JPH0597824A - 1,3-benzoxazine derivative - Google Patents

Abstract

PURPOSE:To obtain a new 1,3-benzoxazine derivative useful for treating and preventing diseases of cardiac and circulatory system, respiratory system and cerebral diseases, having relaxing action on smooth muscle. CONSTITUTION:A compound of formula I {ring A is substitutable benzene ring ; R<1> is homocyclic or heterocyclic group wherein carbon atom is bonded to the 4-position of 1,3-benzoxazine ring, hudrocarbon residue, group of formula II; R<4> is H, 1-4C alkyl or 1-4 alkylcarbonly; Y is S, O or NR<6> [R<6> is H, 1-4C alkyl or 1-11C acrl); Z is N-CN, N-NO2 or CH2-NO2; R<5> is H or alkyl; R<4> and R<5> are bonded to form 3-6C alkylrbnr, etc.; R<5> and R<6> are bonded to form 4-5C alkylene]; R<2> and R<3> are H, 1-6C alkyl or bonded to form 3-6CV alkylene] or its salt such as 2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine. The compound is obtained by reacting a compound of formula III with a compound of formula IV or formula V (R is methyl or ethyl).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to novel 1,3-benzoxazine derivatives and salts thereof which are useful as medicines. INDUSTRIAL APPLICABILITY The novel 1,3-benzoxazine derivative of the present invention has a smooth muscle relaxing action, and has cardiovascular diseases such as congestive heart failure, angina, arrhythmia and hypertension, urinary incontinence, respiratory system such as asthma, etc. It has therapeutic and preventive effects on diseases, cerebral vasospasm, cerebral hemorrhage, epilepsy and other brain diseases.

[0002]

2. Description of the Related Art As agents having a smooth muscle relaxing action, those acting on the contraction system and those acting on the relaxation system are known. Examples of agents acting on the contraction system include β-receptor blockers, α ₁ -receptor blockers, and calcium antagonists, and examples of agents acting on the relaxation system include nitro compounds. Be done.

Recently, a new type of drug called a potassium channel opener, which exhibits this smooth muscle relaxing action by opening (activating) a potassium channel, has been attracting attention.

As an expected effect of the potassium channel opener, for example, when considering a hypotensive action,
It can exert vasodilatory effects without affecting calcium channels, and it can
It can be said that the function using channels is not impaired, and therefore, it can be a drug with few side effects of suppressing cardiac function and having a strong antihypertensive effect.

For example, Japanese Patent Laid-Open No. 58-67683 and Journal of Medicinal Chemistry (J.M.
ed. Chem. ), 1986, Volume 29, 2194-22
01 pages and literature British Journal of Pharmacology (Br. J. Pharmac.), 1986, 8
Vol. 8, pp. 103-111, discloses chroman-3-ol derivatives having a potassium channel opening (activating) action and exhibiting a blood pressure lowering action on spontaneously developing rats.

Further, compounds similar to the present invention are disclosed in
7-130979, JP-A-64-38087 and JP-A-2-193995.

[0007]

DISCLOSURE OF THE INVENTION The present invention has a smooth muscle relaxing action, and is a cardiovascular disease such as angina, arrhythmia, heart failure, hypertension, and peripheral vascular occlusive disease (Raynaud's disease). , Cerebral vasospasm, cerebral hemorrhage, epilepsy and other cerebral diseases, asthma, urinary incontinence (irritating cystitis), etc., and a novel 1,3-benzoxazine derivative useful for local treatment of alopecia It provides salt.

[0008]

The present invention provides (1) general formula [I]

[Chemical 25] [In the formula,

[Chemical formula 26] Represents an optionally substituted benzene ring, R ¹ is a homocyclic or heterocyclic group bonded to the 4-position of the 1,3-benzoxazine ring by a carbon atom, a hydrocarbon residue, or a formula.

[Chemical 27] (In the formula, R ⁴ is a hydrogen atom, a C _1-4 alkyl group or a C _1-4
Alkylcarbonyl, Y is -S-, -O- or formula

[Chemical 28] (In the formula, R ⁶ represents a hydrogen atom, a C _1-4 alkyl or a C _1-11 acyl group), Z is ═N—CN, ═
N—NO ₂ or ═CH—NO ₂ , R ⁵ is a hydrogen atom or a C _1-8 alkyl group, or R ⁴ and R ⁵ are bonded to each other to form a C _3-6 alkylene group or C _3-6 An alkylenecarbonyl group, or R ⁵ and R ⁶ are bonded to each other to form C
_{4-5 represents an} alkylene group. ), The homologous or heterocyclic group and the hydrocarbon residue may be substituted, and R ² and R ³ are each a hydrogen atom or an optionally substituted C _1-6 alkyl. Or a C _3-6 alkylene group in which both are bonded to each other and may be substituted], or a 1,3-benzoxazine derivative or a salt thereof,

(2) General formula [II]

[Chemical 29] [Wherein E represents a halogen or an esterified hydroxyl group, and other symbols have the same meanings as defined above], and a compound or salt thereof represented by the general formula [IV] R ¹ '-M [IV] , R ¹ 'is a homo- or heterocyclic group having a bond at a carbon atom, a hydrocarbon residue or a formula

[Chemical 30] (In the formula, R ⁴ is a hydrogen atom, a C _1-4 alkyl group or a C _1-4
Alkylcarbonyl, Y is -S-, -O- or formula

[Chemical 31] (In the formula, R ⁶ represents a hydrogen atom, a C _1-4 alkyl or a C _1-11 acyl group), Z is ═N—CN, ═
N—NO ₂ or ═CH—NO ₂ , R ⁵ is a hydrogen atom or a C _1-8 alkyl group, or R ⁴ and R ⁵ are bonded to each other to form a C _3-6 alkylene group or C _3-6 An alkylenecarbonyl group, or R ⁵ and R ⁶ are bonded to each other to form C
_{4-5 represents an} alkylene group. ), The homologous or heterocyclic group and the hydrocarbon residue may be substituted, and M represents a leaving group. ] The manufacturing method of the compound or its salt represented by general formula [I] characterized by reacting with the compound represented by

(3) General formula [VII]

[Chemical 32] [Wherein each symbol has the same meaning as defined above]

[Chemical 33] [Wherein R is a methyl or ethyl group, and other symbols have the same meanings as defined above], and the reaction is carried out with a compound represented by the general formula [I] or a salt thereof. ,

(4) General formula [IX]

[Chemical 34] [Wherein each symbol has the same meaning as defined above] or a salt thereof is reacted with the general formula [VIII] or [VIII '] and ammonia, and the general formula [I]
A method for producing a compound represented by or a salt thereof, and

(5) An antihypertensive agent containing a compound represented by the general formula [I] or a salt thereof.

In the above formula

[Chemical 35] As the optionally substituted benzene ring represented by:
Examples include an unsubstituted benzene ring and a benzene ring substituted with 1 to 2 substituents (when they are substituted with 2 substituents, they may be combined to form a ring).

Representative compounds of the formula [I] include, for example, compounds of the general formula [Ia]

[Chemical 36] [Wherein R ¹ , R ² and R ³ are as defined above, R ′ and R ″ are each a hydrogen atom, a hydroxyl group, a halogen atom, nitro, cyano, optionally substituted C _1-6 alkyl, substituted Optionally substituted C _1-6 alkoxy, optionally substituted C _2-6 alkenyl, optionally substituted ethynyl, optionally substituted aryl, optionally substituted heteroaryl, substituted Optionally amino, optionally substituted carbonyl, optionally substituted carboxyl, optionally substituted carbonyloxy, optionally substituted thiocarbonyl, optionally substituted thiocarbonyloxy, Optionally substituted iminoalkyl, optionally substituted mercapto,
It represents an optionally substituted sulfinyl or an optionally substituted sulfonyl group, or R ′ and R ″ are bonded to each other to form —CH═CH—CH═CH— (wherein this group is 1 to 3). C _1-4 alkyl, C _1-4 alkoxy, nitro, halogen, CF ₃ , C _1-4 alkoxycarbonyl and cyano may be substituted),
= N-O-N =, - (CH 2) a- (a is 3 or _{4), - (CH 2)} b-CO- (b is 2 or _{3), - (CH 2)} b -C (= NOH)-or-(CH
₂ ) b-C (= N-O-alkyl)-is shown. ] The compound represented by these is mentioned.

R'and R "in the 1,3-benzoxazine derivative represented by the general formula [Ia] are preferably at the 6-position and 7-position of the 1,3-benzoxazine nucleus. Is 5th, 6th and 5th
It may be ranked 7th, 5th, 8th, 6th and 8th, or 7th and 8th. If one of R'and R "is hydrogen and the other is different from hydrogen, this other group is preferably in the 6-position but not in the 5-, 7- or 8-position. Alternatively, if neither R ′ nor R ″ are hydrogen, or if they are bonded to each other, then 6-position and 7-position
Positions are preferred, but may be 5th and 6th, 7th and 8th.

The substituent in the optionally substituted alkyl, alkoxy, alkenyl, aryl and heteroaryl in the groups represented by R'and R "is C
One or more groups selected from _1-4 alkyl, C _1-4 alkoxy, aryl, arylalkyl, hydroxyl group, nitro, halogen and cyano are included, and aryl in these substituents is also C _1-4 alkyl, C _{1- 4} alkoxy, hydroxyl group,
Nitro, halogen, halo C _1-4 alkyl (CF ₃ etc.),
It may be substituted with one or more groups selected from cyano, halo C _1-4 alkoxy (such as CF ₃ O), mercapto and halo C _1-4 alkylthio (such as CF ₃ S). Examples of the substituent of the optionally substituted ethynyl group include the same groups as the above-mentioned substituents of alkyl, alkoxy, alkenyl, aryl and heteroaryl, and a trimethylsilyl group. The optionally substituted amino substituents are C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkyl (CF ₃ etc.), formyl, thioformyl, hydroxyl group, carbamoyl, aryl, arylalkyl, C _1-4 alkylcarbonyl, arylcarbonyl,
Arylalkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, arylalkyloxycarbonyl, heteroarylcarbonyl, C _1-4 alkylsulfinyl, C _1-4 alkoxysulfinyl, arylsulfinyl, C _1-4 alkylsulfonyl, C _1-4
Alkoxysulfonyl and arylsulfonyl are mentioned, and the aryl in these substituents is also C _1-4 alkyl, C _1-4 alkoxy, hydroxyl group, nitro, halogen,
Halo C _1-4 alkyl (CF ₃ etc.), cyano, halo C _1-4
Alkoxy (CF ₃ O etc.), mercapto and halo C
_It may be substituted with one or more groups selected from _1-4 alkylthio (CF ₃ S etc.). The carbonyl and thiocarbonyl substituents which may be substituted include C _1-4
Alkyl, amino, C _1-4 alkylamino, C _1-4 alkyloxycarbonylamino (di-t-butyloxycarbonylamino etc.), arylamino, arylalkylamino, heteroarylamino, heteroarylalkylamino, aryl, arylalkyl , Heteroarylalkyl and heteroaryl, which may be nuclear-substituted as described above. Substituents for optionally substituted carbonyloxy and thiocarbonyloxy include the same groups as in carbonyl and thiocarbonyl. Examples of the substituent of the optionally substituted carboxyl include C _1-4 alkyl and arylalkyl,
The aryl may be nuclear-substituted as described above. Examples of the substituent of iminoalkyl which may be substituted include hydroxyl group, amino, C _1-4 alkyl, C _1-4 alkoxy, aryl, arylalkyloxy and heteroarylalkyloxy, and these aryl and heteroaryl are Nuclear substitution may be performed as described above. Further, examples of the substituent of mercapto which may be substituted include C _1-4 alkyl, aryl, heteroaryl, arylalkyl and haloC _1-4 alkyl (CF ₃ etc.). Substituents on the optionally substituted sulfinyl and sulfonyl include C _1-4 alkyl, C _1-4 alkoxy, aryl, heteroaryl, arylalkyl and amino. These aryl and heteroaryl may also be nuclear-substituted as described above.

R'and R "are each preferably
Methyl, ethyl, acetyl, propionyl, (methyl,
Optionally substituted with methoxy, halogen, nitro, CF ₃ or cyano) benzoyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, acetoxy, propoxy, propoxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, 1-hydroxyethyl, 1-hydroxybenzyl, methylsulfinyl, ethylsulfinyl, (methyl, methoxy,
Benzenesulfinyl, optionally substituted with halogen, nitro, CF ₃ or cyano), methylsulfonyl, ethylsulfonyl, benzenesulfonyl (optionally substituted with methyl, ethoxy, halogen, nitro, CF ₃ or cyano), methoxy Sulfinyl, ethoxysulfinyl, methoxysulfonyl, ethoxysulfonyl, acetamide, propionamide, benzamide (which may be substituted with methyl, methoxy, halogen, nitro, CF ₃ or cyano), methoxycarbonylamide, ethoxycarbonylamide, thioacetyl, thio propionyl, (methyl, methoxy, halogen, nitro, CF ₃ or optionally substituted by cyano) thiobenzoyl, methoxythiocarbonyl, ethoxythiocarbonyl, thio Acetoxy, thionocarbonate propionohydrazide carboxymethyl, 1-mercaptoethyl, 1-mercaptobenzyl, methylsulfinyl, amino, ethylsulfinyl amino, (methyl, methoxy, halogen, nitro, CF
₃ or may be substituted by cyano) benzene sulfinyl amino, methylsulfonylamino, ethylsulfonylamino, (methyl, methoxy, halogen, nitro, optionally substituted with CF ₃ or cyano) benzenesulfonylamino, methoxysulfinyl Amino, ethoxysulfinylamino, methoxysulfonylamino, ethoxysulfonylamino, 1-propenyl,
(May be substituted with methyl, methoxy, halogen, nitro, CF ₃ or cyano) Styryl, methoxyiminomethyl, ethoxyiminomethyl, 1- (hydroxyimino) ethyl, 1- (hydroxyimino) propyl, 1-hydra Dinoethyl, 1-hydrazinopropyl,
_{1-propynyl, CF 3, CF 3 CF 2} , CF 3 O, HCF
₂ O, CF ₂ = CF, nitro, cyano, halogen, amino, formyl, formamide, hydroxyiminomethyl, CO ₂ H, CONH ₂ , SH, CF ₃ S, thioformamide, CSNH ₂ , SO ₂ NH ₂ , 2- Oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl, nitromethyl, 1-nitroethyl, 2-nitroethyl, vinyl, nitrovinyl, cyanovinyl, trifluorovinyl, ethynyl or

[Chemical 37] Is.

R'and R "are more preferably methyl, ethyl, acetyl, benzoyl (which may be substituted with methyl, methoxy, halogen, nitro, CF or cyano), methoxycarbonyl, methylsulfonyl, (methyl). , Ethoxy, halogen, nitro, CF ₃ or cyano) benzenesulfonyl, CF ₃ , CF ₃ CF ₂ , CF ₃ O, CF ₂ ═CF, nitro, cyano, halogen, amino, formyl, CO
₂ H, CONH ₂ , nitromethyl or ethynyl.

The heteroaryl group in R'and R "is a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl, and a 5- or 6-membered monocyclic heteroaryl is preferred. Furthermore, the 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl is preferably one or two selected from oxygen, carbon and sulfur.
Where there are more than one heteroatom, including one or three heteroatoms, they may be the same or different. One selected from oxygen, carbon and sulfur,
5- or 6-membered monocyclic heteroaryl groups containing 2 or 3 heteroatoms include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl and triazyl. . Examples of 9 or 10 membered bicyclic heteroaryl groups containing 1, 2 or 3 heteroatoms selected from oxygen, carbon and sulfur include benzofuranyl, benzothienyl, indolyl,
Includes indazolyl, quinolyl, isoquinolyl and quinazolinyl.

Suitable examples of optional substituents on heteroaryl are methyl, methoxy, halogen, CF ₃ , nitro or cyano.

When R'and R "are linked to each other, preferably (methyl, methoxy, halogen, nitro, C
F ₃ or may be substituted by cyano) -CH =
CH-CH = CH -, = N-O-N =, - (CH 2) 3 -,
_{- (CH 2) 4 -,} - (CH 2) 2 CO -, - (CH 2) 3 CO-,
_{- (CH 2) 2 C (} = NOH) -, - (CH 2) 2 C (= NOC
_{H 3) -, - (CH} 2) 3 C (= NOH) - or - (CH _{2) 3} C
(= NOCH ₃₎ - it is.

As the optionally substituted homologous or heterocyclic group bonded to the 4-position of the 1,3-benzoxazine ring represented by R ¹ with a carbon atom, phenyl, 2-pyridyl and 3-pyridyl are included. , 4-pyridyl, 1-C _1-4 alkylpyridin-2-yl, 1-C _1-4 alkylpyridin-3-yl, 1-C _1-4 alkylpyridin-4-yl, pyridine-N -Oxide-2-yl, pyridine-N
-Oxide-3-yl, pyridine-N-oxide-4-
Yl, 3 or 4-pyridazinyl, pyridazin-N-oxide-3 or 4-yl, 4 or 5-pyrimidinyl, pyrimidin-N-oxide-4 or 5-yl, 2
-Pyrazinyl, pyrazine-N-oxide-2 or 3-
Yl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, quinolin-N-oxide-2-yl, quinoline-N
-Oxide-3-yl, quinoline-N-oxide-4-
Yl, isoquinoline-1,3 or 4-yl, isoquinoline-N-oxide-1,3 or 4-yl, 2- or 3-indolyl, 2- or 3-pyrrolyl,

[Chemical 38] (B has the same meaning as described above, n is 0, 1 or 2, R ⁷
Represents hydrogen, C _1-6 alkyl, nitroxy, C _1-4 alkyl or aryl), 2,2-dimethyl-1,3-dioxane-4,6-dione-5-yl and the like.
As the hydrocarbon residue which may be substituted, {R ⁷ S
(O) n} ₂ CH—, (R ⁷ CO) ₂ —CH— group (in the formula, each symbol has the same meaning as described above. Halogen, C _1-4 alkyl, C _1-4 alkoxy, nitro, hydroxy C _1-4 alkyloxy, hydroxy C _1-4 alkylaminocarbonyl, trimethylsilyl, trimethylsilyl C _1-4 alkyloxymethyloxy, nitroxy C _1-4 Alkyloxy, nitroxy C _1-4 alkylaminocarbonyl, C
F ₃ , CF ₃ O, C _1-4 alkylsulfonyl, arylsulfonyl, C _1-4 alkylcarbonyl, arylcarbonylcyano, CO ₂ H, C _1-4 alkoxycarbonyl, N
H ₂ , C _1-8 alkanoylamino, C _7-11 aroylamino, 3-C _1-8 alkyl-2-cyano and nitroguanidino may be substituted).

R ¹ is preferably phenyl, tolyl,
Methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, hydroxyphenyl, halogenophenyl, nitrophenyl, CF ₃ - phenyl, CF ₃ O-phenyl,
Cyanophenyl, carboxyphenyl, methoxycarbonylphenyl, ethoxycarbonylphenyl, aminophenyl, acetamidophenyl, methylthiophenyl,
Methylsulfinylphenyl, methanesulfonylphenyl, benzenesulfonylphenyl, toluenesulfonylphenyl, hydroxyethoxyphenyl, hydroxypropoxyphenyl, hydroxyethylaminocarbonylphenyl, nitroxyethoxyphenyl, nitroxypropoxyphenyl, nitroxyethylaminocarbonylphenyl, [3- (T-butyl) -2-cyano (or nitro) guanidino] phenyl, [3- (1,2,2-trimethylpropyl) -2-cyano (or nitro) guanidino] phenyl, 2-pyridyl, 3-pyridyl, 4-
Pyridyl, 1-methylpyridinium-2-yl, 1-methylpyridinium-3-yl, 1-methylpyridinium-4-yl, pyridin-N-oxide-2-yl, pyridin-N-oxide-3-yl, pyridine -N-oxide-4-yl, (di) methylpyridin-2,3 or 4
-Yl, (di) methylpyridine-N-oxide-2,3
Or 4-yl, hydroxypyridin-2,3 or 4
-Yl, hydroxypyridin-N-oxide-2,3 or 4-yl, methoxypyridin-2,3 or 4-yl, methoxypyridin-N-oxide-2,3 or 4
-Yl, ethoxypyridin-2,3 or 4-yl, ethoxypyridin-N-oxide-2,3 or 4-yl, halogenopyridin-2,3 or 4-yl, halogenopyridin-N-oxide-2,3 Or 4-yl, nitropyridin-2,3 or 4-yl, nitropyridin-N-oxide-2,3 or 4-yl, aminopyridin-2,3 or 4-yl, aminopyridin-N-oxide-2 , 3 or 4-yl, trifluoromethylpyridin-2,3 or 4-yl, trifluoromethylpyridin-N-oxide-2,3 or 4-yl, nitroxyethoxypyridin-2,3 or 4-yl, Nitroxyethoxypyridine-N-oxide-2,3 or 4-
1, carboxypyridin-2,3 or 4-yl, carboxypyridin-N-oxide-2,3 or 4-yl, methoxycarbonylpyridin-2,3 or 4-yl, methoxycarbonylpyridin-N-oxide-2,
3 or 4-yl, ethoxycarbonylpyridin-2,
3 or 4-yl, ethoxycarbonylpyridin-N-
Oxide-2,3 or 4-yl, carbamoylpyridin-2,3 or 4-yl, carbamoylpyridin-N
-Oxide-2,3 or 4-yl, cyanopyridine-
2,3 or 4-yl, cyanopyridin-N-oxide-2,3 or 4-yl, nitroxyethylaminocarbonylpyridin-2,3 or 4-yl, nitroxyethylaminocarbonylpyridin-N-oxide-2 , 3
Or 4-yl, [3-methyl-2-cyano (or nitro) guanidino] pyridin-2,3 or 4-yl,
[3-methyl-2-cyano (or nitro) guanidino] pyridin-N-oxide-2,3 or 4-yl,
[3- (t-butyl) -2-cyano (or nitro) guanidino] pyridin-2,3 or 4-yl, [3- (t
-Butyl) -2-cyano (or nitro) guanidino]
Pyridine-N-oxide-2,3- or 4-yl,
[3- (1,2,2-Trimethylpropyl) -2-cyano (or nitro) guanidino] pyridin-2,3- or 4-yl, [3- (1,2,2-trimethylpropyl)
-2-Cyano (or nitro) guanidino] pyridine-
N-oxide-2,3- or 4-yl, acetamidopyridin-2,3- or 4-yl, acetamidopyridin-N-oxide-2,3- or 4-yl, methanesulfonylpyridin-2,3 or 4 -Yl, methanesulfonylpyridin-N-oxide-2,3 or 4-yl, toluenesulfonylpyridin-2,3 or 4-yl, toluenesulfonylpyridin-N-oxide-2,
3 or 4-yl, halogeno-nitropyridin-2,3
Or 4-yl, halogeno-nitropyridin-N-oxide-2,3 or 4-yl, methyl-nitropyridin-2,3 or 4-yl, methyl-nitropyridin-N
-Oxide-2,3 or 4-yl, amino-nitropyridin-2,3 or 4-yl, amino-nitropyridin-N-oxide-2,3 or 4-yl, trifluoromethyl-halogenopyridine-2, 3 or 4-yl,
Trifluoromethyl-halogenopyridin-N-oxide-2,3 or 4-yl, cyano-nitropyridin-2,
3 or 4-yl, cyano-nitropyridin-N-oxide-2,3 or 4-yl, methyl-nitroxyethylaminocarbonylpyridin-2,3 or 4-yl,
Methyl-nitroxyethylaminocarbonylpyridine-
N-oxide-2,3 or 4-yl, 3-pyridazinyl, 4-pyridazinyl, 6-methylpyridazin-3-yl, 6-methoxypyridazin-3-yl, 6-chloropyridazin-3-yl, pyridazine-N -Oxide-3 or 4-yl, 6-methylpyridazine-N-oxide-
3-yl, 6-methoxypyridazine-N-oxide-3
-Yl, 6-chloropyridazin-N-oxide-3-yl, 4-pyrimidinyl, 5-pyrimidinyl, 6-methylpyrimidin-4-yl, pyrimidine-N-oxide-4
Or 5-yl, 6-methylpyrimidin-N-oxide-4-yl, 2-pyrazinyl, pyrazin-N-oxide-2 or 3-yl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, nitroquinoline-2 -Yl, chloroquinolin-2-yl, methylquinolin-2-yl, methoxyquinolin-2-yl, quinolin-N-oxide-
2,3 or 4-yl, nitroquinolin-N-oxide-2-yl, chloroquinolin-N-oxide-2-yl, methylquinolin-N-oxide-2-yl, methoxyquinoline-N-oxide-2- Ill, isoquinoline-
1,3 or 4-yl, isoquinoline-N-oxide-
1,3 or 4-yl, 2- or 3-indolyl, N
-Acetyl indol-2- or 3-yl, N-benzyl indol-2 or 3-yl, N-methylsulfonyl indol-2 or 3-yl, N-benzenesulfonyl indol-2 or 3-yl, N-tosyl indole -2 or 3-yl, 2 or 3-pyrrolyl, N
-Acetylpyrrole-2 or 3-yl, N-benzylpyrrole-2 or 3-yl, N-methylsulfonylpyrrole-2 or 3-yl, N-benzenesulfonylpyrrole-2 or 3-yl, N-tosylpyrrole- 2 or 3-yl,

[0024]

[Chemical Formula 39] _{2,2-dimethyl-1,3-dioxane-4,6-dione-5-yl, (CH 3 S) 2 CH} -, (PhS) 2 CH-,
_{(CH 3 SO) 2 CH -} , (PhSO) 2 CH -, (CH 3 S
_{O 2) 2 CH -, (} PhSO 2) 2 CH-, Ac 2 CH -, (P
hCO) ₂ CH-.

R ¹ is particularly preferably (hydroxy,
Lower alkoxy, lower alkyl, optionally substituted with halogen) 2-pyridyl, (hydroxy, lower alkoxy, lower alkyl, optionally substituted with halogen) pyridin-N-oxide-2-yl, 2-quinolyl , Quinolin-N-oxide-2-yl, 1-methyl-
2-oxo-3-pyrrolidinyl is mentioned.

R ¹ is 3-methyl-2-cyano or nitro-guanidino, 3,3-dimethyl-2-cyano or nitro-guanidino, 3- (t-butyl) -2.
-Cyano or nitro-guanidino, 3- (1,2,2-
Trimethylpropyl) -2-cyano or nitro-guanidino, 3-isopropyl-2-cyano or nitro-
Guanidino, 3-cyclopropyl-2-cyano or nitro-guanidino, 3,3-tetramethylene-2-cyano or nitro-guanidino, 3,3-pentamethylene-2-cyano or nitro-guanidino, (1-methylamino -2-nitroethenyl) amino, (1-isopropylamino-2-nitroethenyl) amino, 2-methyl-3-cyano or nitro-1-isothioureido,
(1-Methylthio-2-nitroethenyl) amino, 2-
Methyl-3-cyano or nitro-1-isoureido,
2-ethyl-3-cyano or nitro-1-isoureido, (1-methoxy-2-nitroethenyl) amino,
(1-Ethoxy-2-nitroethenyl) amino, 2-cyanoimino-imidazolidin-1-yl, 2-nitroimino-imidazolidin-1-yl, 2-cyanoimino or nitroimino-hexahydropyrimidin-1-yl, 2-nitro Ethenylimidazolidin-1-yl, 2
-Nitroethenyl-hexahydropyrimidin-1-yl, 2-cyanoimino or nitroimino-thiazolidin-3-yl, 2-nitroethenyl-thiazolidine-3
Those which are -yl, 2-cyanoimino or nitroimino-oxazolidin-3-yl, 2-nitroethenyl-oxazolidin-3-yl, 2-cyano or nitro-creatinin-3-yl are also preferred.

R ² and R ³ are preferably each
Methyl, ethyl or propyl. When R ² and R ³ are bonded to each other, preferably cyclopropyl,
Cyclopentyl or cyclohexyl. The aryl in each of the above groups is preferably C _6-14 aryl such as phenyl, naphthyl or anthryl.

A preferred specific example of the novel 1,3-benzoxazine derivative represented by the general formula [I] of the present invention is 2,2-dimethyl-4- (2-pyridyl) -2H.
-1,3-benzoxazine, 2- (6-bromo-2,2
-Dimethyl-2H-1,3-benzoxazin-4-yl) pyridine N-oxide, 2- (6-cyano-2,2
-Dimethyl-2H-1,3-benzoxazin-4-yl) pyridine N-oxide, 2- (2,2-dimethyl-
6-nitro-2H-1,3-benzoxazin-4-yl) pyridine N-oxide, 2- (6-acetyl-2,
2-Dimethyl-2H-1,3-benzoxazine-4-
Il) pyridine N-oxide, 2- (6-cyano-2,
2-Dimethyl-7-nitro-2H-1,3-benzoxazin-4-yl) pyridine N-oxide, 2- (6
-Methoxycarbonyl-2,2-dimethyl-2H-1,
3-benzoxazin-4-yl) pyridine N-oxide, 2- (6-ethynyl-2,2-dimethyl-2H-
1,3-benzoxazin-4-yl) pyridine N-
Oxide, 2- (6-chloro-2,2-dimethyl-2H
-1,3-benzoxazin-4-yl) pyridine N
-Oxide, 2- (6-bromo-2,2,7-trimethyl-2H-1,3-benzoxazin-4-yl) pyridine N-oxide, 2- (2,2,7-trimethyl-6-
Nitro-2H-1,3-benzoxazin-4-yl)
Pyridine N-oxide, 2- (6-cyano-2,2,7
-Trimethyl-2H-1,3-benzoxazine-4-
Il) pyridine N-oxide, 2- (6-bromo-7)
-Methoxy-2,2-dimethyl-2H-1,3-benzoxazin-4-yl) pyridine N-oxide, 2-
(7-methoxy-2,2-dimethyl-6-nitro-2H
-1,3-benzoxazin-4-yl) pyridine N
-Oxide, 2- (6-cyano-7-methoxy-2,2
-Dimethyl-2H-1,3-benzoxazin-4-yl) pyridine N-oxide,

2- (6-bromo-7-fluoro-2,2
-Dimethyl-2H-1,3-benzoxazin-4-yl) pyridine N-oxide, 2- (6-cyano-7-fluoro-2,2-dimethyl-
2H-1,3-benzoxazin-4-yl) pyridine N-oxide, 2- (7-fluoro-2,2-dimethyl-6-nitro-
2H-1,3-benzoxazin-4-yl) pyridine N-oxide, 2- (6-trifluoromethyl-2,2-dimethyl-2
H-1,3-benzoxazin-4-yl) pyridine
N-oxide, 2- (6-trifluoromethoxy-2,2-dimethyl-
2H-1,3-benzoxazin-4-yl) pyridine N-oxide, and 2- (6-pentafluoroethyl-2,2-dimethyl-
2H-1,3-benzoxazin-4-yl) pyridine N-oxide 2- (6-trifluorovinyl-2,2-dimethyl-2
H-1,3-benzoxazin-4-yl) pyridine
N-oxide 2- (6,7-dichloro-2,2-dimethyl-2H-1,
3-benzoxazin-4-yl) pyridine N-oxide 2- (6-bromo-7-chloro-2,2-dimethyl-2
H-1,3-benzoxazin-4-yl) pyridine
N-oxide 2- (7-chloro-6-cyano-2,2-dimethyl-2
H-1,3-benzoxazin-4-yl) pyridine
N-oxide 2- (6,7-dibromo-2,2-dimethyl-2H-1,
3-benzoxazin-4-yl) pyridine N-oxide 2- (2,2-dimethyl-2H-naphtho [2,3-e]
[1,3] Oxazin-4-yl) pyridine N-oxide 2- (6-cyano-2,2-dimethyl-2H-1,3-benzoxazin-4-yl) -3-ethoxypyridine
N-oxide 6-cyano-2,2-dimethyl-4- (1-methyl-2-
Oxo-3-pyrrolidinyl) -2H-1,3-benzoxazine 2- (6-bromo-2,2-dimethyl-2H-1,3-benzoxazin-4-yl) quinoline N-oxide 2- (6- Cyano-2,2-dimethyl-2H-1,3-benzoxazin-4-yl) -3-methoxypyridine
N-oxide 2- (6-cyano-2,2-dimethyl-2H-1,3-benzoxazin-4-yl) -3-hydroxypyridine N-oxide 2- (6-cyano-2,2-dimethyl- 2H-1,3-benzoxazin-4-yl) -3-methylpyridine N
-Oxide 3-chloro-2- (6-cyano-2,2-dimethyl-2H
-1,3-benzoxazin-4-yl) pyridine N-
Oxide 2- (6-bromo-2,2-dimethyl-2H-1,3-benzoxazin-4-yl) -3-methoxypyridine
N-oxide

2- (6-bromo-2,2-dimethyl-2H
-1,3-benzoxazin-4-yl) -3-ethoxypyridine N-oxide 2- (6-bromo-2,2-dimethyl-2H-1,3-benzoxazin-4-yl) -3-methyl Pyridine N
-Oxide 2- (6-bromo-2,2-dimethyl-2H-1,3-benzoxazin-4-yl) -3-chloropyridine N
-Oxide 2- (6-bromo-7-chloro-2,2-dimethyl-2H
-1,3-benzoxazin-4-yl) -3-methoxypyridine N-oxide 2- (6-bromo-7-chloro-2,2-dimethyl-2H
-1,3-benzoxazin-4-yl) -3-ethoxypyridine N-oxide 2- (6-bromo-7-chloro-2,2-dimethyl-2H
-1,3-benzoxazin-4-yl) -3-methylpyridine N-oxide 2- (6-bromo-7-chloro-2,2-dimethyl-2H
-1,3-benzoxazin-4-yl) -3-chloropyridine N-oxide 2- (6-trifluoromethyl-2,2-dimethyl-2H
-1,3-benzoxazin-4-yl) -3-methoxypyridine N-oxide 3-ethoxy-2- (6-trifluoromethyl-2,2-
Dimethyl-2H-1,3-benzoxazin-4-yl)
Pyridine N-oxide 2- (6-trifluoromethyl-2,2-dimethyl-2H
-1,3-benzoxazin-4-yl) -3-methylpyridine N-oxide 3-chloro-2- (6-trifluoromethyl-2,2-dimethyl-2H-1,3-benzoxazin-4- Il) pyridine N-oxide.

The novel 1,3-benzoxazine derivative represented by the general formula [I] of the present invention is, for example, the general formula [II]

[Chemical 40] [In the formula,

[Chemical 41] , R ² and R ³ have the same meanings as described above, and E represents halogen or an esterified hydroxyl group. And a compound represented by the general formula [III] R ¹ ′ -W [III] [wherein R ¹ ′ is a homologous or heterocyclic group having a bond at a carbon atom, a hydrocarbon residue, or a formula

[Chemical 42] (In the formula, R ⁴ is a hydrogen atom, a C _1-4 alkyl group or a C _1-4
Alkylcarbonyl, Y is -S-, -O- or formula

[Chemical 43] (In the formula, R ⁶ represents a hydrogen atom, a C _1-4 alkyl or a C _1-11 acyl group), Z is ═N—CN, ═N
—NO ₂ or ═CH—NO ₂ , R ⁵ is a hydrogen atom or a C _1-8 alkyl group, or R ⁴ and R ⁵ are bonded to each other to form a C _3-6 alkylene group or an alkylenecarbonyl group. Alternatively, R ⁵ and R ⁶ are bonded to each other to represent a C _4-5 alkylene group. ), The homologous or heterocyclic group and the hydrocarbon residue may be substituted, and W represents hydrogen or halogen (Cl, Br, I). A compound represented by the formula [IV] R ¹ '-M [IV] [wherein R ¹ ' is as defined above and M represents a leaving group] Then, it can be produced by reacting. In this reaction, if necessary, tetrakis (triphenylphosphine) palladium (O), tetrakis (triphenylphosphine) nickel (O) or the like can be added as a catalyst to smoothly proceed the reaction.

In the general formula [II], the halogen represented by E is preferably chlorine, bromine or iodine, and the esterified hydroxyl group is preferably trifluoromethanesulfonyl, methanesulfonyl or p-toluene. Examples thereof include a hydroxyl group esterified with a reactive group such as sulfonyl. In the general formulas [III] and [IV],
The homologous or heterocyclic group having a bond at the carbon atom represented by R ¹ ′ or the hydrocarbon residue is a carbon atom at the 4-position of the 1,3-benzoxazine ring represented by R ¹ above. Examples include a homologous or heterocyclic group which is bonded, or a group similar to a hydrocarbon residue.

In the general formula [IV], the leaving group represented by M is preferably Li, Na, K, Ca (1/2), MgC.
l, MgBr, MgI, ZnCl, SnCl, Sn (n-Bu) ₃ ,
Examples include CrCl ₂ , CuCl, CuBr, NiCl, PdCl and the like. For example, the condensation reaction is carried out in an inert solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane, hexane, toluene, benzene, methylene chloride, chloroform, 1,2-dichloroethane, DMF,
DMSO, etc., or about -5 in these mixed solvents
It is performed in a temperature range of 0 ° C to 50 ° C. This reaction depends on easiness of formation of the organometallic compound [IV], stability, solubility in a solvent, and the like. Therefore, it is desirable to appropriately change the solvent to be used depending on the kind of the metal reagent (for example, the organic solvent). In the case of lithium, Grignard reagent, etc., tetrahydrofuran, diethyl ether, in the case of organic chromium reagent, DMF, etc.). Further, this reaction is preferably
It is performed under an inert gas (for example, nitrogen, argon, etc.) atmosphere.

The organometallic compound [IV] can be obtained from the compound represented by the formula [III] by a method known per se. For example, this reaction is carried out in the above-mentioned inert solvent,
It is performed in a temperature range of about -78 ° C to 70 ° C, preferably under an inert gas atmosphere. Usually the formula [IV]
The compound of formula (I) is directly reacted with the compound of formula [II] to form the compound of formula [I] without being formed in the reaction system and isolated from the reaction mixture.

The compound represented by the formula [II] used as a starting material is publicly known or can be produced, for example, by the method shown in the following reference example. Furthermore, one or more groups R ′, R ″ and / or R ¹ in the compound of formula [I] can be converted into another R ′, R ″ and / or R ^1. . For example, by a method known per se, a hydrogen atom is replaced with a halogen atom by halogenation, or a nitro group is formed by nitration, and an amino group is formed by reduction of the nitro group, or by acylation or sulfonation of the amino group, It can also be introduced into an acylamino group or a sulfonylamino group. The cyano group is, for example, an aqueous solution of sodium hydroxide / 3
The carbamoyl group can be converted to a thiocarbamoyl group by using hydrogen sulfide in pyridine / triethylamine by treating with 0% hydrogen peroxide. Further, the cyano group is converted into a carboxyl group by heating and hydrolysis in an aqueous solution of sodium hydroxide, or a formyl group using Raney nickel in water / acetic acid / pyridine in the presence of sodium phosphate. You can also do it. The formyl group can be converted into a vinyl group by the Wittig reaction and a hydroxyiminomethyl group or the like by a reaction with hydroxyamine. The hydroxyl group can be converted to an alkoxy group by alkylation, to an acyloxy group by acylation, and the alkyl hydroxyl group can be converted to a nitroxyalkyl group by sulfuric acid / nitric acid.

When R ¹ is, for example, a pyridyl group, a quinolyl group or an isoquinolyl group, metachloroperbenzoic acid, perbenzoic acid, paranitroperbenzoic acid, pentafluoroperbenzoic acid, monoperphthalic acid, magnesium By oxidizing with monoperoxyphthalate, peracetic acid, hydrogen peroxide or the like, it can be converted to a pyridine-N-oxide group, a quinoline-N-oxide group, an isoquinoline-N-oxide group or the like, respectively. In this reaction, it is desirable to change the reaction conditions depending on the oxidizing agent used. For example, when metachloroperbenzoic acid is used, an inert solvent such as dichloromethane, chloroform, 1,2-
Dichloroethane, diethyl ether, acetone, ethyl acetate, etc., or a mixed solvent thereof at -25 ° C
The reaction is carried out in the temperature range from 1 to room temperature.

Further, the compound represented by the general formula [I] can be produced by the reaction represented by the reaction formula [I] as an alternative method. Reaction formula I

[Chemical 44] That is, the general formula [V]

[Chemical 45] [In the formula,

[Chemical 46] Has the same meaning as above, M'represents a leaving group, and R '''represents a hydroxyl-protecting group. And a compound represented by, general formula ^{[VI] R 1 '' -CN} ( or ^{R 1 '''-M')} [VI] [ wherein, R 1 ^'' is bonded with a cyano group and a carbon atom Homogeneous or heterocyclic groups, hydrocarbon residues or formulas

[Chemical 47] (Wherein each symbol has the same meaning as defined above), the homologous or heterocyclic group and the hydrocarbon residue may have a substituent, and R ¹ ′ ″ is a group M. 'Or a homocyclic or heterocyclic group, a hydrocarbon residue or a formula, which is bound to the carbon atom by

[Chemical 48] (Wherein each symbol has the same meaning as defined above), the homologous or heterocyclic group and the hydrocarbon residue may have a substituent, and M ′ represents a leaving group. .. ] The compound represented by the formula [VII] is reacted by deprotection by a method known per se.

[Chemical 49] [In the formula,

[Chemical 50] And R ¹ has the same meaning as described above. ] The imino compound represented by the formula [VIII] is obtained in the presence of an acid catalyst.

[Chemical 51] [In the formula, R ² and R ³ have the same meanings as described above, and R represents a methyl or ethyl group. ] It can manufacture by making it react with the compound represented.

The imino compound represented by the general formula [VII] has the general formula [IX]

[Chemical 52] [In the formula,

[Chemical 53] And R ¹ has the same meaning as described above. ] It can be obtained by reacting the compound represented by Further, the compound represented by the general formula [I] is obtained by reacting the compound represented by the general formula [IX] with ammonia in the presence of an acid catalyst all at once. Can also be manufactured by.

In the general formulas [V] and [VI], the leaving group represented by M ′ is preferably Li, Na, K or Ca.
(1/2), MgCl, MgBr, MgI, ZnCl,
Examples include SnCl and CrCl ₂ . In general formula [V],
The protective group for the hydroxyl group represented by R ′ ″ is preferably
Known protective groups for phenolic hydroxyl groups such as methoxydimethylmethyl group, trimethylsilyl group, t-butyldimethylsilyl group and the like can be mentioned. Each step will be described in detail below. (Step 1) This condensation reaction is carried out in an inert solvent such as tetrahydrofuran, diethyl ether, dimethoxyethane, hexane, toluene, benzene, methylene chloride, DM.
F or the like, or a mixed solvent thereof, at about -70 ° C.
It is carried out in a temperature range of ˜70 ° C. This reaction is preferably
It is performed under an inert gas (eg, nitrogen, argon, etc.) atmosphere.

The deprotection reaction is carried out by known acidic hydrolysis or a fluorinated salt reagent such as tetrabutylammonium fluoride or potassium fluoride. Organometallic compound [V]

[Chemical 54] (Or [VI] R ¹ -M ′) has the formula [X] according to a method known per se.

[Chemical 55] [In the formula,

[Chemical 56] , W and R ′ ″ are as defined above. ] (Or
It can be obtained from the compound represented by the formula [III]) in the same manner as the above-mentioned organometallic compound [IV].

(Step 2) Hydroxyketone compound [IX]
The reaction of ammonia with ammonia is carried out with an inert solvent such as ethanol, benzene, toluene, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran,
It is carried out in a temperature range of about 0 ° C to 100 ° C in diethyl ether or the like or a mixed solvent thereof. Usually, this reaction is 1 to the hydroxyketone compound [IX].
In a solvent containing 10 times the molar amount of ammonia, a dehydrating agent (for example, molecular sieves, anhydrous calcium sulfate,
Anhydrous magnesium sulfate, etc.) in a sealed tube. The imino compound [VII] obtained in Steps 1 and 2 can also be used in the next reaction without isolation and purification.

(Step 3) The ring-closing reaction of the imino compound [VII] and the compound [VIII] is carried out without solvent or with an inert solvent such as benzene, toluene, chloroform, dichloromethane, 1,2-dichloroethane, diethyl ether, or the like. It is carried out in the mixed solvent of 1) in the presence of an acid catalyst and a dehydrating agent in the temperature range of room temperature to 100 ° C. As the acid catalyst, hydrochloric acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, ammonium chloride,
Ammonium acetate or the like can be used. The amount of the acid catalyst to be used is preferably changed depending on the acidity of the catalyst, and is 1/100 to the imino compound [VII].
It is preferably in the range of about 10 times the molar amount. As the dehydrating agent, for example, molecular sieves, anhydrous calcium sulfate, anhydrous magnesium sulfate and the like can be used.

(Step 4) Hydroxyketone compound [I
X], one-pot reaction of ammonia with compound [VIII] can be performed in a solvent-free or inert solvent such as benzene, toluene, chloroform, dichloromethane, 1,2-dichloroethane, diethyl ether, or a mixed solvent thereof. , In the presence of an acid catalyst and a dehydrating agent, 0 ° C to 10
It is carried out in the temperature range of 0 ° C. Usually, this reaction is carried out in a sealed tube in a solvent containing 1 to 10-fold molar amount of ammonia with respect to the hydroxyketone compound [IX]. As the acid catalyst, the one described in step 3 can be used, and the amount of the acid catalyst used is 1/20 with respect to the hydroxyketone compound [IX].
It is preferably in the range of about 10 times by mole. Also,
As the dehydrating agent, the one described in step 3 can be used. Although the starting material in reaction formula [I] is known, it can be produced, for example, by the method shown in the reference example below. Among the 1,3-benzoxazine derivatives represented by the general formula [I], the basic compound can be converted into a salt by using an acid. Suitable acids for this reaction are preferably those which give pharmacologically acceptable salts.
For example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid or sulfamic acid, organic acids such as acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, p-toluenesulfonic acid, methanesulfonic acid or glutamic acid. An acid is mentioned.

The object compound [I] of the present invention thus obtained is separated from the reaction mixture by a conventional separation and purification means such as extraction, concentration, neutralization, filtration, recrystallization, column (or thin layer) chromatography and the like. It can be isolated by using. The 1,3-benzoxazine derivatives represented by the formula [I] and their pharmaceutically acceptable salts are
Animals, especially mammals (eg humans, monkeys, dogs, cats,
Rabbit, guinea pig, rat or mouse etc.) shows smooth muscle relaxing action which is considered to be based on potassium channel opening (activating) action. For example, hypertension, asthma, congestive heart failure, angina, cerebrovascular It is useful as a therapeutic and prophylactic agent for spasms, arrhythmias, cerebral hemorrhage, dysmenorrhea, renal failure, peripheral vascular obstruction, urinary incontinence, gastrointestinal disorders (especially irritable bowel syndrome), epilepsy and the like.

Since the compound of the present invention has low toxicity, is well absorbed by oral administration, and is excellent in stability, when used as the above-mentioned drug, itself or a suitable pharmacologically acceptable carrier or excipient. To be safely administered orally or parenterally as a pharmaceutical composition such as powder, granules, tablets, capsules (including soft capsules and microcapsules), solutions, injections, suppositories, etc. by mixing with agents and diluents. You can The dose varies depending on the administration subject, administration route, and symptom, but when orally administered to an adult patient for the purpose of treating hypertension, for example, a single dose is usually about 0.001
10 mg / kg, preferably 0.001-0.2 mg / kg,
More preferably, it is about 0.001 to 0.02 mg / kg, and it is desirable to administer these doses about 1 to 3 times a day depending on the symptoms.

[0046]

[Examples] Hereinafter, reference examples showing the production of starting materials, examples showing the production of the 1,3-benzoxazine derivative of the present invention represented by the formula [I] and the pharmacological action of the derivative of the formula [I] will be described. The present invention will be described in more detail with reference to the experimental examples shown, but the present invention is not limited thereto.

Reference Example 1 (Production of Compound A-1) A mixture of 5-cyano-salicylic acid (29.0 g) and triethylamine (54.0 g) in dichloromethane (300 ml) was cooled with ice, and acetyl chloride (43.3 g) was added thereto. Dropped. After dropping
The mixture was stirred from ice cooling to room temperature for 2 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and aqueous potassium hydrogen sulfate solution were added to the residue for extraction. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give an oil. This oily substance was dissolved in 1,2-dichloroethane (100 ml), thionyl chloride (42.4 g) and dimethylformamide (0.5 ml) were added, and the mixture was heated under reflux for 1 hr. After air cooling,
The solvent was distilled off under reduced pressure, and the residue was tetrahydrofuran (100
ml)). This solution was cooled with ice, and aqueous ammonia (1
(00 ml) and tetrahydrofuran (100 ml), and the mixture was stirred for 30 minutes. Then, methanol (10 ml) was added and the mixture was stirred at room temperature for 1 hour. Aqueous potassium hydrogen sulfate solution was added to adjust the pH to 2-3, and the mixture was extracted 3 times with a mixed solution of ethyl acetate-tetrahydrofuran. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude 5
-Cyano-salicylic acid amide was obtained. Acetone (200 ml), 2,2-dimethoxypropane (100 m
l) and p-toluenesulfonic acid (6.6 g) were added, and the mixture was heated under reflux for 16 hours. After cooling with air, the solvent was distilled off, and ethyl acetate and an aqueous sodium hydrogen carbonate solution were added to the residue for extraction. The ethyl acetate layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated under reduced pressure. The residue is washed with isopropyl ether and 6-cyano-2,2-dimethyl-
3,4-dihydro-2H-1,3-benzoxazine-4
-One (19.0 g) was obtained (Compound A-1). The physical properties are shown in Table 1. Compounds A-2 to A-11, A-14, A-16 to A- shown in Table 1 and Table 2 according to the compound A-1.
25 was produced.

Reference Example 2 (Production of Compound A-12) 6-iodo-2,2-dimethyl-3,4-dihydro-2H
-1,3-benzoxazin-4-one (Compound A-1
1, 10.0 g), thiophenol (17.2 g), potassium carbonate (10.0 g) and copper powder (1.0 g) were suspended in isoamyl alcohol (100 ml), and the suspension was maintained under an argon atmosphere for 3 days.
Heated to reflux for hours. After air cooling, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer is an aqueous sodium hydrogen carbonate solution,
The extract was washed successively with saturated brine, dried (anhydrous magnesium sulfate), and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, purified (eluted with ethyl acetate / hexane (2: 1)), and 2,2-dimethyl-6-
Phenylthio-3,4-dihydro-2H-1,3-benzoxazin-4-one (2.67 g) was obtained (Compound A-
12). The physical properties are shown in Table 1.

Reference Example 3 (Production of Compound A-13) 2,2-Dimethyl-6-phenylthio-3,4-dihydro-2H-1,3-benzoxazin-4-one (2.24)
To a solution of g) in dichloromethane (50 ml) was added ice-cooled metachloroperbenzoic acid (purity 70%, 4.64 g) to give 30
Stir for minutes. The reaction solution was poured into an aqueous solution of sodium sulfite, and ethyl acetate was added for extraction. The organic layer was washed successively with aqueous sodium carbonate solution and saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated under reduced pressure. The residue was washed with isopropyl ether and 2,2-dimethyl-6-
Phenylsulfonyl-3,4-dihydro-2H-1,3-
Benzoxazin-4-one (2.50 g) was obtained (Compound A-13). The physical properties are shown in Table 1.

Reference Example 4 (Production of Compound A-15) Compound A-11 (7.0 g), trimethylsilylacetylene (11.1 g), palladium (II) acetate (0.49 g)
To triphenylphosphine (1.2 g) were added triethylamine (70 ml), and the mixture was stirred at 60 ° C. for 2 hours under an argon atmosphere. After air cooling, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate and sodium hydrogen carbonate were added to the residue for extraction, the ethyl acetate layer was washed with saturated brine and dried (anhydrous magnesium sulfate). The solvent was concentrated under reduced pressure, the residue was crystallized from a small amount of ethyl acetate, and 2,2-dimethyl-6-
Trimethylsilylethynyl-2H-1,3-benzoxazin-4-one (3.4 g) was obtained (Compound A-1.
5). The physical properties are shown in Table 2.

Reference Example 5 Phosphorus oxychloride (0.5 ml) was added to dimethylformamide (10 ml) under ice cooling and the mixture was stirred for 10 minutes. Then,
6-Cyano-2,2-dimethyl-3,4-dihydro-2H
-1,3-Benzoxazin-4-one (1.0 g) was added, and the mixture was stirred under ice cooling for 1 hr and at room temperature for 2 hr. Ethyl acetate and ice water were added to the reaction solution for extraction, and the ethyl acetate layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, hexane was added to the obtained residue for crystallization, and 4-chloro-6-cyano-2,2-dimethyl-2H-1,3-benzoxazine. (0.41 g, melting point 124-126 ° C.) was obtained.

Reference Example 6 (Production of Compound A-26) 4-chlorosalicylic acid (60 g), sodium acetate (120
Methanol (2.1 l) was added to g), and the mixture was cooled to -70 ° C and stirred. Bromine (55.7g) in methanol (557m
l) The solution was added dropwise over 1.5 hours. After the reaction solution was returned to room temperature, the solvent was distilled off under reduced pressure. Dilute hydrochloric acid (2 liters) was added to the residue to make it acidic, and the precipitate was collected by filtration. This was dissolved in ethyl acetate, dried (anhydrous magnesium sulfate), and concentrated by solvent. The precipitated crystals were recrystallized from hydrous ethanol to give 5
-Bromo-4-chlorosalicylic acid (43.8 g, melting point 20)
8 to 213 ° C) was obtained. Using this as a starting material and reacting it according to Reference Example 1, 6-bromo-7-chloro-2,2-dimethyl-2H-1,3-benzoxazin-4-one (2
9.2 g) was obtained (Compound A-26). The physical properties are shown in Table 2.
From 4-bromosalicylic acid according to compound A-26:
5-dibromosalicylic acid (melting point 227-232 ° C) is obtained,
Furthermore, 6,7-dibromo-2,2-dimethyl-2H-
1,3-benzoxazin-4-one was obtained (Compound A-
27). Further, 5-bromo-4-fluorosalicylic acid (melting point: 203 to 205 ° C.) was obtained from 4-fluorosalicylic acid, and further 6-bromo-7-fluoro-2,2-dimethyl-2H-1,3-benzoxazine-4. − Got on
(Compound A-28). Table 2 shows the physical properties of Compounds A-27 and A-28.

[0053]

[Table 1]

[Table 2]

Reference Example 7 Bromine (15.9 ml) was added to a solution of 4-trifluoromethylphenol (50 g) in dichloromethane (300 ml) at room temperature, and stirring was continued for 38 hours. The reaction mixture was washed successively with aqueous sodium hydrogen sulfite solution and saturated brine, dried (anhydrous magnesium sulfate) and evaporated to give crude 2-bromo-4.
-Trifluoromethylphenol (78.5g) was obtained as an oil. To this and copper (I) cyanide (27.6 g) were added N, N-dimethylformamide (250 ml), and the mixture was heated under reflux for 2 hours under an argon atmosphere. Iron chloride hexahydrate
The hot reaction solution was poured into a solution of (137.5 g) and hydrochloric acid (35 ml) in water (400 ml), and the mixture was stirred for 30 minutes. The mixture was extracted by adding ethyl acetate, washed successively with diluted hydrochloric acid and saturated brine, and dried (anhydrous magnesium sulfate). The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane, and purified to give 2-cyano-4-trifluoromethylphenol (34.6 g, melting point 149.5-151 ° C).
Got

Reference Example 8 5-chloro-2-cyanophenol (1.84 g, melting point 155 to 157 ° C.) synthesized by a method known in the literature, sodium acetate (1.97 g) was added with methanol (100 ml), and -78 was added.
After cooling to ℃, a solution of bromine (1.53 g) in methanol (25 ml) was added dropwise. After stirring at -78 ° C for 30 minutes, the solvent was evaporated under reduced pressure, and ethyl acetate and an aqueous potassium hydrogen sulfate solution were added to the residue. The ethyl acetate layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane and purified to give 4-bromo-5-chloro-2-cyanophenol.
[0.53 g, melting point 229-231 ° C (decomposition)] were obtained.

Reference Example 9 5-Bromo-4-chlorosalicylic acid (11.0 g), lithium hydroxide monohydrate (1.84 g) and anhydrous tetrahydrofuran
(50 ml) was added and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was treated with anhydrous tetrahydrofuran (50 m
It was dissolved in l), molecular sieves 4A was added, and the mixture was left to stand overnight (this is referred to as solution A). Under an argon atmosphere, 2-bromopyridine (10.4 ml) in anhydrous tetrahydrofuran (13
6 ml) solution was cooled to −78 ° C. and 1.6 M n-butyllithium hexane solution (68 ml) was added dropwise over 30 minutes. 10
After stirring for minutes, the solution A was added dropwise over 20 minutes. After the dropping, the temperature was gradually raised to -10 ° C in 40 minutes, and further stirred at -10 to -5 ° C for 1 hour. The reaction was stopped by adding methanol (10 ml), and saturated ammonium chloride and ethyl acetate were added for extraction. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated. The residue was subjected to silica gel column chromatography and eluted with hexane / ethyl acetate. The obtained crystals were washed with hexane to give 5-bromo-4-chloro-2-hydroxyphenyl 2-pyridyl ketone.
(5.44 g) was obtained.

Example 1 (Production of Compound 1) 6-Cyano-2,2-dimethyl-3,4-dihydro-2H
Dichloromethane (20 ml) was added to -1,3-benzoxazin-4-one (0.80 g), and under an argon atmosphere,
Cooled to -78 ° C. Trifluoromethanesulfonic anhydride (1.0 ml) and then 2,6-lutidine (1.0 ml) were added, and the mixture was stirred for 10 minutes. The temperature was raised to 0 ° C., the mixture was further stirred for 30 minutes, and then ethyl acetate and ice water were added to the reaction solution for extraction. The organic layer was washed successively with aqueous sodium hydrogen sulfate solution, aqueous sodium hydrogen carbonate solution and saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (5 ml) to give a triflate solution. On the other hand, a 1.6M n-butyllithium hexane solution (6.8 ml) was added dropwise to a solution of 2-bromopyridine (1.58 g) in anhydrous tetrahydrofuran (20 ml) at -78 ° C under an argon atmosphere. After 30 minutes, zinc chloride (1.
A solution of 36 g) in anhydrous tetrahydrofuran (10 ml) was added, and the mixture was stirred at -78 ° C for 15 minutes and ice-cooled for 15 minutes. Then, under ice-cooling, tetrakis (triphenylphosphine) palladium (O) (0.30 g) and the above-mentioned triflate solution were added. The temperature was raised to room temperature, the mixture was further stirred for 18 hours, and then a saturated aqueous sodium hydrogen carbonate solution was added. Insoluble matter is filtered off,
The filtrate was extracted twice with ethyl acetate. Combine the organic layers,
After washing with saturated saline and drying (anhydrous magnesium sulfate),
It was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified (eluted with hexane / ethyl acetate (1: 5) to (1: 2)) to give 6-cyano-2,2-dimethyl-4- (2-pyridyl). -2H-1,3-benzoxazine (0.28 g) was obtained (Compound 1). Similarly, compounds 2 to 8, 10, 13, 30, 31, 39, 44, 5
0, 54, 55, 61, 68, 70, 74, 76, 7
8, 80, 82, 84, 88, 92 and 94 were produced. Physical properties and spectral data of these compounds and the compounds obtained in the following examples are shown in Tables 3 to 37.

Example 2 (Production of Compound 16) N-phenylsulfonylindole was used in place of 2-bromopyridine in the production of Compound 1 of Example 1,
6-Cyano-2,2-dimethyl-as in Example 1
4- (1-Phenylsulfonyl-indol-2-yl) -2H-1,3-benzoxazine was obtained (Compound 16). Compounds 14 and 17 were prepared in a similar manner.

Example 3 (Production of Compound 15) N-methylpyrrolidone was used instead of 2-bromopyridine in the production of Compound 1 of Example 1, and 1.6M lithium diisopropyl was used instead of 1.6M n-butyllithium hexane solution. Using a mixed solution of amide and tetrahydrofuran in the same manner as in Example 1, 6-cyano-2,2-dimethyl-4- (1-methyl-2-oxopyrrolidine-3)
-Yl) -2H-1,3-benzoxazine was obtained (Compound 15).

Example 4 (Production of Compound 33) 4-trimethylsilyl-3- (2-trimethylsilylethoxymethyloxy) pyridine, 1.6M n instead of 2-bromopyridine in the production of Compound 1 of Example 1
-Butyllithium hexane solution instead of 1.6M t-
6-Cyano-2,2-dimethyl-4- [4-] was used in the same manner as in Example 1 except that a diethyl ether solvent was used instead of the butyllithium pentane solution and the tetrahydrofuran solvent.
Trimethylsilyl-3- (2-trimethylsilylethoxymethyloxy) pyridin-2-yl] -2H-1,3
-Benzoxazine was obtained (compound 33).

Example 5 (Production of Compound 9) 6-Cyano-2,2-dimethyl-4- (2-pyridyl)
To a solution of 2H-1,3-benzoxazine (0.40 g) in tetrahydrofuran (16 ml) was added 2N aqueous sodium hydroxide solution (6 ml) and 30% hydrogen peroxide solution (8 ml) to give 20%.
Dropped over minutes. After stirring at room temperature for 40 minutes,
Ethyl acetate was added to the reaction solution for extraction. The organic layer is washed successively with aqueous sodium hydrogen carbonate solution, aqueous sodium hydrogen sulfite solution and saturated brine, and dried (anhydrous magnesium sulfate).
After that, the solvent was distilled off under reduced pressure. The residue was washed with diethyl ether and 6-carbamoyl-2,2-dimethyl-4-
(2-Pyridyl) -2H-1,3-benzoxazine (0.30 g) was obtained (Compound 9).

Example 6 (Production of Compound 11) 2,2-Dimethyl-4- (2-pyridyl) -2H-1,3
-Benzoxazine (0.50 g) was dissolved in acetic acid (1 ml), and concentrated sulfuric acid (3 ml) was added under ice cooling. Then, concentrated nitric acid (0.2 ml) was added, and ice-cooled stirring was continued for 10 minutes. The reaction solution was added little by little to a sufficiently cooled mixture of 5N sodium hydroxide (50 ml) and saturated aqueous sodium hydrogen carbonate solution (20 ml) to stop the reaction. Ethyl acetate was added for extraction, and the mixture was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine.
After drying (anhydrous magnesium sulfate), the solvent was evaporated under reduced pressure, hexane was added to the obtained residue for crystallization, and 6-nitro-2,2-dimethyl-4- (2-pyridyl) -2H.
-1,3-Benzoxazine (0.58 g) was obtained (Compound 11). Compounds 48, 57, 66 and 72 were similarly prepared.

Example 7 (Production of Compound 12) 6-Cyano-2,2-dimethyl-4- [4-trimethylsilyl-3- (2-trimethylsilylethoxymethyloxy) pyridin-2-yl] -2H-1, To a solution of 3-benzoxazine (2.5 g) in tetrahydrofuran (20 ml) was added Molecular Sieves 5A (5 g) and tetrabutylammonium fluorinated trihydrate (3.2 g) to give 3
Heated to reflux for 0 minutes. After cooling with air, ethyl acetate was added for extraction, and the organic layer was washed with saturated brine. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the obtained residue for crystallization, and 6
-Cyano-2,2-dimethyl-4- (3-hydroxypyridin-2-yl) -2H-1,3-benzoxazine (0.19 g) was obtained (Compound 12).

Example 8 (Production of Compound 18) 6-Cyano-2,2-dimethyl-4- (2-pyridyl)
Methyl iodide (2 ml) was added to a solution of -2H-1,3-benzoxazine (0.20 g) in acetonitrile (14 ml), and the mixture was heated under reflux for 7 hours. After air cooling, the solvent was distilled off under reduced pressure,
Diethyl ether was added to the residue to crystallize, and iodide 2
-(6-Cyano-2,2-dimethyl-2H-1,3-benzoxazin-4-yl) -1-methylpyridinium (0.29 g) was obtained (Compound 18).

Example 9 (Production of Compound 19) 2-Cyanoiminoimidazolidine (1.00 g) was added to sodium hydride (0.24 g) in dimethylformamide (10).
ml) suspension was added under ice cooling. Then, after stirring at room temperature for 10 minutes, 4-chloro-6-cyano-2,2-dimethyl-2
H-1,3-benzoxazine (1.09 g) was added and the mixture was stirred at room temperature for 5 hours. Ethyl acetate and aqueous sodium hydrogen carbonate solution were added to the reaction solution for extraction. The ethyl acetate layer was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated under reduced pressure. Ether was added to the obtained residue for crystallization, and 6-cyano-4- (2-cyanoimino-imidazolin-1-yl) -2,2-dimethyl-2H-1,3-benzoxazine (0.23 g) Was obtained (Compound 19). In the same manner, compound 34 was produced.

Example 10 (Production of Compound 20) 6-Cyano-2,2-dimethyl-4- (2-pyridyl)
-2H-1,3-benzoxazine (0.40g) in dichloromethane (10ml) at -20 ° C, methachloroperbenzoic acid (purity 70%, 0.75g) was added, and further 3
Stir for 0 hours. Aqueous sodium sulfite solution and ethyl acetate were added to the reaction solution for extraction. The organic layer was washed successively with aqueous sodium carbonate solution and saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, purified, and crystallized from isopropyl ether to give 2- (6-cyano-2,2).
-Dimethyl-2H-1,3-benzoxazin-4-yl) pyridine N-oxide (0.09g) was obtained (Compound 20). Similarly, compounds 21 to 29, 32, 36,
38, 43, 45, 47, 49, 51, 56, 58, 6
0, 63, 65, 67, 69, 71, 73, 75, 7
7, 79, 81, 83, 85, 87, 89, 91, 9
3, 95, 97, 106, 107, 108, 109, 1
10, 117, 118, 119 and 144 were produced.

Example 11 (Production of Compound 35) Compound 2 (1.77 g) was added to a mixed solution of chlorosulfuric acid (5.83 g) and chloroform (50 ml) at room temperature and then at 80 ° C.
The temperature was raised to and the mixture was heated under reflux for 3 hours. Then, the reaction solution was ice-cooled, added dropwise to concentrated aqueous ammonia, and stirred for 1 hour. Ethyl acetate was added to the reaction solution for extraction, the organic layer was dried (anhydrous magnesium sulfate), and the solvent was evaporated under reduced pressure. Isopropyl ether was added to the residue for crystallization to give 6-aminosulfonyl-2,2-dimethyl-4- (2-pyridyl) -2H-1,
3-Benzoxazine (0.16 g) was obtained (Compound 3
5).

Example 12 (Production of compound 40) Compound 39 (0.60 g) was added to tetrahydrofuran (20 m).
It was dissolved in a mixed solution of l) and water (10 ml), sodium periodate (1.5 g) was added at room temperature, and the mixture was stirred for 4 hours. The reaction solution was extracted twice with ethyl acetate, the organic layers were combined, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography, and crystallized from isopropyl ether to give 6-cyano-2,2-dimethyl-4- (2-methylsulfinylphenyl) -2,2-1. There was obtained 3,3-benzoxazine (0.38 g) (compound 40). Compound 42 was produced in the same manner.

Example 13 (Production of Compound 41) Example 3 was carried out by using 3,4-dihydro-2H-thiopyran (boiling point 45-50 ° C./20 mmHg) instead of 2-bromopyridine in the production of Compound 1 of Example 1. 6-Cyano-2,2-dimethyl-4- (3,4-dihydro-2H-6-thiopyranyl) -2H-1,3-benzoxazine was obtained in the same manner as in 1 (Compound 41).

Example 14 (Production of compound 46) To a solution of compound 10 (0.50 g) in ethyl acetate (10 ml) was added sodium acetate (0.41 g), and the mixture was cooled to -40 ° C. Then, a solution of bromine (0.32 g) in ethyl acetate (3 ml) was added dropwise over 10 minutes, and the mixture was further stirred for 15 minutes. The reaction solution was poured into an aqueous potassium carbonate solution, and the ethyl acetate layer was washed with saturated saline and dried (anhydrous magnesium sulfate). The solvent was evaporated under reduced pressure and the residue was subjected to silica gel chromatography and purified to give 6-bromo-2,2,7-trimethyl-4-.
(2-Pyridyl) -2H-1,3-benzoxazine (0.47 g) was obtained (Compound 46).

Example 15 (Production of Compound 52) To a solution of Compound 50 (100 mg) in methanol (1 ml) was added potassium carbonate (8 mg), and the mixture was stirred at room temperature for 1.5 hours under an argon atmosphere. Methanol was distilled off under reduced pressure, and ethyl acetate and aqueous sodium hydrogen carbonate solution were added to the residue for extraction. The ethyl acetate layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated. The residue is chromatographed on silica gel and purified to give 6-ethynyl-
2,2-Dimethyl-4- (2-pyridyl) -2H-1,3
-Benzoxazine (42 mg) was obtained (compound 52).
Compound 53 was produced in the same manner.

Example 16 (Production of compound 59) To a solution of compound 10 (1.5 g) in acetic acid (20 ml) was added sodium acetate (1.5 g), and the mixture was cooled to 5 ° C. Then, a solution of bromine (2.0 g) in acetic acid (20 ml) was added dropwise over 15 minutes, the temperature was raised, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and water were added to the reaction solution for extraction. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated. The residue was subjected to silica gel column chromatography and purified to give 6,8-dibromo-2,2,7-trimethyl-4- (2-pyridyl)-.
2H-1,3-benzoxazine (0.33 g) was obtained (Compound 59).

Example 17 (Production of Compound 37) 3-ethoxypyridine (boiling point 90-95 ° C. /
20 mmHg) and N, N, N ′, N′-tetramethylethylenediamine, and 6-cyano-4-as in Example 1.
(3-Ethoxy-2-pyridyl) -2,2-dimethyl-
2H-1,3-benzoxazine was obtained (compound 3
7). Compounds 120 and 121 were similarly prepared. Also, 3-methoxypyridine (boiling point 77-78 ° C /
18 mmHg) in the same manner as compounds 122 and 123
Was manufactured.

Example 18 (Production of compound 62) To a solution of compound 61 (0.84 g) in methanol (25 ml) was added sodium acetate (0.84 g), and the mixture was cooled to -60 ° C. Then bromine (0.48 g) in methanol (1
(0 ml) solution was added dropwise over 30 minutes, then the temperature was raised to 2
Stir for hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and aqueous sodium hydrogen carbonate solution were added to the residue for extraction. The ethyl acetate layer was washed with saturated brine, dried (anhydrous sodium sulfate), and the solvent was evaporated. The obtained crude product was washed with hexane to obtain 6-bromo-7-ethoxy-2,2-dimethyl-4- (2-pyridyl) -2H-1,3-benzoxazine (0.64 g). (Compound 62).

Example 19 (Production of Compound 64) Compound 46 (2.0 g) in dimethylformamide (5 m
l) Cuprous cyanide (1.1 g) was added to the solution, and the mixture was heated under reflux for 23 hours. The reaction mixture was air-cooled, added to a solution of sodium cyanide (2.2 g) in water (6.5 ml), and the mixture was stirred for 15 minutes. The mixture was extracted with ethyl acetate, washed successively with 5% aqueous sodium cyanide and saturated brine, and dried (anhydrous magnesium sulfate). The solvent was distilled off, and the obtained crude product was washed with ether / isopropyl ether to give 6-cyano-2,
2,7-Trimethyl-4- (2-pyridyl) -2H-
1,3-Benzoxazine (0.35 g) was obtained (Compound 64). Compounds 86 and 90 were similarly prepared.

Example 20 (Production of Compound 96) Instead of the anhydrous tetrahydrofuran solution of 2-bromopyridine in the production of the compound 1 of Example 1, an anhydrous diethyl ether solution of 3-bromopyridine and an anhydrous tetrahydrofuran solution of zinc chloride were replaced. An anhydrous diethyl ether solution of zinc chloride was used for 6-cyano-2,2-dimethyl-4- (3-pyridyl) -2H-1, in the same manner as in Example 1.
3-Benzoxazine was obtained (Compound 96). Compound 98 was similarly prepared.

Example 21 (Production of compound 2) 2-Methoxypropene (0.87 g) was added to 2-bromophenol (1.73 g), and the mixture was stirred at room temperature for 30 minutes. 2 in excess
-Methoxypropene was distilled off under reduced pressure, and anhydrous tetrahydrofuran (20 ml) was added to the residue. Cool to -78 ° C,
A 1.6 M n-butyllithium hexane solution (6.9 ml) was added dropwise under an argon atmosphere, and the mixture was stirred at -78 ° C for 20 minutes. Then, a solution of 2-cyanopyridine (1.04 g) in anhydrous tetrahydrofuran (5 ml) was added dropwise, and stirring was continued at -78 ° C for 1 hour. The reaction was stopped by adding an aqueous sodium hydrogen carbonate solution, and ethyl acetate was added for extraction. The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated. Ammonium acetate (5 g) and 2,2-dimethoxypropane (30 ml) were added to the residue, and the mixture was heated under reflux for 1 hr. The solvent was evaporated under reduced pressure, and ethyl acetate and aqueous sodium hydrogen carbonate solution were added for extraction. The ethyl acetate layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane for purification, and 2,2-dimethyl-4- (2-pyridyl) -2H-1,3-benzoxazine (1.0 g) was obtained.
(Compound 2).

Example 22 (Production of Compound 4) Compound 2 (1.19 g) and sodium acetate (0.82 g) were added with methanol (25 ml), cooled to -40 ° C, and bromine (0.9) was added.
6 g) was added. After the addition, the temperature was raised and the mixture was stirred at 5 to 8 ° C for 18 hours. The reaction was stopped by adding an aqueous solution of sodium sulfite, and methanol was distilled off. The residue was extracted with ethyl acetate, the extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane for purification, and purified with 6-bromo-2,2-dimethyl-
4- (2-pyridyl) -2H-1,3-benzoxazine
(0.41 g) was obtained (Compound 4).

Example 23 (Preparation of compound 68) A solution of 4-trifluoromethoxyphenol (4.0 g) in methanol (50 ml) was cooled to -78 ° C and bromine (3.59 g) was added.
Methanol solution (20 ml) was added dropwise. After stirring at −78 ° C. for 1 hour, an aqueous sodium hydrogen sulfite solution was added to stop the reaction, and methanol was distilled off under reduced pressure. Ethyl acetate was added to the residue for extraction, which was washed with saturated brine and dried (anhydrous magnesium sulfate), and the solvent was evaporated. The obtained crude 2-bromo-4-
6-Trifluoromethoxy-2,2-dimethyl-4- (2-pyridyl) -2H-1,3-benzoxazine (1.3 g) was obtained from trifluoromethoxyphenol by a method similar to that in Example 21. (Compound 68).

Example 24 (Preparation of compound 74) A solution of 2-bromopyridine (0.47 g) in anhydrous tetrahydrofuran (5 ml) was cooled to -78 ° C, and 1.6 M n-butyllithium hexane solution (2.1 ml) was added. Was added dropwise under an argon atmosphere and stirred for 30 minutes. Then, a solution of 2-cyano-4-trifluoromethylphenol (0.19 g) in anhydrous tetrahydrofuran (5 ml) was added, and the mixture was further stirred at -78 ° C for 1 hr. The reaction was stopped by adding acetic acid (0.18 g), and the solvent was evaporated under reduced pressure. Ammonium acetate (2g) and 2.2 were added to the residue.
-Dimethoxypropane (5 ml) was added and the mixture was heated under reflux for 3 hours. The solvent was evaporated, and the residue was extracted with ethyl acetate and aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was washed with saturated brine, dried (magnesium sulfate-free), and the solvent was evaporated. The residue was subjected to silica gel column chromatography and purified to give 6-trifluoromethyl-2,2-dimethyl-4-.
(2-pyridyl) -2H-1,3-benzoxazine (0.
19 g) was obtained (compound 74).

Example 25 (Preparation of compound 88) A solution of 2-bromopyridine (316 mg) in anhydrous tetrahydrofuran (5 ml) was cooled to -78 ° C, and 1.6 M n-butyllithium hexane solution (1.3 ml) was charged with argon. The mixture was dropped under an atmosphere and stirred for 30 minutes. Then add a 2.82M magnesium bromide-benzene ether solution (0.78 ml)-
The mixture was stirred at 78 ° C for 30 minutes and at 5 ° C for 15 minutes. Then 5-bromo-4-chloro-2-cyanophenol (1
Anhydrous tetrahydrofuran solution (3 ml) of 16 mg) was added, and the mixture was stirred at 5 ° C for 30 minutes. The solvent was distilled off under reduced pressure, and ammonium acetate (2 g) and 2,2-dimethoxypropane were added to the residue.
(5 ml) was added and the mixture was heated under reflux for 3 hours. The solvent was evaporated, and the residue was extracted with water and ethyl acetate. The ethyl acetate layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine,
It was dried (anhydrous magnesium sulfate) and the solvent was distilled off. The residue was subjected to silica gel column chromatography and purified to give 6-bromo-7-chloro-2,2-dimethyl-4- (2-pyridyl) -2H-1,3-benzoxazine (35 mg).
(Compound 88).

Example 26 (Production of Compound 82) 3-Hydroxy-2-naphthyl 2-pyridyl ketone (30 mg, melting point 104-109 ° C.), ammonium chloride (6 mg) and anhydrous calcium sulfate (30 mg) were added at room temperature with ammonia. Saturated acetone (3 ml) was added and the mixture was stirred in a sealed tube at 85 ° C. for 4 hours. The insoluble matter in the reaction solution was filtered off, saturated aqueous ammonium chloride solution was added to the filtrate,
It was extracted with ethyl acetate. The organic layer was washed with saturated saline,
It was dried (anhydrous magnesium sulfate) and the solvent was distilled off. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate / hexane, and purified to give 2,2-dimethyl-4- (2
-Pyridyl) -2H-naphtho [2,3-e] [1,3]
Oxazine (18 mg) was obtained (Compound 82).

Example 27 (Preparation of compound 88) 5-Bromo-4-chloro-2-hydroxyphenyl 2
-Pyridyl ketone (30g), ammonium chloride (30g)
g), anhydrous calcium sulfate (60 g), acetone (500 ml)
Was placed in a sealed tube and mixed well, and a saturated ammonia-acetone solution (300 ml) was added under ice cooling. The mixture was stirred at 80 ° C. for 7 hours, allowed to cool, sodium hydrogen carbonate (60 g) was added, and the mixture was stirred for 1 hour. The insoluble material was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with hexane / ethyl acetate. The obtained crude crystals were washed with cold hexane to give 6-bromo-7-chloro-2,2-dimethyl-4- (2-pyridyl) -2H-.
1,3-benzoxazine (15.2 g) was obtained (Compound 8
8).

Example 28 (Preparation of compound 89) To a solution of compound 88 (10.0 g) in dichloromethane (130 ml) was added 70% metachloroperbenzoic acid (20.0 g) at 0 ° C, and the mixture was heated at 2-4 ° C at 5 ° C. Stir for hours. Sodium sulfite (3
A solution of 2 g) in water (130 ml) was gradually added, and the mixture was stirred with ice cooling for 1 hour. Remove the organic layer, 5% sodium carbonate solution,
The extract was washed successively with saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated. The residue was purified by silica gel column chromatography and crystallized from diethyl ether to give 2- (6
-Bromo-7-chloro-2,2-dimethyl-2H-1,3
-Benzoxazin-4-yl) pyridine 1-oxide (2.7 g) was obtained. Compounds 124-133 were similarly prepared.

Example 29 (Production of compound 99) To 2,4-dibromophenol (8.76 g) was added 2-methoxypropene (3.0 g), the mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure. did. The residue is anhydrous diethyl ether
(70 ml) and dissolved in argon atmosphere at -78 ° C for 1.6.
M-butyllithium hexane solution (23 ml) was added dropwise over 15 minutes. After 20 minutes, a solution of 4-cyanopyridine (3.32 g) in anhydrous tetrahydrofuran (14 ml) was added in 10 minutes. After the addition, stirring was continued and the temperature was gradually raised to room temperature in 80 minutes. The reaction solution was concentrated under reduced pressure, and ammonium acetate was added to the residue.
(15.0 g) and 2,2-dimethoxypropane (80 ml) were added, and the mixture was heated under reflux for 6 hours. After air cooling, the reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the residue for extraction. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated. The residue was subjected to silica gel column chromatography and purified (eluted with ethyl acetate / hexane) to give 6-bromo-2,2-
Dimethyl-4- (4-pyridyl) -2H-1,3-benzoxazine (3.94 g) was obtained (Compound 99). Similarly, 2-cyano-4-methylpyridine (melting point 89-91
Compound) from 2-benzyloxybenzonitrile (melting point 74 to 75 ° C.), compound 102 from 1-cyanoisoquinoline (melting point 87 ° C.),
-Cyanoquinoline (melting point 96-98 ° C) to compound 103
Compound 104 from 2-cyanopyrimidine (melting point 40-41 ° C), compound 134 from 2-cyano-3-methoxypyridine (melting point 111-112 ° C), 3-chloro-.
Compound 13 from 2-cyanopyridine (melting point 85-86 ° C)
5 to 2-cyano-3-methylpyridine (melting point 82-8
Compound 136 from 2-cyano-3-hydroxypyridine [melting point 211-212 ° C. (decomposition)] was synthesized according to a known method. 2-Cyano-3- (2-trimethylsilylethoxymethyloxy) pyridine (oil Compound) to Compound 1
37 were produced respectively.

Example 30 (Production of compound 105) 1,3-dithiane (1.5 g) in anhydrous tetrahydrofuran (3
5M) solution under argon atmosphere at -78 ° C to 1.6M.
A n-butyllithium hexane solution (13.8 ml) was added dropwise over 10 minutes. After stirring for 30 minutes, it was prepared according to Example 29 from 4-bromo-2-cyanophenol (mp 148-150 ° C, 2.48g) and 2-methoxypropene (1.1g).
A solution of -bromo-2- (2-methoxy-2-methylethoxy) benzonitrile in anhydrous tetrahydrofuran (5 ml) was added. Treated as in Example 29 to give 6-bromo-2,
2-Dimethyl-4- (1,3-dithian-2-yl) -2
H-1,3-benzoxazine (0.90 g) was obtained (Compound 105).

Example 31 (Production of Compound 111) A solution of Compound 105 (600 mg) in methanol (18 ml) was added,
A solution of sodium metaperiodate (430 mg) in water (6 ml) was added, and the mixture was stirred at room temperature for 18 hours. Methanol was distilled off under reduced pressure and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated.
The residue was subjected to silica gel column chromatography, purified, and the obtained solid was recrystallized from ethyl acetate to give 2- (6-bromo-2,2-dimethyl-2H-1,3-benzoxazin-4-yl). ) -1,3-Dithiane-1-oxide (331 m
g) was obtained (compound 111).

Example 32 (Preparation of Compound 112) Compound 9 (2.95 g), di-t-butyl-dicarbonate
(5.73 g) and 4-dimethylaminopyridine (0.13 g) were dissolved in anhydrous tetrahydrofuran (100 ml), and the mixture was heated under reflux for 40 minutes. After air cooling, the solvent was evaporated, the residue was subjected to silica gel column chromatography and purified to give 6- [N, N- (di-t
-Butoxycarbonyl) carbamoyl] -2,2-dimethyl-4- (2-pyridyl) -2H-1,3-benzoxazine (3.93 g) was obtained (Compound 112).

Example 33 (Production of compound 113) A solution of compound 112 (3.50 g) in methanol (60 ml) was added,
A 4N sodium hydroxide aqueous solution (14.5 ml) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, water and diethyl ether were added to the residue for extraction. Potassium hydrogen sulfate was added to the aqueous layer to adjust the pH to 5, and ethyl acetate was added for extraction. The ethyl acetate layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated. Hexane was added to the residue for crystallization to obtain 6-carboxy-2,2-dimethyl-4- (2-pyridyl) -2H-1,3-benzoxazine (0.79 g) (Compound 113).

Example 34 (Production of compound 6) A solution of compound 113 (0.70 g) in tetrahydrofuran (5 ml) was added with a solution of diazomethane diethyl ether at room temperature until the raw materials disappeared. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 6-methoxycarbonyl-2,2-dimethyl-4- (2-pyridyl) -2H-1,3-benzoxazine (0.49 g). ) Got
(Compound 6).

Example 35 (Production of compound 114) To a solution of compound 25 (65 mg) in methanol (1 ml) was added a 2N aqueous sodium hydroxide solution (0.31 ml), and the mixture was stirred at room temperature for 1 hour. Methanol was distilled off under reduced pressure, and chloroform and water were added to the residue for extraction. Sodium hydrogensulfate was added to the aqueous layer to adjust to pH 3, and ethyl acetate was added for extraction.
The ethyl acetate layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated. Diethyl ether was added to the residue for crystallization to give 2- (6-carboxy-2,2-dimethyl-2H-1,3-benzoxazin-4-yl) pyridine 1-oxide (46 mg). ).

Example 36 (Production of compound 115) Compound 113 (200 mg), triethylamine (0.10 m)
To a solution of l) in anhydrous tetrahydrofuran (1 ml) was added ethyl chlorocarbonate (80 mg) at -15 ° C under an argon atmosphere. After stirring at -15 to -10 ° C for 30 minutes, the precipitate was filtered off, and the filtrate was washed with sodium borohydride (67 mg) in water (0.7 mg).
ml) solution at 10 ° C. After the addition, the temperature was raised to room temperature, stirring was continued for 3 hours, and water and ethyl acetate were added for extraction.
The organic layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and the solvent was evaporated. The residue was purified by silica gel column chromatography and 6-hydroxymethyl-2,2-dimethyl-
4- (2-pyridyl) -2H-1,3-benzoxazine
(110 mg) was obtained (Compound 115). In the same manner, compound 114 was prepared from compound 114.

Example 37 (Production of compound 116) To a solution of compound 115 (100 mg) in dichloromethane (3 ml) was added active manganese dioxide (300 mg), and the mixture was stirred at room temperature for 1 hour. The insoluble matter was filtered off through Celite, and the filtrate was evaporated under reduced pressure to give 6-formyl-2,2-dimethyl-4.
-(2-Pyridyl) -2H-1,3-benzoxazine (4
0 mg) was obtained (Compound 116). Similarly, compound 14
Compound 146 was prepared from 5.

Example 38 (Production of Compound 138) Instead of the 1.6M butyllithium hexane solution in the production of Compound 99 of Example 29, a 1.6M butyllithium hexane solution and N, N, N ', N'-tetra were prepared. Using methylethylenediamine, 6-trifluoromethyl-4- (3-methoxy-2-pyridyl) -2,2-from 3-methoxypyridine and 2-cyano-4-trifluoromethylphenol in the same manner as in Example 29. Dimethyl-2H-1,3-
Benzoxazine was obtained (Compound 138). Similarly 3
Compound 139 was prepared from -ethoxypyridine.

Example 39 (Production of Compound 140) Compound 136 (1.68 g) in dimethylformamide (10 m
l) Cuprous cyanide (0.91 g) was added to the solution, and the mixture was heated under reflux for 10 hours under an argon atmosphere. The reaction solution was poured into a mixed solution of ethylenediamine (5 ml) and water (50 ml), and the mixture was diluted with ethyl acetate to 2 times.
Extracted twice. The organic layer is washed successively with water and brine and dried.
(Anhydrous magnesium sulfate) and the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate / hexane for purification to give 6-cyano-2,2-dimethyl-4- (3
-Methyl-2-pyridyl) -2H-1,3-benzoxazine (0.46 g) was obtained (Compound 140). In the same manner, compounds 141 and 142 were produced from compound 135.

Example 40 (Preparation of compound 143) Compound 133 (0.86 g) in tetrahydrofuran (20 ml)
Tetrabutylammonium fluoride trihydrate in solution
(1.13 g) was added and the mixture was heated under reflux for 5 hours. After cooling with air, the solvent was distilled off, and ethyl acetate and a saturated aqueous solution of potassium hydrogen sulfate were added to the residue for extraction. The ethyl acetate layer was dried (anhydrous magnesium sulfate) and the solvent was evaporated. The residue was subjected to silica gel column chromatography, purified (eluted with chloroform / methanol), and crystallized with isopropyl ether to give 2-
(6-Bromo-2,2-dimethyl-2H-1,3-benzoxazin-4-yl) -3-hydroxypyridine N-
Oxide (0.40 g) was obtained (Compound 143).

[0097]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[0098]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[0099]

[Table 16]

[Table 17]

[Table 18]

[Table 19]

[Table 20]

[0100]

[Table 21]

[Table 22]

[Table 23]

[Table 24]

[Table 25]

[0101]

[Table 26]

[Table 27]

[Table 28]

[Table 29]

[Table 30]

[0102]

[Table 31]

[Table 32]

[Table 33]

[Table 34]

[Table 35]

[Table 36]

[Table 37]

[Table 38]

Next, experimental examples showing the pharmacological effect of the 1,3-benzoxazine derivative of the general formula (I) will be given. Experimental Example 1 Effect of vasorelaxation in rat aortic preparation Effect on contraction induced by tetraethylammonium chloride (TEA) and barium chloride (Ba) Experimental method: An experiment was carried out using male Wistar rats (10 to 13 weeks old). After blood removal, the aorta was removed and a ring specimen (5 mm) was prepared, and then oxygen (95% O ₂ -5%) was prepared.
It was suspended in a liquid tank filled with CO ₂ ) -added Krebs solution (36 ° C.). One end of the ring sample was fixed and the other end was connected to a tension measuring transducer (Nihon Kohden), and the tension was measured. After a stable period of 1 hour, TEA (30-4
5 mM) and Ba (0.3 mM) were added to the liquid bath to cause vasoconstriction. After the contraction reached a steady state (after about 15 minutes), the test compound was added and its relaxing effect was investigated. Experimental results: Table 38 shows the inhibition rates.

Experimental Example 2 Effect of vasorelaxation in rat aortic preparation Effect on contraction induced by potassium chloride (KCl) Experimental method: An experiment was conducted using KCl (80 mM) instead of TEA and Ba used in Experimental Example 1. .. The other methods are the same as in Experimental Example 1. Experimental results: Table 39 shows the inhibition rates.

Experimental Example 3 Antihypertensive Action in Rats Experimental Method: Spontaneously hypertensive rats (male, 20 to 23 weeks old) were preliminarily subjected to surgery for placing a cannula for measuring blood pressure in the left femoral artery. The day after the operation, the experiment was performed when the rat was awake. During the experiment, the cannula was connected to a transducer (SpectraMed) to measure blood pressure (Nihon Kohden). The test compound was suspended in gum arabic and orally administered. Experimental results: The maximum average reduction rates of blood pressure (mmHg) are shown in Tables 40 and 41.

[0106]

[Table 39]

[Table 40]

[Table 41]

[Table 42]

[0107]

INDUSTRIAL APPLICABILITY According to the present invention, a novel 1,3-benzo compound useful as a drug, which exhibits a smooth muscle relaxing action by the potassium channel opening action, which has less side effects of a function inhibitor of other organs such as heart. Oxazine derivatives are provided.

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[Procedure amendment]

[Submission date] November 15, 1991

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0002

[Correction method] Change

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[0002]

2. Description of the Related Art As agents having a smooth muscle relaxing action, those acting on the contraction system and those acting on the relaxation system are known. Representative agents that act on the contraction system include β-receptor blockers, α ₁ -receptor blockers, and calcium antagonists, and examples of agents that act on the relaxation system include nitro compounds. ("Development of pharmaceuticals" (Hirokawa Shoten) Volume 8 "Mechanism of action of drugs").

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0003

[Correction method] Change

[Correction content]

Recently, a new type of drug called a potassium channel opener, which exhibits this smooth muscle relaxing action by opening (activating) a potassium channel, has been attracting attention ("Development of pharmaceuticals"). (Hirokawa Shoten) Volume 4, "Synthetic pharmaceuticals").

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0018

[Correction method] Change

[Correction content]

R ′ and R ″ are more preferably methyl, ethyl, acetyl, benzoyl (which may be substituted with methyl, methoxy, halogen, nitro, CF ₃ or cyano), methoxycarbonyl, methylsulfonyl, ( Methyl, ethoxy, halogen, nitro, CF ₃
Or optionally substituted with cyano) benzenesulfonyl, CF ₃ , CF ₃ CF ₂ , CF ₃ O, CF ₂ ═C
F, nitro, cyano, halogen, amino, formyl, C
O ₂ H, CONH ₂ , nitromethyl or ethynyl.

[Procedure correction 4]

[Document name to be amended] Statement

[Name of item to be corrected] 0019

[Correction method] Change

[Correction content]

The heteroaryl group for R'and R "is a 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl, and a 5- or 6-membered monocyclic heteroaryl is preferred. Furthermore, the 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl is preferably one selected from oxygen, nitrogen and sulfur,
If there are two or three heteroatoms and there is more than one heteroatom, they may be the same or different. 1 selected from oxygen, nitrogen and sulfur
5-, 6-membered monocyclic heteroaryl groups containing 1, 2 or 3 heteroatoms include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazyl,
Includes pyrimidyl, pyrazyl and triazyl. Examples of 9- or 10-membered bicyclic heteroaryl groups containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur include benzofuranyl, benzothienyl, indolyl, indazolyl, quinolyl, isoquinolyl and quinazolinyl. included.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location A61K 31/695 ACD 8314-4C C07D 265/12 9283-4C 265/20 9283-4C 413/04 8829 -4C 417/04 9051-4C (31) Priority claim number Japanese Patent Application No. 3-204235 (32) Priority date Hei 3 (1991) August 14 (33) Priority claim country Japan (JP)

Claims (5)

[Claims] 1. A general formula: [In the formula, Represents an optionally substituted benzene ring, R ¹ is 1,
A homo- or heterocyclic group bonded to the 4-position of the 3-benzoxazine ring by a carbon atom, a hydrocarbon residue, or a compound of the formula: (In the formula, R ⁴ is a hydrogen atom, a C _1-4 alkyl group or a C _1-4
Alkylcarbonyl, Y is -S-, -O- or the formula: (In the formula, R ⁶ represents a hydrogen atom, a C _1-4 alkyl or a C _1-11 acyl group), Z is ═N—CN, ═
N—NO ₂ or ═CH—NO ₂ , R ⁵ is a hydrogen atom or a C _1-8 alkyl group, or R ⁴ and R ⁵ are bonded to each other to form a C _3-6 alkylene group or C _3-6 An alkylenecarbonyl group, or R ⁵ and R ⁶ are bonded to each other to form C
_{4-5 represents an} alkylene group. ), The homo or heterocyclic group and the hydrocarbon residue may be substituted, and R ² and R ³ are each a hydrogen atom or an optionally substituted C _1-6. Alkyl or a C _3-6 alkylene group in which both are bonded to each other and may be substituted. ] The 1,3-benzoxazine derivative represented by these or its salt. 2. A general formula: [In the formula, Represents an optionally substituted benzene ring, R ² and R ³ are each a hydrogen atom or an optionally substituted C _1-6 alkyl, or both may be substituted by being bonded to each other. _{Represents a} good C _3-6 alkyl group, and E represents a halogen or an esterified hydroxyl group. Compounds or formula R ¹ '-M [In the formula, R ^1' and a salt thereof] is allotropic or heterocyclic group having a bond to a carbon atom, a hydrocarbon residue or the formula: 7] (In the formula, R ⁴ is a hydrogen atom, a C _1-4 alkyl group or a C _1-4
Alkylcarbonyl, Y is -S-, -O- or the formula: (In the formula, R ⁶ represents a hydrogen atom, C _1-4 alkyl or C _1-11 acyl group.), Z is ═N—CN,
= N-NO ₂ or = a CH-NO _2, R ⁵ is hydrogen atom or a C _1-8 alkyl group, or R ⁴ and R ⁵ are bonded to each other C _3-6 alkylene group or a C _{3- It is a 6} alkylene carbonyl group, or R ⁵ and R ⁶ are bonded to each other to represent a C _4-5 alkylene group. ) Represents a group represented by
These homologous or heterocyclic groups and hydrocarbon residues may be substituted, and M represents a leaving group. ] The compound represented by the general formula: [Wherein Represents an optionally substituted benzene ring, and R ¹ is
A homologous or heterocyclic group bonded to the 4-position of the 1,3-benzoxazine ring by a carbon atom, a hydrocarbon residue, or a compound represented by the formula: (In the formula, R ⁴ is a hydrogen atom, a C _1-4 alkyl group or a C _1-4
Alkylcarbonyl, Y is -S-, -O- or the formula: (In the formula, R ⁶ represents a hydrogen atom, a C _1-4 alkyl or a C _1-11 acyl group), Z is ═N—CN, ═
N—NO ₂ or ═CH—NO ₂ , R ⁵ is a hydrogen atom or a C _1-8 alkyl group, or R ⁴ and R ⁵ are bonded to each other to form a C _3-6 alkylene group or C _3-6 An alkylenecarbonyl group, or R ⁵ and R ⁶ are bonded to each other to form C
_{4-5 represents an} alkylene group. ), The homologous or heterocyclic group and the hydrocarbon residue may be substituted, and other symbols have the same meanings as described above. ] The manufacturing method of the compound or its salt represented by these. 3. A general formula: [Wherein Represents an optionally substituted benzene ring, and R ¹ is
A homologous or heterocyclic group bonded to the 4-position of the 1,3-benzoxazine ring by a carbon atom, a hydrocarbon residue or a formula: (In the formula, R ⁴ represents a hydrogen atom, C _1-4 alkylcarbonyl,
Y is -S-, -O- or the formula: (In the formula, R ⁶ represents a hydrogen atom, a C _1-4 alkyl or a C _1-11 acyl group), Z is ═N—CN, ═
N—NO ₂ or ═CH—NO ₂ , R ⁵ is a hydrogen atom or a C _1-8 alkyl group, or R ⁴ and R ⁵ are bonded to each other to form a C _3-6 alkylene group or C _3-6 An alkylenecarbonyl group, or R ⁵ and R ⁶ are bonded to each other to form C
_{4-5 represents an} alkylene group. And a homocyclic or heterocyclic group and a hydrocarbon residue may be substituted], a compound represented by the general formula: [Wherein, R ² and R ³ are each a hydrogen atom or an optionally substituted C _1-6 alkyl, or a C _3-6 alkylene group which is bonded to each other and may be substituted, Represents a methyl or ethyl group] and is reacted with a compound represented by the general formula: [Wherein each symbol has the same meaning as defined above], or a method for producing a salt thereof. 4. A general formula: [In the formula, Represents an optionally substituted benzene ring, and R ¹ is
A homologous or heterocyclic group bonded to the 4-position of the 1,3-benzoxazine ring by a carbon atom, a hydrocarbon residue or a formula: (In the formula, R ⁴ is a hydrogen atom, a C _1-4 alkyl group or a C _1-4
Alkylcarbonyl, Y is -S-, -O- or the formula: (In the formula, R ⁶ represents a hydrogen atom, a C _1-4 alkyl or a C _1-11 acyl group), Z is ═N—CN, ═
N—NO ₂ or ═CH—NO ₂ , R ⁵ is a hydrogen atom or a C _1-8 alkyl group, or R ⁴ and R ⁵ are bonded to each other to form a C _3-6 alkylene group or C _3-6 An alkylenecarbonyl group, or R ⁵ and R ⁶ are bonded to each other to form C
_{4-5 represents an} alkylene group. And a homocyclic or heterocyclic group and a hydrocarbon residue may be substituted], a compound represented by the general formula: [Wherein, R ² and R ³ are each a hydrogen atom or an optionally substituted C _1-6 alkyl, or a C _3-6 alkylene group which is bonded to each other and may be substituted, Represents a methyl or ethyl group] and a compound represented by the general formula: [Wherein each symbol has the same meaning as defined above], or a method for producing a salt thereof. 5. An antihypertensive agent comprising the compound according to claim 1 or a salt thereof.