JP3111321B2 - Condensed thiazole compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel condensed thiazole derivative or a salt thereof, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient. More specifically, the present invention relates to a novel lipid peroxide production inhibitor and a lipoxygenase inhibitor useful as preventive and therapeutic agents for various diseases such as cancer, arteriosclerosis, liver disease, cerebrovascular disease, and inflammation.

[0002]

2. Description of the Related Art Antioxidant and lipid peroxides have been identified as the formation of lipid peroxide in the body and the accompanying radical reaction have various adverse effects on living organisms through membrane damage and enzyme damage. Various attempts have been made to apply the production inhibitor to medicine. Currently, lipid peroxide production inhibitors used in these fields are mainly derivatives of natural antioxidants such as vitamin C and vitamin E, and phenol derivatives.

[0003]

However, their basic skeletons are limited and are not always practically satisfactory. In order to widely use the lipid peroxide production inhibitor in the field of medicine, it is necessary to develop a lipid peroxide production inhibitor having a new structure. A main object of the present invention is to provide a novel compound having such a lipid peroxide production inhibitory action.

[0004]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have synthesized a number of novel compounds and examined the inhibitory action of each compound on the production of lipid peroxide. The present inventors have previously found that thiazolo [5,4-b] azepine derivatives have an antioxidant effect and an inhibitory effect on lipid peroxide production (European Patent Publication No. 351856).
However, as a result of intensive studies in search of a novel compound having the above-mentioned action, general formula [I]

Embedded image [Wherein, A represents a bond or CH ₂ , R ¹ represents a hydrogen atom or an aliphatic group, a carboxylic acyl group or a sulfonyl acyl group which may have a substituent, R ² represents a hydrogen atom or And an aromatic ring group or an aliphatic group which may have a substituent. Condensed thiazole derivatives or salts thereof represented by the formula [1], and these new compounds have a strong inhibitory action on lipid peroxide production;
It has been found that it has useful effects such as hydroxyheptadecatrienoic acid (hereinafter abbreviated as HHT) and lipoxygenase inhibitory or leukotriene D ₄ (LTD ₄ ) receptor antagonistic effects, and further studies have been carried out. Completed the invention.

That is, the present invention provides a novel condensed thiazole compound represented by the above general formula [I] (hereinafter sometimes simply referred to as compound [I]), a salt thereof, a production method thereof and a pharmaceutical composition containing the same as an active ingredient. Is provided.

In the general formula [I], the aliphatic group represented by R ¹ may be a saturated group or an unsaturated group. Examples thereof include an alkyl group, an alkenyl group and an alkynyl group. Is mentioned. The alkyl group may be linear, branched or cyclic. Among these alkyl groups, a lower alkyl group having about 1 to 6 carbon atoms is preferable. For example, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, Cyclopentyl and the like.
The alkenyl group represented by R ¹ is generally preferably a group having 2 to 6 carbon atoms, for example, vinyl, allyl, propenyl, i-propenyl, 2-butenyl, 1,3-
Butadienyl, 2-pentenyl, 2,4-pentadienyl and the like. The general preferred example ethynyl group having 2 to 6 carbon atoms as the alkynyl group represented by R ^1, 2-propynyl, and the like. The substituent which these aliphatic groups may have may be any group as long as it is a group usually used in medicine, and specifically, for example, hydroxyl, C _1-3 alkoxy, for example, methoxy, ethoxy, n -Propoxy or iso-propoxy and the like (such as in methoxymethyl or 1-ethoxyethyl and the like); aryloxy, such as phenoxy and the like;
_7-10 alkoxy, such as benzyloxy; mercapto; C _1-3 alkylthio, such as methylthio or ethylthio; C _6-10 arylthio, such as phenylthio or naphthylthio; C _7-10 aralkylthio;
Amino or (for example, as in 2-aminoethyl); mono- or disubstituted amino substituted with C _1-3 alkyl, such as methylamino, ethylamino or dimethylamino; halogen, for example chloro or bromo (for example 2 -As in bromoethyl); esterified carboxy, for example _C2-5 alkoxycarbonyl
(Such as methoxycarbonyl or ethoxycarbonyl), or benzyloxycarbonyl; _C2-4 alkoxycarbonyloxy; formyl; _C2-10 acyl such as acetyl, propionyl or benzoyl; _C2-10 acyloxy such as acetoxy, propionyloxy or Pivaloyloxy and the like; cyano; phthalimide; C _2-10 acylamide such as acetamido or benzamide;
C _2-5 alkoxycarbonylamino such as methoxycarbonylamino or ethoxycarbonylamino; or C _7-10 alkoxycarbonylamino such as benzyloxycarbonylamino, cyclic amino group (eg pyrrolidino, morpholino etc.), carboxyl group, carbamoyl group (The group consisting of these groups is hereinafter referred to as Group A.)
And so on. Among these groups A, a carboxyl group, an esterified carboxyl group, a carbamoyl group, a mono- or di- (C _1-3 alkyl) amino group and the like are particularly preferable.

Examples of the acyl sulfonate group represented by R ¹ include an alkylsulfonyl group having preferably 1 to 3 carbon atoms, such as methanesulfonyl, ethanesulfonyl and propanesulfonyl, and a phenylsulfonyl group. Among these, the alkylsulfonyl group may have, for example, a substituent selected from Group A described above. In particular, of these substituents, C such as dimethylamino and diethylamino
Mono- or di-substituted amino substituted with _1-3 alkyl is preferred.

When the phenylsulfonyl group represented by R ¹ has a substituent on the phenyl ring, examples of the substituent include halogen (eg, fluorine, chlorine, bromine, iodine), nitro, amino (C _1-3 alkyl). , C _2-4 alkenyl, C _3-8 cycloalkyl, or phenyl as a substituent (s).), Sulfo, mercapto,
Hydroxy, sulfoxy, sulfamoyl, C _1-6 alkyl (amino, di C _1-3 alkylamino, mono C _1-3 alkylamino, halogen, hydroxy, cyano, carboxy may be substituted. ), C _1-6 alkoxy (which may have C _1-3 alkylthio as a substituent), benzyloxy, C _1-3 alkylthio, C _1-3 alkylsulfonamide, amidino (C _1-3 alkyl, Benzyl), C _1-3 alkoxyformimidoyl, methylenedioxy, C _1-3 alkylsulfonyl, C _1-3 alkylsulfonylamino, esterified carboxy such as C _2-4 alkoxycarbonyl ( such as methoxycarbonyl or ethoxycarbonyl), or benzyloxycarbonyl; C _2-4 alkoxycarbonyloxy; formyl; C _2-10 acyl Example, if acetyl, propionyl or benzoyl, etc.; C _2-10 acyloxy,
Such as acetoxy, etc. propionyloxy or pivaloyloxy, cyano, phthalimido, C _2-10 acyl amides, for example acetamide or benzamide like; C _2-4
Alkoxycarbonylamino, such as methoxycarbonylamino or ethoxycarbonylamino; or C
_7-10 alkoxyalkoxyamino, such as benzyloxycarbonylamino; substituted with a cyclic amino group (eg, pyrrolidino, morpholino, etc.); and a carboxyl group, carbamoyl group, halogen, methoxy, and C _1-3 alkyl group. Phenyl (the group of these substituents is hereinafter referred to as group P). Of these, particularly hydroxyl, C _1-6 alkoxy, C _1-6 alkyl, halogen, nitro, amino, mono- or di- (C _1-6
Alkyl) amino, C _1-6 alkylthio, amidino, amino C _1-6 alkyl, cyano, C _1-6 alkoxycarbonyl, C _1-6 alkoxycarbonyloxy, phenyl, phenylamidino, alkoxyformimidoyl are preferred. Further, methyl, methoxy, chlorine, fluorine, amino and the like are particularly preferable.

The carboxylic acid acyl group represented by R ¹ is generally a compound represented by the formula R ³ CO— (where R ³ is a saturated or unsaturated aliphatic group which may have a substituent or And an aromatic ring group which may have a group.).

The aromatic ring group represented by R ³ includes an aromatic carbon ring group and an aromatic heterocyclic group. Examples of the former include, for example, phenyl and naphthyl. As the aromatic heterocyclic group, for example, a 5- to 6-membered aromatic heterocyclic ring containing 1 to 4, preferably 1 to 2, heteroatoms such as nitrogen, oxygen and sulfur is preferable. Specific examples of the aromatic heterocycle include, for example, pyridyl, furyl, thienyl, pyrazinyl, pyrrolyl, imidazolyl, isoxazolyl and the like.

Further, a group in which the same or another aromatic ring (such as the above-mentioned aromatic heterocyclic ring or aromatic carbon ring) is condensed with such an aromatic ring group is also preferable. Examples of these fused rings include indolyl, benzimidazolyl, quinolyl, imidazopyridyl, thiazolopyridyl and the like.

As the substituent which the aromatic carbocyclic group may have, for example, a group selected from the above group P is preferable.
Examples of the substituent which the aromatic heterocyclic group may have include, for example, amino (C _2-10 acyl, halogen-substituted C _2-4 acyl, phenyl, C _1-3 alkyl). Good), halogen, nitro, sulfo, cyano, hydroxy, carboxy, oxo, C _1-10 alkyl (phenyl, halogen, amino, hydroxy, carboxy, C
_It may have _1-3 alkoxy, C _1-3 alkylsulfonyl, C _1-3 dialkylamino or the like as a substituent. ),
C _3-6 cycloalkyl, C _1-3 alkoxy, C _2-10 acyl, phenyl (optionally having halogen, nitro, alkyl, alkoxy, amino, sulfo, hydroxy, cyano as a substituent), oxo , C _1-10 alkyl-thio (phenyl, halogen, amino, hydroxy, carboxy, C _1-3 alkoxy, C _1-3 alkylsulfonyl, di C _1-3 alkylamino, etc. ) (The above groups of substituents are hereinafter referred to as group H.). Among these H groups, C _1-10 alkyl, amino, mono- or di- (C _1-3 alkyl) amino, halogen, amino C _1-3 alkyl and the like are particularly preferable.

The aliphatic group represented by R ³ may be a saturated group or an unsaturated group, and examples thereof include an alkyl group, an alkenyl group and an alkynyl group. Here, as the alkyl group, in addition to the lower alkyl group as described above as the alkyl group represented by R ¹ ,
Higher alkyl groups having 7 or more carbon atoms such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, heptadecyl and octadecyl are also included. The alkyl group represented by R ^3, but is preferably an alkyl group having 1 to 18 carbon atoms, and more preferably from 1 to 4 carbon atoms.

As the alkenyl group and alkynyl group represented by R ³ , the groups described above for R ¹ are preferable. The alkenyl group and the alkynyl group are particularly preferably those having 2 to 4 carbon atoms.

Examples of the substituent which the saturated or unsaturated aliphatic group represented by R ³ may have include the above-mentioned A
Group, a phenyl group which may be substituted with a substituent selected from the group P as described above, a phenethylamino group or a benzylamino group which may have a substituent selected from the group P on the ring And a heterocyclic group which may be substituted with a substituent selected from the above group H. Here, as the heterocyclic group, in addition to the aromatic heterocyclic group as described above with respect to the aromatic ring group represented by R ³ , a partially or wholly saturated heterocyclic group (eg, morpholino, piperidinyl,
Piperidino, piperazinyl, pyrrolidinyl and the like).

The aliphatic group represented by R ² includes, for example, the saturated or unsaturated aliphatic groups described above for R ¹ . Further, as the alkenyl group of the unsaturated aliphatic group represented by R ² , an alkenyl group having 7 to 10 carbon atoms is preferable in addition to the lower alkenyl group described as examples of R ¹ . Examples of the substituent which the aliphatic group represented by R ² may have include the same groups as the substituents of the aliphatic group represented by R ³ , and further substituted with an oxo group or the like. You may.

The aromatic ring group represented by R ² includes
Examples include the aromatic carbocyclic group and aromatic heterocyclic group and the condensed ring group thereof as described above for R ³ . Further, the substituent which the aromatic carbocyclic group may have is a group selected from the group P, and the substituent which the aromatic heterocyclic group may have is a group selected from the group H. can give.

The number of substituents of the optionally substituted groups represented by R ¹ , R ² and R ³ is preferably 1 to 5, preferably 1
~ 3.

In the formula [I], R ¹ is a hydrogen atom, mono-
Or a C _1-6 alkyl, C _1-3 alkylsulfonyl or carboxylic acid acyl group which may be substituted with a di- (C _1-3 alkyl) amino group (for the acyl group, an acetyl group, a propionyl group, etc.) Preferably, a methyl group in these groups,
The ethyl group may further have a substituent as described above. Is preferred. Particularly, a compound in which R ¹ is a hydrogen atom is preferable. R ² is an optionally substituted aromatic ring (particularly phenyl optionally substituted with C _1-4 alkyl or / and nitro) or an optionally substituted aromatic ring, particularly C ₁ Compounds which are phenyl or imidazolyl which may be substituted with _-4 alkyl, C _1-4 alkoxy and / or C _6-10 aryl, or alkenyl having 2 to 4 carbon atoms which may be substituted with indolyl are preferred. . Particularly, in the formula [I], the aliphatic group which may have a substituent of R ^{2 is} a group represented by the formula R ⁴ Y (wherein R ⁴ is an aromatic ring group which may have a substituent, and Y is thiazoloazepine Compounds which are groups represented by an unsaturated aliphatic group capable of forming a conjugate bond with a thiazole ring of the ring are preferred. Here, as the “aromatic ring” and “substituent” of the “aromatic ring group optionally having substituent (s)” represented by R ⁴ , those described above for R ³ apply as they are. As Y, for example, -CH = CH-, -CH = CH-CH = C
H- and the like. Further, R ¹ is a hydrogen atom, and R ² is a phenyl group optionally having a substituent or a phenyl, thienyl, furyl, pyridyl, pyrazinyl or imidazolyl group having 2 to 4 carbon atoms which may be substituted. A compound which is an alkenyl group conjugated to a thiazole ring is a preferable embodiment from the viewpoint of its action. Particularly preferred examples of the optionally substituted alkenyl group represented by R ² include vinyl and butadienyl substituted with an optionally substituted phenyl.

The compound represented by the general formula [I] is
Although stereoisomers may occur depending on the types of the substituents of R ¹ and R ² , not only these isomers alone but also mixtures thereof are included in the present invention.

The salt of the compound represented by the formula [I] is preferably a pharmaceutically acceptable salt, and examples of the pharmaceutically acceptable salt include hydrogen halide (eg, hydrogen chloride, bromide). Hydrogen), phosphoric acid, sulfuric acid, etc., and organic acids such as organic carboxylic acids (eg, oxalic acid, phthalic acid, fumaric acid, maleic acid) and sulfonic acids (eg, methanesulfonic acid, benzenesulfonic acid). Can be Compound [I] is R ¹
When having an acidic group such as a carboxyl group as a substituent on or R ^2, an alkali metal (e.g., sodium, potassium) or alkaline earth metal (e.g., magnesium) inorganic base salts and organic base (Example of such, dicyclohexyl Amines, amines such as triethylamine and 2,6-lutidine).

Hereinafter, the compound represented by the general formula [I] and a salt thereof are collectively referred to as a compound [I].

The compound [I] of the present invention can be prepared by, for example,
I.

Embedded image [In Scheme-I, A, R ¹ and R ² are as defined above, and R ² C
OZ indicates a reactive derivative of a carboxylic acid. ]

That is, the compound [III] or a salt thereof (the salt includes the salts described above as the salt of the compound [I]) is acylated with a reactive derivative of a carboxylic acid represented by the formula R ² COZ to form a compound Compound [I] can be obtained by obtaining [II] and subsequently treating [II] with a sulfurizing agent. More specifically, examples of the reactive derivative represented by R ² COZ include acid chloride, acid bromide, imidazolide, acid anhydride, acid azide, N-phthalimide ester, and N-oxysuccinimide ester. Instead of using an active ester, a carboxylic acid represented by R ² COOH is replaced with N, N′-dicyclohexylcarbodiimide.
(Hereinafter, may be abbreviated as DCC) in the presence of a coupling reagent such as DCC.

The reactive derivative represented by R ² COZ is used in an amount of about 1 to 3 mol, preferably about 1 to 1 mol, per 1 mol of the compound [III].
Use 1.2 moles. When reacting with a carboxylic acid represented by R ² COOH, usually 1 mol of compound [III] is used.
About 1 to 3 mol, preferably about 1 to 1.2 mol, of carboxylic acid is reacted with the same compound [III] in the presence of about 1 to 1.2 mol of a coupling reagent.

The reaction normally proceeds smoothly under ice cooling to room temperature (specifically, room temperature in the following description of the production method means 5 to 35 ° C.). The solvent used at this time is not particularly limited as long as it is inert to the reaction, and chloroform, methylene chloride, tetrahydrofuran, dioxane, dimethylformamide and the like are often used. When an acid chloride or an acid bromide is used as the acylating agent, it is desirable to add an amine such as triethylamine or pyridine to the reaction system. The reaction time depends on the reagent, solvent and temperature used, but is usually 30 minutes to 1 hour.
It takes about 2 hours.

The reaction for converting the compound [II] to the compound [I] is carried out in the presence of a sulfurizing agent such as phosphorus pentasulfide or Lawesson's reagent. The amount of the sulfurizing agent used at this time is generally the same as that of compound [II]
About 1 to 3 mol, preferably about the same mol as the compound [II] is used per 1 mol. Although pyridine is desirable as the reaction solvent, it is not particularly limited. The reaction is carried out in the range of about 50 ° C to 120 ° C, preferably about 80 ° C to 120 ° C. The time required for the reaction varies depending on the reaction temperature.
If the reaction is carried out in about 12 hours, for example, at about 100 to 120 ° C., the reaction is completed within about 5 hours.

[0028] In Scheme -I, after substituent represented by R ¹ may be converted to other substituent represented by R ¹ at any stage, which usually give compound [I], R ^It is advantageous to convert ^one part. Such R ¹ conversion reactions include:
A compound in which R ¹ is a hydrogen atom is subjected to a reaction such as alkylation, sulfonylation or acylation by a conventional method, and R ¹ is an optionally substituted alkyl group, a sulfonate acyl group or a carboxylate acyl group. A reaction for obtaining a target compound is mentioned.

These reactions can be carried out according to a method known per se, for example, the following method.

Compound wherein R ¹ of compound [I] is a hydrogen atom
[Hereinafter, it may be referred to as compound [I] (R ¹ = H). ]
To obtain a compound in which R ¹ is an acyl group, a compound [I] (R
¹ = H) may be acylated. In order to obtain a compound in which R ¹ is a carboxylic acyl group, a reactive derivative of the acyl carboxylate may be reacted with compound [I] (R ¹ ＝ H). The kind of the reactive derivative of the acyl carboxylate, the reaction conditions, and the like described above for the reaction for obtaining the compound [II] from the compound [III] are usually applied as they are. The reaction proceeds smoothly under these conditions. To convert compound [I] (R ¹ ＨH) to a compound in which R ¹ is acyl sulfonate, compound [I]
A method in which (R ¹ = H) is reacted with a sulfonyl halide is convenient. The reaction is usually performed in the presence of an amine such as triethylamine or pyridine. Any solvent may be used as long as it is inert to the reaction, but acetone, dioxane, dimethylformamide, tetrahydrofuran, chloroform, methylene chloride and the like are preferably used. In some cases, pyridine may be used as a solvent. The reaction proceeds smoothly at 0 ° C. to room temperature,
It takes 30 minutes to 5 hours. At this time, the amount of the amine used is about 1 to 3 mol and the amount of the acylating agent is about 1 to 2 mol per 1 mol of the compound [I].

In order to obtain a compound in which R ¹ is an alkyl group from a compound in which R ¹ is a hydrogen atom in compound [I], compound [I]
(R ¹ = H) may be subjected to an alkylation reaction. Examples of the alkylating agent used at this time include alkyl halides (eg, chlorine, bromine, and iodine as halogens), alkyl esters of sulfonic acids (eg, alkyl esters of p-toluenesulfonic acid, alkyl esters of methanesulfonic acid, and the like). can give. The amount of the alkylating agent to be used is about 1-2 mol per 1 mol of the compound [I]. The reaction is usually performed in the presence of an inorganic base such as potassium carbonate or sodium carbonate, or an organic base such as triethylamine or pyridine. The base is preferably used in an equimolar amount with the alkylating agent. Although the solvent used is not particularly limited, for example, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide and the like are preferably used. The reaction is usually carried out with heating, suitably in the range of about 30 ° to 100 ° C.

The compound [I] in which R ¹ is an alkyl group can be obtained by reducing the compound [I] in which R ¹ is an acyl carboxy group.
The reduction can be carried out according to a conventional method. For example, reduction with a reducing agent such as lithium aluminum hydride or diborane is suitable. At this time, ether, tetrahydrofuran or dioxane is used as a solvent, and the reaction usually proceeds under reflux.

Compound [I] can also be produced by other known methods or methods analogous thereto.

Incidentally, among the compounds [III], which are the starting compounds for the production method of the present invention, compounds in which R ¹ is a hydrogen atom are known compounds, and compounds in which R ¹ is other than a hydrogen atom are described, for example, in J. Am.
P. Snyder et al. [J. P. Snyder et al., Journal of Medicinal Chemistry (J. Med. Chem.),
29 , 251, (1986)].

Embedded image Wherein A and R ¹ are as defined above, Et is an ethyl group, X
Represents a halogen atom, and BOC represents a tert-butoxycarbonyl group.

Further, according to the above-mentioned reaction for converting the R ¹ portion of the compound [I], the compound [III] can be produced from the compound in which R ¹ is a hydrogen atom.

Compound [I] obtained by the above method
Can be isolated and purified by ordinary separation means such as recrystallization, distillation and chromatography. When the compound [I] thus obtained is obtained in a free form, it can be converted into a salt by neutralization or the like by a method known per se. Conversely, when the compound [I] is obtained as a salt, it can be converted into a salt by a conventional method. Can be changed to

The compound [I] of the present invention is a polyunsaturated fatty acid
Metabolism improvement (linoleic acid, γ-linolenic acid, α-linolenic acid, arachidonic acid, dihomo-γ-linolenic acid, eicosapentaenoic acid), especially the action of inhibiting the lipid peroxide-forming reaction (antioxidant action), 5- Lipoxygenase metabolites
[E.g., leukotrienes, 5-hydroperoxyeicosatetraenoic acid (HPETE), 5-hydroxyeicosatetraenoic acid (HETE), lipoxins, leukotoxins, etc.] production inhibiting action, thromboxane A ₂ synthase the inhibitory effect of having prostaglandin I ₂ synthetase retention promoting action, LTD ₄ receptor antagonism, the circulatory system improving action and antiallergic action, such as reactive oxygen species scavenging activity.

Among the above-mentioned effects, the compound [I] of the present invention tends to have a remarkable inhibitory effect on lipid peroxide formation reaction (antioxidant action).

The toxicity and side effects of compound [I] are low.

Therefore, the compound [I] of the present invention is a mammal
Thrombosis due to platelet aggregation in mice (rats, rabbits, dogs, monkeys, humans, etc.), ischemic disease due to contraction of arterial vascular smooth muscle or vasospasm in the heart, lung, brain and kidney (eg, myocardial infarction, stroke) ), Neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, Lou Gehrig's disease, muscular dystrophy), dysfunctions associated with central injuries such as head trauma, spinal cord trauma, memory impairment and emotional disorders (oxygen deficiency, brain injury, stroke, Disorders associated with cerebral infarction, neuronal necrosis caused by cerebral thrombosis, etc.), stroke, seizures and epilepsy after cerebral infarction and brain surgery, head injury, nephritis, lung failure, bronchial asthma, inflammation, arteriosclerosis, atheroma Degenerative arteriosclerosis, hepatitis, acute hepatitis, cirrhosis, hypersensitivity pneumonitis, immunodeficiency, due to reactive oxygen species (superoxide, hydroxyl radical, etc.) Containing, biological tissue, cardiovascular diseases caused by disorders such as cells (myocardial infarction, stroke, cerebral edema, nephritis, etc.), have therapeutic and prophylactic effects against various diseases such as tissue fibrosis phenomena and carcinogenesis,
For example, anti-thrombotic agents, anti-vasospastic agents, anti-asthmatic agents, anti-allergic agents, agents for improving the circulatory system of the heart and brain, therapeutic agents for nephritis, therapeutic agents for hepatitis, inhibitors for tissue fibrosis, scavengers for reactive oxygen species, arachidone It is useful as a medicine such as an acid cascade substance regulation improving agent.

Compound [I] can be orally used as a pharmaceutical composition (eg, tablet, capsule, liquid, injection, suppository) as it is or as a mixture with a pharmaceutically acceptable carrier, excipient and the like known per se. It can be safely administered parenterally or parenterally. The dose varies depending on the administration subject, administration route, symptoms and the like. For example, when orally administered to an adult patient with a circulatory disease, the dose is usually about 0.1 mg as a single dose.
/ Kg to 20 mg / kg body weight, preferably 0.2 mg / kg to
It is convenient to administer about 10 mg / kg body weight about 1 to 3 times a day.

[0042]

EFFECTS OF THE INVENTION According to the present invention, circulatory diseases of mammals and the like having excellent inhibition of lipid peroxide production and antioxidant activity,
A compound useful as a prophylactic / therapeutic agent for an allergic disease is provided.

[0043]

EXAMPLES Hereinafter, Test Examples, Examples and Reference Examples will be described, but the present invention is not limited thereto.

Test Example 1 Effect of Drug on Behavioral Change by Intrathecal Administration of Ferrous Chloride Mouse Spinal Spinal Cord Ten 5-week-old male SIc: ICR mice per group were used. 5 μl of physiological saline in which 50 mM ferrous chloride is dissolved
After injecting the mouse from the sixth lumbar spinal cord into the subarachnoid space of the first sacral spinal cord, behavior observation was performed from 15 minutes to 1 hour, and the behavior change was scored according to the following criteria. Rating Behavioral change 0 point: normal 1 point: bite the lower limbs and lower abdomen. 2 points: a) Biting lower body violently, sometimes rolling around. B) Hypersensitivity to external stimuli is recognized and aggressive. c) Tremor occurs. One of the above three reactions is observed. 3 points: Clonic convulsions are observed. 4 points: Tonic convulsions are observed. Or paralysis of one or both limbs is observed. 5 points: I die. The inhibition rate was shown based on the points evaluated according to the above criteria. The test compound was orally administered 30 minutes before the administration of ferrous chloride.

Table 1 shows the average score and the inhibitory rate of each compound [I] administered orally at 100 mg / kg. From the above results, it is understood that the compound of the present invention has an excellent inhibitory effect on the central nervous system damage caused by the production of lipid peroxide by ferrous chloride.

In the column chromatography of the following Reference Examples and Examples, elution was performed by TLC (Thin Layer Chromatograph).
y, thin-layer chromatography).
In the TLC observation, as a TLC plate (Merck)
Kieselgel 60F ₂₅₀ (70-230 mesh)
, A solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method. As the silica gel for the column, Kieselgel 60 (70-230 mesh) also manufactured by Merck was used. NM
The R spectrum shows proton NMR, and VARIAN JEMIN using tetramethylsilane as an internal standard.
It was measured with I200 (200 MHz spectrometer), and the δ value was shown in ppm.

The abbreviations used in the examples have the following meanings. s: singlet, br: broad (wide), d: doublet, t: triplet, m: multiplet, dd: doublet of Daburettsu, J: coupling constant, Hz: Hertz, CDCl _3: heavy chloroform, d _6-DMSO : Heavy dimethyl sulfoxide,%: weight%

Reference Example 1 3- (2,3-Dimethoxycinnamoyl) amino-δ-valerolactam In 50 ml of a tetrahydrofuran solution of 5.0 g of 2,3-dimethoxycinnamic acid, 4.28 g of N, N'-carbonyldiimidazole was added. Was added and stirred at room temperature for 30 minutes. To this, 3.02 g of 3-amino-δ-valerolactam was added.
Was added and stirred at room temperature overnight. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
(39.8%). Melting point: 164 to 166 ° C (recrystallized from ethanol-hexane) IR (KBr) cm ^-1 : 3358,1695,1661,1622,1579,1538,1480,
_{1226,1067,797,756.NMR (d 6 -DMSO) δ:} 1.50~2.
10 (4H, m), 3.17 (2H, br s), 3.76 (3H, s), 3.83 (3H, s), 4.29
(1H, m), 6.72 (1H, d, J = 15.9Hz), 7.12 (3H, m), 7.64 (1H, d, J
= 15.9Hz), 7.66 (1H, m), 8.35 (1H, d, J = 7.9Hz).

Reference Example 2 3- (3-amino-4-methylbenzoyl) amino-δ-
Valerolactam The title compound was obtained from 3-amino-4-methylbenzoic acid and 3-amino-δ-valerolactam in the same manner as in Reference Example 1 (yield: 56.3%). Melting point 161-164 ° C (recrystallized from ethyl acetate-hexane) IR (KBr) cm ^-1 : 3358,1675,1645,1575,1539,1495,1455,
1424,1333.NMR (d ₆ -DMSO) δ: 1.68 to 2.10 (4H,
m), 3.16 (2H, br s), 4.31 (1H, m), 4.97 (2H, br s), 6.95-7.
15 (3H, m), 7.61 (1H, brs), 8.22 (1H, d, J = 8.1Hz).

Reference Example 3 3- (β-3-Indolylacryloyl) amino-δ-valerolactam By the same method as in Reference Example 1, β- (3-
The title compound was obtained from (indolyl) acrylic acid and 3-amino-δ-valerolactam (63.8% yield). Melting point 231 to 234 ° C (recrystallized from ethyl acetate-ethanol) IR (KBr) cm ^-1 : 3306,3220,1676,1612,1543,1526,1491,14
59,1365,1319,1281,809,752. NMR (d ₆ -DMSO-D ₂ O) δ: 1.54 to 2.15 (4H, m), 3.
18 (2H, m), 4.31 (1H, m), 6.69 (1H, d, J = 15.8Hz), 7.19 (2H, m
m), 7.48 (1H, dd, J = 2.2, 6.4 Hz), 7.60 (1H, m), 7.64 (1H, d, J
= 15.8Hz), 7.75 (1H, s), 7.93 (1H, dd, J = 1.8, 6.3Hz), 8.21
(1H, d, J = 8.0Hz).

Reference Example 4 3- {β- (1-methylimidazol-4-yl) acryloyl} amino-δ-valerolactam β- (1-methylimidazol-4-yl) acrylic acid
To a solution of the hydrochloride (7 g, 37.1 mmol) in dimethylformamide (60 ml) was added triethylamine (7.51 g, 7 ml).
4.2 mmol), 1-hydroxybenzotriazole-
Hydrate (6.25 g, 40.8 mmol) was added and cooled with ice.
Dicyclohexylcarbodiimide (8.42 g, 40.8
Mmol) in dimethylformamide (15 ml) was added dropwise. After stirring at 80 ° C. for 30 minutes and further at room temperature for 30 minutes, 3-amino-δ-valerolactam (5.08) was added to the reaction mixture.
g, 44.5 mmol) and stirred with heating at 50 ° C. for 13 hours. After cooling to room temperature, aqueous sodium bicarbonate was added and chloroform-
After extraction with a mixed solvent of methanol and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel and ethanol /
Recrystallization from chloroform gave 6.72 g (73.0%) of the title compound. Mp 280-282 ° C. (ethyl acetate - recrystallized from ^{ethanol) IR (KBr) cm -1:} . 3340,1673,1630,1527,1493,1454,1444 NMR (d 6 -DMSO-D 2 O) δ: 1.50 ~ 2.05 (4H, m), 3.
65 (3H, s), 4.28 (1H, m), 6.54 (1H, d, J = 15.3Hz), 7.26 (1H,
d, J = 15.3Hz), 7.39 (1H, s), 7.60 (1H, brs), 7.62 (1H, s),
8.20 (1H, d, J = 8.3Hz).

Reference Example 5 3- {β- (1-ethyl-2-phenylimidazole-)
4-yl) acryloyl {amino-δ-valerolactam β- (1-ethyl-2-phenylimidazol-4-yl) acrylic acid hydrochloride (5.49 g, 20.3 mmol)
Was heated and stirred in thionyl chloride (50 ml) for 50 minutes. After the excess thionyl chloride was completely distilled off under reduced pressure, tetrahydrofuran (50 ml) and triethylamine (4.12 g, 4 ml) were added.
(0.7 mmol), and 3-amino-δ-valerolactam (2.79 g, 24.4 mmol) was added thereto while cooling with ice, followed by stirring at room temperature overnight. Aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with a chloroform-methanol mixed solvent, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 4.29 g (62.3%) of the title compound. 270-272 ° C (recrystallized from ethyl acetate-ethanol) IR (KBr) cm ^-1 : 3338,1680,1652,1633,1509,1474,1446,
_{. 1361,796 NMR (d 6 -DMSO)} δ: 1.32 (3H, t, J = 7.3Hz), 1.50~
2.07 (4H, m), 3.15 (2H, brs), 4.05 (2H, q, J = 7.3Hz), 4.27 (1
H, m), 6.63 (1H, d, J = 15.3Hz), 7.30 (1H, d, J = 15.3Hz), 7.4
3 to 7.68 (7H, m), 8.20 (1H, d, J = 8.1Hz).

Reference Example 6 3- {3- (4-methoxyphenyl)} propionylamino-δ-valerolactam In the same manner as in Reference Example 1, 3- (4-methoxyphenyl) propionic acid and 3-amino-δ 5.29 g of the title compound were obtained from valerolactam (yield 86.3).
%). 184-186 ° C (recrystallized from ethyl acetate-ethanol) IR (KBr) cm ^-1 : 3308,1667,1640,1540,1514,1496,1454,
1247,1035,822. NMR (d ₆ -DMSO) δ: 1.43 to 2.00 (4H, m), 2.34 (2H,
m), 2.75 (2H, m), 3.12 (2H, m), 3.71 (3H, s), 4.14 (1H, m),
6.81 (1H, d, J = 8.7Hz), 7.12 (1H, d, J = 8.7Hz), 7.58 (1H,
br s), 8.02 (1H, d, J = 8.1Hz).

Example 1 2- (2,3-dimethoxystyryl) -4,5,6,7-tetrahydrothiazolo [5,4-b] pyridine 3- (2,3-dimethoxycinnamoyl) amino-δ 2.76 g of valerolactam and 2.02 g of phosphorus pentasulfide were added to 20 ml of pyridine and refluxed for 3 hours. After cooling, the reaction solution was diluted with chloroform-methanol, washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from ethyl acetate to give 260 mg of the title compound.
(10.5%). 122-124 ° C (recrystallized from ethyl acetate) IR (KBr) cm ^-1 : 3376,1615,1577,1538,1478,1445,1423,
_{. 1365,1353,1339,1262,1246,1068,960,782 NMR (d 6 -DMSO)} δ: 1.86 (2H, m), 2.69 (2H, t, J = 6.
4Hz), 3.18 (2H, m), 3.74 (3H, s), 3.81 (3H, s), 6.28 (1H, br
s), 6.95 (1H, dd, J = 1.4Hz, 8.1Hz), 7.05 (1H, t, J = 7.9Hz),
7.11 (1H, d, J = 16.4Hz), 7.21 (1H, d, J = 16.4Hz), 7.25 (1H,
dd, J = 1.4 Hz, 7.8 Hz). Elemental analysis: Calculated for C ₁₆ H ₁₈ N ₂ SO ₂ Calculated: C, 63.55; H, 6.00; N, 9.26; S, 10.60. Found: C, 63.66 ; H, 6.11; N, 9.22; S, 10.57.

Example 2 2- (3-amino-4-methylphenyl) -4,5,6,7
-Tetrahydrothiazolo [5,4-b] pyridine In the same manner as in Example 1, 3- (3-amino-4-
The title compound was obtained from methylbenzoyl) amino-δ-valerolactam and phosphorus pentasulfide (30.3% yield). Melting point 98-101 ° C (recrystallized from ethyl acetate-hexane) IR (KBr) cm ^-1 : 3256,1621,1568,1544,1513,1471,1372,
1345,1309,866,819. NMR (CDCl ₃ ) δ: 1.99 (2H, m),
2.17 (3H, s), 2.86 (2H, t, J = 6.4Hz), 3.29 (2H, t, J = 5.4H
. z), 3.67 (3H, br s), 7.00~7.20 (3H, m) Elemental analysis: C ₁₃ H ₁₅ N ₃ S Calculated: C, 63.64; H, 6.16 ; N, 17.13; S, 13.07 Found: C, 63.36; H, 6.40; N, 16.78; S, 13.08.

Example 3 2- (3-amino-4-methylphenyl) -4,5,6,7
-Tetrahydrothiazolo [5,4-b] pyridine dihydrochloride 2- (3-amino-4-methylphenyl) -4,5,6,7
-Tetrahydrothiazolo [5,4-b] pyridine was neutralized with hydrochloric acid and recrystallized from ethanol to give the title compound.
(48.1% yield). Melting point 186-189 ° C (recrystallized from ethanol) IR (KBr) cm ^-1 : 3438,1602,1523,1480,1466,1348,1282,
836. NMR (d ₆ -DMSO-D ₂ O) δ: 1.93 (2H, m), 2.37 (3H,
s), 2.77 (2H, t, J = 6.2Hz), 3.25 (2H, m), 7.39 (1H, d, J = 8.1
Hz), 7.64 (1H, dd, J = 1.7Hz, 8.1Hz), 7.84 (1H, d, J = 1.7H
z).

Example 4 2- {2- (indol-3-yl) ethenyl} -4,5,
6,7-Tetrahydrothiazolo [5,4-b] pyridine hydrochloride 3- (β-3-indolylacryloyl) amino-δ-valerolactam and phosphorus pentasulfide are reacted in the same manner as in Example 1. After purification, the title compound was obtained by neutralization with hydrogen chloride (yield 7.4%). Melting point 202-205 ° C (recrystallized from ethanol) IR (KBr) cm ^-1 : 3218,1596,1572,1528,1455,1404,1355,
1334,1284,743. NMR (CDCl ₃ ) δ: 1.89 (2H, br s), 2.75 (2H, br s), 3.
26 (2H, brs), 4.19 (1H, brs), 7.21 (2H, m), 7.30 (1H, d, J = 1
6.2Hz), 7.49 (1H, m), 7.70 (1H, d, J = 16.2Hz), 7.8 1-8.0
0 (2H, m), 11.88 (1H, s). Elemental analysis: C ₁₆ H ₁₅ N ₃ S.HCl Calculated: C, 60.46; H, 5.07; N, 13.22; S, 10.09; Cl, 11.15 Found: C, 60.37; H, 5.05; N, 13.16; S, 10.19; Cl, 11.29.

Example 5 2- {2- (1-methylimidazol-4-yl) ethenyl} -4,5,6,7-tetrahydrothiazolo [5,4-b]
Pyridine dihydrochloride 3- {β- (1-methylimidazol-4-yl) acryloyl} amino-δ-valerolactam and phosphorus pentasulfide are reacted in the same manner as in Example 1, purified, and neutralized with hydrogen chloride. This gave the title compound (14.1% yield). 184-187 ° C (recrystallized from ethanol-chloroform) IR (KBr) cm ^-1 : 3410,1635,1598,1521,1471,1446,1350,
837. NMR (CDCl ₃ ) δ: 1.89 (2H, m), 2.74 (2H, t, J = 6.3H)
z), 3.24 (2H, t, J = 5.0Hz), 3.86 (3H, s), 4.46 (1H, br s),
7.03 (1H, d, J = 16.5Hz), 7.47 (1H, d, J = 16.5Hz), 7.81 (1
H, s). Elemental analysis: C ₁₂ H ₁₄ N ₄ S.2HCl.0.5H ₂ O Calculated: C, 43.91; H, 5.22; N, 17.07; S, 9.77; Cl, 21.60. : C, 43.90; H, 5.34; N, 16.67; S, 10.06; Cl, 21.63.

Example 6 2- {2- (1-ethyl-2-phenylimidazole)
4-yl) ethenyl} -4,5,6,7-tetrahydrothiazolo [5,4-b] pyridine In a similar manner to Example 1, 3- {β- (1-ethyl-
2-phenylimidazol-4-yl) acryloyl
The title compound was obtained from amino-δ-valerolactam and phosphorus pentasulfide (8.4% yield). 140-142 ° C (recrystallized from ethyl acetate) IR (KBr) cm ^-1 : 3234,1628,1552,1538,1446,1371,1344,
1283,821. NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.3 Hz), 1.97 (2H,
m), 2.82 (2H, t, J = 6.4Hz), 3.27 (2H, t, J = 5.4Hz), 4.02
(2H, q, J = 7.3Hz), 7.08 (1H, d, J = 16.0Hz), 7.10 (1H, s),
7.24 (1H, d, J = 16.0Hz), 7.41 to 7.52 (3H, m), 7.53 to 7.64 (2
. H, m) Elemental analysis: C ₁₉ H ₂₀ N ₄ S Calculated:. C, 67.83; H, 5.99; N, 16.65; S, 9.53 Found: C, 67.59; H, 5.98 ; N, 16.26 ; S, 9.51.

Example 7 2- (2,3-dimethoxystyryl) -4,5,6,7-tetrahydrothiazolo [5,4-b] pyridine dihydrochloride 2- (2,3-dimethoxystyryl) -4,5,6,7-tetrahydrothiazolo [5,4-b] pyridine is neutralized with hydrochloric acid,
Recrystallization from ethanol-diethyl ether gave the title compound (92.7% yield). Melting point: 174 to 177 ° C (recrystallized from ethanol-diethyl ether) IR (KBr) cm ^-1 : 2546,1626,1609,1592,1574,1478,1443,
1431,1345,1272,1066,795. NMR (d ₆ -DMSO-D ₂ O) δ: 1.93 (2H, t, J = 4.9H)
z), 2.79 (2H, t, J = 6.1 Hz), 3.30 (2H, t, J = 4.8 Hz), 3.79
(3H, s), 3.84 (3H, s), 7.08 (1H, br d, J = 8.8Hz), 7.16 (1
H, d, J = 8.1Hz), 7.28 (1H, br d, J = 7.4Hz), 7.36 (1H, d, J =
. 16.5Hz), 7.48 (1H, d, J = 16.5Hz) Elemental _{analysis: C 16 H 18 N 2 SO} 2 · 2HCl Calculated: C, 51.20; H, 5.37 ; N, 7.46; S, 8.54; Cl, 18.89. Found: C, 52.11; H, 5.41; N, 7.46; S, 8.97; Cl, 18.41.

Example 8 2- {2- (1-ethyl-2-phenylimidazole)
4-yl) ethenyl} -4,5,6,7-tetrahydrothiazolo [5,4-b] pyridine dihydrochloride 2- {2- (1-ethyl-2-phenylimidazole)
4-yl) ethenyl {-4,5,6,7-tetrahydrothiazolo [5,4-b] pyridine is neutralized with hydrochloric acid and ethanol-
Recrystallization from diethyl ether gave the title compound. (Yield 94.2%). Melting point: 181 to 184 ° C. (recrystallized from ethanol-diethyl ether) IR (KBr) cm ⁻¹ : 3420, 1586, 1532, 1480, 1464, 1340. NMR (d ₆ -DMSO) δ: 1.41 (3H, t, J = 7.3Hz), 1.89 (2
H, m), 2.74 (2H, t, J = 6.2Hz), 3.24 (2H, t, J = 5.0Hz), 4.17
(2H, q, J = 7.3Hz), 5.22 (1H, brs), 7.01 (1H, d, J = 16.4H
z), 7.55 (1H, d, J = 16.4Hz), 7.62-7.75 (3H, m), 7.78-7.8
8 (2H, m), 8.09 (1H, s). Elemental analysis: C ₁₉ H ₂₀ N ₄ S.2HCl.0.5H ₂ O Calculated: C, 54.54; H, 5.54; N, 13.39; S , 7.66; Cl, 16.95. Found: C, 54.70; H, 5.60; N, 13.37; S, 7.80; Cl, 16.83.

Example 9 4-acetyl-2- (2,3-dimethoxystyryl) -4,
5,6,7-Tetrahydrothiazolo [5,4-b] pyridine 2- (2,3-dimethoxystyryl) -4,5,6,7-tetrahydrothiazolo [5,4-b] pyridine (1. 0g, 3.3
Acetic anhydride (0.68 g, 6.6 mmol) was added dropwise while a solution of pyridine (10 mmol) in pyridine (10 ml) was cooled with ice. After the reaction solution was heated and stirred at 80 ° C. for 3 hours, aqueous sodium bicarbonate was added, and the mixture was extracted with a mixed solvent of chloroform and methanol. The extract was dried over magnesium sulfate and concentrated, and the residue was purified by flash column chromatography. The obtained crystals were further recrystallized from hexane-ethyl acetate to give 867 mg of the title compound (yield: 76. 0%). 185-187 ° C (recrystallized from hexane-ethyl acetate) IR (KBr) cm ^-1 : 1651,1593,1575,1536,1478,1446,1273,
1065,962,785,762. NMR (CDCl ₃ ) δ: 2.16 (2H, m), 2.34 (3H, s), 2.95 (2H,
t, J = 6.3Hz), 3.87 (8H, m), 6.86 (1H, dd, J = 1.4Hz, 8.0Hz),
7.06 (1H, t, J = 8.1Hz), 7.16 ~ 7.33 (2H, m), 7.61 (1H, d, J =
Elemental analysis: C ₁₈ H ₂₀ N ₂ SO ₃ Calculated: C, 62.77; H, 5.85; N, 8.13; S, 9.31. Found: C, 62.67; H, 5.79; N, 8.12 ; S, 9.45.

Example 10 2- (2,3-dimethoxystyryl) -4-methanesulfonyl-4,5,6,7-tetrahydrothiazolo [5,4-b]
Pyridine 2- (2,3-dimethoxystyryl) -4,5,6,7-tetrahydrothiazolo [5,4-b] pyridine (1.0 g, 3.3
Methylenesulfonyl chloride (0.45 g, 3.97 mmol) was added dropwise while a solution of pyridine (10 ml) in pyridine (10 ml) was cooled with ice. After the reaction solution was stirred with heating at room temperature for 3 hours, aqueous sodium bicarbonate was added, and the mixture was extracted with a mixed solvent of chloroform and methanol. The extract was dried over magnesium sulfate and concentrated, and the residue was purified by flash column chromatography. The obtained crystals were recrystallized from hexane-ethyl acetate to give 1.09 g of the title compound (yield) 8
6.8%). 134-136 ° C (recrystallized from hexane-ethyl acetate) IR (KBr) cm ^-1 : 1623,1577,1535,1472,1445,1348,1338,
1261,1155,1085,970,808,760. NMR (CDCl ₃ ) δ: 2.09 (2H, m), 2.91 (2H, t, J = 6.5H
z), 2.98 (3H, s), 3.83 (2H, m), 3.87 (3H, s), 3.88 (3H, s), 6.8
8 (1H, dd, J = 1.6Hz, 8.0Hz), 7.06 (1H, t, J = 7.9Hz), 7.17 (1
H, dd, J = 1.6Hz, 7.9Hz), 7.21 (1H, d, J = 16.5Hz), 7.56 (1H,
d, J = 16.5 Hz). Elemental analysis: C ₁₇ H ₂₀ N ₂ S ₂ O ₄ Calculated: C, 53.66; H, 5.30; N, 7.36; S, 16.86. Found: C, 53.71; H , 5.42; N, 7.58; S, 16.85.

Example 11 2- (2,3-dimethoxystyryl) -4- (2-dimethylaminoethyl) -4,5,6,7-tetrahydrothiazolo
[5,4-b] pyridine dihydrochloride 2- (2,3-dimethoxystyryl) -4,5,6,7-tetrahydrothiazolo [5,4-b] pyridine (1.0 g, 3.3
Mmol) and powdered potassium carbonate (1.37 g, 9.92
Mmol) was suspended in dimethylformamide solution (20 ml), N, N-dimethylaminoethyl chloride hydrochloride (0.57 g, 3.97 mmol) was added thereto, and the mixture was heated with stirring at 90 ° C. for 4 hours, and then added with water. Was added, and organic matter was extracted with a mixed solvent of chloroform and methanol. The extract was dried over magnesium sulfate and concentrated. The oily compound obtained by purifying the residue by flash column chromatography was neutralized with hydrochloric acid and recrystallized from diethyl ether-ethanol to obtain 870 mg of the title compound. (Yield 5
4.4%). Melting point 118-121 ° C (recrystallized from diethyl ether-ethanol) IR (KBr) cm ^-1 : 2694,1692,1602,1576,1505,1480,1344,1
271,1190,1064,790,750 NMR (d ₆ -DMSO) δ: 2.02
(2H, m), 2.79 (2H, m), 2.81 (3H, s), 2.83 (3H, s), 3.47 (2H,
m), 3.78 (3H, s), 3.83 (3H, s), 3.92 (2H, m), 4.54 (2H, m), 7.0
2 (1H, dd, J = 1.8Hz, 8.1Hz), 7.09 (1H, t, J = 7.8Hz), 7.33 (1
H, dd, J = 1.8Hz, 7.6Hz), 7.34 (1H, d, J = 16.4Hz), 7.54 (1H,
. d, J = 16.4Hz) Elemental _{analysis: C 20 H 27 N 3 SO} 2 · 2HCl · 2H 2 O Calculated: C, 49.79; H, 6.89 ; N, 8.71; S, 6.65; Cl, 14.70. Found: C, 49.33; H, 6.41; N, 8.21; S, 6.62; Cl, 14.37.

Example 12 2- {2- (4-methoxyphenyl) ethyl} -4,5,
6,7-Tetrahydrothiazodolo [5,4-b] pyridine The title compound is obtained from 3- {2- (4-methoxyphenyl)} propionylamino-δ-valerolactam and phosphorus pentasulfide in the same manner as in Example 1. Was obtained (yield 21.5).
%). Melting point 89-91 ° C (recrystallized from petroleum ether-diethyl ether) IR (KBr) cm ^-1 : 2952,1610,1558,1513,1490,1443,1350,
1303,1282,1242,1034,815. NMR (CDCl ₃ ) δ: 1.94 (2H, m), 2.78 (2H, t, J = 6.4H)
z), 2.95 (2H, m), 3.10 (2H, m), 3.24 (2H, t, J = 5.4Hz), 3.79
. (3H, s), 6.83 (1H, d, J = 8.6Hz), 7.14 (1H, d, J = 8.6Hz) Elemental analysis: C ₁₅ H ₁₈ N ₂ SO Calculated: C, 65.66; H , 6.61; N, 10.21; S, 11.65. Found: C, 65.42; H, 6.60; N, 10.03; S, 11.73.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 25/28 A61P 25/28 C07D 207/273 C07D 207/273 211/76 211/76 (56) References JP-A-64- 79162 (JP, A) JP-A-59-130890 (JP, A) JP-A-58-969 (JP, A) EP 351856 (EP, A2) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 513/04 343 C07D 513/04 325 A61K 31/429 A61K 31/437 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound of the formula [I] [In the formula, A represents a bond or CH ₂ , R ¹ represents a hydrogen atom or an aliphatic group, a carboxylic acyl group or a sulfonyl acyl group which may have a substituent, R ² represents a hydrogen atom or And an aromatic ring group or an aliphatic group which may have a substituent. Or a salt thereof. 2. A compound having 2 to 4 carbon atoms, wherein R ¹ is a hydrogen atom and R ² is an optionally substituted aromatic ring group or an optionally substituted aromatic ring group. The compound according to claim 1, which is an alkenyl group. 3. A compound of the formula [II] Wherein, A, R ¹ and R ² are as defined in claim 1] preparation of a compound according to claim 1, characterized in that Ru is reacted with sulfurizing agent a compound represented by. [4] A compound containing the compound according to [1].
Central nervous system disorder inhibitor.