JPH07242663A - Benzoxazine compound - Google Patents

Abstract

PURPOSE:To provide the novel compound having a phospholipase A2-inhibiting action, an interleukin-1 production-inhibiting action and a carageening podedema- inhibiting action, and useful for treating and preventing allergic diseases, inflammatory diseases, ischemic angiopathy, etc. CONSTITUTION:This compound is expressed by formula I (R<1> is H, benzoyl, etc.; R<2> is H, halogen, etc.; R<3>, R<4> are H, alkyl; Het is 2-aminothiazol-4-yl, 5- ethoxycarbonyl-4-phenylthiazol-2-yl, etc.), e.g. 4-acetyl-8-(2-aminothiazol-4-yl)-6- chloro-3,4-dihydro-2H-1,4-benzoxazine hydrobromide. The compound is obtained e.g. by brominating a compound of formula II (R<13> is H, carboxyl, etc.) with bromine in chloroform and subsequently reacting the reaction product with a compound of formula II [R<7> is alkyl, phenyl, etc., and R<8> is =N-R<9> (R<9> is phenyl, etc.), or R<7> is H and R<8> is alkyl, amino, etc.] in ethanol.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to phospholipase A.
₂ A novel benzoxazine compound useful as a drug having an inhibitory effect on PLA ₂ (hereinafter referred to as PLA ₂ ), an inhibitory effect on interleukin-1 (hereinafter referred to as IL-1) and an inhibitory effect on carrageenin foot edema or a pharmaceutically acceptable compound thereof Regarding salt.

[0002]

[Prior Art] [Problems to be Solved by the Invention]
From JP-A-28182, there is known a benzoxazine compound having a 5-HT ₃ receptor blocking action and used as an antiemetic agent. By the way, physiologically active lipids such as prostaglandins, leukotrienes and thromboxane not only play a regulatory role for maintaining homeostasis in the living body, but their abnormal production causes various diseases such as allergy, asthma and inflammation. Is believed to be directly involved in. PLA ₂ is an enzyme that hydrolyzes a fatty acid ester bond existing at the 2-position of the glycerol skeleton of glycerophospholipids, and catalyzes the reaction of releasing arachidonic acid, which is a precursor of these physiologically active lipids, from membrane phospholipids. It is known that this reaction step is a rate-determining step in a series of bioactive lipid production processes.

Recently, IL-1 is PLA₂Gene expression of
Promote PLA₂Induction or inflammation using experimental animals
Human inflammatory diseases such as models and rheumatoid arthritis
Extracellular PLA₂Since the activity was found, in the place of inflammation
PLA in₂The role of is attracting attention. Meanwhile, anti-inflammatory
The drugs are steroids such as glucocorticoids and Indian drugs.
Non-steroidal anti-inflammatory such as tasine, diclofenac
Broadly divided into agents. Steroids are the most clinically potent
Anti-inflammatory agent. The mechanism of its expression is PL
A ₂By inducing the biosynthesis of a protein that inhibits
It suppresses the release of lachidonic acid and exerts an anti-inflammatory effect.
Has been. However, due to serious side effects, its clinical indication
Is restricted. Non-steroidal anti-inflammatory drugs are currently in widespread use.
It is widely used, but its action is weaker than that of steroids.
In addition, side effects such as gastrointestinal disorders have become a problem.

Recent studies of PLA ₂ inhibitors show that P
There are low molecular weight type I and type II and high molecular weight subtypes of LA ₂ , and PLA _{2 in} gastric mucosa is the same as that of pancreas, and it has been proved that it is low molecular weight type I PLA _2. And, the enzyme involved in inflammation is said to be a 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 steroid drugs such as gastrointestinal hepatic disorder and can be expected to have a safe and strong anti-inflammatory action. Further, the compound that inhibits PLA ₂ is
JP-A-3-258749, JP-A-4-49236
It is known from JP-A No. 4-49237 and Japanese Patent Laid-Open No. 4-49237 that it is also effective for ischemic vascular disorders and sepsis.

Known PLA ₂ inhibitors to date include synthetic products such as mepacrine and p-bromophenacyl bromide, and natural products include sponge-derived manoalide, blue mold-derived plastatin, and bacterial-derived prepata. There are statins. However, these anti-inflammatory effects are weaker than those of non-steroidal anti-inflammatory drugs, and there is a problem in specificity of action, and they are not practically useful as anti-inflammatory drugs.

Therefore, a strong low molecular weight type II PLA
₂The development of inhibitors is eagerly awaited, and the object of the present invention is inflammation.
Diseases, allergic diseases, anaphylactic shock
It is thought to be an extremely effective and safe drug for
Low molecular weight type II PLA ₂Selectively suppress the activity of
It is to provide a compound.

[0007]

[Means for Solving the Problems] The inventors of the present invention are keen to create a substance which exhibits a low molecular weight type II PLA ₂ inhibitory action, an IL-1 production inhibitory action and a carrageenin paw edema inhibitory action, and which is useful as a medicine. As a result of repeated research, they have found that a certain benzoxazine compound achieves its purpose, and completed the present invention.

That is, the present invention has the general formula

[0009]

[Chemical 4]

[In the formula, R ¹ represents hydrogen, alkyl, optionally substituted alkanoyl, benzoyl, substituted benzoyl, cinnamoyl, substituted cinnamoyl or phenoxyalkyl. R ² is hydrogen, halogen, hydroxyl group,
Alkyl, alkoxy, phenoxyalkoxy, or a group represented by the formula —N (R ⁵ ) (R ⁶ ), wherein R ⁵ represents alkyl or phenoxyalkyl, and R ⁶ represents alkanoyl. R ³ and R ⁴ are the same or different and each represents hydrogen or alkyl. Het is a formula

[0011]

[Chemical 5]

(In the formula, R ⁷ represents unsubstituted alkyl, phenyl or substituted phenyl, and when R ⁷ is alkyl, phenyl or substituted phenyl, the bonding site with a dotted line between the nitrogen and carbon to which R ⁷ is bonded is A single bond, R ⁸ represents the formula ═N—R ⁹ (in the formula, R ⁹ represents alkyl, phenyl or substituted phenyl), and when R ⁷ is unsubstituted, the nitrogen-carbon bond to which R ⁷ is bonded. The binding site with the dotted line is a double bond, R
⁸ alkyl, amino, during guanidino or formula -NH-R ¹⁰ (wherein, R ¹⁰ 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 11}} ) (R 12) ( wherein, m is an integer of 1 to 3, or R ^11, R ¹² represents an alkyl identical or different, R ¹¹ and R ¹² are adjacent Represents a group that forms a heterocycle by bonding with a nitrogen atom,
The heterocycle may have a substituent. ) Shows the group represented by. ) Represents a group represented by
^The bonding site with a dotted line between the nitrogen and carbon to which ⁷ is bonded represents a single bond, and R ⁷ and R ⁸ together form the formula — (CH ₂ ) _p —N = (wherein p is 2 or 3 Represents a group that forms a ring with a nitrogen-containing alkylene chain. R ¹³
Represents hydrogen, carboxy, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl. ) Represents a group represented by

[0013]

[Chemical 6]

(In the formula, A ¹ represents an oxygen atom, a sulfur atom or NH, A ² is a nitrogen atom or a formula C—R ¹⁴ (in the formula, R ¹⁴ represents hydrogen, alkyl, phenyl or substituted phenyl). And R ¹⁵ represents hydrogen, alkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl.). ] The benzoxazine compound represented by these, or its pharmaceutically acceptable salt.

In the present specification, the alkyl in R ¹ is a linear or branched alkyl having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl and propyl. , Isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl,
It shows octyl, and methyl and hexyl are particularly preferable. R
^The alkanoyl which may have a substituent in ¹ means phenyl as a substituent or halogen (fluorine, chlorine, bromine, etc.), amino, nitro, cyano, hydroxyl group, methylsulfonyl, trifluoromethyl, carbon on the phenyl nucleus. 1-3 optionally selected from alkyl having 1 to 4 (as defined above), alkoxy having 1 to 4 carbons (methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, etc.) A linear or branched alkanoyl having 2 to 7 carbon atoms which may be substituted with phenyl having 4 substituents,
Preferred substituents are phenyl or a phenyl having 1 to 3 substituents selected from hydroxyl groups and alkoxy having 1 to 4 carbon atoms, such as acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, 2-phenyl. Acetyl, 3-phenylpropionyl, 4-phenylbutyryl, 2- (3,4-dimethoxyphenyl) acetyl, 2- (3,4-dihydroxyphenyl) acetyl, 3- (3,4-dimethoxyphenyl) propionyl, 3 -(3,4-dihydroxyphenyl) propionyl is shown, and acetyl, heptanoyl, 3- (3,4-dimethoxyphenyl) propionyl and 3- (3,4-dihydroxyphenyl) propionyl are particularly preferable.

The substituted benzoyl in R ¹ is halogen (as defined above), amino, nitro, cyano, hydroxyl group, methylsulfonyl, trifluoromethyl, alkyl having 1 to 4 carbon atoms (as defined above) on the phenyl nucleus. , Benzoyl having 1 to 3 substituents arbitrarily selected from alkoxy having 1 to 4 carbons (synonymous with the above) and the like, and preferable substituents are a hydroxyl group and alkoxy having 1 to 4 carbons. In particular, hydroxyl group and methoxy are preferable, and specific examples thereof include 3-methoxybenzoyl, 4-methoxybenzoyl, 3,4-dimethoxybenzoyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl and 3,4.
-Dihydroxybenzoyl and the like are mentioned, and 4-methoxybenzoyl is particularly preferable.

Substituted cinnamoyl in R ¹ means halogen (as defined above), amino, nitro, on the phenyl nucleus.
1 to 3 substituents arbitrarily selected from cyano, hydroxyl group, methylsulfonyl, trifluoromethyl, alkyl having 1 to 4 carbons (as defined above), alkoxy having 1 to 4 carbons (as defined above), and the like. Shows a cinnamoyl having a group,
Preferred substituents are hydroxyl group, methylsulfonyl and alkoxy having 1 to 4 carbon atoms, and specific examples thereof include 3-hydroxycinnamoyl, 4-hydroxycinnamoyl, 3-methoxycinnamoyl and 4-methoxycinnamoyl. , 4-hydroxy-3-methoxycinnamoyl, 3-hydroxy-4-methoxycinnamoyl, 3,
4-dimethoxycinnamoyl, 3,4-dihydroxycinnamoyl, 4-hydroxy-3,5-dimethoxycinnamoyl, 4-methylsulfonylcinnamoyl and the like can be mentioned.

Phenoxyalkyl in R ¹ is an alkyl having 1 to 4 carbon atoms (as defined above) substituted by phenoxy, such as phenoxymethyl, 2
-Phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl, especially 2-phenoxyethyl, 3
-Phenoxypropyl is preferred. The halogen in R ² is fluorine, chlorine, bromine or iodine, and chlorine is particularly preferable.

Alkyl for R ² has 1 to 6 carbon atoms.
A straight-chain or branched-chain alkyl (as defined above), with hexyl being particularly preferred. The alkoxy in R ² is a linear or branched alkoxy having 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyl. It represents oxy, and methoxy, isopropoxy and hexyloxy are particularly preferable.

Phenoxyalkoxy in R ² is
Phenoxy is substituted on the alkoxy having 1 to 4 carbon atoms (synonymous with the above), and for example, phenoxymethoxy, 2-phenoxyethoxy, 3-phenoxypropoxy, 4-phenoxybutoxy, particularly phenoxymethoxy, 3 -Phenoxypropoxy is preferred. The alkyl in R ⁵ is a linear or branched alkyl having 1 to 6 carbon atoms (as defined above), and hexyl is particularly preferable.

Phenoxyalkyl in R ⁵ is R
It has the same meaning as phenoxyalkyl in ¹ , and phenoxymethyl is particularly preferable. The alkanoyl in R ⁶ is a straight or branched chain alkanoyl having 2 to 5 carbon atoms, and is, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or pivaloyl, and acetyl is particularly preferable.

The alkyl in R ³ and R ⁴ is a linear or branched alkyl having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (as defined above), especially methyl,
Ethyl, propyl and butyl are preferred. Alkyl in R ⁷ has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
A straight-chain or branched-chain alkyl (as defined above), with methyl and ethyl being particularly preferred.

The substituted phenyl in R ⁷ means halogen (as defined above), amino, nitro, cyano, hydroxyl group, methylsulfonyl, trifluoromethyl, on the phenyl nucleus,
C1-C4 alkyl (as defined above), C1-C1
It shows phenyl having 1 to 3 substituents arbitrarily selected from 4 alkoxys (synonymous with the above), and preferable substituents are halogen, hydroxyl group, and alkoxy having 1 to 4 carbon atoms, Examples include 4-chlorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl and the like, with 4-methoxyphenyl being particularly preferred.

Alkyl for R ⁸ has 1 to 4 carbon atoms.
Alkyl (as defined above), with methyl being particularly preferred. The alkyl in R ⁹ has the same meaning as the alkyl in R ⁷ . Substituted phenyl in R ⁹ is R
It is synonymous with the substituted phenyl in ⁷ . The alkyl in R ¹⁰ has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
Straight-chain or branched-chain alkyl (as defined above), with ethyl being particularly preferred.

The substituted piperidyl in R ¹⁰ means alkyl having 1 to 4 carbon atoms (as defined above) at the nitrogen atom of the piperidine ring, phenyl, aralkyl (benzyl, 2-phenethyl, 3-phenylpropyl, 4-phenylbutyl). Etc.) and piperidyl having a substituent such as C1-4, preferably alkyl having 1 to 4 carbons or aralkyl, and particularly preferably methyl or 2-phenethyl. Specific examples thereof include 1-methyl-4-piperidyl, 1- (2-phenethyl) -4-piperidyl and the like.

Alkenyl in R ¹⁰ has 2 to 2 carbon atoms.
Five linear or branched alkenyl, for example, vinyl, allyl, propenyl, isopropenyl, butenyl, pentenyl and the like can be mentioned, with allyl being particularly preferable. The substituted phenyl in R ^{10 has the same} meaning as the substituted phenyl in R ⁷ and R ⁹ .

Aralkyl in R ¹⁰ has 1 to 1 carbon atoms.
4 alkyl (as defined above) substituted with phenyl, such as benzyl, 1-phenethyl, 2-
Phenethyl, 3-phenylpropyl and 4-phenylbutyl are shown, and 2-phenethyl is particularly preferable. The substituted aralkyl in R ¹⁰ is halogen (as defined above), amino, nitro, cyano, hydroxyl group, methylsulfonyl, trifluoromethyl, alkyl having 1 to 4 carbons (as defined above), carbon number on the phenyl nucleus. It shows an aralkyl having 1 to 3 substituents arbitrarily selected from 1 to 4 alkoxys (synonymous with the above) and the like, and a preferable substituent is a hydroxyl group, an alkoxy having 1 to 4 carbon atoms, and particularly a hydroxyl group. Are preferred, and specific examples thereof include 2- (3,4-dihydroxyphenyl) ethyl, 2- (3,4-dimethoxyphenyl) ethyl and the like.

The substituted benzoyl for R ¹⁰ has the same meaning as the substituted benzoyl for R ¹ . The alkyl in R ¹¹ and R ¹² has 1 to 6 carbon atoms, preferably 1 carbon atom.
~ 4 straight or branched chain alkyls (as defined above)
Of these, methyl and ethyl are particularly preferable.

The group in which R ¹¹ and R ¹² are combined with the adjacent nitrogen atom to form a heterocycle is, for example, 1-pyrrolidinyl, piperidino, 1-piperazinyl, 1-homopiperazinyl or morpholino, and of these, preferred Piperidino and morpholino. Further, the heterocycle has 1 to 4 carbon alkyl (synonymous with the above) and 1 to 4 carbon atoms.
It may have a substituent such as four alkoxys (as defined above) and a hydroxyl group, and a preferable substituent has 1 carbon atom.
It is preferably 4 to 4 alkyls, particularly preferably methyl, and specific examples thereof include 4-methylpiperidino.

Specific examples of the group represented by the formula-(CH ₂ ) _m N (R ¹¹ ) (R ¹² ) in R ¹⁰ include 3-morpholinopropyl, 3- (4-methylpiperidino) propyl, 2-
Examples include diethylaminoethyl. Carboxyalkyl in R ¹³ is alkyl having 1 to 4 carbon atoms (as defined above) substituted with carboxy,
For example carboxymethyl, 2-carboxyethyl, 1
-Carboxyethyl, 3-carboxypropyl and 4-carboxybutyl are shown, and carboxymethyl is particularly preferable.

The alkoxy in the alkoxycarbonyl in R ¹³ is an alkoxy having 1 to 4 carbon atoms (as defined above), and is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl. , And tertiary butoxycarbonyl, with ethoxycarbonyl being particularly preferred.

Alkoxycarbonylalkyl in R ¹³ is an alkyl having 1 to 4 carbon atoms (as defined above) substituted with alkoxycarbonyl (as defined above), such as methoxycarbonylmethyl, 2- (methoxy). Carbonyl) ethyl, 3- (methoxycarbonyl)
Propyl, 4- (methoxycarbonyl) butyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, butoxycarbonylmethyl are shown, and ethoxycarbonylmethyl is particularly preferable.

A specific example of Het in the formula (II) is 2
-Aminothiazol-4-yl, 2-guanidinothiazol-4-yl, 5,6-dihydroimidazo [2,1-
b] thiazol-3-yl, 2-methylthiazol-4
-Yl, 2-hydrazinothiazol-4-yl, 3-methyl-2-methylimino-4-thiazolin-4-yl,
3-phenyl-2-phenylimino-4-thiazoline-
4-yl, 2-benzoylaminothiazol-4-yl, 2- (2-diethylaminoethyl) aminothiazol-4-yl, 2- (1-methyl-4-piperidyl) aminothiazol-4-yl, 2-ethoxy Carbonylmethyl-5,6-dihydroimidazo [2,1-b] thiazol-3-yl, 2-ethylaminothiazol-4-yl, 2- (4-piperidyl) aminothiazol-4-yl, 2- (1 -(2-phenethyl) -4-piperidyl)
Aminothiazol-4-yl, 2-allylaminothiazol-4-yl, 2-phenylaminothiazol-4-
2- (4-methoxyphenyl) aminothiazol-4-yl, 2- (2-phenethyl) aminothiazol-4-yl, 2- (2- (3,4-dihydroxyphenyl) ethyl) aminothiazol-4 -Yl, 2- (4-
Methoxybenzoyl) aminothiazol-4-yl, 2
-(3-morpholinopropyl) aminothiazole-4-
2- (3- (4-methylpiperidino) propyl)
Aminothiazol-4-yl, 3- (4-methoxyphenyl) -2- (4-methoxyphenyl) imino-4-thiazolin-4-yl, 6,7-dihydro-5H-thiazolo [3,2-a] Pyrimidin-3-yl, 2-carboxy-5,6-dihydroimidazo [2,1-b] thiazol-3-yl, 2-carboxymethyl-5,6-dihydroimidazo [2,1-b] thiazole-3 -Ill, 2-
Ethoxycarbonyl-5,6-dihydroimidazo [2,2
1-b] thiazol-3-yl and the like.

Alkyl for R ¹⁴ has 1 to 6 carbon atoms.
And preferably linear or branched alkyl having 1 to 4 carbon atoms (as defined above), with methyl being particularly preferred. Substituted phenyl in R ¹⁴ means R ⁷ , R ⁹ , R ¹⁰
Is the same as the substituted phenyl in the above. The alkyl in R ¹⁵ 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 in R ¹⁵ is an alkyl having 1 to 4 carbon atoms (synonymous with the above) substituted by hydroxy, such as hydroxymethyl and 1
-Hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl and 4-hydroxybutyl are shown, and hydroxymethyl is particularly preferable. The carboxyalkyl in R ¹⁵ has the same meaning as the carboxyalkyl in R ¹³ .

Alkoxycarbonyl for R ¹⁵ is
It is synonymous with the alkoxycarbonyl in R ¹³ . R ¹⁵
The alkoxycarbonylalkyl in R has the same meaning as the alkoxycarbonylalkyl in R ¹³ . He
Specific examples of t in formula (III) include 5-ethoxycarbonyl-4-phenylthiazol-2-yl and 5-ethoxycarbonylmethyl-4-phenylthiazol-2-.
4-phenylthiazol-2-yl, 5-ethoxycarbonyl-4-methylthiazol-2-yl, 5-
Ethoxycarbonylmethylthiazol-2-yl, 5-
Carboxymethyl-4-phenylthiazol-2-yl, 5-methyl-1,3,4-oxadiazole-2-
-Yl, 5-ethoxycarbonyl-4-methyloxazol-2-yl, 5-ethoxycarbonyl-4-methylimidazol-2-yl, 5-carboxy-4-phenylthiazol-2-yl, 5-carboxy-4-methyl Oxazol-2-yl, 5-carboxy-4-methylimidazol-2-yl, 5-hydroxymethyl-4-methyloxazol-2-yl, 5-carboxymethyl-
4- (4-methoxyphenyl) thiazol-2-yl and the like can be mentioned.

The pharmaceutically acceptable salt of the compound of the present invention includes hydrochloride, sulfate, hydrobromide, phosphate, nitrate, methanesulfonate, ethanesulfonate, fumarate and maleic acid. Salt, benzoate, citrate, malate, mandelate, paratoluenesulfonate, benzenesulfonate, acetate, succinate, malonate,
Lactates, salicylates, gallates, picrates, carbonates, ascorbic acid, trifluoroacetates, acid addition salts such as tartrates, sodium salts, potassium salts, lithium salts, magnesium salts, calcium salts and other metals Amine salts (including quaternary ammonium salts) such as salts, ammonium salts, triethylamine salts, pyridine salts, picoline salts, benzylamine salts, and ethanolamine salts, glutamate salts, aspartate salts, arginine salts, lysine salts, ornithine salts, etc. The amino acid salts of Further, the compound of the present invention is a hydrate (monohydrate, hemihydrate, 3/2
Hydrate) and solvates.

When the compound of the present invention has an asymmetric carbon atom,
It exists as a racemate, an optical isomer or a diastereoisomer. When geometric isomers exist, cis isomers,
It exists as a trans form or a mixture thereof, but the present invention includes all of them. The benzoxazine 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.

[0039]

[Chemical 7]

(In the formula, each symbol has the same meaning as described above.) That is, the compound (IV) is halogenated in a suitable solvent, and then the compound (V) is reacted in a suitable solvent. To be done. Examples of the solvent used for halogenating the compound (IV) include methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, dioxane, benzene, pyridine, acetic acid and water, with chloroform being particularly preferable. The reaction temperature varies depending on the type of solvent used, but is usually 0 to 100 ° C., preferably 30 to 50 ° C., and the reaction time varies depending on the reaction temperature and the like, but is usually 1 to 24 hours, preferably 1 to 3 hours.
It's time. Examples of the halogenating agent used for halogenation include halogens such as chlorine and bromine, thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide and the like, preferably chlorine. , Halogen such as bromine, and bromine is particularly preferable. The obtained halide can be used for the next reaction without isolation and purification. As the solvent used for the reaction with the compound (V),
Examples thereof include methanol, ethanol, propanol, isopropyl alcohol, 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 is usually 1 to 24 hours, preferably 4 to 8 hours, depending on the reaction temperature and the like.

When R ¹ is particularly hydrogen, compound (IV) is optionally reacted with acetyl chloride, benzoyl chloride or the like in the presence of a base in a suitable solvent to protect the amino group and then halogen. It can be produced by reacting with compound (V) after deprotection with acid or base. Examples of the solvent used for protecting the amino group include water, methylene chloride, chloroform, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, or a mixture thereof, and a water-chloroform mixed solution is particularly preferable. Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, pyridine and the like, and sodium hydrogencarbonate and potassium carbonate are particularly preferable. The reaction temperature varies depending on the type of solvent used, but it is usually -20 to 50 ° C, preferably -10 to 10 ° C, and the reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 12 hours, preferably 30 minutes to
3 hours.

The solvent used for deprotection is methano
Alcohol, ethanol, propanol, isopropyl alcohol
, Butanol, acetone, dimethylformamide,
Such as dimethyl sulfoxide or a mixture thereof.
In particular, ethanol is preferable. The acid used is
Hydrochloric acid is preferred, and the base is sodium hydroxide, hydroxide
Preferred is sodium hydroxide, such as potassium iodide.
The reaction temperature is usually 0 ° C to the boiling point of the solvent used,
The time varies depending on the reaction temperature, etc., but usually 1 to 24 hours
Period, preferably 2 to 5 hours. Method 2: In the general formula (I), Het is represented by the formula (III)
In the group represented by ¹Is an oxygen atom, A²Is a nitrogen atom
The compound can be synthesized by the following method
It

[0043]

[Chemical 8]

(Where R is^15aRepresents hydrogen or alkyl,
Other symbols are as defined above. ) That is, the compound (VI) is added to an orthos in a suitable solvent.
By reacting with tellurium and then treating with base
Manufactured. Solvent used for reaction with orthoester
For example, methanol, ethanol, propanol,
Sopropyl alcohol, butanol, etc.
Particularly preferred is methanol. With orthoester used
Trimethyl orthoformate, triethyl orthoformate
And tripropyl orthoformate, etc.
Triethyl formate is preferred. As the base used
Is potassium tertiary butoxide, sodium hydride, water
Potassium iodide and the like, especially potassium tertiary but
Xides are preferred. The base treatment is preferably performed in a solvent,
Such solvents include methanol, ethanol and
Propanol, isopropyl alcohol, butanol, etc.
Butanol is particularly preferable. Reaction temperature is normal
It is the boiling point of the solvent used from 0 ℃, the reaction time is the reaction temperature
It depends on the conditions, but usually 1 to 24 hours, preferably 2
~ 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, A²
Is C-R¹⁴(R¹⁴Is as defined above. ) Is a compound
Can be synthesized by the following method.

[0045]

[Chemical 9]

(In the formula, Hal represents halogen such as chlorine, bromine, iodine, etc., A ^1a represents an oxygen atom or NH, and other symbols have the same meanings as described above.) That is, compound (VII) and compound (VIII) Is esterified in the presence of a base in a suitable solvent, and the resulting ester compound is ring-closed with formamide in the presence of an acid catalyst.

Examples of the solvent used for esterification include acetone, methyl ethyl ketone, tetrahydrofuran, diethyl ether, dimethylformamide, dimethylsulfoxide, methylene chloride, chloroform, ethyl acetate 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 and the like, and sodium carbonate and potassium carbonate are particularly preferable. The reaction temperature varies depending on the type of solvent used, but is usually 0 to 100 ° C,
It is preferably 50 to 80 ° C., and 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 in the ring closure reaction include:
Examples thereof include hydrochloric acid, sulfuric acid and phosphoric acid, and sulfuric acid is particularly preferable. The reaction temperature varies depending on the type of solvent used, but is usually 50 to 150 ° C, preferably 100 to 140 ° C,
The reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to
It is 5 hours, preferably 20 minutes to 1 hour.

In this reaction, A^1aIs a mixture of oxygen atoms and NH
Obtained in the presence of an acid catalyst.^1aIs an oxygen atom
Is preferentially produced. 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, A³Is C-R¹⁴
(R¹⁴Is as defined above. ) Is a compound
It can be synthesized by a method.

[0049]

[Chemical 10]

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

[0051]

[Chemical 11]

(In the formula, R ^1a represents R ¹ excluding hydrogen, and Y ¹
Represents a leaving group such as halogen (as defined above), and other symbols have the same meanings as defined above. That is, it is produced by reacting compound (X) with compound (XI) in the presence of a base in a suitable solvent.

Examples of the solvent used in this reaction include methylene chloride, chloroform, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, dimethylsulfoxide and the like, and dimethylformamide is particularly preferable. 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 will differ depending on the type of solvent used, but will usually be -20 to 100.
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.

Hereinafter, methods 6 to 14 show methods for synthesizing intermediate compounds. Method 6: In compound (IV), the compound in which R ¹ is hydrogen is produced by the following route.

[0055]

[Chemical 12]

(Wherein

[0057]

[Chemical 13]

Is dimethyl acetal, 1,3-dioxolane, 1,3-dioxane, 5,5-dimethyl-1,3
-Represents an acetal such as dioxane, X represents a halogen such as chlorine, bromine, iodine, a hydroxyl group, alkyl such as methyl and ethyl, and the other symbols have the same meanings as described above. That is, the compound (IV-a) is obtained by reacting the compound (XII) with the compound (XIII) in the presence of a base in a suitable solvent, and then ring-closing the compound (XII) with a condensing agent or a base, if necessary. Can be produced by reducing the compound with a reducing agent and deprotecting it.

Examples of the solvent used in the reaction with the compound (XIII) include water, acetone, methylene chloride, chloroform, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide or a mixture thereof, and particularly a water-chloroform mixture. preferable. Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, pyridine and the like, and sodium hydrogencarbonate is particularly preferable. The reaction temperature varies depending on the type of solvent used, but it is usually -20 to 50 ° C, preferably -10 to 10 ° C, and the reaction time varies depending on the reaction temperature and the like, but is usually 10 minutes to 12 hours, preferably 30 minutes to 3 hours.

A solvent may be used for the ring-closing reaction, and examples of such a solvent include methylene chloride, chloroform, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, dimethylsulfoxide and the like, and dimethylformamide is particularly preferable. Examples of the condensing agent used as necessary include dicyclohexylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride, carbonyldiimidazole, N-methyl-2-chloropyridinium iodide and the like. To 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 solvent used, but is usually 0 to 120 ° C., preferably 50 to 80 ° C., and the reaction time is 1 to 24 hours, preferably 5 to 12 hours, although varying depending on the reaction temperature and the like. .

A solvent may be used for protecting the ketone. Examples of such a solvent include alcohols such as methanol and ethanol, benzene, toluene, xylene and the like, with toluene being particularly preferred. To protect ketones, ethylene glycol, 1,3-propanediol, 2,2-
Diols such as dimethyl-1,3-propanediol,
Alcohols such as methanol and ethanol are used, and 2,2-dimethyl-1,3-propanediol is particularly preferable. Further, an acid catalyst may be used to accelerate the reaction, and examples of such an acid catalyst include sulfuric acid, paratoluenesulfonic acid, camphorsulfonic acid, phosphorus oxychloride, boron trifluoride diethyl ether complex, oxalic acid and the like. And paratoluenesulfonic acid is particularly preferable. Further, a water separator (Dean-Stark device or the like) or a dehydrating agent (orthoester, molecular sieve or the like) may be used if necessary. 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 8 to 12
It's time.

As the reducing agent used in the reduction reaction, sodium borohydride, lithium aluminum hydride,
Examples thereof include diborane, and diborane is particularly preferable. Examples of the solvent include methanol, ethanol, propanol, isopropyl alcohol, butanol, tetrahydrofuran, diethyl ether, dioxane and the like, and tetrahydrofuran is particularly preferable. Reaction temperature is usually 0 ℃
Is 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 5
It's time.

Deprotection is carried out in an aqueous solution under acidic conditions, if necessary, and as the acid to be used, acetic acid, hydrochloric acid, sulfuric acid,
Oxalic acid and the like, preferably acetic acid, and particularly preferably using acetic acid in an aqueous solution. Reaction temperature is usually 0 to 1
The temperature is 00 ° C, preferably 20 to 60 ° C, and the reaction time is usually 30 minutes to 8 hours, preferably 1 to 3 hours, although it varies depending on the reaction temperature and the like. Method 7: In compound (IV), the compound in which R ¹ is hydrogen can be produced by the following method.

[0064]

[Chemical 14]

(In the formula, X represents halogen such as chlorine, bromine and iodine, Q represents an amino protecting group such as acetyl and benzoyl, and other symbols have the same meanings as described above.) That is, the compound (IV-b ) Is produced by reacting compound (XVII) with compound (XVIII) in the presence of a base in a suitable solvent for ring closure and then deprotection.

Examples of the solvent used in the reaction with the compound (XVIII) include methylene chloride, chloroform, tetrahydrofuran, diethyl ether, dioxane, acetone, 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 and the like, and potassium carbonate is particularly preferable. The reaction temperature varies depending on the type of solvent used, but is usually 0 to 120 ° C., preferably 50 to
The reaction time is 80 ° C., and the reaction time varies depending on the reaction temperature and the like, but is usually 1 to 24 hours, preferably 5 to 12 hours.

Deprotection is carried out using an acid (hydrochloric acid or the like) or an alkali (sodium hydroxide, potassium hydroxide or the like, preferably sodium hydroxide). Further, a solvent may be used, and examples of such a solvent include methanol, ethanol, propanol, isopropyl alcohol, acetone, dimethylformamide, dimethyl sulfoxide, or a mixture thereof, 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 is usually 1 to though it varies depending on the reaction temperature and the like.
24 hours, preferably 2-5 hours. Method 8: In compound (IV), the compound in which R ¹ has a group other than hydrogen can be produced by the following method.

[0068]

[Chemical 15]

(In the formula, each symbol has the same meaning as described above.) That is, it is produced by reacting compound (XX) with compound (XI) in the presence of a base in a suitable solvent. The solvent used in this reaction includes methylene chloride,
Examples thereof include chloroform, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, dimethylsulfoxide, etc., and dimethylformamide is particularly preferable. As the base used, sodium carbonate,
Examples thereof include potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, pyridine, and potassium tertiary butoxide, and sodium hydride and potassium carbonate are particularly preferable. The reaction temperature varies depending on the type of solvent used, but is usually -20 to 100 ° C, preferably 0 to 30 ° C, and 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's time. Method 9: In the compound (IV), the compound in which R ¹ is hydrogen or alkyl can be produced by the following method.

[0070]

[Chemical 16]

(In the formula, R ^1b represents hydrogen, alkyl and the like, and other symbols have the same meanings as described above.) That is, the compound (XXI) is converted into the compound (XXII) in the presence of a catalyst in a suitable solvent. Manufactured by subjecting to the Friedel-Crafts reaction. As the solvent used in this reaction, methylene chloride, chloroform, carbon tetrachloride,
Examples thereof include dichloroethane, carbon disulfide and nitrobenzene, and methylene chloride is particularly preferable. 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 solvent used, but it is usually 0 to 100 ° C., preferably 30 to 60 ° C., and the reaction time varies depending on the reaction temperature and the like, but usually 1 to
24 hours, preferably 2-5 hours. Method 10: In Compound (XXI), the compound in which R ² is alkyl can be produced by the following route.

[0072]

[Chemical 17]

(Wherein, T ¹ and T ² are each hydrogen or an oxygen atom together, R ^2a is an alkyl having 1 to 5 carbon atoms (as defined above), and R ^2b is 1 to 6 carbon atoms). Alkyl (synonymous with the above) and other symbols have the same meanings as described above. That is, the compound (XXI-a) is the same as the compound (XXII).
I) in the presence of a catalyst in a suitable solvent to give compound (XXI
V) is subjected to Friedel-Crafts reaction to give compound (XXV), which is further reduced.

Examples of the solvent used in the reaction with the compound (XXIV) include methylene chloride, chloroform, carbon tetrachloride, dichloroethane, carbon disulfide, nitrobenzene and the like, and methylene chloride is particularly preferable. 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 solvent used, but it is usually 0 to 100 ° C., preferably 30 to 60 ° C., and the reaction time varies depending on the reaction temperature and the like, but usually 1 to
24 hours, preferably 2-5 hours.

As the reducing agent used in the reduction reaction, sodium borohydride, lithium aluminum hydride,
Examples thereof include diborane, and lithium aluminum hydride is particularly preferable. The reduction reaction is carried out in a solvent, and examples of such a solvent include methanol, ethanol, propanol, isopropyl alcohol, butanol, tetrahydrofuran, diethyl ether, dioxane and the like, and tetrahydrofuran is particularly preferable. The reaction temperature is usually from 0 ° C. to the boiling point of the solvent used, and the reaction time is usually 1 to 24 hours, preferably 1 to 5 hours, depending on the reaction temperature and the like. Method 11: In compound (IV), the compound in which R ² is hydrogen is produced by catalytically reducing the compound in which R ² is halogen in a suitable solvent under hydrogen atmosphere in the presence of alkali. It

Examples of the solvent used include methanol, ethanol, isopropyl alcohol, water, ethyl acetate and the like, with ethanol being particularly preferable. Examples of the alkali used include sodium hydroxide and potassium hydroxide, and sodium hydroxide is particularly preferable. 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 12: In the compound (IV), a compound in which R ¹⁴ is particularly carboxymethyl or alkoxycarbonylmethyl can be produced by the following method.

[0077]

[Chemical 18]

(In the formula, R ^b and R ^c each represent alkyl such as methyl and ethyl, and other symbols are as defined above.) That is, the compound (IV-g) is the compound (IV-e).
In a suitable solvent with formaldehyde and a secondary amine (Mannich reaction) to give compound (XXVI),
This is reacted with an alkylating agent in a suitable solvent to give compound (XXVII). Then, the compound (XXVIII) is reacted with a cyanating agent in a suitable solvent, hydrolyzed, and esterified in a suitable solvent.

As the solvent used in the Mannich reaction, 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, with dimethylamine being particularly preferred. The reaction temperature varies depending on the type of solvent used, but is usually 0 to 100 ° C., preferably 50 to 80 ° C., and the reaction time is usually 1 to 24 hours, preferably 2 to 5 hours, although varying depending on the reaction temperature and the like. .

Examples of the solvent used in the reaction of the compound (XXVI) with the alkylating agent include methylene chloride, chloroform, diethyl ether, tetrahydrofuran, dioxane, acetone, dimethylformamide, dimethyl sulfoxide and the like, with acetone being particularly preferable. The alkylating agent used is an alkyl halide such as methyl iodide, ethyl iodide, methyl bromide and ethyl bromide, and methyl iodide is particularly preferable. The reaction temperature varies depending on the type of solvent used, but is usually -20 to 50.
The reaction time is usually 1 to 24 hours, preferably 30 minutes to 3 hours, although the reaction time varies depending on the reaction temperature and the like.

Examples of the solvent used for the reaction with the cyanating agent include methanol, ethanol, propanol, isopropyl alcohol, ethyl acetate, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, nitromethane, N-methylpyrrolidone and the like. However, methanol is particularly preferable. Examples of the cyanating agent used include sodium cyanide and potassium cyanide, with potassium cyanide being particularly preferred. The reaction temperature varies depending on the type of solvent used, but is usually 0 to 100 ° C., preferably 30 to 50 ° C., and the reaction time varies depending on the reaction temperature and the like, but is usually 1 to 48 hours,
It is preferably 2 to 5 hours.

A solvent may be used for the hydrolysis, and examples of such a solvent include water, methanol, ethanol, propanol, isopropyl alcohol, ethylene glycol, acetic acid and formic acid, and acetic acid is particularly preferable.
Mineral acids such as hydrochloric acid and sulfuric acid, sodium hydroxide, potassium hydroxide and the like are used for the hydrolysis, and hydrochloric acid is particularly preferable. The reaction temperature is usually 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
The time is preferably 1 to 3 hours.

The esterification of compound (IV-f) 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, a methylation method with diazomethane and the like. Preferably, it is a method of reacting with an alkylating agent in the presence of a base. As the alkylating agent used in this reaction, methyl iodide,
Alkyl halides such as ethyl iodide, propyl iodide, methyl bromide, ethyl bromide and propyl bromide, and particularly methyl iodide and ethyl iodide are preferred. 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 in the reaction with the alkylating agent, and examples of such a solvent include methylene chloride, chloroform, diethyl ether, tetrahydrofuran, dioxane, acetone, dimethylformamide, dimethylsulfoxide, and the like, with dimethylformamide being particularly preferred. . The reaction temperature varies depending on the type of solvent used, but is usually 0 to 100 ° C., preferably 40 to 60 ° C., and the reaction time is usually 1 to 24 hours, preferably 1 to 3 hours, although varying depending on the reaction temperature and the like. . Method 13: Compound (VI) can be produced by the following method.

[0084]

[Chemical 19]

(In the formula, R ^d represents alkyl such as methyl and ethyl, and other symbols have the same meanings as described above.) That is, the compound (VI) is obtained by converting the compound (XXIX) into hydrazine in a suitable solvent. It is produced by reacting.

Examples of the solvent used in this reaction include methanol, ethanol, propanol, isopropyl alcohol, diethyl ether, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide and the like, with ethanol being particularly preferable. The reaction temperature varies depending on the type of solvent used, but is usually 0 to 100 ° C,
It is preferably the boiling point of the solvent used, and the reaction time is usually 1 to 48 hours, preferably 20 to 24 hours, varying depending on the reaction temperature and the like. The compound used (XX
IX) is produced according to the method described in JP-A-2-28182. Method 14: Compound (IX) can be produced by the following method.

[0087]

[Chemical 20]

(In the formula, each symbol has the same meaning as described above.) That is, the compound (IX) is prepared by reacting the compound (VII) in a suitable solvent, if necessary, with a reactive derivative of carboxy, and then reacting with an amine. It is produced by treating (XXX) with a sulfurizing agent.

The solvent used in the amidation reaction is
Examples thereof include methylene chloride, chloroform, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, ethyl acetate, acetonitrile and the like, and tetrahydrofuran is particularly preferable. The reactive derivative of carboxy is synthesized by reacting a halogenating agent or chloroformates in the presence of a base or using a condensing agent.
Examples of the base used 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 the chloroformates to be used include methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate and isobutyl chloroformate, with isobutyl chloroformate being particularly preferred. The condensing agent used is dicyclohexylcarbodiimide, 1-
Ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride, carbonyldiimidazole, N-methyl-2-chloropyridinium iodide and the like can be mentioned. Examples of the amine used include ammonia water, ammonium carbonate, ammonium hydrogen carbonate, urea and the like, and ammonia water is particularly preferable. The reaction temperature varies depending on the type of solvent used, but it is usually 0 to 100 ° C., preferably room temperature, and the reaction time varies depending on the reaction temperature and the like, but is usually 1 to 24 hours, preferably 5 to 10 hours.

Sulfurizing agents used in the sulfurization reaction include tetraphosphorus heptasulfide, diphosphorus pentasulfide, and 2,4-bis (4-
Methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson)
Reagent) and the like, and diphosphorus pentasulfide is particularly preferable.
A solvent may be used in this reaction, and examples of such a solvent include methylene chloride, chloroform, diethyl ether,
Tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, ethyl acetate and the like can be mentioned, with chloroform being particularly preferable. The reaction temperature is usually from 0 ° C. to the boiling point of the solvent used, and the reaction time is usually 1 to 24 hours, preferably 2 to 6 hours, although varying depending on the reaction temperature and the like.

In the compound 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 can be produced by treating the corresponding alkoxy with boron tribromide by a conventional method or by hydrolyzing the corresponding acyloxy by a conventional method. The compound having an alkoxy as a substituent can be obtained by treating the corresponding hydroxyl group with an alkyl halide (methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl iodide, etc.) by a conventional method, or a metal alkoxide ( It is produced by transesterification with sodium methoxide, sodium ethoxide, etc.). The compound having hydroxymethyl as a substituent is produced by using the corresponding carboxy as a reactive derivative thereof as necessary 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 general formula (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization or chromatography. When an asymmetric carbon is present in the compound of the general formula (I) of the present invention and a pharmaceutically acceptable salt thereof, it is usually produced as a racemate, but these are optically isolated by a conventional method such as fractional recrystallization or chromatography. It can be resolved into isomers. Further, an optical isomer can be produced using an optically active raw material compound. Furthermore, the compound having two asymmetric carbons is obtained as an individual diastereoisomer or a mixture thereof, and the individual diastereoisomers can be separated by a conventional method such as fractional recrystallization or chromatography. When the compound of the present invention has geometrical isomers, cis-trans isomers exist, and these can be produced by using a cis- or trans-form starting compound. When it is obtained as a mixture thereof, it can be separated into a cis form and a trans form by treatment by a conventional method such as fractional recrystallization or chromatography.

[0093]

The compounds of the present invention and salts thereof have PLA ₂ inhibitory activity, as shown in the following test.
IL-1 production inhibitory effect and carrageenin foot edema inhibitory effect, allergic diseases such as atopic disease, various inflammatory diseases including bronchial asthma, arthritis, pancreatitis, ischemic vascular disorder, treatment and prevention of 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 a PLA ₂ source, a partially purified product of rat inflammatory PLA ₂ (type II) was used. A solution prepared by adjusting the concentration of calcium chloride and Tris-hydrochloric acid buffer (pH 7.5) to 4 mM and 100 mM, respectively, was added to the above enzyme solution (0.0
2 ml) and a test solution prepared in advance (final concentration 0.5
0.02 ml), consisting of mM and 0.1 mM),
The total volume was 240 μl and preincubated at 37 ° C. for 1 hour.

Next, 0.85 nmol (0.
Added 0.01ml of 1-acyl-2- [1- ¹⁴ C] arachidonyl -L-3- phosphatidylethanolamine (phosphatidylethanolamine containing Amersham) (final concentration 0.1mM) 045μCi), at 37 ° C. Incubated for 20 minutes. 2 ml doll (Dol
es) reagent was added to stop the reaction, and n-heptane (1 ml) and water (1.
5 ml) was added and the mixture was stirred for 30 seconds with a vortex mixer. After centrifugation at 2000 rpm for 10 minutes, 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,
It was centrifuged at room temperature at 2000 rpm for 10 minutes. The supernatant (1 ml) was placed 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 conducted with 2 vials per group.

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

[0097]

[Equation 1]

Compound 1 of the present invention measured by the above test example
The PLA ₂ inhibition rate at 0 μM is shown in Table 1. Table 1 ──────────────────────────────────── Example No. PLA ₂ inhibition rate (%) Example 6 37 Example 11 37 Example 13 68 ───────────────────────────────── ───── When the compound of the present invention or a pharmaceutically acceptable salt thereof is used as a medicine, it is usually used as it is or a pharmaceutically acceptable carrier, excipient, filler, diluent or other additive. Using, tablets, buccal, pills, capsules, powders, fine granules, granules, solutions, oral solutions (including syrups), injections, inhalants, suppositories, transdermal solutions, ointments, A pharmaceutical composition such as a transdermal patch, a transmucosal patch (for example, an oral patch), and a transmucosal solution (for example, a nasal solution) can be safely orally administered to a patient orally or parenterally. Pharmaceutically acceptable carriers, excipients, fillers, diluents and other additives include solid or liquid non-toxic pharmaceutical substances. Examples of these include 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 compound selected, the disease, symptoms, body weight, age, sex of the patient, administration method, etc., but is usually orally 1 to 2000 mg per adult per day, preferably 10 to 300 mg, This is administered once a day or divided into 2 to 4 times a day.

[0099]

The present invention will be described below with reference to Reference Examples and Examples.
Specifically, the present invention is not limited to these.
It is not something that can be done. Reference Example 1 6-Acetyl-2-amino-4-chlorophenol 34
g of chloroform 500 ml, potassium carbonate 47 g, water
Add to 100 ml and add 22 m of acetyl chloride under stirring at 0 ° C.
1 was added dropwise. After extraction with chloroform, magnesium sulfate
6-acetyl-2-acetyl
24 g of amino-4-chlorophenol was obtained. Melting point 10
2 to 105 ° C. Reference Example 2 6-Acetyl-2-acetylamino-4-chloropheno
24 g of dimethylformamide was added to 500 ml of dimethylformamide,
Add 29 g of potassium carbonate and add 18 ml of dibromoethane.
The mixture was added dropwise at the same temperature and stirred at 70 ° C for 8 hours. Reduce the reaction pressure
It was concentrated and the resulting residue was extracted with ethyl acetate. Carbonic acid
After washing with an aqueous solution of lithium, drying with magnesium sulfate,
By concentrating under pressure, 6-chloro-4,8-diaceti
Le-3,4-dihydro-2H-1,4-benzoxadi
24g was obtained. Melting point 68-71 ° C Reference Example 3 4,8-Diacetyl-6-chloro-3,4-dihydro-
2H-1,4-benzoxazine 60 g ethanol 2
Add 00 ml, 600 ml of 1N sodium hydroxide and add 2
Heated to reflux for hours. Add ice and collect the precipitated crystals by filtration.
As a result, 8-acetyl-6-chloro-3,4-dihi
40 g of Doro-2H-1,4-benzoxazine was obtained.
¹ H-NMR (CDCl ₃ , ppm) δ: 2.54 (3H, s), 3.42 (2H, t), 4.28 (2
H, t), 7.6.62 (1H, d), 6.99 (1H, d) Reference Example 4 8-Acetyl-6-chloro-3,4-dihydro-2H-
1,4-benzoxazine 2.1 g chloroform 40
In addition to ml, 2.8 g of potassium carbonate was added. Ben chloride
2.0 g of zoyl was added dropwise, and the mixture was stirred at room temperature for 8 hours. reaction
Aqueous potassium carbonate solution was added to the solution and extracted with chloroform.
It was After drying over magnesium sulfate, concentration under reduced pressure
8-acetyl-4-benzoyl-6-chloro-3,
4-dihydro-2H-1,4-benzoxazine 2.3
g was obtained. Melting point 145 ° C. Reference example 5 50 ml of dimethylformamide was hydrogenated under stirring at 0 ° C.
Sodium 0.69 g, 6-chloro-8- (5,6-di
Hydroimidazo [2,1-b] thiazol-3-yl)
-3,4-dihydro-2H-1,4-benzoxazine
2.1 g was added, and the mixture was stirred at 60 ° C. for 30 minutes. Stir at 0 ° C
Bottom, 3-acetoxy-4-methoxycinnamoyl chloride
5.5 g was added. After stirring at room temperature for 2 hours, depressurize the reaction solution.
After concentration, the obtained residue was extracted with chloroform. Sulfuric acid
After drying over magnesium, concentration under reduced pressure gives 4-
(3-acetoxy-4-methoxycinnamoyl) -6-
Chloro-8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -3,4-dihydro-2H
-1,4-benzoxazine was obtained as an oil. this
The oily substance was used in the next reaction without purification. Reference Example 6 6-chloro-8- (5,6-dihydroimidazo [2,1
-B] thiazol-3-yl) -3,4-dihydro-2
Starting from 2.0 g of H-1,4-benzoxazine
4-acetoxy-3-methoxycinnamoyl chloride
The same procedure as in Reference Example 5 was performed using 5.1 g of 4- (4-acetoxy).
Ci-3-methoxycinnamoyl) -6-chloro-8-
(5,6-dihydroimidazo [2,1-b] thiazole
-3-yl) -3,4-dihydro-2H-1,4-ben
Zoxazine was obtained as an oil. This oil is purified
Used in the next reaction without any reaction. Reference Example 7 6-chloro-8- (5,6-dihydroimidazo [2,1
-B] thiazol-3-yl) -3,4-dihydro-2
Starting from 2.0 g of H-1,4-benzoxazine
4-acetoxy-3,5-dimethoxycinnamo chloride
And 5.1 g of 4- (4-acetate).
Toxy-3,5-dimethoxycinnamoyl) -6-chloro
Ro-8- (5,6-dihydroimidazo [2,1-b] thio
Azol-3-yl) -3,4-dihydro-2H-1,
4-benzoxazine was obtained as an oil. This oil
Was used in the next reaction without purification. Reference Example 8 6-Chloro-4-methyl-3,4-dihydro-2H-
To 68 g of 1,4-benzoxazine-8-carboxylic acid was added
600 ml of trahydrofuran, 40 g of triethylamine
Was added and cooled to -15 ° C, and isobutyl chloroformate 41 was added.
g, and add 200 ml of 23% aqueous ammonia,
Stir at warm for 8 hours. After concentrating the reaction mixture under reduced pressure,
Aqueous triumnium solution was added and the mixture was extracted with ethyl acetate. Sulfuric acid mug
After drying with Nesium, it was concentrated under reduced pressure to give 6-chloro
Rho-4-methyl-3,4-dihydro-2H-1,4-be
23 g of benzoxazine-8-carboxamide was obtained.
Melting point 218-222 ° C Reference Example 9 6-chloro-4-methyl-3,4-dihydro-2H-
1,4-benzoxazine-8-carboxamide 23
To 500 g, add 500 ml of chloroform and 11 g of phosphorus pentasulfide.
Then, the mixture was stirred under reflux for 4 hours. Pour the reaction mixture into ice water and
Extracted with Loform. After drying over magnesium sulfate, decompression
By concentrating, 6-chloro-4-methyl-3,4
-Dihydro-2H-1,4-benzoxazine-8-ca
12 g of rubothioamide was obtained. Melting point 179 [deg.] C. (decomposition) Example 1 6-chloro-4,8-diacetyl-3,4-dihydro-
1.5 g of 2H-1,4-benzoxazine
Bromine 0.94g under stirring at 40 ℃.
Defeated After the reaction solution was concentrated under reduced pressure, the residue obtained was diluted with ethanol.
Add 50 ml of knoll and 0.45 g of thiourea and return for 8 hours
Stirred under flow. After cooling, the crystals were collected by filtration to give 4-
Acetyl-8- (2-aminothiazol-4-yl)-
6-chloro-3,4-dihydro-2H-1,4-benzo
1.0 g of oxazine hydrobromide was obtained. Melting point 233-
235 ° C Example 2 6-Chloro-4,8-diacetyl-3,4-dihydro-
1.5 g of 2H-1,4-benzoxazine as a starting material
And carried out with 0.70 g of 1-amidinothiourea
The same procedure as in Example 1 was carried out, but 4-acetyl-6-chloro-8-
(2-guanidinothiazol-4-yl) -3,4-di
Hydro-2H-1,4-benzoxazine hydrobromide
1.0 g was obtained. Melting point 200-205 [deg.] C. Example 3 6-chloro-4,8-diacetyl-3,4-dihydro-
1.5 g of 2H-1,4-benzoxazine as a starting material
Then, with Example 1 using 0.6 g of ethylenethiourea.
The same procedure was followed to obtain 4-acetyl-6-chloro-8- (5,6
-Dihydroimidazo [2,1-b] thiazol-3-i
) -3,4-Dihydro-2H-1,4-benzooxa
1.2 g of gin hydrobromide was obtained. Melting point 223 ° C (min
Solution) Example 4 6-chloro-4,8-diacetyl-3,4-dihydro-
Chloroform in 30 g of 2H-1,4-benzoxazine
Add 300 ml and add 19 g of bromine dropwise at 40 ° C. with stirring.
It was The reaction mixture was concentrated under reduced pressure, and the resulting residue was treated with ethanol.
60 ml of 1N hydrochloric acid and 300 ml of 1N hydrochloric acid added
Shed After cooling with ice water, use 2N sodium hydroxide to
(PH 9-10). The precipitated crystals are collected by filtration
After drying, 450 ml of ethanol and ethylenethioure
16g was added and the mixture was stirred under reflux for 8 hours. After cooling, the crystals are filtered.
After taking out and neutralizing with potassium carbonate aqueous solution, chloroform
It was extracted with. After drying over magnesium sulfate, concentrate under reduced pressure
Thereby, 6-chloro-8- (5,6-dihydroimid
Dazo [2,1-b] thiazol-3-yl) -3,4-
Dihydro-2H-1,4-benzoxazine hydrobromic acid
53 g of salt was obtained. Melting point 250 ° C. (decomposition) Example 5 8-Acetyl-4-benzoyl-6-chloro-3,4-
1.6 g of dihydro-2H-1,4-benzoxazine
As the starting material, 0.51 g of ethylene thiourea was used
And 4-benzoyl-6-chloro as described in Example 1.
-8- (5,6-dihydroimidazo [2,1-b] thia
Zol-3-yl) -3,4-dihydro-2H-1,4
-1.3 g of benzoxazine hydrobromide were obtained. Melting point
235-237 ° C Example 6 Hydrogenation of 50 ml of dimethylformamide under stirring at 0 ° C.
Sodium 0.33 g, 6-chloro-8- (5,6-di
Hydroimidazo [2,1-b] thiazol-3-yl)
-3,4-dihydro-2H-1,4-benzoxazine
1 g was added, and the mixture was stirred at 60 ° C. for 30 minutes. With stirring at 0 ° C,
0.62 g of cinnamoyl chloride was added. Stir at room temperature for 2 hours
After stirring, the reaction solution was concentrated under reduced pressure, and the resulting residue was chloro
Extracted with form. After drying over magnesium sulfate, concentrate under reduced pressure.
Contracted. Silica gel column chromatography (chloro
Purified with form: methanol = 20: 1), 20% salt
By treating with acid-ethanol, 6-chloro-4
-Cinnamoyl-8- (5,6-dihydroimidazo
[2,1-b] thiazol-3-yl) -3,4-dihi
Doro-2H-1,4-benzoxazine hydrochloride 0.54
g was obtained. Mp 175-177 ° C Example 7 6-chloro-8- (5,6-dihydroimidazo [2,1
-B] thiazol-3-yl) -3,4-dihydro-2
Starting from 1.0 g of H-1,4-benzoxazine
2.3 g of 4-methylsulfonylcinnamoyl chloride
Using 6-chloro-8- (5,
6-dihydroimidazo [2,1-b] thiazole-3-
Yl) -4- (4-methylsulfonylcinnamoyl)-
3,4-dihydro-2H-1,4-benzoxazine salt
0.11 g of the acid salt was obtained. Melting point 210-213 [deg.] C. Example 8 6-chloro-8- (5,6-dihydroimidazo [2,1
-B] thiazol-3-yl) -3,4-dihydro-2
Starting from 0.7 g of H-1,4-benzoxazine
Use 1.2 g of 3,4-dimethoxycinnamoyl chloride
And 6-chloro-8- (5,6
-Dihydroimidazo [2,1-b] thiazol-3-i
) -4- (3,4-dimethoxycinnamoyl) -3,
4-dihydro-2H-1,4-benzoxazine hydrochloride
1.0 g was obtained. Melting point 163-165 ° C (decomposition) Example 9 6-chloro-8- (5,6-dihydroimidazo [2,1
-B] thiazol-3-yl) -3,4-dihydro-2
Starting from 2 g of H-1,4-benzoxazine,
Example using 4.0 g of 3-methoxycinnamoyl chloride
6-chloro-8- (5,6-dihydro
Imidazo [2,1-b] thiazol-3-yl) -4-
(3-Methoxycinnamoyl) -3,4-dihydro-2
1.3 g of H-1,4-benzoxazine hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ , ppm) δ: 3.78 (3H, s), 3.96-4.48 (8H, m),
6.82-7.96 (9H, m) Example 10 6-chloro-8- (5,6-dihydroimidazo [2,1]
-B] thiazol-3-yl) -3,4-dihydro-2
Starting from 1.5 g of H-1,4-benzoxazine
Then, using 3.9 g of 4-methoxycinnamoyl chloride,
The same procedure as in Example 6 was carried out to give 6-chloro-8- (5,6-dihydroxy).
Droimidazo [2,1-b] thiazol-3-yl)-
4- (4-methoxycinnamoyl) -3,4-dihydro
-2H-1,4-benzoxazine hydrochloride 0.62 g
Obtained. Melting point 249-253 ° C (decomposition) Example 11 6-chloro-8- (5,6-dihydroimidazo [2,1
-B] thiazol-3-yl) -3,4-dihydro-2
Starting from 2 g of H-1,4-benzoxazine,
3- (3,4-dimethoxyphenyl) propionyl chloride
The same procedure as in Example 6 was carried out using 4.7 g of 6-chloro-
8- (5,6-dihydroimidazo [2,1-b] thiazo
Ol-3-yl) -4- (3- (3,4-dimethoxyphen)
Phenyl) propionyl) -3,4-dihydro-2H-
2.0 g of 1,4-benzoxazine hydrochloride was obtained. Melting point
195-198 ° C Example 12 4- (3-acetoxy-4-methoxycinnamoyl)-
6-chloro-8- (5,6-dihydroimidazo [2,1
-B] thiazol-3-yl) -3,4-dihydro-2
H-1,4-benzoxazine (3.4 g) was added to methanol (5).
Add 0 ml and add 28% sodium methoxide under stirring at 0 ° C.
1.3 g of side was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Reaction liquid
Is poured into ice water, extracted with chloroform, and magnesium sulfate is extracted.
After drying with um, it was concentrated under reduced pressure. Silica gel column chroma
Tography (chloroform: methanol = 20: 1)
6-chloro-8- (5,6-
Dihydroimidazo [2,1-b] thiazol-3-i
) -4- (3-Hydroxy-4-methoxycinnamoy)
) -3,4-Dihydro-2H-1,4-benzooxa
0.27 g of gin was obtained. Melting point 227 to 229 ° C. or less, and the following compound was produced in the same manner as in Example 12.
It (13) 6-chloro-8- (5,6-dihydroimidazole
Zo [2,1-b] thiazol-3-yl) -4- (4-
Hydroxy-3-methoxycinnamoyl) -3,4-di
Hydro-2H-1,4-benzoxazine, melting point 232
~ 235 ° C (14) 6-chloro-8- (5,6-dihydroimidazole
Zo [2,1-b] thiazol-3-yl) -4- (4-
Hydroxy-3,5-dimethoxycinnamoyl) -3,
4-dihydro-2H-1,4-benzoxazine, melting point
145-148 ° C Example 15 6-chloro-8- (5,6-dihydroimidazo [2,1
-B] thiazol-3-yl) -4- (3,4-dimeth)
Xycinnamoyl) -3,4-dihydro-2H-1,4
-Benzoxazine hydrochloride 1g dichloroethane 20m
In addition to 1, 2.9 g of boron tribromide was added dropwise with stirring at 0 ° C.
And stirred at room temperature for 2 hours. Add ice to the reaction mixture and add 1N water.
Weakly alkaline (pH 7-8) with sodium oxide, and deposit
The crystals thus taken out were collected by filtration to give 6-chloro-8-
(5,6-dihydroimidazo [2,1-b] thiazole
-3-yl) -4- (3,4-dihydroxycinnamoy
) -3,4-Dihydro-2H-1,4-benzooxa
0.71 g of gin hydrobromide was obtained. Melting point 265 ° C (min
Solution) Hereinafter, the following compound was produced in the same manner as in Example 15.
It (16) 6-chloro-8- (5,6-dihydroimidazole
Zo [2,1-b] thiazol-3-yl) -4- (3-
Hydroxycycinnamoyl) -3,4-dihydro-2H
-1,4-benzoxazine hydrobromide, melting point 257
C (decomposition) (17) 6-chloro-8- (5,6-dihydroimidazole
Zo [2,1-b] thiazol-3-yl) -4- (4-
Hydroxycinnamoyl) -3,4-dihydro-2H-
1,4-benzoxazine hydrochloride, ¹ H-NMR (DMSO-d ₆ , pp
m) δ: 3.96-4.50 (8H, m), 6.72-7.96 (9H, m), 10.08 (1H, br) (18) 6-chloro-8- (5,6-dihydroimidazole
Zo [2,1-b] thiazol-3-yl) -4- (3-
(3,4-dihydroxyphenyl) propionyl)-
3,4-dihydro-2H-1,4-benzoxazine odor
Hydrohydrate, ¹ H-NMR (DMSO-d ₆ , ppm) δ: 2.58-2.90 (4H,
m), 3.98 (2H, t), 4,28 (6H, m), 6.35-7.22 (6H, m), 8.60 (2H, b
r) Example 19 6-Chloro-4-methyl-3,4-dihydro-2H-
1,4-benzoxazine-8-carbothioamide 2.
4g ethanol 50ml, 2-bromo-3-phenyl
Ethyl-3-oxopropionate (2.7 g) was added for 4 hours.
The mixture was stirred under reflux. The reaction mixture was concentrated under reduced pressure to give a residue.
Add 0.5M sodium hydrogen carbonate and extract with ethyl acetate
And concentrated under reduced pressure. Silica gel column chromatography
-(Chloroform: methanol = 20: 1)
Thereby, 2- (6-chloro-4-methyl-3,4-
Dihydro-2H-1,4-benzoxazin-8-i
Ethyl) -4-phenylthiazole-5-carboxylate
0.61 g was obtained. Melting point 210-211 [deg.] C. Example 20 6-Chloro-4-methyl-3,4-dihydro-2H-
1,4-benzoxazine-8-carbothioamide 2.
Starting from 4 g, 3-bromo-4-phenyl-4
-As in Example 19 but using 2.9 g of ethyl oxobutyrate.
And 2- (6-chloro-4-methyl-3,4-dihi).
Doro-2H-1,4-benzoxazin-8-yl)-
1.7 g of ethyl 4-phenylthiazole-5-acetate was obtained.
It was Melting point 118-120 ° C Example 21 6-Chloro-4-methyl-3,4-dihydro-2H-
1,4-benzoxazine-8-carbothioamide 2.
Starting from 5 g, 2-bromoacetophenone 2.
The procedure of Example 19 was repeated using 0 g of 6-chloro-4.
-Methyl-8- (4-phenylthiazol-2-yl)
-3,4-dihydro-2H-1,4-benzoxazine
0.25 g was obtained. Melting point 200 [deg.] C. Example 22 6-Chloro-4-methyl-3,4-dihydro-2H-
1,4-benzoxazine-8-carbothioamide 2.
Starting from 4 g of 2-chloro-3-oxobutyric acid
As in Example 19, using 1.6 g of chill,
(6-chloro-4-methyl-3,4-dihydro-2H-
1,4-benzoxazin-8-yl) -4-methylthio
1.4 g of ethyl azole-5-carboxylate was obtained. Melting point
165-166 ° C Example 23 6-chloro-4-methyl-3,4-dihydro-2H-
1,4-benzoxazine-8-carbothioamide 2.
Starting from 4 g, 4-chloro-3-oxobutyric acid
As in Example 19, using 1.6 g of chill,
(6-chloro-4-methyl-3,4-dihydro-2H-
1,4-benzoxazin-8-yl) thiazol-5
-0.8 g of ethyl acetate was obtained. Melting point 71-72 ° C Example 24 2- (6-chloro-4-methyl-3,4-dihydro-2
H-1,4-benzoxazin-8-yl) -4-phen
Nylthiazole-5-ethyl acetate (1.1 g) with ethanol
50 ml, 2 ml of 2N sodium hydroxide was added, and 1 hour
The mixture was stirred under reflux. The reaction mixture was concentrated under reduced pressure and the resulting residue was added to 4
Acidified with N hydrochloric acid. After extracting with chloroform, depressurize
By concentrating, 2- (6-chloro-4-methyl-
3,4-dihydro-2H-1,4-benzoxazine-
8-yl) -4-phenylthiazol-5-acetic acid 0.5
6 g was obtained. Melting point 238 ° C. (decomposition) Hereinafter, the following compounds are produced in the same manner. (25) 8- (2-aminothiazol-4-yl)-
6-chloro-4-methyl-3,4-dihydro-2H-
1,4-benzoxazine (26) 8- (2-aminothiazol-4-yl)-
6-chloro-2,2,4-trimethyl-3,4-dihydride
B-2H-1,4-benzoxazine (27) 8- (2-aminothiazol-4-yl)-
6-chloro-2-ethyl-4-methyl-3,4-dihydride
B-2H-1,4-benzoxazine (28) 8- (2-aminothiazol-4-yl)-
6-chloro-4-methyl-2-propyl-3,4-dihi
Doro-2H-1,4-benzoxazine (29) 8- (2-aminothiazol-4-yl)-
6-methoxy-4-methyl-3,4-dihydro-2H-
1,4-benzoxazine (30) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -6-hydroxy-4-me
Cyl-3,4-dihydro-2H-1,4-benzoxa
Gin (31) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -4-methyl-6-pheno
Xymethoxy-3,4-dihydro-2H-1,4-ben
Zoxazine (32) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -6-hexyloxy-4
-Methyl-3,4-dihydro-2H-1,4-benzoo
Xazine (33) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -6-isopropoxy-4
-Methyl-3,4-dihydro-2H-1,4-benzoo
Xazine (34) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -6- (N-acetyl-N
-Hexyl) amino-4-methyl-3,4-dihydro-
2H-1,4-benzoxazine (35) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -6- (N-acetyl-N
-Phenoxymethyl) amino-4-methyl-3,4-di
Hydro-2H-1,4-benzoxazine (36) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -6-hexyl-4-methyi
Le-3,4-dihydro-2H-1,4-benzoxadi
(37) 4-Acetyl-8- (2-aminothiazole
-4-yl) -6-chloro-2,2-dimethyl-3,4
-Dihydro-2H-1,4-benzoxazine (38) 4-acetyl-6-chloro-2,2-dimethyl
Lu-8- (2-guanidinothiazol-4-yl)-
3,4-Dihydro-2H-1,4-benzoxazine (39) 4-Acetyl-6-chloro-8- (5,6-
Dihydroimidazo [2,1-b] thiazol-3-i
) -2,2-Dimethyl-3,4-dihydro-2H-
1,4-benzoxazine (40) 6-chloro-4-methyl-8- (2-methyl
Thiazol-4-yl) -3,4-dihydro-2H-
1,4-benzoxazine (41) 6-chloro-8- (2-hydrazinothiazo
Lu-4-yl) -4-methyl-3,4-dihydro-2H
-1,4-benzoxazine (42) 6-chloro-4-methyl-8- (3-methyl
-2-Methylimino-4-thiazolin-4-yl)-
3,4-Dihydro-2H-1,4-benzoxazine (43) 6-chloro-4-methyl-8- (3-phenyl
Lu-2-phenylimino-4-thiazolin-4-yl)
-3,4-Dihydro-2H-1,4-benzoxazine (44) 6-chloro-4-methyl-8- (2-benzo
Ilaminothiazol-4-yl) -3,4-dihydro
-2H-1,4-benzoxazine (45) 6-chloro-8- (2- (2-diethylamido)
Noethyl) aminothiazol-4-yl) -4-methyl
-3,4-Dihydro-2H-1,4-benzoxazine (46) 6-chloro-4-methyl-8- (2- (1-
Methyl-4-piperidyl) aminothiazol-4-i
) -3,4-Dihydro-2H-1,4-benzooxa
Gin (47) 4-acetyl-6-chloro-8- (2-methyl
Luthiazol-4-yl) -3,4-dihydro-2H-
1,4-benzoxazine (48) 4-acetyl-6-chloro-8- (2-hydr
Lazinothiazol-4-yl) -3,4-dihydro-2
H-1,4-benzoxazine (49) 4-acetyl-6-chloro-8- (3-methyl
Lu-2-methylimino-4-thiazolin-4-yl)-
3,4-dihydro-2H-1,4-benzoxazine (50) 4-acetyl-6-chloro-8- (3-phen
Nyl-2-phenylimino-4-thiazolin-4-i
) -3,4-Dihydro-2H-1,4-benzooxa
Gin (51) 4-acetyl-6-chloro-8- (2-ben
Zoylaminothiazol-4-yl) -3,4-dihydr
B-2H-1,4-benzoxazine (52) 4-acetyl-6-chloro-8- (2- (2
-Diethylaminoethyl) aminothiazol-4-i
) -3,4-Dihydro-2H-1,4-benzooxa
Gin (53) 4-acetyl-6-chloro-8- (2- (1
-Methyl-4-piperidyl) aminothiazol-4-i
) -3,4-Dihydro-2H-1,4-benzooxa
Gin (54) 6-chloro-8- (5,6-dihydroimidazole
Zo [2,1-b] thiazol-3-yl) -4-hexyl
Le-3,4-dihydro-2H-1,4-benzoxadi
(55) 6-chloro-8- (5,6-dihydroimidazole
Zo [2,1-b] thiazol-3-yl) -4-hepta
Noyl-3,4-dihydro-2H-1,4-benzox
Sadine (56) 6-chloro-8- (5,6-dihydroimidazole
Zo [2,1-b] thiazol-3-yl) -4- (2-
Phenoxyethyl) -3,4-dihydro-2H-1,4
-Benzoxazine (57) 6-chloro-8- (5,6-dihydroimidazole
Zo [2,1-b] thiazol-3-yl) -4- (3-
Phenoxypropyl) -3,4-dihydro-2H-1,
4-benzoxazine (58) 3- (6-chloro-4- (3-phenoxyp
Ropyr) -3,4-dihydro-2H-1,4-benzoo
Xazin-8-yl) -5,6-dihydroimidazo
[2,1-b] Thiazole-2-ethyl acetate (59) 6-chloro-8- (5,6-dihydroimidazole
Zo [2,1-b] thiazol-3-yl) -4- (4-
Methoxybenzoyl) -3,4-dihydro-2H-1,
4-benzoxazine (60) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -4-methyl-3,4-di
Hydro-2H-1,4-benzoxazine (61) 6-chloro-8- (2-ethylaminothiazo
Ol-4-yl) -4-methyl-3,4-dihydro-2
H-1,4-benzoxazine (62) 6-chloro-4-methyl-8- (2- (4-
Piperidyl) aminothiazol-4-yl) -3,4-
Dihydro-2H-1,4-benzoxazine (63) 6-chloro-4-methyl-8- (2- (1-
(2-phenethyl) -4-piperidyl) aminothiazo
Ru-4-yl) -3,4-dihydro-2H-1,4-be
Nzoxazine (64) 8- (2-allylaminothiazol-4-i
) -6-Chloro-4-methyl-3,4-dihydro-2
H-1,4-benzoxazine (65) 6-chloro-4-methyl-8- (2-phenyl
Luminothiazol-4-yl) -3,4-dihydro-
2H-1,4-benzoxazine (66) 6-chloro-8- (2- (4-methoxyphen
Nyl) aminothiazol-4-yl) -4-methyl-
3,4-Dihydro-2H-1,4-benzoxazine (67) 6-chloro-4-methyl-8- (2- (2-
Phenethyl) aminothiazol-4-yl) -3,4-
Dihydro-2H-1,4-benzoxazine (68) 6-chloro-8- (2- (2- (3,4-di
Hydroxyphenyl) ethyl) aminothiazole-4-
Yl) -4-methyl-3,4-dihydro-2H-1,4
-Benzoxazine (69) 8- (2- (4-methoxybenzoyl) ami
Nothiazol-4-yl) -4-methyl-3,4-dihi
Doro-2H-1,4-benzoxazine (70) 6-chloro-4-methyl-8- (2- (3-
Morpholinopropyl) aminothiazol-4-yl)-
3,4-Dihydro-2H-1,4-benzoxazine (71) 6-chloro-4-methyl-8- (2- (3-
(4-Methylpiperidino) propyl) aminothiazole
-4-yl) -3,4-dihydro-2H-1,4-ben
Zoxazine (72) 6-chloro-8- (3- (4-methoxyphen
Nyl) -2- (4-methoxyphenyl) imino-4-thi
Azolin-4-yl) -4-methyl-3,4-dihydro
-2H-1,4-benzoxazine (73) 6-chloro-8- (6,7-dihydro-5H
-Thiazolo [3,2-a] pyrimidin-3-yl) -4
-Methyl-3,4-dihydro-2H-1,4-benzoo
Xazine (74) 3- (6-chloro-4-methyl-3,4-di
Hydro-2H-1,4-benzoxazin-8-yl)
-5,6-Dihydroimidazo [2,1-b] thiazole
-2-carboxylic acid (75) 3- (6-chloro-4-methyl-3,4-di
Hydro-2H-1,4-benzoxazin-8-yl)
-5,6-Dihydroimidazo [2,1-b] thiazole
2-Acetic acid (76) 3- (6-chloro-4-methyl-3,4-di
Hydro-2H-1,4-benzoxazin-8-yl)
-5,6-Dihydroimidazo [2,1-b] thiazole
Ethyl-2-carboxylate (77) 6-chloro-4-methyl-8- (5-methyl
-1,3,4-oxadiazol-2-yl) -3,4
-Dihydro-2H-1,4-benzoxazine (78) 2- (6-chloro-4-methyl-3,4-di
Hydro-2H-1,4-benzoxazin-8-yl)
Ethyl-4-methyloxazole-5-carboxylate (79) 2- (6-chloro-4-methyl-3,4-di
Hydro-2H-1,4-benzoxazin-8-yl)
Ethyl-4-methylimidazole-5-carboxylate (80) 2- (6-chloro-4-methyl-3,4-di
Hydro-2H-1,4-benzoxazin-8-yl)
-4-Phenylthiazole-5-carboxylic acid (81) 2- (4-acetyl-6-chloro-3,4-
Dihydro-2H-1,4-benzoxazin-8-i
) -4-Phenylthiazole-5-carboxylic acid (82) 2- (6-chloro-4-methyl-3,4-di
Hydro-2H-1,4-benzoxazin-8-yl)
-4-Methyloxazole-5-carboxylic acid (83) 2- (6-chloro-4-methyl-3,4-di
Hydro-2H-1,4-benzoxazin-8-yl)
-4-Methylimidazole-5-carboxylic acid (84) 6-chloro-4-methyl-8- (5-hydro
Xymethyl-4-methyloxazol-2-yl)-
3,4-Dihydro-2H-1,4-benzoxazine (85) 2- (6-chloro-4-methyl-3,4-di
Hydro-2H-1,4-benzoxazin-8-yl)
-4- (4-Methoxyphenyl) thiazole-5-acetic acid (86) 8- (5,6-dihydroimidazo [2,1-
b] thiazol-3-yl) -4-methyl-6- (3-
Phenoxypropoxy) -3,4-dihydro-2H-
1,4-benzoxazine The structural formulas of the above examples are listed below. In addition, parentheses
The numbers inside indicate the example numbers.

[0100]

[Chemical 21]

[0101]

[Chemical formula 22]

[0102]

[Chemical formula 23]

[0103]

[Chemical formula 24]

[0104]

[Chemical 25]

[0105]

[Chemical formula 26]

[0106]

[Chemical 27]

[0107]

[Chemical 28]

[0108]

[Chemical 29]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location A61K 31/535 ABF ABG ABN ABR ACF ADA AED C07D 417/04 265 513/04 331 355 // (C07D 413/04 265: 36 271: 06) (C07D 413/04 263: 30 265: 36) (C07D 413/04 249: 08 265: 36) (C07D 413/04 239: 24 265: 36) (C07D 417 / 04 265: 36 277: 20) (72) Inventor Michio Terasawa, 955 Address, Yoshitomi-cho, Tsukigami-gun, Fukuoka Prefecture, Yoshitsuto Pharmaceutical Co., Ltd. Drug Discovery Research Center (72) Inventor Hitoshi Okamoto 1 Murasaki-cho, Takatsuki-shi, Osaka No. 1 in Japan Tobacco Inc. Pharmaceutical Research Institute

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ represents hydrogen, alkyl, optionally substituted alkanoyl, benzoyl, substituted benzoyl, cinnamoyl, substituted cinnamoyl or phenoxyalkyl. R ² is hydrogen, halogen, hydroxyl group, alkyl, alkoxy, phenoxyalkoxy or the formula —N (R ⁵ ) (R ⁶ ), wherein R ⁵ represents alkyl or phenoxyalkyl, and R ⁶ represents alkanoyl. The groups shown are shown. R ³ and R ⁴ are the same or different and each represents hydrogen or alkyl. Het is the formula (In the formula, R ⁷ represents unsubstituted alkyl, phenyl or substituted phenyl, and when R ⁷ is alkyl, phenyl or substituted phenyl, the bonding site with a dotted line between the nitrogen and carbon to which R ⁷ is bonded is a single bond. , R ⁸ represents the formula ═N—R ⁹ (wherein R ⁹ represents alkyl, phenyl or substituted phenyl), and when R ⁷ is unsubstituted, the dotted line between the nitrogen and carbon to which R ⁷ is bonded is The associated binding site is a double bond, R
⁸ alkyl, amino, during guanidino or formula -NH-R ¹⁰ (wherein, R ¹⁰ 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 11}} ) (R 12) ( wherein, m is an integer of 1 to 3, or R ^11, R ¹² represents an alkyl identical or different, R ¹¹ and R ¹² are adjacent Represents a group that forms a heterocycle by bonding with a nitrogen atom,
The heterocycle may have a substituent. ) Shows the group represented by. ) Represents a group represented by
^The bonding site with a dotted line between the nitrogen and carbon to which ⁷ is bonded represents a single bond, and R ⁷ and R ⁸ together form the formula — (CH ₂ ) _p —N = (wherein p is 2 or 3 Represents a group that forms a ring with a nitrogen-containing alkylene chain. R ¹³
Represents hydrogen, carboxy, carboxyalkyl, alkoxycarbonyl or alkoxycarbonylalkyl. ) Or a group of the formula (In the formula, A ¹ represents an oxygen atom, a sulfur atom or NH,
A ² represents a nitrogen atom or a formula C—R ¹⁴ (in the formula, R ¹⁴ represents hydrogen, alkyl, phenyl or substituted phenyl), and R ¹⁵ represents hydrogen, alkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkoxycarbonyl. Alternatively, it represents an alkoxycarbonylalkyl. ) Shows the group represented by. ] The benzoxazine compound represented by these, or its pharmaceutically acceptable salt.