.0 g (21 mmo 1) of potassium carbonate were added, and the mixture was stirred at room temperature for 2 days. Ethyl acetate was added to the reaction solution, washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure to give 1- (5-chloro-2-isopropoxyphenyl) -16-trifluoro. Oromethyl-2 (1H) -quinoxalinone was obtained as an oil. This was dissolved in 2 ml of ethanol, 5% palladium on carbon was added, and the mixture was vigorously stirred at room temperature under a hydrogen stream. After the absorption of the calculated amount of hydrogen gas was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from getyl ether / hexane to give 0.35 g (0.91 mmol) of the desired product as colorless crystals As obtained. Melting point 123-125 ° C

Example 11

 1- (2-acetoxy 5-chlorophenyl) 1-6-trifluoromethyl 2 (1H) -Preparation of quinoxalinone:

 1- (5-chloro-2-hydroxyfurunyl) -16-trifluoromethyl-2 (1H) -quinoxalinonone obtained in Example 9 1. Og (2.9 mmo 1) was added to 1 Oml (0 1 mo 1), added with 1.0 g (7.2 mmo 1) of potassium carbonate, and stirred overnight at room temperature. The reaction solution was poured into an aqueous sodium bicarbonate solution, stirred for a while, extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 1.0 g (2.6 mmo 1) of the desired product as colorless crystals. Melting point 167-169 ° 〇

Example 12

 Preparation of 1- (1-chloro-2-1-methoxy) -1-3-methoxy-6-trifluoromethyl-2 (1H) -quinoxalinone:

1.1- (5-chloro-2-methoxyfuryl) obtained in Example 1-3,4-dihydro 6-trifluoromethyl-2 (1H) -quinoxalinone 1.0 g (2.8 mmo 1) Was dissolved in 20 ml of acetone, 3.2 ml (5 lmmo 1) of methyl iodide and 1.4 g (10 mmo) of potassium carbonate were added, and the mixture was heated under reflux overnight with stirring. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to give acetate Echiru _/ to eluent: hexane, the desired product was further recrystallized from hexane to Jefferies chill ether / 0. 69 g of (1. 8mmo 1) as colorless crystals Was. Melting point 198 ~ 200 ° C Example 13

 Preparation of 1- (5-chloro-2-methoxyphenyl) -1,3-dihydro-6-trifluoromethyl-2 (1H) monoquinoxalinethione:

 1.1 g (5.6 mmo 1) of 1,1- (5-chloro-2-methoxyphenyl) -1,3-dihydro-1-6-trifluoromethyl-2 (1 H) -quinoxalinone obtained in Example 1 was dissolved in toluene. Then, 0.9 g (4. Ommo 1) of diphosphorus pentasulfide was added, and the mixture was heated and stirred at 60 ° C for 4 hours under a nitrogen stream. After cooling, the reaction solution was added with ethyl acetate, washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform, purified, and recrystallized from getyl ether / hexane to obtain 0.79 g (2.lmmol) of the desired product as brown crystals. Was. 149-151 ° C

Example 14

 Preparation of 1- (5-chloro-1-2-methoxyphenyl) -1-6-trifluoromethyl-2 (1H) -quinoxalinethione:

 2.0 g (5.6 mmo 1) of 1- (5-chloro-2-methoxyfurunyl) 1-3,4-dihydrobione 6-trifluoromethyl-2 (1H) -quinoxalinone obtained in Example 1 was obtained. After dissolving in toluene, 2.0 g (9. Ommo 1) of diphosphorus pentasulfide was added, and the mixture was heated under reflux for 1 hour. After cooling, ethyl acetate was added to the reaction solution, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane, purified and recrystallized from getyl ether / hexane to obtain 0.62 g (1.7 mmo 1) of the target product as yellow crystals. Obtained. Melting point 199-203 ° C

Example 15 Preparation of 1- (5-chloro-1-2-methoxyphenyl) -1,3,4-dihydro-4-methoxymethyl-6-trifluoromethyl-1-2 (1H) -quinoxalinone:

1- (5-chloro-1--2-methoxylunyl) -1,3-dihydro-6-trifluoromethyl-2 (1H) -quinoxalinone 15.0 g (42. Ommo 1) obtained in Example 1 ) Was dissolved in 15 Om 1 of tetrahydrofuran, 3.8 m 1 of chloromethyl methyl ether and 11.3 m 1 of diisopropylethylamine were added, and the mixture was heated under reflux with stirring for 30 minutes. After cooling, 1 Om1 of methanol and 10 ml of triethylamine were added, and the mixture was stirred for a while, and the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane, purified and recrystallized from getyl ether / hexane to obtain 12.0 g (29.9 mmo 1) of the desired product as colorless crystals. Was. Melting point 110 ~ 11 11 ° C

Example 16

 1- (5-Chloro-2-methoxyphenyl) -1,3-diethyl-3,4-dihydro 6-Trifluoromethyl-2 (1H) Production of 1-quinoxalinone:

 1.1- (5-Chloro-2-methoxyphenyl) 1-3,4-dihydro-4-methoxymethyl-6-trifluoromethyl-2 (1H) monoquinoxalinone obtained in Example 15 1.0 g (2.5 mmol) Was dissolved in 10 ml of tetrahydrofuran, and 5 ml of a tetrahydrofuran solution of lithium diisopropylamide (3.7 mm 01) was gradually added at a temperature of 78 ° C. Then, 0.4 ml of iodide chill (δ. Ommo) was added. 1) was added, and the temperature was raised to 140 ° C in 2.5 hours with stirring. After stopping the reaction by adding methanol, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

 The residue was dissolved in methanol (10 ml), concentrated hydrochloric acid (0.5 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction solution, washed with an aqueous solution of sodium bicarbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane, purified and recrystallized from getyl ether / hexane to give 0.29 g (0.94 mmo 1) of the desired product as colorless crystals Was obtained. 180-181 ° C

Example 17

1- (5-Chloro-2-methoxyphenyl) 13,4-dihydro-13,3-dimethyl-16-trifluoromethyl-2 (1H) 1-quinoxalinone 5—Black mouth 2—Methoxy fuyuru) 1, 3, Dissolve 3.2 g (8. Ommo 1) of 4-dihydroxy 4- 4-methoxymethyl-6-trifluoromethyl-2 (1H) quinoxalinone in 30 ml of tetrahydrofuran, and add lithium diisopropylamide (2 Ommo) at 78 ° C. After slowly adding 1 Oml of the tetrahydrofuran solution of 1), 1.5 ml (24 mmo) of methyl iodide was added, and the mixture was stirred for 30 minutes. After stopping the reaction by adding methanol, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water and then with a saturated saline solution, and concentrated under reduced pressure.

 The residue was dissolved in methanol (1 Oml), concentrated hydrochloric acid (0: 5 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added to the reaction solution, washed with an aqueous solution of sodium bicarbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with ethyl acetate hexane, and further recrystallized from chloroform-hexane to give 0.16 g (0.4 mmo 1) of the desired product as colorless crystals. . Melting point 179-182 ° C

Example 18

 Preparation of 1- (5-chloro-2-hydroxyphenyl) 1,3,4-dihydro 3,3-dimethyl-16-trifluoromethyl-2 (1H) -quinoxalinone:

 Example 1 Using 1- (5-chloro-2-methoxyphenyl) -1,3-dihydro-3,3-dimethyl-6-trifluoromethyl-2 (1H) -quinoxalinone obtained in Example 17 as a raw material, In the same manner as in 2, 2- (1-chloro-2-hydroxyphenyl) -1,3-dihydro-3,3-dimethyl-16-trifluoromethyl-2 (1H) -quinoxalinone was obtained. Melting point 169-: 170. C

Example 19 Preparation of 4-acetyl-1-1 (5-chloro-2-methoxyphenyl) -1,3,4-dihydro-6-trifluoromethyl-2 (1H) -quinoxalinone: 2-Methoxyphenyl) 1,3,4-dihydro 6-Trifluoromethyl-2 (1H) -quinoxalinone 1.0 g (2.8 mmo 1) was dissolved in 10 ml of acetic anhydride (0. lmo 1) and potassium carbonate was added. 1.0 g (7.2 mmo 1) was added and the mixture was stirred at room temperature overnight. The reaction solution was poured into an aqueous sodium bicarbonate solution, stirred for a while, extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from getyl ether / hexane to give 1.0 g (2.5 mmo 1) of the desired product as colorless crystals. Melting point 160-: L62. C

Example 20

 4-Acetyl-1- (5-chloro-2-hydroxyphenyl) -1,3,4-dihydro-6-trifluoromethyl-1- (1H) -quinoxalinone

 Example 2 Using 4-acetyl-1-1 (5-chloro-1--2-methoxyphenyl) -13,4-dihydro-6-trifluoromethyl-12 (1H) -quinoxalinone obtained in Example 19 as a raw material In the same manner as described above, 41-acetyl-1-1 (5-chloro-2-hydroxyphenyl) -13,4-dihydro-16-trifluoromethyl-2 (1H) -quinoxalinone was obtained. Melting point 210-2 12 ° C

Example 21

 Production of 1- (5-chloro-1--2-methoxyphenyl) -1-6-methoxycarbonyl-2 (1H) -quinoxalinone:

1,1- (5-chloro-2-methoxyphenyl) -1,3 obtained in Example 1 4-Dihydro 6-trifluoromethyl-1- (1H) -quinoxalinone 1.0 g (2.8 mmo 1) is dissolved in n-butanol (5 ml), 15% aqueous sodium hydroxide is added, and the mixture is stirred for 1 hour. Heated to reflux. After cooling, water and ethyl acetate were added to the reaction solution, concentrated hydrochloric acid was added dropwise to make it acidic, and the insolubles were filtered off. The organic layer was separated and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran, a calculated amount of a dimethyl ether solution of diazomethane was added, the mixture was stirred, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane, purified, and recrystallized from methanol to give [2- (5-chloro-1--2-methoxyphenyl) amino-5-methoxy] Carbonylanilino] 0.40 g (1. Immo 1) of methyl acetate was obtained. Melting point 147-149. C

 0.35 g (0.92 mmol) of this was dissolved in 10 ml of toluene, 0.10 g (0.43 mmol) of d-camphorsulfonate was added, and the mixture was heated under reflux for 1 hour. After cooling, ethyl acetate was added to the reaction solution, washed with aqueous sodium bicarbonate and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with ethyl acetate hexane, and recrystallized from getyl ether / hexane to give 0.22 g (0.64 mmo 1) of the desired product as colorless crystals. Obtained. Melting point 147-148 ° C

Example 22

 Preparation of 1- (5-chloro-1-2-methoxyphenyl) -1-6-carboxy-1 (1H) -quinoxalinone:

1.5 g (4.4 mmol) of 1- (5-chloro-2-methoxyphenyl) -16-methoxycarbonyl-12 (1H) -quinoxalinone obtained in Example 21 was dissolved in 15 ml of methanol. 15% aqueous sodium hydroxide solution 3 ml was added, and the mixture was heated under reflux with stirring for 2 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with 5% hydrochloric acid and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate and purified, and further recrystallized from getyl ether ethyl acetate to obtain 0.75 g (2.3 mmol) of the desired product as colorless crystals. . 230-232 ° C

Example 23

 Preparation of 1- (5-chloro-1-2-methoxy-3-nitrophenyl) 1-6-trifluoromethyl-2 (1H) -quinoxalinone:

 1- (5-chloro-2-methoxyphenyl) -1,3,4-dihydro-6-trifluoromethyl-1 2 (1H) -quinoxalinone 2.0 g (5.6 mmo 1) obtained in Example 1 was used. The solution was dissolved in 20 ml of concentrated sulfuric acid, and 10 ml of a concentrated sulfuric acid solution containing 0.85 g (8.4 mmo 1) of potassium nitrate was added at 0 ° C., followed by stirring for 30 minutes. The reaction solution was poured into ice water and stirred for a while, and the deposited precipitate was collected by filtration, washed with water, and dried. This was subjected to silica gel gel chromatography, eluted with ethyl acetate / hexane, purified, and recrystallized from getyl ether ethyl acetate to obtain 0.36 g (0.90 mmol) of the target product as yellow crystals. Obtained. Melting point 212-214 ° C

Example 24

 Preparation of 6-bromo-11- (5-chloro-2-methoxyphenyl) -1,4-dihydro 2 (1H) -quinoxalinone:

Dissolve 5_chloro-0-anisidine 11.3 g (71.2 mol) and 2,4-dibromonitrobenzene 20.0 g (71.2 mmol) in N, N-dimethylformamide 8 Om1 Then, 11.3 g (78.3 mmo 1) of copper bromide and 30.0 g (214 mmo 1) of potassium carbonate were added to obtain 1 The mixture was heated and stirred at 20 ° C for 4 hours. After cooling, the reaction solution was filtered and concentrated under reduced pressure. The residue was subjected to column chromatography, eluted and purified with chloroform / hexane, and recrystallized from chloroform / methanol to give 4-promo-N- (5-chloro-1--2-methoxy-2-ene). 1) 1-2-Nitroaniline (14.6 g, 40.8 mmo 1) was obtained as orange crystals. Melting point 198-199 1.0 g (2.8 mmo 1) of this was dissolved in 40 ml of ethanol and 20 ml of water, and 1.5 g (28 mmo 1) of iron and 1.5 g (28 mmo 1) of ammonium chloride were added thereto. And heated and stirred at 100 ° C for 2 hours. The reaction solution is concentrated under reduced pressure, ethyl acetate is added, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5-bromo-2- (5-chloro-2-methoxyphenyl). 94 g (2.8 mmo 1) of aminoaniline were obtained as a colorless oil.

 This was dissolved in 20 ml of tetrahydrofuran, 2.0 ml (2 Ommo) of methyl bromoacetate and 3.0 ml (22 mmo 1) of triethylamine were added, and the mixture was heated under reflux with stirring for 8 hours. The reaction solution is concentrated under reduced pressure, added with ethyl acetate, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude [5-bromo-2- (5-chloro-2) —Methoxyphenyl) aminoazirino] methyl acetate was obtained as a pale yellow oil.

This was dissolved in 1 Om 1 of toluene, 0.50 g (2.2 mmol) of d-camphorsulfonic acid was added, and the mixture was heated under reflux with stirring for 30 minutes. After cooling, the reaction mixture was added with ethyl acetate, washed with aqueous sodium bicarbonate and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with ethyl hexane acetate, and the residue was recrystallized from getyl ether hexane to obtain 0.35 g (0.95 mmo 1) of the desired product as colorless crystals. Was. 132-134 ° C Example 25

 Preparation of 1- (5-chloro-2-hydroxyphenyl) -3-phenyl-6-trifluoromethyl-2 (1H) -quinoxalinone:

 2- (5-Chloro-2-hydroxyphenyl) amino-5-trifluoromethyldiamine hydrochloride 1.0 g (3. Ommo 1) was dissolved in 1 OmI of ethanol, and methyl phenylglyoxylate 2.1 ml (15 mmo 1 ) And stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, washed with an aqueous sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane and purified, and recrystallized from getyl ether / hexane to give 0.50 g (l.2 mmol) of the target compound as colorless crystals. I got it. Melting point 216-223 ° C

Example 26

 Preparation of 1- (5-chloro_2-hydroxyphenyl) -1-methyl-6-trifluoromethyl-1- (2H) -quinoxalinone:

 Dissolve 0.50 g (l. 5 mmo 1) of 2- (5-chloro-2-hydroxyphenyl) amino-5-trifluoromethyladiline hydrochloride in 5 ml of concentrated sulfuric acid and add 1.2 ml (18 mmo I) of pyruvic acid. The mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water, stirred for a while, made basic by adding sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane, purified and recrystallized from getyl ether / hexane to give 0.12 g (0.34 mmo 1) of the target product as colorless crystals. I got it. 208-212 ° C

Example 27 Preparation of 1- (2-acetoxy 5-chlorophenyl) 1-3-methyl-6-trifluoromethyl-2 (1H) monoquinoxalinone:

 Using 1- (5-chloro-2-hydroxyphenyl) -13-methyl-16-trifluoromethyl-2 (1H) -1-quinoxalinone obtained in Example 26 as a raw material, 1 1- (2-acetoxy-5-chlorophenyl) -1-methyl-6-trifluoromethyl-2 (1H) -quinoxalinone was obtained. Melting point 169-171 ° C

Example 28

Preparation of 1- (2-acetoxy-5-chlorophenyl) 1-3,4-dihydro-13-methyl-16-trifluoromethyl-2 (1H) 1-quinoxaline: 2-acetoxy-5-chlorophenyl) ― 3-methyl-6-trifluoromethyl-2 (1H) monoquinoxalinone 0.3 δ g (0.88 mmo 1) was dissolved in 20 ml of ethyl acetate, and 5% palladium ゥThen, 0.05 g of carbon was added, and the mixture was vigorously stirred at room temperature under a hydrogen stream. After absorption of the calculated amount of hydrogen gas, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane, and purified to purify the target compound. 23 g (0.58 mmo 1) were obtained as a colorless oil. IR spectrum (neat): 3340, 1770, 1690, 1370, 1180, 1120 cm- ¹

Example 29 "'

 Preparation of 1- (5-chloro-2-hydroxyphenyl) -1,3,4-dihydro 6-trifluoromethyl-2 (1H) -quinoxalinone (identical to the compound of Example 2):

[2- (5-Chloro-2-hydroxyfurnyl) aminnow 5-trifluoromethylanilino] obtained in Reference Example 3 Methyl acetate was converted to methanol 3 Om It was dissolved in I, and anhydrous potassium carbonate (5.0 g, 36 mmo 1) was added, followed by stirring at 45 ° C for 2 hours. After cooling, the reaction solution was extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure.

 The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane, and purified to obtain a crude target compound. This was further subjected to medium-pressure ram chromatography using Diaion C HP-20P (trademark) (high-porous polystyrene resin (75 to 150 m), Mitsubishi Kasei) to obtain aceto nitrirno water (0 to 50% concentration). After elution and purification on a gradient, the residue was recrystallized from getyl ternohexane to give 2.8 g (yield 55%) of the desired product as colorless crystals. Melting point 190 ~: 191 ° C

Example 30

 Preparation of 6-chloro-4- (5-chloro-2-methoxyphenyl) -1H-1, 4-benzoxazine-1 (4H) one:

 A mixture of 20 g (0.13 mol 1) of 5-chloro-0-anisidine and 22 g (0.1 Omo 1) of 2-bromo-4-monochlorodisole was added to the mixture, and 19 g of copper iodide (I) (0.10 m 01) and 21 g (0.15 mo1) of potassium carbonate were added and heated and stirred at 170 ° C for 20 hours. After cooling, ethyl acetate was added to the reaction solution, which was washed with a 10% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane and purified to obtain 4.8 g (16 mmol) of di (5-chloro-2-methoxyphenyl) amine as colorless crystals. Melting point 118-120 ° C

Dissolve 2.0 g (6.7 mm o 1) of this in 2 O ml of methylene chloride, and add 3.4 m 1 (3.4 mm o 1) of a 1 M solution of boron tribromide in methylene chloride at 20 ° C. Then, the mixture was stirred at room temperature for 5 hours. Add water to the reaction solution, After stirring, the mixture was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium bicarbonate and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane, purified and purified with 4-chloro-2- (5-chloro-2-methoxyphenyl) aminophenol 1.lg (3.9mmo 1). Obtained as an oil. This was dissolved in 4 Om 1 of tetrahydrofuran, 4.8 ml (5 Ommo 1) of methyl bromoacetate and 6.Oml (43 mmo 1) of triethylamine were added, and the mixture was heated under reflux with stirring for 1 day. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted and purified with ethyl acetate / hexane. [4-Chloro-2- (5-chloro-1--2-methoxyphenyl) aminophenoxy] methyl acetate 1.4 g ( 3.8 mm 01) was obtained as an oil.

 This was dissolved in 5 Om1 of toluene, 0.1 g (0.43 mmo1) of d-camphorsulfonic acid was added, and the mixture was heated under reflux with stirring for 1.5 hours. After cooling, ethyl acetate was added to the reaction solution, which was washed with aqueous sodium bicarbonate and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and the residue was recrystallized from getyl ether to give 1.0 g (3.lmmo 1) of the desired product as colorless crystals. Melting point 149-152 ° C

Example 31

 Preparation of 6-chloro-1-41- (5-chloro-2-hydroxyphenyl) -2-H-1,4-benzoxazine-3 (4H) one

Using 6-chloro-41- (5-chloro-1--2-methoxyphenyl) -1-2H-1,4-benzoxazine-13 (4H) -one obtained in Example 30 as a raw material In the same manner as in Example 2, 6-chloro-41- (5-chloro-2-hydroxyphenyl) -12H-1,4,4-benzoxazine-13 (4H) one was obtained. Melting point 250-253 ° C

Example 32

 Preparation of 4- (5-chloro-2-methoxyphenyl) -1 7-trifluoromethyl-1 2H-1,4,4-benzoxazin-1 3 (4H) -one:

 0.80 g (2 Ommo 1) of 60% sodium hydride in oil was washed with hexane, dried under reduced pressure, suspended in 30 ml of N, N-dimethylformamide, and fluorinated at 0 ° C. —Trifluoromethylphenol 2. δ g (14 mmo 1) was added and stirred for 10 minutes. Then, 2.3 g (15 mm 01) of methyl bromoacetate was added, and the mixture was further stirred at 0 ° C for 15 minutes. The reaction solution was poured into a mixed solvent of ice water and ethyl acetate Z hexane 1: 1. The organic layer was separated, washed with a 10% aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. did. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate Z-hexane and purified to give 3.0 g (12 mmo 1) of methyl (2-fluoro-5-trifluoromethylphenoxy) acetate. Obtained.

To 2.5 g (1 Ommo 1) of this was added 1.8 g (l lmmol) of 5-chloro-o-anisidine, and the mixture was dissolved by heating at 100 ° C for 30 minutes. Then, potassium t-butoxide 0.20 g (l. 8 mmo 1) was added and the mixture was further heated and stirred at 100 ° C. After cooling, ethyl acetate was added to the reaction solution, washed with 10% hydrochloric acid and then with an aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel gel chromatography, eluted with ethyl acetate and hexane and purified to give N- (5-chloro-2-methoxyphenyl) -12-fluoro-5-trifluoromethylphenoxyacetic acid. 2.0 g (δ. Immo 1) were obtained as colorless crystals. 156 ~ 15 7 ° C

0.10 g (0.26 mmol) of this was dissolved in 1 ml of N, N-dimethylformamide, 0.10 g (0.72 mmol) of potassium carbonate was added, and the mixture was heated under reflux with stirring for 30 minutes. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane and purified to obtain 0.070 g (0.20 mmol) of the desired product as a colorless oil. IR (neat): 1710, 1500, 1330, 1120 cm- ¹ Example 33

 Preparation of 4- (5-chloro-1--2-hydroxyphenyl) -1-7-trifluoromethyl-2H-1,4-benzoxazine-1 3 (4H) -one:

 Using the 4- (5-chloro-2-methoxyfuryl) -17-trifluoromethyl-1 2H-1,4-benzoxazine-13 (4H) -one obtained in Example 32 as the starting material, Example 2 In the same manner as described above, 4- (5-chloro-2-hydroxyfurnyl) -17-trifluoromethyl-1 2H-1,4-benzoxazin-13 (4H) -one was obtained. Melting point 198 ~ 199 ° C

Example 34

 Preparation of 4- (5-chloro-2-methoxyphenyl) -1-6-trifluoromethyl-2H-1,4,4-benzoxazine-1 (4H) one:

3.2 g (8 Ommo 1) of 60% sodium hydride in oil was washed with hexane, dried under reduced pressure, suspended in 100 ml of N, N-dimethylformamide, and dried at 0 ° C for 2-fluoro- After 10 g (56 mmo 1) of 4-trifluoromethylphenol was added dropwise over 5 minutes, the mixture was stirred for 10 minutes. Then, 9.2 g (6 Ommo 1) of methyl bromoacetate was added, and the mixture was further stirred at 0 ° C for 15 minutes. The reaction solution was poured into a mixed solvent of ice water and ethyl acetate hexane = 1/1. Thereafter, the organic layer was separated, washed with a 5% aqueous sodium hydroxide solution, then with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (2-fluoro-14-trifluoromethylphenoloxy). 12.2 g (48.4 mmol) of methyl acetate were obtained as colorless crystals.

 To 11.0 g (43.6 mmo) of this, add 16.0 g (102 mmo 1) of 5-chloro-0-anisidine, heat and dissolve at 100 ° C, and add potassium t-butoxide 1. Og (9. Ommo 1) was added, and the mixture was further heated and stirred at 100 ° C for 30 minutes. After cooling, ethyl acetate was added to the reaction solution, which was washed with 10% hydrochloric acid, an aqueous solution of sodium bicarbonate and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were triturated with hexane to give 8.4 g (22 mmo 1) of N- (5-chloro-1--2-methoxyphenyl) -12-fluoro-4-trifluoromethylphenoxyacetic acid amide. Was obtained as colorless crystals.

 Of these, 7.5 g (19 mmo 1) was dissolved in 50 ml of N, N-dimethylformamide, 10 g (72 mmo 1) of potassium carbonate was added, and the mixture was heated under reflux with stirring for 1 hour. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, purified by elution with ethyl acetate hexane, and further recrystallized from ether hexane to obtain 5.4 g (15 mmol) of the desired product as colorless crystals. Melting point 110-111 ° C

Example 35

 Preparation of 4- (5-chloro-2-hydroxyphenyl) -1-6-trifluoromethyl-2H-1,4-benzoxazine-13 (4H) -one:

4- (5-chloro-2-methoxyphenyl) -16-trifluoromethyl-2H-1,4-benzoxazine-13 (4H)-obtained in Example 34 Using ON as a raw material, 4- (5-chloro-2-hydroxyphenyl) -6-trifluoromethyl-l-2H-l, 4-benzoxazin-l- (4H) -l-one was obtained in the same manner as in Example 2. Was. 210 ~ 211 ° C

Example 36

 Preparation of 4- (2-acetoxy-5-chlorophenyl) -6-trifluoromethyl-1 2H-1,4-benzoxazine-1 3 (4H) one: 4- (5-chloro-2) obtained in Example 35 —Hydroxyphenyl) -1 6-Trifluoromethyl-2H— 1,4 Benzoxazine 13 (4H) 1one as a starting material, in the same manner as in Example 11, to obtain 4- (2-acetoxy-5-chlorophenyl) 1 6-Trifluoromethyl-1 2 H-1,4 benzoxazine-3 (4H) one was obtained. Melting point 98-99 ° C

Example 37

 Preparation of 6-bromo-41- (5-chloro-2-methoxyphenyl) -1H-2,4-benzoxazine-1-3 (4H) one:

10.3 g (257 mmo 1) of 60% sodium hydride in oil was washed with hexane, dried under reduced pressure, suspended in 200 ml of N, N-dimethylformamide, and dried at 0 ° C for 2,4-dibs. 50.0 g (198 mmo 1) of mouth morphol was added dropwise over 10 minutes, followed by stirring for 10 minutes. Then, 20.6 ml (218 mmo 1) of methyl bromoacetate was added dropwise over 10 minutes, and the mixture was further stirred at 0 ° C for 15 minutes. The reaction solution was poured into a mixed solvent of ice water and ethyl acetate Z hexane = 1/1, and the organic layer was separated, washed with a 5% aqueous sodium hydroxide solution, then with a saturated saline solution, and dried over anhydrous magnesium sulfate. After drying over, the mixture was concentrated under reduced pressure. The residue was recrystallized from getyl ether hexane to obtain methyl 2,4-dibromofunooxyacetate (56.91 g, 176ramo 1) as colorless crystals. 1.6 g (1 Ommo 1) of 5-chloro-o-anisidine was added to 3.0 g (9.2 mmol) of this, dissolved by heating at 100 ° C, and then 0.2 g of potassium tert-butoxide (l Then, the mixture was heated and stirred at 100 ° C for 15 minutes. After cooling, ethyl acetate was added to the reaction solution, which was washed with 10% hydrochloric acid, an aqueous solution of sodium bicarbonate and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from chloroform to give N- (5-chloro-2-methoxyphenyl) -1,2,4-dibromophenoxyacetic acid amide 1.lg (2.4 mmo 1) as colorless crystals. 223-224 ° C

 1.0 g (2.2 mmol) of this was N, N-dimethylformamide

After dissolving in 5 ml, 1.0 g (7 mm 01) of potassium carbonate and 0.32 g (2.2 mmo 1) of copper (I) bromide were added, and the mixture was heated and stirred at 100 ° C overnight. A heated and stirred mixed solvent of ethyl acetate / hexane = 1/2 was added to the reaction solution, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from ether hexane to give the desired product.

60 g (1.6 mmo 1) were obtained as colorless crystals. Melting point 133-: L 34 Example 38

 Preparation of 6-bromo-1- (5-chloro-2-hydroxyphenyl) -1-H-1,4-benzoxazine-1 (4H) one:

The same procedure as in Example 2 was carried out except that the 6-bromo-1- (5-chloro-2-methoxif: nil) -1-H-1,4-benzoxazine-13 (4H) one obtained in Example 37 was used as a raw material. This gave 6-promo 41- (5-chloro-1-2-hydroxyphenyl) -12H-1,4-benzoxazine-13 (4H) one. 258-260 ° C Example 39

 Preparation of 4- (5-chloro-2-2-methoxyphenoxy) -1-6-cyano 2H-1,4-benzoxazine-1 (4H) one:

 6-Promo 4- (5-chloro-2-methoxyphenyl) -1-2H-1,4-benzoxazine-1 3 (4H) -one obtained in Example 37 2.0 g (5.411111110 1)? ^ N-Dimethylformamide was dissolved in 5 ml, copper cyanide (1) 0.54 g (6. Ommo 1) was added, and the mixture was heated and stirred at 130 ° C for 20 hours. The reaction solution was cooled to 50 ° C., 3.0 g (18 mmo 1) of iron chloride (ΊI1) and 30 ml of 15% hydrochloric acid were added, and the mixture was stirred with heating for 10 minutes. After cooling, the reaction solution was poured into ice water containing sodium bicarbonate, stirred for a while, extracted with ethyl acetate, the organic rhino was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with ethyl acetate / hexane, and recrystallized from ethyl acetate / ethyl ether to obtain 0.93 g (2.9 mmo 1) of the desired product as colorless crystals. Was. Melting point 259-261 ° C

Example 40

 Preparation of 6-Rubamoyl-4-1 (5-Chr-1 -Methoxyphenyl) -1 2H-1 1,4 -Benzoxazine-1 3 (4H) -one:

Forty-one (5-chloro-2-methoxyfurunyl) -1-6-cyano 2H-1,4 obtained from Example 39, 1-benzoxazine-13 (4H) -one 1.0 g (3.2 mmo 1) and polyphosphoric acid 6 g Was added, and the mixture was heated and stirred at 120 ° C for 30 minutes. After cooling to 60 ° C, water was added and the mixture was stirred for a while. The precipitated solid was collected by filtration, washed with water, and dried. This was subjected to silica gel column chromatography, eluted with ethyl acetate and purified, and further recrystallized from ethyl acetate to obtain 0.80 g (2.4 mmo 1) of the target substance as colorless crystals. Melting point 247 ~ 2 δ 0. C

Example 41

 Preparation of 6-potassium 4- (5-chloro-2-hydroxyphenyl) -1-H-1,4-benzoxazine-3- (4H) one:

 The same procedure as in Example 2 was carried out using 6-force rubamoyl-4-1 (5-chloro-2-methoxyphenyl) -1-2H-1,4-benzodoxazine-13 (4H) -one obtained in Example 40 as a raw material. 6-force rubamoyl-41- (5-chloro-2-hydroxyphenyl) -1-2H-1,4-benzoxazine-13 (4H) -one was obtained. 285-287 ° C

Example 42

 Preparation of 4- (5-chloro-2-methoxyphenyl) -1-6- (5-tetrazolyl) -2H- 1,4-benzoxazine-1 3 (4H) -one:

0.41 g (1.311111110 1) of 1- (5-chloro-2-methoxyphenyl) -1-6-cyano 2H-1,4-benzoxazine-1-3 (4H) -one obtained in Example 39 was added to 1 Dissolved in 5 ml of ^, N-dimethylformamide, added 0.17 g (2.6 mmo 1) of sodium azide and 0.14 g (2.6 mmo 1) of ammonium chloride, and heated and stirred at 90 ° C overnight. . After cooling, water was added to the reaction solution, acidified by adding concentrated hydrochloric acid, extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the residue _c concentrated under reduced pressure was subjected to silica gel column chromatography. The residue was purified by elution with chloroform / methanol, and further recrystallized from methanol-Z-ethyl ester to give 0.22 g (0.61 mmo〗) of the desired product as colorless crystals. Melting point 2

37-239 ° C (decomposition)

Example 43

4- (5-chloro-2-hydroxyphenyl) -1-6-cyano 2H-1, Preparation of 4 Benzoxazine 1 3 (4H) — ON:

 Using the 4-one (5-chloro-2-methoxyphenyl) 16-cyano-2H, —1,4,4-benzoxazine-13 (4H) one obtained in Example 39 as a raw material, In a similar manner, 4- (5-chloro-2-hydroxyphenyl) -16-cyano-2H-1,4-benzoxazine-3 (4H) one was obtained. 272-274 ° C

Example 44

 Preparation of 4- (5-chloro-2-hydroxyphenyl) 6- (5-tetrazolyl) -1H-1, 4-benzoxazine-13 (4H) one One: 4- (5-) obtained in Example 43 Chloro-2-hydroxyfurnil) 1-6-Cyanol 2H-1,4-Benzoxazine-1 3 (4H) 1-0.9

6 g (3.21111110 1) was dissolved in 10 ml of 1 ^, N-dimethylformamide, and 0.62 g (9.5 mmo 1) of sodium azide and 0.54 g of ammonium chloride (1 Ommo 1 ) And stirred under heating at 90 ° C for 22 hours. After cooling, water was added to the reaction solution, acidified by further adding concentrated hydrochloric acid, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform-formanol, and further recrystallized from methanol to afford the desired product.

79 g (2.3 mmo 1) were obtained as colorless crystals. Melting point> 300 ° C (decomposition) Example 45

 Preparation of 6-carboxy-1- (5-chloro-2-methoxyphenyl) -1-H- 1,4-benzoxazine-l-3 (4H) -one:

3.0 g (9.5 mmo 1) of 4- (5-chloro-2-methoxyfurnyl) 16-cyano-2H—1,4-benzoxazine 13 (4H) -one obtained in Example 39 was added. Dissolve in 50 ml of ethanol and add 15% sodium hydroxide 3 Om 1 was added thereto, and the mixture was heated under reflux for 3 hours with stirring. 50 ml of ethanol and 15 ml of concentrated hydrochloric acid were added to the reaction solution, and the mixture was heated under reflux for 1 hour with stirring. Water was added to the reaction solution, ethanol was distilled off under reduced pressure, and the precipitate was collected by filtration, washed with water and dried. This was subjected to silica gel column chromatography, eluted and purified with ^ ethyl, and further recrystallized from ethyl acetate to obtain 2.1 g (6.3 mmo 1) of the desired product as colorless crystals. Melting point 258-259 °

Example 46

 Preparation of 6-carboxy-1- (5-chloro-2-hydroxyphenyl) -1H-1,4-benzoxazine-1 (4H) one:

 Using 6-carboxy-41- (5-chloro-2-methoxyphenyl) -12H-1,4-benzoxazine-13 (4H) one obtained in Example 45 as a raw material in the same manner as in Example 2 6-carboxy-41- (5-chloro-1--2-hydroxyphenyl) -12H-1,4-benzoxazine-13 (4H) one was obtained. Melting point 288-290 ° C

Example 47

 Preparation of 4- (5-chloro-2-hydroxyphenyl) -1-6-methoxycarbonyl 2H— 1,4-benzoxazine-1 3 (4H) -one:

6-Carboxy-41- (5-chloro-2-hydroxyphenyl) -1-H-1.4-Benzoxazine-13 (4H) one obtained in Example 46 0.30 g (0.94 mmo 1) was converted to methanol. It was dissolved in a mixed solvent of 8 ml and 2 ml of toluene, 4 ml of a hexane solution of trimethylsilyldiazomethane (2 M) was added, and the mixture was stirred at room temperature for a while. After the reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, eluted and purified with chloroform / methanol, and recrystallized from getyl ether / hexane to obtain 22 g of the desired product (0.66 mmo 1) was obtained as colorless crystals. Melting point 25 1 to 253 ° C

Example 48

 Preparation of 4- (5-chloro-1--2-methoxyphenyl) -1-6-methoxycarbonyl-2H-1,4-benzoxazine-1- (4H) -one:

 0.40 g (1.2 mmo 1) of 6-carboxy-1- (5-chloro-2-methoxyphenyl) -1-2H-1,4-benzoxazine-13 (4H) -one obtained in Example 45 was added. After dissolving in 30 ml of methanol, a calculated amount of a solution of dimethylmethane in getyl ether was added, and the mixture was stirred at room temperature. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from getyl ether hexane to give 0.39 g (l. Lmmo 1) of the desired product as colorless crystals. 149-151 ° C

Example 49

Preparation of 4- (5-chloro-2-methoxyphenyl) -1-3 (4H) -oxo-2H-1,4-benzoxazine-6-potassium sodium sorbate: 6-potassium obtained in Example 45 — (5—Chloro-2-methoxyphenyl) 1 2H— 1,4-benzoxazine 13 (4H) —one 0.40 g (1.2 mmo 1) is suspended in 30 ml of water, and sodium bicarbonate 0.17 g (2.0 mm 01) was added and stirred. The reaction solution was concentrated under reduced pressure to 10 ml, and sodium chloride was added to precipitate crystals. This was collected by filtration to obtain 0.43 g (l. Lmmo 1) of the desired product, 0.75 hydrate, as colorless crystals. Melting point 2 25-235 ° C Example 50

 Preparation of 1- (5-chloro-2-methoxyphenyl) -1-6-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione:

 Dissolve 20.0 g (127 mmo 1) of 5-chloro-0-anisidine in 20 Om 1 of methylene chloride, add 10. Oml (13 Ommo 1) of methyl carbonate and 13.5 ml (13 Ommo 1) of pyridine. The mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 15% hydrochloric acid and then with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from getyl i-ternohexane to give 26.8 g (124 mmo 1) of N-methoxycarbonyl-5-chloro-0-anisidine as colorless crystals.

 17 g (79 mmo1) and 10 g (48 mmo1) of 2-fluoro-5-trifluoromethylbenzamide were dissolved in 10 ml of N, N-dimethylformamide, and 30 g of potassium carbonate (22 mmo1) was dissolved. ) Was added and the mixture was heated and stirred at 140 to 150 ° C. for 2 hours. Ethyl acetate was added to the reaction solution, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from getyl ether to give 3.9 g (1 lmmo 1) of the desired product as colorless crystals. With melting point 288-289

Example 51

 Production of 1- (5-chloro-2-methoxyphenyl) 1- (2-ditroxethyl) 1-6-trifluoromethyl-1,2,4 (1H, 3H) -quinazolinedione:

1- (5-Chloro-2-methoxyfurnyl) 1-6-trifluoromethyl-2,4 (1H, .3H) -quinazolinedione obtained in Example 50 1.0 g (2.771111110 1) Was dissolved in 2 ml of 1 \ N-dimethylformamide, and 2 g of 2-bromonitroxetane and 2.0 g of potassium carbonate (14 mm o 1) was added and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate hexane, and purified to give 1.lg (2.4 mmol) of the desired product as a colorless oil. IR (neat): L 1720, 1680, 1630, 1330, 1280, 1130 cm- ¹

Example 52

 Preparation of 1- (5-chloro-1-2-hydroxyphenyl) -6-trifluoromethyl-1,2,4 (1H, 3H) -quinazolinedione:

 The same procedure as in Example 2 was carried out, except that 1- (5-chloro-1--2-methoxyphenyl) -6-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione obtained in Example 50 was used as a raw material. 1- (5-chloro-1--2-hydroxyphenyl) -1-6-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione was obtained. Melting point 238-239

Example 53

 1- (5-chloro-2-phenyloxy) 1-3- (2-nitroxyethyl) 1-6-trifluoromethyl-2,4 (1H, 3H) -Preparation of quinazoline dione:

1- (5-chloro-2-hydroxyphenyl) -1-6-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione obtained in Example 52 was converted from 0.4 δg (1.311111 0 1) to 1 Dissolve in 5 ml of N-dimethylformamide, add 0.25 g (1.5 mmol) of 2-bromonitroxetane and 0.41 g (3. Ommo 1) of potassium carbonate and add room temperature For 1 hour. Ethyl acetate was added to the reaction solution, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Residue is silica gel column Applied to oral chromatography, eluted with ethyl acetate hexane

0.32 g (0.72 mmo 1) was obtained as a colorless oil. IR (neat): 3320, 1720, 1650, 1630, 1330, 1280, 1130 cm " ¹

Example 54

 1- [5-Chloro-2- (2-hydroxyethoxy) phenyl] 1-3- (2-Hydroxitytyl) 6-Trifluoromethyl-2,4 (1H, 3H) -Quinazolinedione: '

 0.70 g (2. Ommol) of 0.71 g (2. Ommol) of 11- (5-chloro-1--2-hydroxyphenyl) -1 6-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione obtained in Example 52 was , N-dimethylformamide dissolved in 5 ml, 2-bromoethyl methoxymethyl ether 1.Og (6.Ommo 1) and potassium carbonate 3.0 g (22 mmo 1) were added and stirred at 80 ° C for 1 hour did. Ethyl acetate was added to the reaction solution, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol 2 Om], 15% hydrochloric acid 11111 was added, and the mixture was heated under reflux with stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate. ♦ Purified, and recrystallized from getyl ether to obtain 0.56 g (l.3 mmo 1) of the desired product Obtained as colorless crystals. Melting point 125-126 ° C

Example 55

 1- (5-chloro-2-phenyloxy) 1-3- (2-hydroxyethyl) 16-trifluoromethyl1.2,4 (1H, 3H) -Quinazoline dione: '

1- (5-chloro-2-methoxyphenyl) -1 obtained in Example 50 —Trifluoromethyl-2,4 (1H, 3H) -quinazolinedione 0.80 g (2.2 mmol) is dissolved in N, N-dimethylformamide 10 m], and 2-bromoethyl methoxymethyl ether is dissolved. 0.51 g (3. Ommo 1) and 1.5 g (1 lmmo 1) of potassium carbonate were added, and the mixture was stirred at 80 ° C for 1 hour. Ethyl acetate was added to the reaction solution, washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 5 ml of methylene chloride, and 10 ml (1 Ommo 1) of a solution of boron tribromide in methylene chloride (1 M) was added at 0 ° C., followed by stirring at 0 ° C. for 30 minutes. Water was added to the reaction solution, stirred for a while, extracted with ethyl acetate, and the organic layer was washed with aqueous sodium bicarbonate and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with ethyl acetate Z-hexane, and further recrystallized from getyl ether to obtain 0.25 g (0.62 mmol) of the desired product as colorless crystals. 201-202 ° C

Example 56

 Preparation of 1- (5-chloro-2-methoxyphenyl) -1 7-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione:

N-Methoxycarboxy 5-5-chloro-0-anisidine 0.77 g (3.7 mmo 1) and 2-fluoro-4-trifluoromethylbenzamide 0.80 g (3.7 mmo 1) plus potassium carbonate 1 5 g (l lmmol) was added, and the mixture was heated and stirred at 150 ° C for 30 minutes. Ethyl acetate was added to the reaction solution, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from chloroform-hexane to give 0.30 g (0.8 lmmo 1) of the desired product as colorless crystals. Was. Melting point 219-221 ° C Example 57

 Preparation of 1- (5-chloro-2-methoxyphenyl) -1-3- (2-nitroxethyl) -17-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione:

Using 1- (5-chloro-2-methoxyphenyl) 17-trifluoromethyl-1,2,4 (1H, 3H) -quinazolinedione obtained in Example 56 as a raw material, 1 1- (5-chloro-1--2-methoxyphenyl) 1-3- (2-nitroxie 80-tyl) 1-7-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione as a colorless oil . IR (neat): 1720, 1680, 1640, 1460, 1350, 1280, 1130 cm " ¹

Example 58

 Preparation of 1- (5-chloro-2-hydroxyphenyl) -1 7-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione:

 The same procedure as in Example 2 was carried out except that the 1- (5-chloro-1--2-methoxyphenyl) -17-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione obtained in Example 56 was used as a raw material. There was obtained 1- (5-chloro-1--2-hydroxyphenyl) -17-trifluoromethyl-2,4 (1H, 3H) -quinazolinedione. Melting point 249-251 ° C

Industrial applicability

 The compound (I) and the alkali metal salt thereof of the present invention have excellent vasodilatory and hypotensive effects based on smooth muscle relaxing effects, and are therefore useful as drugs such as therapeutic drugs for cardiovascular diseases.

Claims

Compound represented by the following formula (I) or an alkali metal salt thereof _c Request

Wherein A represents an oxygen atom, a carbonyl group or NR ¹ , wherein R ¹ is A hydrogen atom, a lower alkyl group, a hydroxyalkyl-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, a lower alkanol group or an aroyl group, B is NR ² or CR ³ R ⁴ , where R ² is A hydrogen atom, a lower alkyl group, a hydroxy-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, or a nitroxy-substituted lower alkyl group, wherein R ³ and R ⁴ are the same or different and are a hydrogen atom, a lower alkyl group, Hydroxy-substituted lower alkyl group, lower alkoxy-substituted lower alkyl group, nitroxy-substituted lower alkyl group, phenyl-substituted lower alkyl group, hydroxyphenyl-substituted lower alkyl group, lower alkoxyphenyl-substituted lower alkyl group, phenyl group, lower alkoxy Represents a substituted fuunyl group or a halogen-substituted funyl group, or A is NR ¹ , When B is CR ³ R ⁴ , R ³ together with R ¹ is between A and B A double bond may be formed, in which case R ⁴ also means a hydroxy group or a lower alkoxy group, W represents an oxygen atom or a sulfur atom, X ¹ and X ² represent at least one atom or group other than a hydrogen atom, which is the same or different and is a hydrogen atom, a halogen atom, a trifluoromethyl group, a dinitro group, a cyano group, a lower alkoxycarbonyl group, carboxyl group means a 5-tetrazolyl group, a force Rubamoiru group, arsenate Dorokishi group, C! -C ₂ Furuoroa alkoxy group, a sulfamoyl group, a lower alkylsulfamoyl group, a di-lower alkylsulfamoyl group, or Benzoiru group, Y ¹ represents a hydrogen atom, a halogen atom or a nitro group, Y ² represents a hydrogen atom, or together with Y ³ together with the benzene ring to which they are attached to form a naphthalene ring, Y ³ represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a nitro group or a fluorine group, Y ⁴ represents a hydrogen atom or a lower alkyl group, or forms a naphthalene ring together with Y ³ together with the benzene ring to which they are attached; Z represents a hydrogen atom, a lower alkyl group, a lower alkoxy-substituted lower alkyl group, a hydroxy-substituted lower alkyl group, a nitroxy-substituted lower alkyl group, or a group which can be converted to a hydrogen atom in vivo. However, (i) when A is an oxygen atom or NR ¹ , B is CR ³ R ⁴ , and (ii) when A is a carbonyl group, B is NR ² , W is an oxygen atom, and Y ³ Is a halogen atom, a trifluoromethyl group, a nitro group or a fuunyl group. ] 2. A compound represented by the following formula (Ia) or an alkali metal salt thereof.

[Wherein R ^la is a hydrogen atom, d-C ₃ alkyl group; hydroxy-substituted Ci-C ₃ alkyl group, C! -C ₃ alkoxy-substituted C! -C ₃ alkyl group, C ₂ -C ₄ alkanoyl group or A benzoyl group, R ^3a and R are the same or different and each represent a hydrogen atom, a C, -C ₃ alkyl group, a hydroxy-substituted C! -C ₃ alkyl group, a C! -C ₃ alkoxy substitution d-a C ₃ alkyl group, a nitroxy substitution- C ₃ alkyl group, phenyl substituted C! To C ₃ alkyl group, hydroxyphenyl substituted d to C ₃ alkyl group, Ci to C ₃ alkoxy phenyl substituted d to C ₃ alkyl group, phenyl group, d to c ₃ alkoxy substituted It means a phenyl group or a halogen-substituted phenyl group, or R ^3a together with R ^la may form a double bond between the 3, 4-positions of the 3,4-dihydroquinoxaline ring, in which case R ^4a also means a pyridine group or a Ci-C ₃ alkoxy group, W represents an oxygen atom or a sulfur atom, One of X and X ^2a is a halogen atom, a trifluoromethyl group, a nitro group, a cyano group, a C] to C ₃ alkoxycarbonyl group, a carboxyl group, a 5-tetrazolyl group, a carbamoyl group or a ~ C ₂ fluoro group. And a hydrogen atom or a halogen atom, Y ^{] a} represents a hydrogen atom, a halogen atom or a nitro group, Y ^2a represents a hydrogen atom or, together with Y ^3a , forms a naphthalene ring together with the vesigen ring to which they are bonded, Y ^3a represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a phenyl group, Y ^4a represents a hydrogen atom or a d-C ₃ alkyl group, or forms a naphthalene ring together with Y ^3a together with the benzene ring to which they are attached; Z ^a is a hydrogen atom, d -C ₃ alkyl group, d -C ₃ alkoxy-substituted d To c ₃ alkyl group, human Dorokishi substituted c! To c ₃ alkyl group, means a nitroxy substitution Ci to c ₃ alkyl group or Ashiru group. ]  3. A compound represented by the following formula (Ib) or an alkali metal salt thereof.

[Wherein, R ^3b is a hydrogen atom, a C ₃ alkyl group, hydroxy-substituted - (:! ₃ alkyl group, C ~C ₃ alkoxy-substituted ~C ₃ alkyl group, two Torokishi substituted C ~C ₃ alkyl group, Fuweniru replacement - (- ₃ alkyl group, human Dorokishifuweniru replacement (:] ~C ₃ alkyl Group or (:) to (: ₃ alkoxyphenyl-substituted d to (: ₃ means an alkyl group, R ^4b is a hydrogen atom, d to C ₃ alkyl group, hydroxy-substituted C! To (: ₃ alkyl group, Ci to C ₃ alkoxy substituted C! To (: ₃ alkyl group, nitroxy substituted d to C ₃ alkyl group, phenyl substituted Ci to c ₃ alkyl group , Hydroxyphenyl substitution c〗 to c ₃ Means an alkyl group, C! -C ₃ alkoxy off We-substituted d to c ₃ alkyl group, phenyl group, d to c ₃ alkoxy substituent Fuweniru group or a halogen-substituted Hue group,  W represents an oxygen atom or a sulfur atom, While the halogen atom of X physician and x ^2a, triflumizole Ruo Russia methyl group, a nitro group, Shiano group, C! ~ C ₃ alkoxycarbonyl group, a carboxyl group, 5-te Torazoriru group, forces Rubamoiru group or d to c ₂ Full Alkoxy group, the other being a hydrogen atom or a halogen atom, '' Y ^3a represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a phenyl group, Y ^4b represents a hydrogen atom, or together with Y ^3b, together with the benzene ring to which they are attached, forms a naphthalene ring, z ^b represents a hydrogen atom, a -c ₃ alkyl group or an acyl group. ] 4. A compound represented by the following formula (Ic) or an alkali metal salt thereof.

[In the formula, R ^2a represents a hydrogen atom, a d-C ₃ alkyl group, a hydroquine-substituted C,-( ₃ alkyl group, a -C ₃ alkoxy-substituted C, -C ₃ alkyl group or a nitroxy-substituted C〗 -C ₃ alkyl group. Means one of x ^lb and x ^2b represents a halogen atom, a trifluoromethyl group or a nitro group, the other represents a hydrogen atom or a halogen atom, Y ^la represents a hydrogen atom or a halogen atom, Y ^2a represents a hydrogen atom, or together with Y ^3e, together with the benzene ring to which they are attached, forms a naphthalene ring, Y ^3C represents a halogen atom, a trifluoromethyl group or a fuiryl group; Y ^4a represents a hydrogen atom or d to (: ₃ alkyl group, or they are combined with Y ³ ′ Together with the benzene ring to form a naphthalene ring, Z ^a is a hydrogen atom, d -C ₃ alkyl group, Ci -C ₃ alkoxy-substituted d -C ₃ alkyl group, human Dorokishi substituted Ci -C ₃ alkyl group, Nitorokin substitution ^ to c ₃ alkyl group or Ashiru group I do. ] 5. A smooth muscle relaxant comprising the compound according to claim 1 or a metal salt thereof as an active ingredient.