JP3348505B2 - Benzoxazin-3-one compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention
Novel benzoxazin-3-one compounds or pharmaceuticals useful as pharmaceuticals having ₂ (hereinafter referred to as PLA ₂ ) inhibitory action, interleukin-1 (hereinafter referred to as IL-1) production inhibitory action, and carrageenan foot edema inhibitory action Pertaining to the above acceptable salts.

[0002]

BACKGROUND OF THE INVENTION Problems to be Solved by the Invention
JP-28182-A discloses a benzoxazine compound having a 5-HT ₃ receptor blocking action and used as an antiemetic. By the way, physiologically active lipids such as prostaglandins, leukotrienes and thromboxanes not only play a regulatory role for maintaining homeostasis of the living body, but also have abnormal production of various diseases, such as allergies, asthma and inflammation. Is believed to be directly involved. PLA ₂ is an enzyme that hydrolyzes a fatty acid ester bond present at position 2 of the glycerol skeleton of glycerophospholipid, and catalyzes a reaction to release arachidonic acid, a precursor of these physiologically active lipids, from membrane phospholipids. It is known that this reaction step is the rate-limiting step in a series of bioactive lipid production processes.

[0003] Recently, IL-1 has been_TwoGene expression
Promote PLA_TwoInduces or inflames in laboratory animals
For human inflammatory diseases such as models and rheumatoid arthritis
Extracellular PLA_TwoThe activity was found, so inflammation
PLA_TwoThe role of is attracting attention. Meanwhile, anti-inflammatory
Steroids such as glucocorticoids and Indian
Non-steroidal anti-inflammatory such as tacin, diclofenac
Agents. Steroids are the most clinically powerful
Is an anti-inflammatory agent. The mechanism of the onset of action is PL
A _TwoBy inducing biosynthesis of proteins that inhibit
Suppresses release of rachidonic acid and exerts anti-inflammatory effect
Have been. However, due to serious side effects, its clinical indication
Is restricted. Non-steroidal anti-inflammatory drugs are
Commonly used, but less effective than steroids
In addition, side effects such as gastrointestinal disorders are problematic.

According to recent studies of PLA ₂ inhibitors, P
The LA ₂ has subtypes of low molecular weight type I and II and high molecular weight, PLA ₂ in the gastric mucosa is an identical to that of pancreatic, it has proven to be a PLA ₂ of low molecular weight type I It is said that the enzyme involved in inflammation is of low molecular weight type II found in other tissues. Therefore, it is considered that a compound that selectively inhibits low molecular weight type II PLA ₂ does not have side effects peculiar to steroids such as gastrointestinal hepatic disorder, and can be expected to have a safe and strong anti-inflammatory effect. Further, compounds that inhibit PLA ₂ are known to be also effective in ischemic vascular disorders and sepsis according to JP-A-3-25849, JP-A-4-49236, JP-A-4-49237 and the like. ing.

[0005] As PLA ₂ inhibitors known to date, mepacrine and p-bromophenacyl bromide are used as synthetic products, and sponge-derived manoalide, blue mold-derived plastatin, and bacterial preparate are used as natural products. There are statins. However, these anti-inflammatory actions are weaker than non-steroidal anti-inflammatory drugs, and there is also a problem in the specificity of action, which makes them less practical as anti-inflammatory drugs.

Accordingly, a powerful low molecular weight type II PLA
_TwoThere is a strong desire for the development of inhibitors and the purpose of the present invention is to
Sexual diseases, allergic diseases, anaphylactic shock
Is considered to be an extremely effective and safe drug for
Low molecular weight type II PLA _TwoSelectively inhibits the activity of
To provide a compound.

[0007]

Means for Solving the Problems The present inventors have been keen to create a substance which exhibits a low molecular weight type II PLA ₂ inhibitory action, an inhibitory action on IL-1 production and an inhibitory action on carrageenan paw edema and is useful as a medicament. As a result of repeated studies, they have found that certain benzoxazine compounds achieve their purpose, and have completed the present invention.

That is, the present invention provides a compound represented by the general formula

[0009]

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Wherein R ¹ is hydrogen, alkyl, aralkyl, substituted aralkyl or a compound of the formula — (CH ₂ ) _n —X—R ⁵ (wherein R ⁵ is alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, , X represents an oxygen atom, a sulfur atom, a carbonyl or NR ⁶ (wherein R ⁶ represents alkyl or benzyl, or a group in which R ⁵ and R ⁶ are bonded together with an adjacent nitrogen atom to form a heterocyclic ring; The heterocyclic ring may have a substituent.), And n represents an integer of 1 to 6.). R ² is hydrogen, halogen, hydroxyl, alkyl, alkoxy, phenoxyalkoxy or a formula —N (R ⁷ ) (R ^7a ), wherein R ⁷ represents alkyl or phenoxyalkyl, and R ^7a represents alkanoyl. Shows the group represented. R ³ and R ⁴ are the same or different and represent hydrogen or alkyl. Het is the formula

[0011]

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(Wherein R ⁸ represents unsubstituted, alkyl, phenyl or substituted phenyl, and when R ⁸ is alkyl, phenyl or substituted phenyl, the bonding site with a dotted line between nitrogen and carbon to which R ⁸ is bonded is A single bond, R ⁹ represents the formula ＮN—R ¹⁰ (wherein R ¹⁰ represents alkyl, phenyl or substituted phenyl), and when R ⁸ is unsubstituted, the nitrogen-carbon bond to which R ⁸ is bonded; Is a double bond, R
⁹ is alkyl, amino, during guanidino or formula -NH-R ¹¹ (wherein, R ¹¹ is alkyl, piperidyl, substituted piperidyl, alkenyl, phenyl, substituted phenyl, aralkyl, substituted aralkyl, benzoyl, substituted benzoyl, amino or of the formula - ( CH ₂ ) _m N (R ¹² ) (R ¹³ ) (wherein, m represents an integer of 1 to 3, and R ¹² and R ¹³ are the same or different and represent alkyl, or R ¹² and R ¹³ are adjacent to each other. A group which forms a heterocyclic ring by bonding together with a nitrogen atom,
The heterocyclic ring may have a substituent. ) Is shown. Or a group represented by R
^The bonding site with a dotted line between the nitrogen and carbon to which ⁸ is bonded indicates a single bond, and R ⁸ and R ⁹ together form the formula-(CH ₂ ) _p -N = (where p is 2 or 3 Represents a ring-forming group with a nitrogen-containing alkylene chain represented by R ¹⁴
Represents hydrogen, carboxy, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl. ) Represents a group represented by

[0013]

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Wherein A ¹ represents an oxygen atom, a sulfur atom or NH, A ² represents a nitrogen atom or a formula C—R ¹⁵ (where R ¹⁵ represents hydrogen, alkyl, phenyl or substituted phenyl) And R ¹⁶ represents hydrogen, alkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl.) A benzoxazin-3-one compound represented by the formula: or a pharmaceutically acceptable salt thereof.

In the present specification, the alkyl in R ¹ is a linear or branched alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary alkyl. Tert-butyl, pentyl, hexyl, heptyl and octyl, with methyl, hexyl and octyl being particularly preferred. The aralkyl in R ¹ has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
Linear or branched alkyl (methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, etc.) substituted with phenyl, such as benzyl, 1-phenethyl,
2-phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and 6-phenylhexyl are shown, and benzyl, 2-phenethyl, 3-phenylpropyl and 4-phenylbutyl are particularly preferred.

The substituted aralkyl in R ¹ is defined as halogen (fluorine, chlorine, bromine, etc.), amino, nitro, cyano, hydroxyl, trifluoromethyl, alkyl having 1 to 4 carbons (methyl, ethyl, Propyl,
Isopropyl, butyl, isobutyl, tertiary butyl, etc.), alkoxy having 1 to 4 carbon atoms (methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, etc.), phenyl, phenylalkoxy (benzyloxy, 2-phenylethoxy, 3-
Aralkyl having 1 to 3 substituents arbitrarily selected from phenylpropoxy, 4-phenylbutoxy and the like (as defined above), and preferred substituents are a hydroxyl group, an alkoxy having 1 to 4 carbon atoms, phenyl And phenylalkoxy, particularly preferably methoxy, phenyl and benzyloxy, and specific examples thereof include 4-methoxybenzyl, 4-biphenylmethyl and 4-benzyloxybenzyl.

The alkyl in R ⁵ has 1 to 6 carbon atoms.
And preferably linear or branched alkyl having 1 to 4 carbon atoms (as defined above), and particularly preferably methyl. The substituted phenyl in R ⁵ means halogen (as defined above), amino, nitro, cyano, hydroxyl, trifluoromethyl, alkyl having 1 to 4 carbons (as defined above), carbon number having 1 to 4 on the phenyl nucleus. Alkoxy (as defined above), phenyl, phenylalkoxy (as defined above)
Represents phenyl having 1 to 3 substituents arbitrarily selected from, and the like, and preferable substituents are halogen, a hydroxyl group, alkoxy having 1 to 4 carbon atoms, particularly fluorine,
Chlorine is preferred, and specific examples thereof include 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl,
4-methoxyphenyl and the like.

The substituted benzyl for R ⁵ is defined as halogen (as defined above), amino, nitro, cyano, hydroxyl, trifluoromethyl, alkyl having 1 to 4 carbons (as defined above), carbon number on the phenyl nucleus. Benzyl having 1 to 4 substituents arbitrarily selected from 1 to 4 alkoxy (as defined above), phenyl, phenylalkoxy (as defined above), and preferred substituents are halogen, hydroxyl, carbon, It is an alkoxy of 1 to 4 and particularly preferably methoxy, and specific examples thereof include 4-chlorobenzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-methoxybenzyl and the like.

The alkyl in R ⁶ has the same meaning as the alkyl in R ⁵ . The group in which R ⁵ and R ⁶ are bonded together with an adjacent nitrogen atom to form a heterocyclic ring is, for example, 1
-Pyrrolidinyl, piperidino, 1-piperazinyl, 1-
Homopiperazinyl and morpholino are preferred, and piperidino and morpholino are preferred. Further, the heterocycle has a substituent such as alkyl having 1 to 4 carbon atoms (as defined above), phenyl, substituted phenyl (as defined above), aralkyl (as defined above), and substituted aralkyl (as defined above). Phenyl is preferable as a substituent, and specific examples thereof include 4-methylpiperidino and 4-methylpiperidino.
Examples thereof include phenylpiperidino, 4- (4-fluorophenyl) piperidino, 4-benzylpiperidino, and 4- (4-methoxybenzyl) piperidino, with 4-phenylpiperidino being particularly preferred.

Specific examples of the group represented by the formula — (CH ₂ ) _n —X—R ⁵ in R ¹ include 3-phenoxypropyl, 2-morpholinoethyl, 3-methoxypropyl, 2- (4-phenyl) Piperidino) ethyl, 2-piperidinoethyl, 2-phenoxyethyl, 4-phenoxybutyl, 3-benzyloxypropyl, 3- (4-fluorophenoxy) propyl, 3- (4-chlorophenoxy) propyl, 4- (4 -Chlorophenoxy) butyl,
5- (4-chlorophenoxy) pentyl, 6- (4-chlorophenoxy) hexyl, 3-phenylthiopropyl, 3-benzylthiopropyl, 3- (N-benzyl-
N-methylamino) propyl, 4- (4-fluorophenyl) -4-oxobutyl, 3- (4-methoxybenzyloxy) propyl, 3-dimethylaminopropyl and the like.

The halogen in R ² is fluorine, chlorine, bromine or iodine, and chlorine is particularly preferred. The alkyl in R ² is a straight or branched alkyl having 1 to 6 carbon atoms (as defined above), and hexyl is particularly preferable. Alkoxy in R ² has 1 to 1 carbon atoms.
6 straight or branched alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, especially methoxy, isopropoxy, hexyl Oxy is preferred.

The phenoxyalkoxy for R ² is
Alkoxy having 1 to 4 carbon atoms (as defined above) is substituted by phenoxy, for example, phenoxymethoxy, 2-phenoxyethoxy, 3-phenoxypropoxy, 4-phenoxybutoxy, and especially 3-phenoxypropoxy. Is preferred. Alkyl at R ⁷ is
It is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms (as defined above), and hexyl is particularly preferred.

The phenoxyalkyl for R ⁷ is an alkyl having 1 to 4 carbon atoms (as defined above) substituted with phenoxy, for example, phenoxymethyl,
-Phenoxyethyl, 3-phenoxypropyl and 4-phenoxybutyl, with 3-phenoxypropyl being particularly preferred. The alkanoyl for R ^7a has 2 to 2 carbon atoms.
5 straight-chain or branched alkanoyls such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl, with acetyl being particularly preferred.

The alkyl in R ³ and R ⁴ is a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (as defined above).
Ethyl, propyl and butyl are preferred. The alkyl in R ⁸ has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
Linear or branched alkyl (as defined above), and particularly preferably methyl and ethyl.

The substituted phenyl in R ⁸ is defined as halogen (as defined above), amino, nitro, cyano, hydroxyl, trifluoromethyl, alkyl having 1 to 4 carbons (as defined above), carbon number on the phenyl nucleus. A phenyl having 1 to 4 substituents arbitrarily selected from 1 to 4 alkoxy (as defined above), phenyl, phenylalkoxy (as defined above), and a preferred substituent is a hydroxyl group,
It is an alkoxy having 1 to 4 carbon atoms, particularly preferably methoxy, and specific examples thereof include 4-methoxyphenyl,
-Hydroxyphenyl and the like.

Alkyl at R ⁹ has 1 to 4 carbon atoms.
Alkyl (as defined above), and particularly preferably methyl. The alkyl in R ¹⁰ has the same meaning as the alkyl in R ⁸ . The substituted phenyl for R ¹⁰ is represented by R
Synonymous with substituted phenyl in ⁸ . Alkyl for R ¹¹ has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
Linear or branched alkyl (as defined above), and butyl is particularly preferred.

The substituted piperidyl for R ¹¹ is piperidyl having a substituent of alkyl (as defined above), phenyl, or aralkyl (as defined above) having 1 to 4 carbon atoms at the nitrogen atom of the piperidine ring. The group is aralkyl, particularly preferably 2-phenethyl. Specific examples thereof include 1- (2-phenethyl) -4-piperidyl.

The alkenyl in R ¹¹ has 2 to 2 carbon atoms.
Five straight-chain or branched alkenyls such as vinyl, allyl, propenyl, isopropenyl, butenyl, pentenyl and the like, with allyl being particularly preferred. The substituted phenyl for R ^{11 has the same} meaning as the substituted phenyl for R ⁸ and R ¹⁰ .

The aralkyl for R ¹¹ has the same meaning as the aralkyl for R ¹ , and 2-phenethyl is particularly preferred. The substituted aralkyl for R ¹¹ has the same meaning as the substituted aralkyl for R ¹ , and preferred substituents are a hydroxyl group and an alkoxy having 1 to 4 carbon atoms, and particularly preferred are a hydroxyl group and methoxy.
(3,4-dihydroxyphenyl) ethyl, 2- (3,
4-dimethoxyphenyl) ethyl and the like.

The substituted benzoyl for R ¹¹ is defined as halogen (as defined above), amino, nitro, cyano, hydroxyl, trifluoromethyl, alkyl having 1 to 4 carbons (as defined above), carbon number on the phenyl nucleus. Benzoyl having 1 to 4 substituents arbitrarily selected from 1 to 4 alkoxy (as defined above), phenyl, phenylalkoxy (as defined above) and the like, and preferred substituents are a hydroxyl group, a carbon number of 1 To 4 alkoxy, particularly preferably methoxy, and specific examples thereof include 4-methoxybenzoyl, 4-hydroxybenzoyl and the like.

The alkyl in R ¹² and R ¹³ is a straight or branched alkyl having 1 to 6 carbon atoms (as defined above), and particularly preferably methyl and ethyl. R ¹² ,
The group in which R ¹³ is bonded to an adjacent nitrogen atom to form a heterocyclic ring is, for example, 1-pyrrolidinyl, piperidino,
1-piperazinyl, 1-homopiperazinyl and morpholino, among which piperidino and morpholino are preferred. Further, the heterocycle may have a substituent such as an alkyl having 1 to 4 carbons (as defined above), an alkoxy having 1 to 4 carbons (as defined above), a hydroxyl group, and the like. It is an alkyl having 1 to 4 carbon atoms, particularly preferably methyl, and specific examples thereof include 4-methylpiperidino.

Specific examples of the group represented by the formula-(CH ₂ ) _m N (R ¹² ) (R ¹³ ) in R ¹¹ include 3-morpholinopropyl, 3- (4-methylpiperidino) propyl and 2-
Dimethylaminoethyl and the like. The carboxyalkyl for R ¹⁴ is an alkyl having 1 to 4 carbons (as defined above) substituted with carboxy,
For example, carboxymethyl, 2-carboxyethyl, 1
-Carboxyethyl, 3-carboxypropyl and 4-carboxybutyl, particularly preferably carboxymethyl.

The alkoxy in the alkoxycarbonyl for R ¹⁴ is an alkoxy having 1 to 4 carbon atoms (as defined above), for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl And tertiary butoxycarbonyl, particularly preferably ethoxycarbonyl.

The alkoxycarbonylalkyl for R ¹⁴ is an alkyl having 1 to 4 carbon atoms (as defined above) substituted by alkoxycarbonyl (as defined above), for example, methoxycarbonylmethyl, 2- (methoxy) Carbonyl) ethyl, 3- (methoxycarbonyl)
Propyl, 4- (methoxycarbonyl) butyl, ethoxycarbonylmethyl, propoxycarbonylmethyl and butoxycarbonylmethyl are preferred, with ethoxycarbonylmethyl being particularly preferred.

Het is, as a specific example of the formula (II), for example, 2-aminothiazol-4-yl, 2-guanidinothiazol-4-yl, 2-allylaminothiazol-4-yl, 2-butylaminothiazol- 4-yl,
2-phenylaminothiazol-4-yl, 2- (2-
(3,4-dimethoxyphenyl) ethyl) aminothiazol-4-yl, 2-benzoylaminothiazole-4
-Yl, 2- (3-morpholinopropyl) aminothiazol-4-yl, 2- (1- (2-phenethyl) -4-
Piperidyl) aminothiazol-4-yl, 2- (3-
(4-methylpiperidino) propyl) aminothiazol-4-yl, 2- (2-dimethylaminoethyl) aminothiazol-4-yl, 3-methyl-2-methylimino-4-thiazolin-4-yl, 3-ethyl- 2-ethylimino-4-thiazolin-4-yl, 2-methylthiazol-4-yl, 2-hydrazinothiazol-4-yl, 3-phenyl-2-phenylimino-4-thiazolin-4-yl, 6, 7-dihydro-5H-thiazolo [3,2-a] pyrimidin-3-yl, 5,6-dihydroimidazo [2,1-b] thiazol-3-yl, 2-
Ethoxycarbonylmethyl-5,6-dihydroimidazo [2,1-b] thiazol-3-yl, 2-carboxymethyl-5,6-dihydroimidazo [2,1-b] thiazol-3-yl, 2- ( 2- (3,4-dihydroxyphenyl) ethyl) aminothiazol-4-yl, 3-
(4-methoxyphenyl) -2- (4-methoxyphenyl) imino-4-thiazolin-4-yl, 2- (4-piperidyl) aminothiazol-4-yl, 2- (4-methoxyphenyl) aminothiazole- 4-yl, 2-
(2-phenethyl) aminothiazol-4-yl, 2-
(4-methoxybenzoyl) aminothiazol-4-yl, 2-carboxy-5,6-dihydroimidazo [2,
1-b] thiazol-3-yl and 2-ethoxycarbonyl-5,6-dihydroimidazo [2,1-b] thiazol-3-yl.

The alkyl represented by R ¹⁵ has 1 to 6 carbon atoms.
And preferably linear or branched alkyl having 1 to 4 carbon atoms (as defined above), and particularly preferably methyl. The substituted phenyl for R ¹⁵ includes R ⁸ , R ¹⁰ , R ¹¹
Has the same meaning as the substituted phenyl. The alkyl in R ¹⁶ is a linear or branched alkyl having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (as defined above), and particularly preferably methyl.

The hydroxyalkyl represented by R ¹⁶ is an alkyl having 1 to 4 carbon atoms (as defined above) substituted with hydroxy.
-Hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl and 4-hydroxybutyl are shown, and hydroxymethyl is particularly preferred. The carboxyalkyl for R ¹⁶ has the same meaning as the carboxyalkyl for R ¹⁴ .

The alkoxycarbonyl for R ¹⁶ is
It is synonymous with alkoxycarbonyl of R ^14. R ¹⁶
The alkoxycarbonylalkyl in the same meaning as alkoxycarbonylalkyl in R ^14. He
When t is a specific example of the formula (III), for example, 5-methyl-1,3,4-oxadiazol-2-yl, 5-ethoxycarbonyl-4-methyloxazol-2-yl, 5-ethoxycarbonyl- 4-methylimidazol-2-yl, 5-carboxy-4-methyloxazol-2-yl, 5-carboxy-4-methylimidazol-2-yl, 5-hydroxymethyl-4-methyloxazol-2-yl, -Ethoxycarbonyl-4-phenylthiazol-2-yl, 5-ethoxycarbonylmethyl-4-phenylthiazol-2-yl, 4-phenylthiazol-2-yl, 5-ethoxycarbonyl-4
-Methylthiazol-2-yl, 5-carboxymethyl-4-phenylthiazol-2-yl, 5-carboxymethyl-4- (4-methoxyphenyl) thiazol-2
-Yl, 5-ethoxycarbonylmethylthiazole-2
-Ill.

The pharmaceutically acceptable salts of the compounds of the present invention include hydrochloride, sulfate, hydrobromide, phosphate, nitrate, methanesulfonate, ethanesulfonate, fumarate, and maleic acid. Salt, benzoate, citrate, malate, mandelate, paratoluenesulfonate, benzenesulfonate, acetate, succinate, malonate,
Metals such as lactate, salicylate, gallate, picrate, carbonate, acid addition salts such as ascorbic acid, trifluoroacetate, tartrate, sodium, potassium, lithium, magnesium, calcium, etc. Amine salts (including quaternary ammonium salts) such as salts, ammonium salts, triethylamine salts, pyridine salts, picoline salts, benzylamine salts, ethanolamine salts, etc., glutamates, aspartates, arginine salts, lysine salts, ornithine salts, etc. Amino acid salts and the like. Oxalic acid can also be used for crystallization of the target compound. Further, the compound of the present invention may be a hydrate (monohydrate, hemihydrate, 3 / 2hydrate, etc.) or a solvate.

When an asymmetric carbon is present in the compound of the present invention,
It exists as a racemate, an optical isomer or a diastereomer. When a geometric isomer is present, a cis isomer,
The present invention includes all of them, which exist as trans forms or mixtures thereof. The benzoxazin-3-one compound of the present invention can be produced by the following method. Method 1: In the general formula (I), a compound in which Het is a group represented by the formula (II) can be synthesized by the following method.

[0041]

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(Wherein the symbols have the same meanings as described above).
And then reacting compound (V) in a suitable solvent
It is manufactured by Halogenation of compound (IV)
Solvents used for methylene chloride, chloroform
System, carbon tetrachloride, tetrahydrofuran, diethyl ether
, Dioxane, benzene, pyridine, acetic acid, water, etc.
And chloroform is particularly preferred. Reaction temperature is required
Although it varies depending on the type of solvent used,
Preferably, the temperature is 30 to 50 ° C, and the reaction time is the reaction temperature.
It usually varies from 1 to 24 hours, preferably
Time. Halogenating agent used for halogenation
Halogens such as chlorine and bromine, thionyl chloride, bromide
Thionyl, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, pentaodor
Phosphorus chloride and the like, preferably chlorine, bromine and the like.
And bromine is particularly preferred. The obtained halogen
Can be used for the next reaction without isolation and purification.
You. As the solvent used for the reaction with the compound (V),
Methanol, ethanol, propanol, isopropyl
Alcohol, butanol, etc., especially ethanol
Are preferred. The reaction temperature is usually from 0 ° C to the boiling point of the solvent used.
The reaction time varies depending on the reaction temperature, etc.
It is usually 1 to 24 hours, preferably 4 to 8 hours. Method 2: In the general formula (I), Het is represented by the formula (III)
In the group represented by ¹Is an oxygen atom, A^TwoIs a nitrogen atom
Can be synthesized by the following method.
You.

[0043]

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(Where R^16aRepresents hydrogen or alkyl,
Other symbols are as defined above. That is, compound (VI) was dissolved in an appropriate solvent in an
After reacting with ter, then by treating with base
Manufactured. Solvent used for reaction with orthoester
Include methanol, ethanol, propanol,
Isopropyl alcohol, butanol, etc.
Methanol is preferred. Orthoester used
Are trimethyl orthoformate and triethyl orthoformate.
And tripropyl orthoformate.
Triethyl tomate is preferred. As the base used
Is potassium tertiary butoxide, sodium hydride, water
Potassium iodide, etc., especially potassium tertiary butane
Oxide is preferred. The base treatment is preferably performed in a solvent,
Such solvents include methanol, ethanol,
Panol, isopropyl alcohol, butanol, etc.
And butanol is particularly preferred. Reaction temperature is usually
It is the boiling point of the solvent used from 0 ° C, and the reaction time is the reaction temperature
Etc., but usually 1 to 24 hours, preferably 2 hours
~ 4 hours. Method 3: In the general formula (I), Het is represented by the formula (III)
In the group represented by ¹Is an oxygen atom or NH, A^Two
Is C-R^Fifteen(R^FifteenIs as defined above. ) Is a compound
Can be synthesized by the following method.

[0045]

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(Wherein Hal represents a halogen such as chlorine, bromine or iodine, A ^1a represents an oxygen atom or NH, and other symbols are as defined above.) That is, the compound (VII) and the compound (VIII) Is esterified in a suitable solvent in the presence of a base, and the resulting ester compound is closed with formamide in the presence of an acid catalyst.

Examples of the solvent used for the esterification include acetone, methyl ethyl ketone, tetrahydrofuran, diethyl ether, dimethylformamide, dimethylsulfoxide, methylene chloride, chloroform and the like, with dimethylformamide being particularly preferred. As the base used, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide,
Examples thereof include potassium hydroxide, triethylamine, diisopropylethylamine, and pyridine, and particularly preferred are sodium carbonate and potassium carbonate. The reaction temperature varies depending on the type of the solvent used, but is usually 0 to 100 ° C, preferably 50 to 80 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 1 to 12 hours, preferably 1 to 3 hours. . Examples of the acid catalyst used for the ring closure reaction include hydrochloric acid, sulfuric acid, and phosphoric acid, and sulfuric acid is particularly preferable. The reaction temperature varies depending on the type of the solvent used, but is usually 50 to 1
The reaction temperature is 50 ° C., preferably 100 to 140 ° C., and the reaction time varies depending on the reaction temperature and the like.
Preferably, it is 20 minutes to 1 hour.

In this reaction, A^1aIs a mixture of oxygen atoms and NH
But in the presence of an acid catalyst¹Is an oxygen atom
Is preferentially formed. The resulting mixture is
By combining crystals and chromatography as appropriate
Can be separated. Method 4: In the general formula (I), Het is represented by the formula (III)
In the group represented by ¹Is a sulfur atom, A^TwoIs C-R^Fifteen
(R^FifteenIs as defined above. Is a compound of the following
It can be synthesized by a method.

[0049]

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(Wherein each symbol is as defined above). That is, Compound (IX) is added to Compound (V) in an appropriate solvent.
Produced by reacting with III). Examples of the solvent used in this reaction include methanol, ethanol, propanol, isopropyl alcohol, and butanol, and ethanol is particularly preferable. The reaction temperature is usually from 0 ° C. to the boiling point of the solvent used, and the reaction time varies depending on the reaction temperature and the like, but is usually 1 to 24 hours, preferably 1 to 5 hours. Method 5: Compound (I) in which R ¹ has a group other than hydrogen can be produced by the following method.

[0051]

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(Wherein R ^1a represents R ¹ except hydrogen, and Y ¹
Represents a leaving group such as halogen (as defined above), and other symbols are as defined above. That is, it is produced by reacting compound (X) with compound (XI) in an appropriate solvent in the presence of a base.
Examples of the solvent used in this reaction include methylene chloride, chloroform, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, dimethylsulfoxide and the like, with dimethylformamide being particularly preferred. Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, pyridine, potassium tertiary butoxide, sodium hydride, and the like. Sodium hydride is preferred. The reaction temperature varies depending on the type of the solvent used, but is usually -20 to 100 ° C, preferably 0 to 30 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 24 hours, preferably 5 to 10 hours. It is.

The methods for synthesizing intermediate compounds are shown below in Methods 6 to 13. Method 6: Compound (IV) wherein R ¹ is hydrogen can be synthesized by the following method.

[0054]

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(Wherein X represents a halogen such as chlorine, bromine or iodine, a hydroxyl group or an alkoxy such as methoxy or ethoxy, and other symbols are as defined above). The compound (XIII) is reacted with a compound (XIII) in the presence of a base, and then treated with a condensing agent or a base, if necessary, in a suitable solvent to produce a ring.

Examples of the solvent used for the reaction with the compound (XIII) include water, methylene chloride, chloroform, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide and a mixture thereof, and a water-chloroform mixture is particularly preferred. Examples of the base used include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, pyridine and the like, with sodium bicarbonate being particularly preferred. The reaction temperature varies depending on the type of the solvent used, but is usually -20 to 50 ° C, preferably -10 to -1.
0 ° C., and the reaction time varies depending on the reaction temperature, etc.
It is usually 10 minutes to 12 hours, preferably 30 minutes to 3 hours. The amide compound obtained by this reaction can be used for the next reaction without isolation and purification. Examples of the solvent used for the ring closure reaction include methylene chloride, chloroform, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, dimethylsulfoxide and the like, with dimethylformamide being particularly preferred. Examples of the condensing agent used as needed include dicyclohexylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride, carbonyldiimidazole, and N-methyl-2-chloropyridinium iodide. Can be Examples of the base used as necessary include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, pyridine and the like, and potassium carbonate is particularly preferable. The reaction temperature varies depending on the type of the solvent used, but is usually -20 to 120 ° C, preferably 50 to 80 ° C,
The reaction time varies depending on the reaction temperature and the like.
Hours, preferably 5 to 12 hours. Method 7: Compound (IV) in which R ¹ has a group other than hydrogen can be synthesized by the following method.

[0057]

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(Wherein each symbol is as defined above). That is, it is produced by reacting compound (XIV) with compound (XI) in an appropriate solvent in the presence of a base. As the solvent used in this reaction, methylene chloride,
Examples include chloroform, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, dimethylsulfoxide and the like, with dimethylformamide being particularly preferred. The base used is sodium carbonate,
Potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, pyridine, potassium tertiary butoxide and the like, especially potassium tertiary butoxide
Grade butoxide is preferred. The reaction temperature varies depending on the type of the solvent used, but is usually -20 to 100 ° C, preferably 5 to 100 ° C.
The reaction time is usually 10 minutes to 24 hours, preferably 5 to 10 hours, depending on the reaction temperature and the like. Method 8: Compound (IV) wherein R ¹ is hydrogen or alkyl can be produced by the following method.

[0059]

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(Wherein, R ^1b represents hydrogen, alkyl, etc., and other symbols are as defined above.) That is, compound (XV) is compounded with compound (XVI) in an appropriate solvent in the presence of a catalyst. It is produced by subjecting it to the Friedel-Crafts reaction. Examples of the solvent used in this reaction include methylene chloride, chloroform, carbon tetrachloride, dichloroethane, carbon disulfide, nitrobenzene, and the like, with methylene chloride being particularly preferred. Examples of the catalyst used include Lewis acids such as aluminum chloride, ferrous chloride, ferric chloride, titanium tetrachloride, boron trifluoride, stannic chloride, and zinc chloride, with aluminum chloride being particularly preferred. The reaction temperature varies depending on the type of the solvent used, but is usually 0 to 100 ° C, preferably 30 to 60 ° C. The reaction time varies depending on the reaction temperature and the like, and is usually 1 to 24 hours, preferably 2 to 5 hours. . Method 9: Compound (XV) wherein R ² is alkyl can be synthesized by the following route.

[0061]

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(Wherein, R ^2a represents alkyl having 1 to 5 carbons (as defined above), R ^2b represents alkyl having 1 to 6 carbons (as defined above), and the other symbols are as defined above. That is, the compound (XVII) is subjected to a Friedel-Crafts reaction with the compound (XVIII) in a suitable solvent in the presence of a catalyst to give a compound (XIX), which is further reduced to produce the compound (XIX). Is done.

Examples of the solvent used for the reaction with the compound (XVIII) include methylene chloride, chloroform, carbon tetrachloride, dichloroethane, carbon disulfide, nitrobenzene and the like, with methylene chloride being particularly preferred. As the catalyst used, aluminum chloride, ferrous chloride, ferric chloride, titanium tetrachloride, boron trifluoride, stannic chloride,
Examples include Lewis acids such as zinc chloride, and aluminum chloride is particularly preferred. The reaction temperature varies depending on the type of the solvent used, but is usually from 0 to 100 ° C, preferably from 30 to 60 ° C. The reaction time varies depending on the reaction temperature and the like.
２４24 hours, preferably 2-5 hours.

The reduction reaction is carried out in a solvent such as alcohol (methanol, ethanol, isopropyl alcohol, etc.), ether (diethyl ether, tetrahydrofuran, etc.), acetic acid, acetic anhydride, etc.
Amalgam, a method using a reducing agent such as a zinc-copper alloy (Kremensen reduction), a solvent such as an alcohol (as defined above), in the presence of a strong base such as an alkali metal alkoxide (sodium methoxide, sodium ethoxide), Heating using hydrazine, semicarbazide, etc. (Wolf-Kishner reduction), hydrazine in a solvent such as glycols (diethylene glycol, triethylene glycol, etc.) in the presence of an alkali catalyst such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc. , A method of heating using hydrazine hydrate, hydrazine dihydrochloride (Hang-Minlon method), a method of reducing with sodium borohydride using paratoluenesulfonylhydrazine, or an acid catalyst (hydrochloric acid, hydrogen chloride,
In the presence of hydrogen bromide, calcium chloride, ammonium chloride, p-toluenesulfonic acid, aluminum chloride, alumina, boron trifluoride, etc.), use a dehydrating agent (such as molecular sieve) or a water separator (such as a Dean-Stark device) Acetal and alcohol (methanol, ethanol, diethylene glycol, triethylene glycol, etc.) or thiol (methanethiol, ethanethiol, 1,2-ethanedithiol, 1,3-propanedithiol, thiophenol, etc.) while removing water After that, reduction is performed by Raney nickel or the like. Of the above methods, reduction by the Hang-Minlon method is preferred, and the reaction temperature is usually 100 to 2
The temperature is 80 ° C, preferably 120 to 160 ° C, and the reaction time is generally 1 to 12 hours, preferably 2 to 4 hours. Method 10: Compound (IV) in which R ² is hydrogen is prepared by reducing a compound in which R ² is halogen in a suitable solvent under a hydrogen atmosphere in the presence of an alkali using a catalyst. You.

As the solvent to be used, methanol, ethanol, isopropyl alcohol, water, ethyl acetate and the like can be mentioned, and ethanol is particularly preferable. Examples of the alkali used include sodium hydroxide and potassium hydroxide, and sodium hydroxide is particularly preferred. Examples of the catalyst used include palladium carbon, palladium, platinum, rhodium, Raney nickel and the like, and palladium carbon is particularly preferable. The reaction temperature is preferably room temperature, and the reaction time is 1 to 24 hours, preferably 2 to 5 hours. Method 11: Compound (IV) wherein R ¹⁴ is particularly carboxymethyl or alkoxycarbonylmethyl can be produced by the following method.

[0066]

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(Wherein R ^b and R ^c each represent alkyl such as methyl and ethyl, and other symbols are as defined above.) That is, compound (IV-f) is the same as compound (IV-d) The compound (XX) is reacted with formaldehyde and a secondary amine in a suitable solvent (Mannich reaction) to give a compound (XX), which is reacted with an alkylating agent in a suitable solvent to give a compound (XX)
I). Next, the compound (XXII) is reacted with a cyanating agent in a suitable solvent, and then hydrolyzed, and further esterified in a suitable solvent.

Solvents used in the Mannich reaction include water, methanol, ethanol, propanol, isopropyl alcohol, tetrahydrofuran, diethyl ether, dioxane, methylene chloride, chloroform, dichloroethane, benzene, toluene, xylene, acetic acid,
Examples thereof include acetic anhydride, and acetic anhydride is particularly preferable. Examples of the secondary amine used include dimethylamine and diethylamine, and dimethylamine is particularly preferred. The reaction temperature varies depending on the type of the solvent used, but is usually from 0 to 100 ° C, preferably from 50 to 80 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually from 1 to 24 hours, preferably from 2 to 5 hours. .

The solvent used in the reaction of the compound (XX) with the alkylating agent includes methylene chloride, chloroform, diethyl ether, tetrahydrofuran, dioxane, acetone, dimethylformamide, dimethylsulfoxide and the like, and acetone is particularly preferred. The alkylating agent used is an alkyl halide such as methyl iodide, ethyl iodide, methyl bromide, and ethyl bromide, and methyl iodide is particularly preferred. The reaction temperature varies depending on the type of the solvent used, but is usually -20 to 100.
° C, preferably -5 to 50 ° C, and the reaction time varies depending on the reaction temperature and the like, but is usually 1 to 24 hours, preferably 30 minutes to 3 hours.

Examples of the solvent used in the reaction with the cyanating agent include methanol, ethanol, propanol, isopropyl alcohol, ethyl acetate, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, nitromethane, N-methylpyrrolidone and the like. And methanol is particularly preferred. Examples of the cyanating agent to be used include sodium cyanide and potassium cyanide, and potassium cyanide is particularly preferable. The reaction temperature varies depending on the type of the solvent used, and is usually 0 to 100 ° C., preferably 30 to 50 ° C., and the reaction time varies depending on the reaction temperature and the like.
Preferably, it is 2 to 5 hours.

A solvent may be used for the hydrolysis. Examples of such a solvent include water, methanol, ethanol, propanol, isopropyl alcohol, ethylene glycol, acetic acid, and formic acid, and acetic acid is particularly preferred.
For the hydrolysis, mineral acids such as hydrochloric acid and sulfuric acid, sodium hydroxide, potassium hydroxide and the like are used, and hydrochloric acid is particularly preferable. The reaction temperature is usually from 0 ° C. to the boiling point of the solvent used,
The reaction time varies depending on the reaction temperature and the like, but is usually 1 to 12
Hours, preferably 1 to 3 hours.

The esterification of compound (IV-e) includes a thionyl chloride method, a method of reacting with an alcohol in the presence of an acid catalyst, a method of reacting with an alkylating agent in the presence of a base, and a methylation method with diazomethane. Reaction with an alkylating agent, preferably in the presence of a base. Examples of the alkylating agent used in this reaction include methyl iodide,
It is an alkyl halide such as ethyl iodide, propyl iodide, methyl bromide, ethyl bromide and propyl bromide, and particularly preferred is methyl iodide and ethyl iodide. As the base used, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine,
Examples thereof include diisopropylethylamine and pyridine, and potassium carbonate is particularly preferable. A solvent may be used for the reaction with the alkylating agent, and examples of such a solvent include methylene chloride, chloroform, diethyl ether, tetrahydrofuran, dioxane, acetone, dimethylformamide, and dimethylsulfoxide, and dimethylformamide is particularly preferred. . The reaction temperature varies depending on the type of the solvent used, but is usually 0 to 100 ° C, preferably 40 to 60 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 1 to 24 hours, preferably 1 to 3 hours. . Method 12: Compound (VI) can be produced by the following method.

[0073]

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(Wherein R ^d represents alkyl such as methyl and ethyl, and the other symbols are as defined above.) That is, the compound (XXIII) is produced by reacting the compound (XXIII) with hydrazine in a suitable solvent. You. Examples of the solvent used in this reaction include methanol, ethanol, propanol, isopropyl alcohol, diethyl ether, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide and the like, with ethanol being particularly preferred. The reaction temperature varies depending on the type of the solvent used, but is usually from 0 to 100 ° C., preferably the boiling point of the solvent used, and the reaction time varies depending on the reaction temperature and the like, but is usually from 1 to 48 hours, preferably from 20 to 24 hours. . The compound (XXIII) used is produced according to the method described in JP-A-2-28182. Method 13: Compound (IX) can be produced by the following method.

[0075]

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(Wherein each symbol is as defined above). That is, the compound (IX) is prepared by converting the compound (VII) into a carboxy reactive derivative in a suitable solvent, if necessary, and then reacting with a amine. (XXIV), followed by treatment with a sulfurizing agent. Examples of the solvent used for the amidation reaction include methylene chloride, chloroform, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, ethyl acetate, acetonitrile, and the like, with tetrahydrofuran being particularly preferred. The synthesis of a reactive derivative of carboxy is carried out by reacting a halogenating agent or chloroformate in the presence of a base, or by using a condensing agent. As the base used,
Examples include triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine and the like, with triethylamine being particularly preferred. Examples of the halogenating agent used include thionyl chloride, phosphorus trichloride, phosphorus pentachloride and the like. Examples of chloroformates used include:
Examples include methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl chloroformate, and the like, with isobutyl chloroformate being particularly preferred. Examples of the condensing agent used include dicyclohexylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride, carbonyldiimidazole, and N-methyl-2-chloropyridinium iodide. Examples of the amine to be used include aqueous ammonia, ammonium carbonate, ammonium hydrogencarbonate, urea, and the like, and aqueous ammonia is particularly preferable. The reaction temperature varies depending on the type of the solvent used, but is usually from 0 to 100 ° C., preferably room temperature.
Preferably, it is 5 to 10 hours.

The sulfurizing agent used in the sulfurization reaction includes tetraphosphorus heptasulfide, diphosphorus pentasulfide, 2,4-bis (4-
(Methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson)
Reagent), and diphosphorus pentasulfide is particularly preferred.
In this reaction, a solvent may be used. Examples of such a solvent include methylene chloride, chloroform, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene,
Examples thereof include xylene, dimethylformamide, and ethyl acetate, and chloroform is particularly preferable. The reaction temperature is
It is usually from 0 ° C. to the boiling point of the solvent used, and the reaction time varies depending on the reaction temperature and the like, but is usually 1 to 24 hours, preferably 2 to 6 hours.

Among the compounds of the present invention, the compound having carboxy as a substituent is produced by hydrolyzing the corresponding alkoxycarbonyl by a conventional method. The compound having a hydroxyl group as a substituent is produced by treating the corresponding alkoxy with boron tribromide in a conventional manner, or hydrolyzing the corresponding acyloxy in a conventional manner. The compound having alkoxy as a substituent is produced by treating the corresponding hydroxyl group with an alkyl halide (eg, methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl iodide) in a conventional manner. The compound having hydroxymethyl as a substituent is produced by using the corresponding carboxy or, if necessary, a reactive derivative thereof, and then using a reducing agent such as sodium borohydride or diborane. The compound having a ketone as a substituent is produced by hydrolyzing the corresponding ketal under acidic conditions such as acetic acid, hydrochloric acid, sulfuric acid, and hydrobromic acid.

The compound of the formula (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization, chromatography and the like. When an asymmetric carbon is present in the compound of the general formula (I) of the present invention and a pharmaceutically acceptable salt thereof, the compound is usually produced as a racemic form. It can be optically resolved into isomers. Optical isomers can also be produced using optically active starting compounds. Further, compounds having two asymmetric carbons are obtained as individual diastereoisomers or a mixture thereof, and individual diastereoisomers can be separated by a conventional method such as fractional recrystallization or chromatography. When geometric isomers exist in the compound of the present invention, cis-trans isomers exist, and these can be produced using cis- or trans-form starting compounds. When they are obtained as a mixture thereof, they can be separated into cis-forms and trans-forms by a conventional method such as fractional recrystallization or chromatography.

[0080]

The compounds of the present invention and salts thereof have PLA ₂ inhibitory activity, as shown in the following tests.
It has an IL-1 production inhibitory action and a carrageenin foot edema inhibitory action, and is used for treatment and prevention of allergic diseases such as atopic diseases, various inflammatory diseases including bronchial asthma, arthritis, pancreatitis, ischemic vascular disorder, and sepsis. It is useful as a medicine.

Test examples are shown below. Test Example 1: PLA ₂ inhibitory activity (test method using rat inflammatory PLA ₂ ) As the PLA ₂ source, a partially purified product of rat inflammatory PLA ₂ (type II) was used. The above enzyme solution (0.0%) was added to a solution prepared so that calcium chloride and Tris-hydrochloric acid buffer (pH 7.5) were adjusted to a final concentration of 4 mM and 100 mM, respectively.
2 ml) and a previously prepared test solution (final concentration 0.5
0.02 ml).
The total volume was 240 μl and pre-incubated at 37 ° C. for 1 hour.

Next, 0.85 nmol (0.
045 μCi) of phosphatidylethanolamine (final concentration 0.1 mM) containing 1-acyl-2- [1- ¹⁴ C] arachidonyl-L-3-phosphatidylethanolamine (manufactured by Amersham) was added, and the mixture was added at 37 ° C. Incubated for 20 minutes. 2ml doll (Dol
es) The reaction was stopped by adding a reagent, and n-heptane (1 ml) and water (1.
5 ml) and stirred with a vortex mixer for 30 seconds. After centrifugation at 2000 rpm for 10 minutes, the upper layer (1 ml)
Was transferred to a test tube containing 2 ml of n-heptane and 150 mg of silicic acid, and stirred with a vortex mixer for 40 seconds.
Centrifugation was performed at 2,000 rpm for 10 minutes at room temperature. The supernatant (1 ml) was taken in a vial, 3 ml of ACS-2 (manufactured by Amersham) was added, and measurement was performed with a liquid scintillation counter. The test was performed in two vials per group.

The PLA ₂ inhibition rate was calculated by the following equation.

[0084]

(Equation 1)

Compound 1 of the present invention determined by the above test example
Table 1 shows the PLA ₂ inhibition rate at 0 μM. Table 1 ──────────────────────────────────── Example No. PLA ₂ inhibition rate (%) Example 24 40 Example 39 53 Example 66 38 ───────────────────────────────用 い る When the compound of the present invention or a pharmaceutically acceptable salt thereof is used as a medicament, the compound itself or a pharmaceutically acceptable carrier, excipient, extender, diluent, or other additive is usually used. For use, tablets, buccals, pills, capsules, powders, fine granules, granules, solutions, oral solutions (including syrups), injections, inhalants, suppositories, transdermal solutions, ointments, Pharmaceutical compositions such as transdermal patches, transmucosal patches (eg, oral patches), and transmucosal solutions (eg, nasal solutions) can be safely orally administered to patients orally or parenterally. Pharmaceutically acceptable carriers, excipients, extenders, diluents, and other additives include solid or liquid non-toxic pharmaceutical substances. Examples of these include, for example, lactose, magnesium stearate, starch, talc, gelatin,
Agar, pectin, gum arabic, olive oil, sesame oil,
Examples include cocoa butter, ethylene glycol and other commonly used ones. The dose of the compound of the present invention may vary depending on the selected compound, disease, symptom, body weight, age, sex, administration method, and the like of the patient, but is usually 1 to 2000 mg, preferably 10 to 300 mg orally per adult day. This is administered once a day or divided into 2 to 4 times.

[0086]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Reference Examples and Examples, but the present invention is not limited thereto. Reference Example 1 6-acetyl-2-amino-4-chlorophenol 12
0 g was added to a mixture of 1000 ml of chloroform and 1000 ml of a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was stirred at 0 ° C.
50 ml of chloroacetyl chloride was added dropwise. The mixture was extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure.
The obtained residue was dissolved in dimethylformamide (2000 ml), potassium carbonate (180 g) was added, and the mixture was stirred at 70 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with an aqueous solution of potassium carbonate, dried over magnesium sulfate, and concentrated under reduced pressure to give 8-acetyl-6-chloro-3-oxo-3,4-dihydro-.
146 g of 2H-1,4-benzoxazine was obtained. 232-234 ° C. Reference Example 2 6-acetyl-2-amino-4-chlorophenol 19
g as a starting material, 28 g of 2-bromoisobutyryl bromide
In the same manner as in Reference Example 1 to obtain 22 g of 8-acetyl-6-chloro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine. 180-183 ° C. Reference Example 3 6-acetyl-2-amino-4-chlorophenol 14
g as a starting material, 15 g of 2-bromopentanoyl chloride
In the same manner as in Reference Example 1 to give 8-acetyl-6-chloro-3-oxo-2-propyl-3,4-dihydro-
22 g of 2H-1,4-benzoxazine was obtained. Melting point 1
67-169 ° C. Reference Example 4 6-acetyl-2-amino-4-chlorophenol9.
Using 1 g as a starting material, 2-bromohexanoyl chloride 11
g, using the same procedure as in Reference Example 1 to give 8-acetyl-2-
Butyl-6-chloro-3-oxo-3,4-dihydro-
9.2 g of 2H-1,4-benzoxazine was obtained. Melting point 181-183C. Reference Example 5 6-acetyl-2-amino-4-methoxyphenol 3
Using 2-g as a starting material and using chloroacetyl chloride in the same manner as in Reference Example 1, 8-acetyl-6-methoxy-
26 g of 3-oxo-3,4-dihydro-2H-1,4-benzoxazine were obtained. 229-231 ° C. Reference Example 6 8-acetyl-6- (N-acetylamino) -3- was performed in the same manner as in Reference Example 1 using 12 g of 6-acetyl-4- (N-acetylamino) -2-aminophenol as a starting material.
5.5 g of oxo-3,4-dihydro-2H-1,4-benzoxazine were obtained. Melting point 250 ° C or higher. Reference Example 7 Aluminum chloride 6 in 200 ml of methylene chloride under ice cooling
2 g was added, and 25 g of hexanoyl chloride was added dropwise at the same temperature. 3-Oxo-3,4-dihydro-2H-
23 g of 1,4-benzoxazine was added, and the mixture was stirred at 40 ° C. for 4 hours. The reaction solution was poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 36 g of 6-hexanoyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine. Was. 113-115 ° C. Reference Example 8 6-Hexanoyl-3-oxo-3,4-dihydro-2
300 ml of diethylene glycol, 35 ml of hydrazine hydrate and 51 g of potassium hydroxide were added to 30 g of H-1,4-benzoxazine, and the mixture was refluxed and stirred at 125 ° C. for 2 hours. After distilling off hydrazine, the mixture was stirred at 160 ° C. for 3 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure to give 6-hexyl-3-oxo-3,4-dihydro-2H-1,4.
-21 g of benzoxazine were obtained. Melting point 106-107
° C. Reference Example 9 6-hexyl-3-oxo-3,4-dihydro-2H-
Using 21 g of 1,4-benzoxazine as a starting material and 9.5 ml of acetyl chloride, the same procedure as in Reference Example 7 was carried out.
4.8 g of -acetyl-6-hexyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine were obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
0.71-1.78 (11H, m), 2.49 (2H,
m), 2.64 (3H, s), 4.62 (2H, s),
6.83 (1H, d), 7.28 (1H, d), 9.9
8 (1H, br). Reference Example 10 50 g of 8-acetyl-6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine was added to 500 ml of dimethylformamide and cooled to 0 ° C.
Add 30 g of potassium tertiary butoxide, and add 30 g at room temperature.
For a minute. 27 ml of methyl iodide was added dropwise at the same temperature.
Stirred at 0 ° C. for 8 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with an aqueous solution of potassium carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. By adding ethanol to the obtained residue, 42 g of 8-acetyl-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine was obtained. 104-108 ° C. Reference Example 11 1.1 g of 8-acetyl-6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine was added to 20 ml of dimethylformamide, cooled to 0 ° C.
0.66 g of potassium tertiary butoxide was added. After stirring at room temperature for 30 minutes, 0.8 g of hexyl iodide was added dropwise at the same temperature, and the mixture was stirred at 70 ° C for 8 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate. The extract was washed with an aqueous solution of potassium carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform) to give 8-acetyl-6-chloro-4-hexyl-3-oxo-3,4-.
1.3 g of dihydro-2H-1,4-benzoxazine were obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
0.73 to 1.95 (11H, m), 2.59 (3H,
s), 3.92 (2H, t), 4.65 (2H, s),
7.02 (1H, d), 7.32 (1H, d). Less than,
The following compounds are produced in the same manner as in the above Reference Example. (12) 8-acetyl-6-chloro-4-octyl-3
-Oxo-3,4-dihydro-2H-1,4-benzoxazine, ¹ H-NMR (CDCl ₃ ) δ ppm: 0.1.
65 to 1.97 (15H, m), 2.58 (3H,
s), 3.87 (2H, t), 4.61 (2H, s),
6.98 (1H, d), 7.30 (1H, d). (13) 8-acetyl-6-chloro-4- (3-methoxypropyl) -3-oxo-3,4-dihydro-2H-
1,4-benzoxazine, ¹ H-NMR (CDC
l ₃ ) δ ppm: 1.80 (2H, m), 2.62 (3
H, s), 3.35 (2H, t), 3.96 (2H,
t), 4.28 (3H, s), 4.76 (2H, s),
6.98 (1H, d), 7.38 (1H, d). (14) 8-acetyl-4-benzyl-6-chloro-3
-Oxo-3,4-dihydro-2H-1,4-benzoxazine, mp 106-109 ° C. (15) 8-acetyl-6-chloro-4- (4-methoxybenzyl) -3-oxo-3,4-dihydro-2H-
1,4-benzoxazine, mp 103-105 ° C. (16) 8-acetyl-6-chloro-4- (4-biphenylmethyl) -3-oxo-3,4-dihydro-2H-
1,4-benzoxazine, mp 158-160 ° C. (17) 8-acetyl-6-chloro-4- (4-benzyloxybenzyl) -3-oxo-3,4-dihydro-
2H-1,4-benzoxazine, melting point 134-135
° C. (18) 8-acetyl-6-chloro-3-oxo-4-
(2- (4-phenylpiperidin-1-yl) ethyl)
-3,4-dihydro-2H-1,4-benzoxazine, ¹ H-NMR (CDCl ₃ ) δ ppm: 1.73 to
2.78 (11H, m), 2.66 (3H, s), 3.
07 (2H, t), 4.10 (2H, t), 4.67
(2H, s), 7.15-7.55 (7H, m). (19) 8-acetyl-6-chloro-3-oxo-4-
(2-piperidinoethyl) -3,4-dihydro-2H-
1,4-benzoxazine hydrochloride, melting point 190 [deg.] C (decomposition). (20) 8-acetyl-6-chloro-4- (2-morpholinoethyl) -3-oxo-3,4-dihydro-2H-
1,4-benzoxazine, ¹ H-NMR (CDC
l ₃ ) δ ppm: 2.38 to 2.72 (6H, m),
2.60 (3H, s), 3.55-3.78 (4H,
m), 4.03 (2H, t), 4.64 (2H, s),
7.16-7.40 (2H, m). (21) 8-acetyl-6-chloro-3-oxo-4-
(2-phenethyl) -3,4-dihydro-2H-1,4
-Benzoxazine, mp 124-126 ° C. (22) 8-acetyl-6-chloro-3-oxo-4-
(3-phenylpropyl) -3,4-dihydro-2H-
1,4-benzoxazine, ¹ H-NMR (CDC
l ₃ ) δ ppm: 1.99 (2H, m), 2.58 (3
H, s), 2.72 (2H, t), 3.90 (2H,
t), 4.62 (2H, s), 6.81 (1H, d),
8.20 (5H, m), 8.34 (1H, d). (23) 8-acetyl-6-chloro-3-oxo-4-
(4-phenylbutyl) -3,4-dihydro-2H-
1,4-benzoxazine, ¹ H-NMR (CDC
l ₃ ) δ ppm: 1.70 (4H, m), 2.60 (3
H, s), 2.68 (2H, t), 3.92 (2H,
t), 4.66 (2H, s), 7.00 (1H, d),
7.20 (5H, m), 7.38 (1H, d). (24) 8-acetyl-6-chloro-3-oxo-4-
(2-phenoxyethyl) -3,4-dihydro-2H-
1,4-benzoxazine, mp 115-117 ° C. (25) 8-acetyl-6-chloro-3-oxo-4-
(3-phenoxypropyl) -3,4-dihydro-2H
-1,4-benzoxazine, melting point 105-106 ° C. (26) 8-acetyl-6-chloro-3-oxo-4-
(4-phenoxybutyl) -3,4-dihydro-2H-
1,4-benzoxazine, melting point 98-100 ° C. (27) 8-acetyl-4- (3-benzyloxypropyl) -6-chloro-3-oxo-3,4-dihydro-
2H-1,4-benzoxazine, ¹ H-NMR (CD
Cl ₃ ) δ ppm: 2.10 (2H, m), 2.62
(3H, s), 3.66 (2H, t), 4.16 (2
H, t), 4.64 (2H, s), 4.75 (2H,
s), 7.18-7.65 (7H, m). (28) 8-acetyl-6-chloro-4- (3- (4-
Fluorophenoxy) propyl) -3-oxo-3,4
-Dihydro-2H-1,4-benzoxazine, melting point 1
18-120 ° C. (29) 8-acetyl-6-chloro-4- (3- (4-
Chlorophenoxy) propyl) -3-oxo-3,4-
Dihydro-2H-1,4-benzoxazine, melting point 20
8-210 ° C. (30) 8-acetyl-6-chloro-4- (4- (4-
Chlorophenoxy) butyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine, melting point 220
° C. (31) 8-acetyl-6-chloro-4- (5- (4-
Chlorophenoxy) pentyl) -3-oxo-3,4-
Dihydro-2H-1,4-benzoxazine, melting point 23
3-235 ° C. (32) 8-acetyl-6-chloro-4- (6- (4-
Chlorophenoxy) hexyl) -3-oxo-3,4-
Dihydro-2H-1,4-benzoxazine, melting point 64
~ 66 ° C. (33) 8-acetyl-6-chloro-4- (3-phenylthiopropyl) -3-oxo-3,4-dihydro-2
H-1,4-benzoxazine, ¹ H-NMR (CDC
l ₃ ) δ ppm: 1.96 (2H, m), 2.60 (3
H, s), 3.00 (2H, t), 4.08 (2H,
m), 4.64 (2H, s), 7.08 to 7.41 (7
H, m). (34) 8-acetyl-4- (3-benzylthiopropyl) -6-chloro-3-oxo-3,4-dihydro-2
H-1,4-benzoxazine, ¹ H-NMR (CDC
l ₃ ) δ ppm: 1.88 (2H, m), 2.50 (2
H, m), 2.60 (3H, s), 3.73 (2H,
s), 3.93 (2H, m), 4.65 (2H, s),
7.18-7.42 (7H, m). (35) 8-acetyl-6-chloro-4- (3- (N-
Benzyl-N-methylamino) propyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine, ¹ H-NMR (CDCl ₃ ) δ ppm: 1.72 to
2.20 (2H, m), 2.60 (3H, s), 2.6
8 (3H, s), 3.22 (2H, t), 3.36 (2
H, s), 4.00 (2H, t), 4.90 (2H,
s), 6.96 (1H, d), 7.28 to 7.42 (5
H, m), 7.36 (1H, d). (36) 8-acetyl-6-chloro-3-oxo-2,
2,4-trimethyl-3,4-dihydro-2H-1,4
-Benzoxazine, mp 124-126 ° C. (37) 8-acetyl-6-chloro-4-methyl-3-
Oxo-2-propyl-3,4-dihydro-2H-1,
4-benzoxazine, mp 55-56 ° C. (38) 8-acetyl-2-butyl-6-chloro-4-
Methyl-3-oxo-3,4-dihydro-2H-1,4
-Benzoxazine, mp 78-80 <0> C. (39) 8-acetyl-6-methoxy-4-methyl-3
-Oxo-3,4-dihydro-2H-1,4-benzoxazine, mp 115-117 ° C. (40) 8-acetyl-6-methoxy-3-oxo-4
-(3-phenoxypropyl) -3,4-dihydro-2
H-1,4-benzoxazine, melting point 91-92 ° C. (41) 8-acetyl-6-hexyl-3-oxo-4
-(3-phenoxypropyl) -3,4-dihydro-2
H-1,4-benzoxazine, ¹ H-NMR (CDC
l ₃ ) δ ppm: 0.65 to 1.74 (11H, m);
2.51 (2H, t), 2.60 (3H, s), 3.9
3-4.22 (4H, m), 4.66 (2H, s),
6.76-7.26 (7H, m). (42) 8-acetyl-6- (N-acetyl-N- (3
-Phenoxypropyl) amino) -3-oxo-4-
(3-phenoxypropyl) -3,4-dihydro-2H
-1,4-benzoxazine, ¹ H-NMR (CDCl
₃ ) δ ppm: 1.82 (3H, s), 1.88-2.
27 (4H, m), 2.62 (3H, s), 3.70-
4.44 (8H, m), 4.68 (2H, s), 6.6
8-7.36 (12H, m). (43) 8-acetyl-6- (N-acetyl-N-hexylamino) -4-hexyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine, ¹ H-NM
R (CDCl ₃ ) δ ppm: 0.68 to 1.94 (25
H, m), 2.64 (3H, s), 3.66 (2H,
t), 3.96 (2H, t), 4.75 (3H, s),
6.87 (1H, d), 7.26 (1H, d). (44) 8-acetyl-6-chloro-4- (3- (2-
(4-fluorophenyl) -1,3-dioxolan-2
-Yl) propyl) -3-oxo-3,4-dihydro-
2H-1,4-benzoxazine, melting point 130 [deg.] C. Reference Example 45 8-acetyl-6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine 2
g to ethanol 20ml, 1N sodium hydroxide 10m
Then, 4.7 g of 10% palladium carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. After filtering off the palladium carbon, the mixture was extracted with ethyl acetate. After drying over magnesium sulfate,
By concentrating under reduced pressure, 8-acetyl-4-methyl-
1.0 g of 3-oxo-3,4-dihydro-2H-1,4-benzoxazine was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
2.64 (3H, s), 4.56 (2H, s), 6.9
8-7.45 (3H, m), 9.93 (1H, br). Reference Example 46 12 g of dimethylamine hydrochloride and 12 g of 35% formaldehyde water were stirred at 50 to 60 ° C. for 30 minutes, and 35 ml of acetic anhydride was added dropwise at the same temperature. Then, after stirring at 70 to 75 ° C. for 1 hour, 8-acetyl-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-
23 g of benzoxazine was added and the mixture was stirred at 60 to 65 ° C for 3 hours. The reaction solution is concentrated under reduced pressure, and acetone is added thereto to give 6-chloro-8- (3-dimethylaminopropionyl) -4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine hydrochloride. 26 g of salt were obtained. Melting point 186-187 [deg.] C. Reference Example 47 8-acetyl-6-chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4
Reference Example 46 using 50 g of benzoxazine as a starting material
34-g of 6-chloro-8- (3-dimethylaminopropionyl) -3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-benzoxazine hydrochloride. Obtained. 148-149 ° C. Reference Example 48 6-chloro-8- (3-dimethylaminopropionyl)
-4-Methyl-3-oxo-3,4-dihydro-2H-
26 g of 1,4-benzoxazine hydrochloride was added to a 0.5 M aqueous sodium hydrogen carbonate solution and extracted with chloroform.
After drying over magnesium sulfate, the mixture was concentrated under reduced pressure. After dissolving the obtained residue in 250 ml of acetone, 19 ml of methyl iodide was added under ice cooling. The precipitated crystals were collected by filtration to give 3- (6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
24 g of 8-yl) -3-oxopropyltrimethylammonium iodide was obtained. 188 ° C (decomposition). Reference Example 49 6-chloro-8- (3-dimethylaminopropionyl)
-3-oxo-4- (3-phenoxypropyl) -3,
Performed in the same manner as in Reference Example 48 using 34 g of 4-dihydro-2H-1,4-benzoxazine hydrochloride as a starting material,
33 g of (6-chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-benzoxazin-8-yl) -3-oxopropyltrimethylammonium iodide was obtained. . Melting point 152 ° C
(Disassembly). Reference Example 50 3- (6-chloro-4-methyl-3-oxo-3,4-
240 ml of methanol is added to 24 g of dihydro-2H-1,4-benzoxazin-8-yl) -3-oxopropyltrimethylammonium iodide, 23 ml of an aqueous potassium cyanide (9 g) solution is added at room temperature with stirring, and the mixture is added at 40 ° C. for 3 hours. Stirred. Chloroform was added to the reaction solution, washed with an aqueous solution of potassium carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. By adding ethanol to the obtained residue, 4- (6-chloro-4-methyl-
3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl) -4-oxobutyronitrile 1
0 g was obtained. 151-153 ° C. Reference Example 51 3- (6-chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-benzoxazin-8-yl) -3-oxopropyltrimethylammonium ion Performed in the same manner as in Reference Example 50 using 33 g of dyde as a starting material, and preparing 4- (6-chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-benzoxazine-8. -Yl) -4-
9.2 g of oxobutyronitrile were obtained. Melting point 179-1
82 ° C. Reference Example 52 4- (6-chloro-4-methyl-3-oxo-3,4-
Dihydro-2H-1,4-benzoxazin-8-yl) -4-oxobutyronitrile was added to 10 g of concentrated hydrochloric acid in 50 m.
1 and 50 ml of acetic acid were added and refluxed for 2 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. By adding isopropyl alcohol to the obtained residue, 4- (6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-
Benzoxazin-8-yl) -4-oxobutyric acid 9.4
g was obtained. Melting point 167-169 [deg.] C. Reference Example 53 4- (6-chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-benzoxazin-8-yl) -4-oxobutyronitrile 9 .2 g as a starting material in the same manner as in Reference Example 52.
6.1 g of-(6-chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-benzoxazin-8-yl) -4-oxobutyric acid was obtained. Melting point 154-157 [deg.] C. Reference Example 54 4- (6-chloro-4-methyl-3-oxo-3,4-
100 ml of dimethylformamide and 4.8 g of potassium carbonate were added to 9.4 g of dihydro-2H-1,4-benzoxazin-8-yl) -4-oxobutyric acid, and 3.8 ml of ethyl iodide was added dropwise at room temperature. After stirring at 50 ° C. for 1 hour, the reaction solution was concentrated under reduced pressure. An aqueous potassium carbonate solution was added to the obtained residue, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. By adding isopropyl alcohol to the obtained residue, 4- (6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-
8.2 g of ethyl 1,4-benzoxazin-8-yl) -4-oxobutyrate was obtained. 122-125 ° C. Reference Example 55 6.1 g of 4- (6-chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-benzoxazin-8-yl) -4-oxobutyric acid In the same manner as in Reference Example 54, using 4- (6-chloro-3-oxo-4- (3-phenoxypropyl)-
3,4-dihydro-2H-1,4-benzoxazine-
6.0 g of ethyl 8-yl) -4-oxobutyrate were obtained. 113-115 ° C. Reference Example 56 The same as Reference Example 54 using 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid as a starting material and methyl iodide. 6-chloro-4-methyl-3-oxo-3,
4-dihydro-2H-1,4-benzoxazine-8-
Methyl carboxylate was obtained. 147-148 ° C. Reference Example 57 150 ml of ethanol and 12 g of hydrazine monohydrate were added to 15 g of methyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate, and 24 The mixture was stirred under reflux for an hour. The reaction solution was cooled on ice and the precipitated crystals were collected by filtration to give 6-chloro-
4-methyl-3-oxo-3,4-dihydro-2H-
13 g of 1,4-benzoxazine-8-carboxylic acid hydrazide was obtained. 243-246 ° C. Reference Example 58 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (3 g) was added to dimethylformamide (30 ml), sodium carbonate (1.3 g), and 2-chloroacetoacetic acid. 2.6 g of ethyl was added and the mixture was stirred at 70 ° C. for 2 hours. Pour the reaction solution into ice water,
Extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure to give 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid-1-ethoxycarbonyl-2-.
4.2 g of oxopropyl were obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.34 (3H, t), 2.99 (3H, s), 3.3
0 (3H, s), 4.33 (2H, q), 4.73 (2
H, s), 4.88 (1H, s), 7.16 (1H,
d), 8.04 (1H, d). Reference Example 59 8-acetyl-6-chloro-4- (3- (2- (4-fluorophenyl) -1,3-dioxolan-2-yl)
Propyl) -3-oxo-3,4-dihydro-2H-
2 g of 1,4-benzoxazine in 50 ml of chloroform
And 0.74 g of bromine was added dropwise at 40 ° C. with stirring. After concentrating the reaction solution, the obtained residue was
l, 0.6 g of ethylenethiourea were added, and the mixture was stirred under reflux for 8 hours. After allowing to cool, the crystals were collected by filtration to give 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -4- (3─ (2─ (4─ Fluorophenyl) -1,3-dioxolan-2-yl) propyl) -3-oxo-3,4-dihydro-2H-1,4
-0.35 g of benzoxazine hydrobromide was obtained. 255 ° C (decomposition). Example 1 8-acetyl-6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine 5
g was dissolved in 100 ml of chloroform, and 3.4 g of bromine was added dropwise at 40 ° C. while stirring. After the reaction solution was concentrated, 100 ml of ethanol and 1.6 g of thiourea were added to the obtained residue, and the mixture was stirred under reflux for 8 hours. After cooling, the crystals were collected by filtration to give 8- (2-aminothiazol-4-yl)-.
6. 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide
1 g was obtained. Melting point 300 [deg.] C. Example 2 8-acetyl-6-chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4
Example 1 using 15 g of benzoxazine as a starting material
8- (2-aminothiazol-4-yl) -6-chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-benzoxazine odor 16 g of hydrochloride were obtained. Melting point 249-2
51 ° C. Example 3 8-acetyl-6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine 3
g as a starting material and using 1-amidinothiourea in the same manner as in Example 1 to give 6-chloro-8- (2-guanidinothiazol-4-yl) -4-methyl-3-oxo-3,4-. 4.0 g of dihydro-2H-1,4-benzoxazine hydrobromide was obtained. 297-298 ° C. Example 4 8-acetyl-6-chloro-4- (2-morpholinoethyl) -3-oxo-3,4-dihydro-2H-1,4-
Starting from 2.5 g of benzoxazine as a starting material and using 0.86 g of 1-amidinothiourea, the procedure of Example 1 was repeated to give 6-chloro-8- (2-guanidinothiazole-4).
-Yl) -4- (2-morpholinoethyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine dihydrobromide (1.2 g) was obtained. Melting point 225-227
° C. Example 5 8-acetyl-6-chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4
Performed in the same manner as in Example 1 using 1.57 g of -benzoxazine as a starting material and 0.47 g of 1-amidinothiourea to give 6-chloro-8- (2-guanidinothiazole-
0.53 g of 4-yl) -4- (3-phenoxypropyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide was obtained. Melting point 245-24
8 ° C. Example 6 8-acetyl-6-chloro-4-methyl-3-oxo-
Starting from 1.7 g of 3,4-dihydro-2H-1,4-benzoxazine as a starting material, 0.1 g of 1-allylthiourea was used.
Using 82 g, the same procedure as in Example 1 was carried out to give 8- (2-allylaminothiazol-4-yl) -6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-
1.6 g of benzoxazine hydrobromide were obtained. Melting point 1
65-166 ° C. Example 7 8-acetyl-6-chloro-4-methyl-3-oxo-
Starting from 1.5 g of 3,4-dihydro-2H-1,4-benzoxazine as a starting material, 0.1 g of 1-butylthiourea was added.
The same procedure as in Example 1 was carried out using 83 g of 8- (2-butylaminothiazol-4-yl) -6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-
1.7 g of benzoxazine hydrobromide were obtained. Melting point 1
79-181 ° C. Example 8 8-acetyl-6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine 2
g as a starting material, 1.3 g of 1-phenylthiourea
In the same manner as in Example 1 except for using 6-chloro-4-methyl-3-oxo-8- (2-phenylaminothiazol-4-yl) -3,4-dihydro-2H-1,4-benzoic acid. 2.2 g of oxazine hydrobromide were obtained. Melting point 256
° C (decomposition). Example 9 8-acetyl-6-chloro-4-methyl-3-oxo-
In the same manner as in Example 1 except that 1.5 g of 3,4-dihydro-2H-1,4-benzoxazine was used as a starting material and 1.5 g of 1- (2- (3,4-dimethoxyphenyl) ethyl) thiourea was used. And 6-chloro-8- (2- (2-
(3,4-dimethoxyphenyl) ethyl) aminothiazol-4-yl) -4-methyl-3-oxo-3,4-
2.2 g of dihydro-2H-1,4-benzoxazine hydrobromide were obtained. 200-202 ° C. Example 10 8-acetyl-6-chloro-4-methyl-3-oxo-
Using 1.7 g of 3,4-dihydro-2H-1,4-benzoxazine as a starting material and 1.3 g of 1-benzoylthiourea, the same procedure as in Example 1 was carried out to give 8- (2-benzoylaminothiazole-4). -Yl) -6-chloro-
4-methyl-3-oxo-3,4-dihydro-2H-
1.9 g of 1,4-benzoxazine hydrobromide was obtained. 229-231 ° C. Example 11 8-acetyl-6-chloro-4-methyl-3-oxo-
Performed in the same manner as in Example 1 using 1.7 g of 3,4-dihydro-2H-1,4-benzoxazine as a starting material and 1.4 g of 1- (3-morpholinopropyl) thiourea to obtain 6-chloro-8. 2.2 g of-(2- (3-morpholinopropylamino) thiazol-4-yl) -4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide were obtained. Was. 235-236
° C. Example 12 8-acetyl-6-chloro-4-methyl-3-oxo-
As in Example 1 using 1.7 g of 3,4-dihydro-2H-1,4-benzoxazine as a starting material and 1.9 g of 1- (1- (2-phenethyl) -4-piperidyl) thiourea. 6-chloro-4-methyl-3-oxo-8- (2- (1- (2-phenethyl) -4-piperidyl) aminothiazol-4-yl) -3,4-dihydro-2H-1, 2.4 g of 4-benzoxazine hydrobromide were obtained. Melting point 261-262 [deg.] C. Example 13 8-acetyl-6-chloro-4-methyl-3-oxo-
Performed in the same manner as in Example 1 by using 1.7 g of 3,4-dihydro-2H-1,4-benzoxazine as a starting material and 1.4 g of 1- (3- (4-methylpiperidino) propyl) thiourea. -Chloro-4-methyl-8- (2-
(3- (4-methylpiperidino) propylamino) thiazol-4-yl) -3-oxo-3,4-dihydro-
2.6 g of 2H-1,4-benzoxazine hydrobromide
I got 258-259 ° C. Example 14 8-acetyl-6-chloro-4-methyl-3-oxo-
The same procedure as in Example 1 was repeated, except that 1.7 g of 3,4-dihydro-2H-1,4-benzoxazine was used as a starting material and 1.2 g of 1- (2-dimethylaminoethyl) thiourea was used. 8- (2- (2-dimethylaminoethylamino) thiazol-4-yl) -4-methyl-3
2.3 g of -oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide were obtained. Melting point 300 ° C or higher. Example 15 8-acetyl-6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine 2
g as a starting material, using 1,3-dimethylthiourea 0.1 g as a starting material.
The same procedure as in Example 1 was carried out using 87 g, and 6-chloro-4
-Methyl-8- (3-methyl-2-methylimino-4-
Thiazolin-4-yl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide
4 g were obtained. 245 DEG C. (decomposition). Example 16 8-acetyl-6-chloro-4-methyl-3-oxo-
Starting from 1.5 g of 3,4-dihydro-2H-1,4-benzoxazine as a starting material and using 0.83 g of 1,3-diethylthiourea, the procedure of Example 1 was repeated to give 6-chloro-8- (3 -Ethyl-2-ethylimino-4-thiazolin-4-yl) -4-methyl-3-oxo-3,4-
0.37 g of dihydro-2H-1,4-benzoxazine dioxalate was obtained. Melting point 231 [deg.] C (decomposition). Example 17 8-acetyl-6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine 2
g as a starting material and using 0.63 g of thioacetamide in the same manner as in Example 1 to give 6-chloro-4-methyl-
1.0 g of 8- (2-methylthiazol-4-yl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine was obtained. Melting point 194 [deg.] C. Example 18 8-acetyl-6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine 2
g as a starting material and using 0.76 g of thiosemicarbazide in the same manner as in Example 1 to obtain 6-chloro-8- (2-
Hydrazinothiazol-4-yl) -4-methyl-3-
1.4 g of oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide were obtained. 227 ° C (decomposition). Example 19 8-acetyl-6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine 2
g as a starting material, using 1.9 g of thiocarbanilide as in Example 1, to give 6-chloro-4-methyl-
3-oxo-8- (3-phenyl-2-phenylimino-4-thiazolin-4-yl) -3,4-dihydro-2
2.4 g of H-1,4-benzoxazine hydrobromide were obtained. Melting point 277 [deg.] C. Example 20 8-acetyl-6-chloro-3-oxo-2,2,4-
Using 1.4 g of trimethyl-3,4-dihydro-2H-1,4-benzoxazine as a starting material and 0.61 g of 1-amidinothiourea, the same procedure as in Example 1 was carried out.
-Chloro-8- (2-guanidinothiazol-4-yl) -3-oxo-2,2,4-trimethyl-3,4-
1.4 g of dihydro-2H-1,4-benzoxazine hydrobromide were obtained. 270 ° C or higher. Example 21 8-acetyl-6-chloro-4-methyl-3-oxo-
Performed in the same manner as in Example 1 using 1.5 g of 3,4-dihydro-2H-1,4-benzoxazine as a starting material and 0.73 g of 3,4,5,6-tetrahydro-2-pyrimidinethiol, 6-chloro-8- (6,7-dihydro-5H-thiazolo [3,2-a] pyrimidin-3-yl) -4-methyl-3-oxo-3,4-dihydro-2
H-1,4-benzoxazine hydrobromide 0.70 g
I got 214-216 ° C. Example 22 8-Acetyl-6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (5 g) was dissolved in chloroform (50 ml), and stirred at 40 ° C. under stirring at 3.5 g of bromine.
Was added dropwise. After concentration of the reaction solution, 50 ml of ethanol and 2.3 g of ethylenethiourea were added to the obtained residue, and the mixture was stirred under reflux for 8 hours. After allowing to cool, the crystals are collected by filtration.
-Chloro-8- (5,6-dihydroimidazo [2,1-
b] 16 g of thiazol-3-yl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide were obtained. Melting point 300 ° C or higher.

The following compounds are prepared in the same manner as in Example 22. (23) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -4-methyl-
3-oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide, melting point 295 ° C. or higher. (24) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -4-hexyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine hydrobromide, melting point 230 ° C (decomposition). (25) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -4-octyl-3-oxo-3,4-dihydro-2H-1,4- Benzoxazine hydrobromide, mp 277-279 ° C (decomposition). (26) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -4- (3-methoxypropyl) -3-oxo-3,4-dihydro-2
H-1,4-benzoxazine hydrobromide, melting point 23
0-234 ° C (decomposition). (27) 4-benzyl-6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl)
-3-oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide, melting point 270 ° C or higher. (28) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -4- (4-methoxybenzyl) -3-oxo-3,4-dihydro-2
H-1,4-benzoxazine hydrobromide, melting point 27
3-276 ° C (decomposition). (29) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -4- (4-biphenylmethyl) -3-oxo-3,4-dihydro-2
H-1,4-benzoxazine hydrobromide, melting point 28
2-284 ° C (decomposition). (30) 4- (4-benzyloxybenzyl) -6-chloro-8- (5,6-dihydroimidazo [2,1-b]
Thiazol-3-yl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide, mp 257-259 ° C. (31) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
4- (2- (4-phenylpiperidino) ethyl) -3,
4-dihydro-2H-1,4-benzoxazine dihydrobromide, mp 293 [deg.] C (decomposition). (32) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
4- (2-piperidinoethyl) -3,4-dihydro-2
H-1,4-benzoxazine dihydrobromide, melting point 2
70 ° C or higher. (33) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -4- (2-morpholinoethyl) -3-oxo-3,4-dihydro-2
H-1,4-benzoxazine dihydrobromide, melting point 3
00 ° C or higher. (34) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
4- (2-phenethyl) -3,4-dihydro-2H-
1,4-benzoxazine hydrobromide, mp 237-
240 ° C. (35) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
4- (3-phenylpropyl) -3,4-dihydro-2
H-1,4-benzoxazine hydrobromide, melting point 24
6-248 ° C. (36) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
4- (4-phenylbutyl) -3,4-dihydro-2H
-1,4-benzoxazine hydrobromide, melting point 237
２238 ° C. (decomposition). (37) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
4- (2-phenoxyethyl) -3,4-dihydro-2
H-1,4-benzoxazine hydrobromide, melting point 23
5-237 ° C. (38) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
4- (3-phenoxypropyl) -3,4-dihydro-
2H-1,4-benzoxazine hydrobromide, melting point 2
38-240 ° C (decomposition). (39) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
4- (4-phenoxybutyl) -3,4-dihydro-2
H-1,4-benzoxazine hydrobromide, melting point 22
9-230 ° C. (40) 4- (3-benzyloxypropyl) -6-chloro-8- (5,6-dihydroimidazo [2,1-b]
Thiazol-3-yl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine hydrochloride, melting point 23
3-234 ° C. (41) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -4- (3-
(4-Fluorophenoxy) propyl) -3-oxo-
3,4-dihydro-2H-1,4-benzoxazine hydrobromide, mp 250-251 ° C. (42) 6-chloro-4- (3- (4-chlorophenoxy) propyl) -8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
3,4-dihydro-2H-1,4-benzoxazine hydrobromide, mp 238-239 ° C. (43) 6-chloro-4- (4- (4-chlorophenoxy) butyl) -8- (5,6-dihydroimidazo [2,
1-b] thiazol-3-yl) -3-oxo-3,4
-Dihydro-2H-l, 4-benzoxazine hydrobromide, mp 220 ° C. (44) 6-chloro-4- (5- (4-chlorophenoxy) pentyl) -8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
3,4-dihydro-2H-1,4-benzoxazine hydrobromide, mp 233-235 ° C. (45) 6-chloro-4- (6- (4-chlorophenoxy) hexyl) -8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
3,4-dihydro-2H-1,4-benzoxazine hydrobromide, melting point 230 [deg.] C (decomposition). (46) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
4- (3-Phenylthiopropyl) -3,4-dihydro-2H-1,4-benzoxazine hydrobromide, mp 214-218 ° C. (47) 4- (3-benzylthiopropyl) -6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-3,4-dihydro- 2H-1,4-benzoxazine hydrobromide, mp 200-204 ° C (decomposition). (48) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -4- (3-
(N-benzyl-N-methylamino) propyl) -3-
Oxo-3,4-dihydro-2H-1,4-benzoxazine dioxalate, mp 211-213 ° C. (49) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -3-oxo-
2,2,4-trimethyl-3,4-dihydro-2H-
1,4-benzoxazine hydrobromide, mp 270
° C. (50) 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -4-methyl-
3-oxo-2-propyl-3,4-dihydro-2H-
1,4-benzoxazine hydrobromide, mp 273-
276 ° C (decomposition). (51) 2-butyl-6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl)-
4-methyl-3-oxo-3,4-dihydro-2H-
1,4-benzoxazine hydrobromide, melting point 240-
242 ° C. (52) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -6-methoxy-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide, mp 264-266 ° C.
(Disassembly). (53) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -6-methoxy-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-benzoxazine hydrobromide, mp 211-212. ° C. (54) 8- (5,6-dihydroimidazo [2,1-
b] Thiazol-3-yl) -6-hexyl-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-benzoxazine hydrochloride, melting point 13
8-140 ° C. (55) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -3-oxo-4- (3-
Phenoxypropyl) -6- (N- (3-phenoxypropyl) -N-acetylamino) -3,4-dihydro-
2H-1,4-benzoxazine, ¹ H-NMR (CD
_{Cl 3) δppm: 1.72~2.32 (7H} , m),
3.54 to 4.36 (12H, m), 4.66 (2H,
s), 5.72 (1H, s), 6.66 to 7.40 (1
2H, m). (56) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -4-hexyl-6- (N
-Hexyl-N-acetylamino) -3-oxo-3,
4-dihydro-2H-1,4-benzoxazine hydrobromide, mp 194-196 ° C. (57) 3- (6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
8-yl) -5,6-dihydroimidazo [2,1-b]
Thiazole-2-ethyl acetate hydrobromide, mp 158
~ 160 ° C. (58) 3- (6-Chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4
-Benzoxazin-8-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-ethyl acetate hydrobromide, mp 97-99 ° C. (59) 8- (5,6-dihydroimidazo [2,1-
b] Thiazol-3-yl) -4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide, mp 158-160 ° C. Example 60 3- (6-chloro-4-methyl-3-oxo-3,4-
Dihydro-2H-1,4-benzoxazin-8-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-ethyl acetate hydrobromide (2 g) was dissolved in ethanol (2).
0 ml, and 4.5 ml of 2N sodium hydroxide under ice-cooling.
Was added and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure,
Water was added to the obtained residue, and the mixture was acidified with concentrated hydrochloric acid under ice cooling (pH
2) to 3), and the precipitated crystals are collected by filtration.
-(6-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)
0.45 g of -5,6-dihydroimidazo [2,1-b] thiazole-2-acetic acid hydrochloride was obtained. Melting point 267-26
8 ° C (decomposition). Example 61 3- (6-chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-benzoxazin-8-yl) -5,6-dihydroimidazo [ 2,1-b] thiazole-2-ethyl acetate hydrobromide (2 g) was used as a starting material, in the same manner as in Example 60.
(6-chloro-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-benzoxazin-8-yl) -5,6-dihydroimidazo [2,
1-b] Thiazole-2-acetic acid hydrochloride (1.6 g) was obtained.
222-224 ° C (decomposition). Example 62 6-chloro-8- (5,6-dihydroimidazo [2,1
-B] thiazol-3-yl) -4- (3- (2- (4
-Fluorophenyl) -1,3-dioxolan-2-yl) propyl) -3-oxo-3,4-dihydro-2H
To 0.35 g of -1,4-benzoxazine hydrobromide, 50 ml of methanol, 2 ml of a 47% aqueous solution of hydrobromic acid,
2 ml of water was added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, and ethanol was added to the obtained residue to give 6-chloro-8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -4- (4-
(4-fluorophenyl) -4-oxobutyl) -3-
Oxo-3,4-dihydro-2H-1,4-benzoxazine hydrobromide 0.08 g was obtained. Melting point 269-2
71 ° C (decomposition). Example 63 6-methoxy-8- (5,6-dihydroimidazo [2,
1-b] thiazol-3-yl) -3-oxo-4-
(3-phenoxypropyl) -3,4-dihydro-2H
9.1 g of -1,4-benzoxazine hydrobromide was added to 90 ml of dichloroethane, 26 g of boron tribromide was added dropwise at 0 ° C. with stirring, and the mixture was stirred at room temperature for 2 hours. Ice is added to the reaction solution and neutralized with 1N sodium hydroxide (pH 7 to 8)
did. By filtering the precipitated crystals, 8- (5,5)
6-dihydroimidazo [2,1-b] thiazole-3-
Yl) -6-hydroxy-3-oxo-4- (3-phenoxypropyl) -3,4-dihydro-2H-1,4-
7.6 g of benzoxazine hydrobromide were obtained. Melting point 1
65-168 ° C (decomposition). Example 64 6-chloro-8- (2- (2- (3,4-dimethoxyphenyl) ethylaminothiazol-4-yl) -4-methyl-3-oxo-3,4-dihydro-2H-1, 4-
Performed in the same manner as in Example 63, using 3 g of benzoxazine hydrobromide as a starting material, to obtain 6-chloro-8- (2- (2-
(3,4-dihydroxyphenyl) ethylamino) thiazol-4-yl) -4-methyl-3-oxo-3,4
1.8 g of -dihydro-2H-1,4-benzoxazine hydrobromide were obtained. 245-247 ° C. Example 65 8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -6-hydroxy-3-oxo-4-
(3-phenoxypropyl) -3,4-dihydro-2H
3 g of -1,4-benzoxazine hydrobromide was added to an aqueous potassium carbonate solution under ice cooling, and extracted with chloroform. After drying over magnesium sulfate, 30 ml of dimethylformamide was added to the residue obtained by concentration under reduced pressure, and 0.34 g of sodium hydride was added with stirring at 0 ° C. 3 at room temperature
After stirring for 0 minutes, isopropyl iodide (1.0 ml) was added at the same temperature, followed by stirring at 100 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure,
The obtained residue was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure. After purification by silica gel column chromatography (chloroform: methanol = 10: 1), treatment with 23% hydrochloric acid-ethanol gave 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -6-isopropyloxy-3-oxo-4- (3-phenoxypropyl) -3,
0.66 g of 4-dihydro-2H-1,4-benzoxazine hydrochloride was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.34 (6H, m), 2.20 (2H, m), 3.9
0 to 4.26 (5H, m), 4.46 (4H, m),
4.61 (2H, s), 6.56-7.42 (8H,
m). Example 66 8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -6-hydroxy-3-oxo-4-
(3-phenoxypropyl) -3,4-dihydro-2H
Example 65 Using 2 g of -1,4-benzoxazine hydrobromide as a starting material and 0.56 ml of hexyl bromide
And 8- (5,6-dihydroimidazo [2,
1-b] thiazol-3-yl) -6-hexyloxy-3-oxo-4- (3-phenoxypropyl) -3,
0.26 g of 4-dihydro-2H-1,4-benzoxazine hydrochloride was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
0.62 to 1.81 (11H, m), 2.06 (2H,
m), 3.61-4.18 (10H, m), 4.44.
(2H, s), 6.40-7.20 (8H, m). Example 67 8- (5,6-dihydroimidazo [2,1-b] thiazol-3-yl) -6-hydroxy-3-oxo-4-
(3-phenoxypropyl) -3,4-dihydro-2H
Starting from 2.5 g of -1,4-benzoxazine hydrobromide and using 1.4 ml of 3-phenoxypropyl bromide as in Example 65, 8- (5,6-dihydroimidazo [ 2,1-b] thiazol-3-yl) -3
-Oxo-6- (3-phenoxypropyloxy) -4
-(3-phenoxypropyl) -3,4-dihydro-2
0.39 g of H-1,4-benzoxazine was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
2.22 (4H, m), 3.92 to 4.26 (12H,
m), 4.57 (2H, s), 5.69 (1H, s),
6.47-7.36 (12H, m). Example 68 To 5 g of 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid hydrazide were added 80 ml of methanol and 32 g of ethyl orthoformate, and the mixture was refluxed for 4 hours. Stirred. After the reaction solution was concentrated under reduced pressure, 80 ml of n-butanol and 3.3 g of potassium tert-butoxide were added, and the mixture was stirred under reflux for 2 hours. After the reaction solution was concentrated under reduced pressure, chloroform was added, and the mixture was extracted with a 2M aqueous solution of potassium carbonate. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude crystals were recrystallized with a mixture of methanol and ethanol (1: 1) to give 6-chloro-
2.1 g of 4-methyl-8- (5-methyl-1,3,4-oxadiazol-2-yl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazine was obtained. . 218 ° C. Example 69 To 11 g of formamide was added 1.4 ml of concentrated sulfuric acid under ice-cooling, and 6-chloro-4-methyl-3-oxo-3,4-dihydro-2.
H-1,4-benzoxazine-8-carboxylic acid-1
4.2 g of ethoxycarbonyl-2-oxopropyl was added, and the mixture was stirred at 140 ° C for 20 minutes. Ethanol was added, and the precipitated crystals were collected by filtration and purified by silica gel column chromatography (chloroform) to give 2
-(6-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)
Ethyl-4-methyloxazole-5-carboxylate
89 g were obtained. Melting point 223 [deg.] C. Example 70 3.8 g of the crude crystals obtained in Example 69 were subjected to silica gel column chromatography (chloroform: methanol = 2).
0: 1) to give 2- (6-chloro-
4-methyl-3-oxo-3,4-dihydro-2H-
220 mg of ethyl 1,4-benzoxazin-8-yl) -4-methylimidazole-5-carboxylate was obtained.
245 ° C. Example 71 2- (6-chloro-4-methyl-3-oxo-3,4-
To 3 g of ethyl dihydro-2H-1,4-benzoxazin-8-yl) -4-methyloxazole-5-carboxylate, 100 ml of ethanol and 5 ml of a 2N aqueous sodium hydroxide solution were added, and the mixture was stirred under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, the obtained residue was acidified with 4N hydrochloric acid, extracted with chloroform, and concentrated under reduced pressure to give 2-
(6-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)-
2.2 g of 4-methyloxazole-5-carboxylic acid were obtained. 302-304 ° C. Example 72 2- (6-chloro-4-methyl-3-oxo-3,4-
To 3 g of ethyl dihydro-2H-1,4-benzoxazin-8-yl) -4-methylimidazole-5-carboxylate was added 100 ml of ethanol and 9.9 ml of a 2N aqueous sodium hydroxide solution, and the mixture was stirred under reflux for 8 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was acidified with 4N hydrochloric acid.
The precipitated crystals were collected by filtration to give 2- (6-chloro-4-methyl-3-oxo-3,4-dihydro-2H.
2.3 g of -1,4-benzoxazin-8-yl) -4-methylimidazole-5-carboxylic acid were obtained. Melting point 2
49-252 ° C. Example 73 2- (6-chloro-4-methyl-3-oxo-3,4-
To 3 g of dihydro-2H-1,4-benzoxazin-8-yl) -4-methyloxazole-5-carboxylic acid, 60 ml of tetrahydrofuran, 2 g of triethylamine,
10 ml of dimethylformamide was added, and the mixture was stirred at 60 ° C. for 30 minutes. Thereafter, 1.3 g of isobutyl chloroformate was added dropwise at -15 ° C, and sodium borohydride 0.1 g was added at the same temperature.
53 g was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, an aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate and concentration under reduced pressure, 6-chloro-8- (5-hydroxymethyl-4-methyloxazol-2-yl) -4-.
Methyl-3-oxo-3,4-dihydro-2H-1,4
-1.2 g of benzoxazine were obtained. Melting point 245-24
7 ° C.

Hereinafter, the following compounds are produced in the same manner. (74) 8- (2-aminothiazol-4-yl) -6
-Chloro-4- (3- (4-methoxybenzyloxy)
Propyl) -3-oxo-3,4-dihydro-2H-
1,4-benzoxazine (75) 8- (2-aminothiazol-4-yl) -6
-Chloro-4- (3-dimethylaminopropyl) -3-
Oxo-3,4-dihydro-2H-1,4-benzoxazine (76) 6-chloro-4-methyl-8- (3- (4-methoxyphenyl) -2- (4-methoxyphenyl) imino-4 -Thiazolin-4-yl) -3-oxo-3,4
-Dihydro-2H-1,4-benzoxazine (77) 6-chloro-4-methyl-8- (2- (4-piperidyl) aminothiazol-4-yl) -3-oxo-3,4-dihydro- 2H-1,4-benzoxazine (78) 6-chloro-4-methyl-8- (2- (4-methoxyphenyl) aminothiazol-4-yl) -3-
Oxo-3,4-dihydro-2H-1,4-benzoxazine (79) 6-chloro-4-methyl-8- (2- (2-phenethyl) aminothiazol-4-yl) -3-oxo-3 , 4-Dihydro-2H-1,4-benzoxazine (80) 6-chloro-4-methyl-8- (2- (4-methoxybenzoyl) aminothiazol-4-yl) -3
-Oxo-3,4-dihydro-2H-1,4-benzoxazine (81) 3- (6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
8-yl) -5,6-dihydroimidazo [2,1-b]
Thiazole-2-carboxylic acid (82) 3- (6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
8-yl) -5,6-dihydroimidazo [2,1-b]
Ethyl thiazole-2-carboxylate (83) 2- (6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
Ethyl 8-yl) -4-phenylthiazole-5-carboxylate (84) 2- (6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
8-yl) -4-phenylthiazole-5-ethyl acetate (85) 6-chloro-4-methyl-8- (4-phenylthiazol-2-yl) -3-oxo-3,4-dihydro-2H- 1,4-benzoxazine (86) 2- (6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
Ethyl 8-yl) -4-methylthiazole-5-carboxylate (87) 2- (6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
8-yl) -4-phenylthiazole-5-acetic acid (88) 2- (6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
8-yl) -4- (4-methoxyphenyl) thiazole-5-acetic acid (89) 2- (6-chloro-4-methyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
8-yl) thiazole-5-ethyl acetate The structural formulas of the above compounds are listed. The numbers in parentheses indicate the example numbers.

[0096]

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[0097]

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[0098]

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[0099]

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[0100]

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[0101]

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[0102]

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[0103]

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[0104]

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──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61P 37/08 A61P 37/08 43/00 43/00 (72) Inventor Michio Terasawa 955 Komatsuri, Yoshitomi-cho, Yoshitomi-gun, Chikugami-gun, Fukuoka Yoshitomi Pharmaceutical Co., Ltd. (72) Inventor Hitoshi Okamoto 1-1, Murasakicho, Takatsuki City, Osaka Prefecture Japan Tobacco Inc. Pharmaceutical Research Institute (58) Field surveyed (Int. Cl. ⁷ , DB name) ) C07D 413/04 C07D 417/04 C07D 513/04 331 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula [Wherein, R ¹ is hydrogen, alkyl, aralkyl, substituted aralkyl or a formula — (CH ₂ ) _n —X—R ⁵ (where R ⁵ is alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, and X is An oxygen atom, a sulfur atom, a carbonyl or NR ⁶ (wherein, R ⁶ represents alkyl or benzyl, or a group in which R ⁵ and R ⁶ are bonded together with an adjacent nitrogen atom to form a heterocyclic ring; May have a substituent.), And n represents an integer of 1 to 6.). R ² is hydrogen, halogen, hydroxyl, alkyl, alkoxy, phenoxyalkoxy or a formula —N (R ⁷ ) (R ^7a ), wherein R ⁷ represents alkyl or phenoxyalkyl, and R ^7a represents alkanoyl. Shows the group represented. R ³ and R ⁴ are the same or different and represent hydrogen or alkyl. Het is of the formula (Wherein, R ⁸ represents unsubstituted, alkyl, phenyl or substituted phenyl, and when R ⁸ is alkyl, phenyl or substituted phenyl, the bonding site with a dotted line between nitrogen and carbon to which R ⁸ is bonded has a single bond. , R ⁹ represents the formula ＮNR ¹⁰ (wherein R ¹⁰ represents alkyl, phenyl or substituted phenyl). When R ⁸ is unsubstituted, a dotted line between the nitrogen and carbon to which R ⁸ is bonded is represented by The associated binding site is a double bond, R
⁹ is alkyl, amino, during guanidino or formula -NH-R ¹¹ (wherein, R ¹¹ is alkyl, piperidyl, substituted piperidyl, alkenyl, phenyl, substituted phenyl, aralkyl, substituted aralkyl, benzoyl, substituted benzoyl, amino or of the formula - ( CH ₂ ) _m N (R ¹² ) (R ¹³ ) (wherein, m represents an integer of 1 to 3, and R ¹² and R ¹³ are the same or different and represent alkyl, or R ¹² and R ¹³ are adjacent to each other. A group which forms a heterocyclic ring by bonding together with a nitrogen atom,
The heterocyclic ring may have a substituent. ) Is shown. Or a group represented by R
^The bonding site with a dotted line between the nitrogen and carbon to which ⁸ is bonded indicates a single bond, and R ⁸ and R ⁹ together form the formula-(CH ₂ ) _p -N = (where p is 2 or 3 Represents a ring-forming group with a nitrogen-containing alkylene chain represented by R ¹⁴
Represents hydrogen, carboxy, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl. Or a group represented by the formula: (Wherein A ¹ represents an oxygen atom, a sulfur atom or NH,
A ² represents a nitrogen atom or a formula C—R ¹⁵ (where R ¹⁵ represents hydrogen, alkyl, phenyl or substituted phenyl), and R ¹⁶ represents hydrogen, alkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkoxycarbonyl Or an alkoxycarbonylalkyl. ) Is shown. A benzoxazin-3-one compound or a pharmaceutically acceptable salt thereof.