JPH0770136A - New condensed thiazole derivative - Google Patents

Abstract

PURPOSE:To obtain a new condensed thiazole derivative having 5-HT3 receptor agonistic activity and useful e.g. as an agent for the treatment of diseases such as digestive system disorder. CONSTITUTION:A compound of formula I (ring A is thiophene ring, benzothiophene ring, pyrrole ring, N-benzoylpyrrole ring, pyridine ring, pyridine- N-oxide ring, indole ring, N-benzoylindole ring, quinoline ring or quinoline-N- oxide ring; L and La are lower alkylenes; Im is imidazole ring; Im is bonded to L through cyclic C atom) or its pharmacologically permissible salt, e.g. 2-(4- imidazolylmethyl)-4,5-dihydrothieno[3,2-e]benzothiazole. The compound can be produced by reacting an alpha-halogenoketone compound of formula II (X is a halogen) with an amide compound of formula III (Im<1> is Im which may be protected at the ring-forming imino) to form a cyclized product and optionally removing the protecting group from the product.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to pharmaceuticals, especially 5-HT ₃
The present invention relates to a novel condensed thiazole derivative useful as a receptor agonist or a pharmaceutically acceptable salt thereof.

[0002]

The compounds of the present invention act as effective and selective agonists of neuronal serotonin (5-HT) receptors located in the primary afferents of the enteric nervous system or central nervous system. Receptors of this type currently believed to 5-HT ₃ receptor. The compound of the present invention exerts its action by releasing acetylcholine from the efferent nerve endings in the digestive tract. Stimulation of acetylcholine receptors in the gastrointestinal tract is known to enhance gastrointestinal motility and improve gastrointestinal dysfunction [Goodman and Gilman's
The Pharmacological Basis of Therapeutics 8th edi
tion, p125, (1990), Pergamon Press]. Furthermore, in the central nervous system, 5-HT ₃ receptors are present in the presynaptic region,
It is known that the stimulation suppresses nerve activity [J. Neurosci., 11, 1881 (1991)].

Therefore, 5-HT ₃ receptor agonists are considered to be particularly useful for digestive system disorders.

To date, no compound having a selective agonistic activity for the 5-HT ₃ receptor has been found, but
The present inventors have to thiazole derivatives as disclosed in WO92 / 07,849, it has reported that there is a selective agonist activity 5-HT ₃ receptor.

[0005]

DISCLOSURE OF THE INVENTION The present inventors
Further studies have been conducted on the agonistic activity of T ₃ receptor, and Bez, which has been conventionally regarded as an index of 5-HT ₃ receptor agonistic activity,
old-Jarisch reflection [ASPaintal et al., Physiol. Re
v., 53, 159 (1973 )] indicator independent 5-HT ₃ receptor agonist activity and, namely 5-H via 5-HT ₃ receptor
Focusing on the contractile action of T on the isolated colon of guinea pig, as a result of proceeding with synthetic research, it was found that a 2- (imidazolyl) alkyl-substituted condensed thiazole derivative has excellent 5-HT ₃ receptor agonistic activity, and completed the present invention. did.

[0006]

According to the present invention, there is provided a fused thiazole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0007]

[Chemical 2]

(The symbols in the formulas have the following meanings.

Ring A: thiophene ring, benzothiophene ring, pyrrole ring, N-benzoylpyrrole ring, pyridine ring, pyridine-N-oxide ring, indole ring, N-benzoylindole ring, quinoline ring, or quinoline-N.
-Oxide ring L and La: same or different, lower alkylene group, Im: imidazole ring. However, Im is bonded to L at a carbon atom on the ring. ) The condensed thiazole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof has a high affinity for 5-HT ₃ receptor and 5-concentration action in guinea pig isolated colon is used as an index. It is characterized by having HT ₃ receptor agonistic activity.

The compounds of the present invention will be described in detail below.

In the definition of general formulas herein, "lower"
Unless otherwise specified, the term means a straight or branched carbon chain having 1 to 6 carbon atoms.

Therefore, the "lower alkylene group" represented by L and La is methylene group, ethylene group, methylmethylene group, trimethylene group, 1-methylethylene group, 2-
Methylethylene group, tetramethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 3-methyltrimethylene group, 1-ethylethylene group, 2-ethylethylene group, 1,2-dimethylethylene group, propyl Methylene group, pentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene group, 1-ethyltrimethylene group, 2-ethyltrimethylene group, 3 -Ethyltrimethylene group, 1,1-dimethyltrimethylene group,
2,2-dimethyltrimethylene group, 3,3-dimethyltrimethylene group, hexamethylene group, 1-methylpentamethylene group, 2-methylpentamethylene group, 3-methylpentamethylene group, 4-methylpentamethylene group, Examples thereof include a 5-methylpentamethylene group, a 1,1-dimethyltetramethylene group, and a 4,4-dimethyltetramethylene group. Among them, a linear or branched C _{1 to} C ₄ alkylene group, particularly a linear or branched chain. C ₁ -C ₃ alkylene groups of are preferred.

Ring A has a nitrogen atom or a sulfur atom.
To 6 heterocycles, which may be condensed with a benzene ring, which may be substituted at the N-position with a benzoyl group, and which may be optionally oxidized at the N-position, And the heterocyclic group portion is condensed with a ring containing La.

The compound (I) of the present invention forms an acid addition salt. The present invention also includes a pharmaceutically acceptable salt of compound (I), and examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, Acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
Examples thereof include acid addition salts with organic acids such as carbonic acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid and glutamic acid, and salts with bases such as inorganic bases such as potassium, sodium, magnesium and calcium.

Further, the compound of the present invention has 1H and 3H tautomers due to the presence of the imidazole ring. Also,
Some groups may contain an asymmetric carbon atom. The present invention includes isolated isomers and mixtures thereof.

Further, the compound of the present invention may be isolated as a hydrate, a solvate, or a polymorphism, and the present invention also includes these substances.

(Production Method) The compound (I) of the present invention and a pharmaceutically acceptable salt thereof are produced by applying various synthetic methods utilizing the characteristics based on the kind of the basic skeleton or the substituent. can do. At that time, in the production technique, the ring-forming imino group (> NH) of the compound of the present invention is optionally substituted with a suitable protecting group, that is, a functional group which can be easily converted into the ring-forming imino group (> NH). Sometimes effective. Examples of such protecting groups include, for example, “Protective Groups in Organic Synth” by Greene and Wuts.
The protective groups described in "esis", 2nd edition can be mentioned, and these can be appropriately used depending on the reaction conditions.

Hereinafter, typical methods for producing the compound (I) of the present invention and salts thereof will be exemplified.

First production method (ring closure reaction)

[0020]

[Chemical 3]

(In the formulae, ring A, La, L and Im have the above-mentioned meanings, and other symbols have the following meanings.

A ¹ ring: the same ring as A ring in which the ring-forming imino group may be protected, X: halogen atom, Im ¹ : the same group as Im in which the ring-forming imino group may be protected. The compound (I) of the present invention is obtained by reacting an α-halogenoketone compound represented by the general formula (II) with a thioamide compound represented by the general formula (III) or a salt thereof to effect ring closure, and then, if desired, a protecting group. Can be produced by removing

Examples of the halogen atom represented by X include iodine atom, bromine atom and chlorine atom.

The reaction is carried out using isopropanol, methanol,
Alcohol-based solvent such as ethanol or hydrous alcohol-based solvent, etc., in an inert organic solvent for the reaction, using the reaction-corresponding amount of (II) and (III), or one of them in an excess mole, at room temperature or under heating, preferably by heating under reflux. It is advantageous to do it below.

The protecting group can be removed by a conventional method. For example, when a trityl group or a benzhydryl group is used as a protecting group for the ring-forming imino group, it can be easily removed by acid or catalytic reduction. As the acid, hydrochloric acid, acetic acid, trifluoroacetic acid or a mixture of these acids and dioxane is used, and the catalytic reduction can be carried out in the presence of a catalyst such as palladium carbon, palladium oxide, palladium hydroxide, platinum, platinum oxide, Raney nickel. it can.

When the protecting group is a substituted or unsubstituted benzyloxycarbonyl group or the like, the catalytic reduction similar to the above is suitable, and the acid treatment similar to the above is used in some cases. For other urethane type protecting groups such as tert-butoxycarbonyl group, the same acid treatment as above is advantageous.

Second production method (interconversion between target compounds A)

[0028]

[Chemical 4]

(In the formula, La, L and Im have the above-mentioned meanings, and the A ² ring means a pyrrole ring or an indole ring) In the compound of the present invention, a fused thiazole in which the A ring is a pyrrole ring or an indole ring The derivative (Ib) can be produced by debenzoylating the corresponding A ring from the N-benzoylpyrrole derivative (Ia).

For this debenzoylation, it is advantageous to apply a method of treating with an alkali.
In an alcohol-inert solvent such as ethanol or isopropanol or a hydroalcoholic solvent,
It is suitable to add an alkali such as sodium hydroxide or potassium hydroxide or an aqueous solution thereof, and usually perform the reaction at room temperature, if necessary, while heating.

Third method (interconversion between target compounds B)

[0032]

[Chemical 5]

(In the formula, La, L and Im have the above-mentioned meanings, and the A ³ ring means a pyridine ring or a quinoline ring.) In the compound of the present invention, the A ring is a pyridine-N-oxide ring or a quinoline. The N-oxide compound (Id) which is a -N-oxide ring can be produced by oxidizing the compound (Ic) in which the corresponding A ring is a pyridine ring or a quinoline ring.

For this N-oxidation, a conventional method for N-oxidizing the nitrogen atom of a nitrogen-containing aromatic heterocycle can be applied. As the oxidant, m-chloroperbenzoic acid, perbenzoic acid, Organic peracids such as peracetic acid, hydrogen peroxide and tert-
Hydroperoxides such as butyl hydroperoxide and tert-amyl hydroperoxide can be used.

The reaction is usually carried out at room temperature by adding an oxidizing agent to compound (Ic) in a solvent inert to the reaction such as dichloromethane, dichloroethane, methanol, ethanol, tert-butyl alcohol, tert-amyl alcohol, ether or water. When hydroperoxide is used as an oxidant, it may be effective to treat it under the catalyst of vanadium or molybdenum.

The compound (I) of the present invention thus produced is isolated and purified as a free compound, its salt, hydrate, solvate and the like. The compound of the present invention (I)
The pharmaceutically acceptable salt of can also be produced by subjecting to an ordinary salt forming reaction.

Isolation and purification are carried out by applying ordinary chemical operations such as extraction, fractional crystallization, recrystallization and various fractionation chromatography.

Tautomers can be separated by utilizing the difference in physicochemical properties between isomers.

The racemic compound may be prepared by using an appropriate starting material compound or by a general racemic resolution method [for example, a method of conducting a diastereomeric salt with a general optically active acid (tartaric acid, etc.) and performing optical resolution, etc. ] It can lead to a stereochemically pure isomer. The mixture of diastereomers can be separated by a conventional method, for example, fractional crystallization or chromatography.

[0040]

INDUSTRIAL APPLICABILITY The compounds of the present invention show a remarkable effect on 5-HT ₃ receptor agonistic activity, particularly on the contractile activity of isolated guinea pig colon. The action will be described below together with the measuring method.

1) 5-HT ₃ Receptor Agonist Activity The distal colon of a Hertley male guinea pig (500 to 800 g) was excised and a section of about 20 mm was prepared.

The contraction response was measured isometrically by suspending it in the longitudinal direction of the Magnus tube.

5-HT evoked a dose-dependent contractile response at a concentration of 0.1 to 30 μM and showed a maximum response at 10 to 30 μM (the action of 5-HT is mediated by the 5-HT ₃ receptor: J .Pharmacol. Exp. Ther., 259, 15-21, 1991).

The action of the compound was determined by 5-HT in each specimen.
It is shown as a relative value by comparison with the action of.

Max. Response is shown as a percentage of the maximum reaction by the compound when the maximum contraction reaction by 5-HT is 100%, and Relative potency is the E of 5-HT.
The EC ₅₀ value of the compound when the C ₅₀ value is used as the standard (1) is shown as a relative value.

[0046]

[Equation 1]

The compound of the present invention showed a concentration-dependent contractile action on the isolated guinea pig colon at 300 µM or less.

The contractile action of the isolated guinea pig colon by the compound of the present invention is antagonized by 0.3 μM of the compound described in Example 44 of JP-A-3-223278 which is a selective 5-HT ₃ receptor antagonist. It was

As a result, it was shown that the compound of the present invention, its salt, its solvate, and its hydrate are potent 5-HT ₃ receptor agonists.

The preferred compounds of the present invention have the above-mentioned activities, while the Bezold-Jarisch reflex (S. Paintal), which has been conventionally regarded as an index of 5-HT ₃ receptor agonistic activity.
et al., Physiol. Rev., 53, 159 (1973)) is a compound in which the 5-HT ₃ receptor agonistic activity is hardly recognized.

The present invention includes compounds having a 5-HT ₃ receptor antagonistic action, and such compounds form another aspect of the present invention. Such compounds are used for the pharmaceutical applications described in the patent applications of the present inventors regarding the tetrahydrobenzimidazole derivative, for example, JP-A-3-223278, for example, anticancer agents such as cisplatin and suppression of vomiting due to irradiation, migraine. , Prophylactic / therapeutic effects for complex headache, trigeminal neuralgia, anxiety symptoms, gastrointestinal motility disorder, peptic ulcer, irritable bowel syndrome, etc. can be expected.

The compound (I) of the present invention or a pharmaceutically acceptable salt, solvate or hydrate thereof acts specifically on the neuronal 5-HT ₃ receptor of the enteric nerve, Digestive system disorders, such as senile, flaccid, and rectal constipation, acute / chronic gastritis, gastric / duodenal ulcer, gastric neuropathy, gastric ptosis, reflux esophagitis, diabetes, and other gastrointestinal motility disorders , It is useful in the treatment of gastrointestinal dysfunction after anesthesia, gastric stasis, dyspepsia, bloating, etc. Further, it can be used for treatment of diseases associated with pancreatic insufficiency such as fat malabsorption.

Furthermore, the compounds of the present invention are also useful in the treatment of conditions such as mental disorders (eg schizophrenia and depression), anxiety, memory disorders.

The compound (I) of the present invention, a pharmaceutically acceptable salt thereof, a hydrate thereof and the like are tableted using a commonly used pharmaceutically acceptable carrier, excipient or other additive. , Powder, fine granules, capsules, pills, liquids, injections,
It is prepared as a suppository, ointment, patch, etc. and administered orally (including sublingual administration) or parenterally.

The carriers and excipients for the preparation include solid or liquid non-toxic medicinal substances. Examples of these include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol and the like, and other commonly used ones.

[0056]

EXAMPLES The present invention will be described in more detail with reference to the following examples. The raw material compounds of the present invention include novel compounds. A reference example is shown to show the production method of the raw material compounds.

Reference Example 1 To a solution of 0.25 g of 5,6-dihydro-7H-1-pyrindin-7-one in 10 ml of acetic acid was added 1 ml of a 25% hydrobromic acid acetic acid solution, and 0.10 ml of bromine was added dropwise. After stirring at room temperature for 30 minutes, the solvent was evaporated and the obtained residue was washed with diethyl ether to give 0.55 g of 6-bromo-
5,6-dihydro-7H-1-pyrindin-7-one
A hydrobromide salt was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ: 3.34 (1H, dd), 3.8-4.1 (1H,
m), 5.05 (1H, dd) Reference Example 2 Similar to Reference Example 1, from 5,6,7,8-tetrahydroquinolin-8-one to 7-bromo-5,6,7,8-tetrahydroquinoline. -8-one hydrobromide was obtained.

Mass spectrum (m / z): 225,227
(M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.4-2.5 (1H, m), 2.7-2.8 (1
H, m), 3.1-3.2 (2H, m), 5.23 (1
H, dd) Reference Example 3 a) 1,2,3,4-tetrahydrocarbazole-4-
Sodium hydride (60%) 0.40 g was added to a 1.85 g dimethylformamide 25 ml solution and stirred at room temperature for 30 minutes, then benzoyl chloride 1.41 g dimethylformamide 10 ml was added and stirred at room temperature for 1 hour. . Ethyl acetate was added to the residue obtained by distilling off the solvent,
It was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by silica gel column chromatography (chloroform).
2.07 g of 9-benzoyl-1,2,3,4-tetrahydrocarbazol-4-one was obtained.

Nuclear magnetic resonance spectrum (CDCl ₃ , TM
S internal standard) δ: 2.19 (2H, quintuplet), 2.61 (2H,
t), 2.98 (2H, t), 7.0-7.9 (7H,
m), 8.1-8.4 (2H, m) b) 9-benzoyl-1,2,3,4-obtained in a)
To a solution of tetrahydrocarbazol-4-one (1.16 g) in tetrahydrofuran (12 ml) was added phenyltrimethylammonium tribromide (1.50 g) in tetrahydrofuran (4 ml), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were filtered off, the solvent was evaporated, ethyl acetate was added,
The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform: hexane = 3: 1) to give 0.65 g of 9-benzoyl-3-bromo-1,
2,3,4-Tetrahydrocarbazol-4-one was obtained.

Mass spectrum (m / z): 368,370
(M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 4.65 (1H, t) Example 1 5-Bromo-4,5,6,7-tetrahydrobenzo [b] thiophene-4 -One 0.92 g (4 mmol)
And 4-imidazolylthioacetamide hydrochloride 0.71 g
(4 mmol) was dissolved by heating in 30 ml of 2-propanol and refluxed for 16 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure and the obtained residue was partitioned between chloroform and a saturated aqueous solution of sodium hydrogen carbonate. The aqueous layer was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was subjected to silica gel column chromatography (chloroform: methanol: 29% aqueous ammonia = 5).
It was purified with 00: 10: 1) and 0.13 g of 2- (4-
Imidazolylmethyl) -4,5-dihydrothieno [3
2-e] benzothiazole was obtained. This free base was dissolved in methanol, 0.055 g of fumaric acid was added for crystallization, and recrystallization from methanol gave 0.13 g of fumarate.

Melting point 176-177 ° C. Methanol Elemental analysis value (as C ₁₃ H ₁₁ N ₃ S ₂ .C ₄ H ₄ O ₄ ) C (%) H (%) N (%) S (%) theoretical value 52. 43 3.88 10.79 16.47 Experimental value 52.20 3.94 10.67 16.17 Mass spectrum value (m / z): 273 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , inside TMS) Standard) δ: 3.05 (6H, s), 4.23 (2H, s),
6.63 (2H, s), 7.05 (1H, s), 7.2
9 (1H, d), 7.37 (1H, d), 7.72 (1
H, s), 9.0-11.0 (2H, br) Example 2 2- (4-Imidazolylmethyl) -7H-thieno [3 ', 2': 4,5] cyclopenta [1,2-d]. ] Thiazole Raw material compound: 5-Bromo-4,5-dihydro-6H-cyclopenta [b] thiophen-6-one, 4-imidazolylthioacetamide hydrochloride Melting point 164-166 ° C Methanol-ethyl acetate Elemental analysis value (C ₁₂ H ₉ N ₃ S ₂ ) C (%) H (%) N (%) S (%) Theoretical value 55.57 3.50 16.20 24.73 Experimental value 55.30 3.44 15.97 24. 80 Mass spectrum (m / z): 259 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 3.65 (2H, s), 4.42 (2H, s),
6.99 (1H, s), 7.09 (1H, d), 7.2
4 (1H, d), 7.63 (1H, s) Example 3 2- (4-imidazolylmethyl) -8H-thiazolo [5,4-g] [1] pyrindine Raw material compound: 6-bromo-5,5 6-dihydro-7H-1
- pyrindine-7-one hydrobromide, 4-imidazolylmethyl thioacetamide hydrochloride mp 189-191 ° C. Ethyl acetate Mass spectrometry value (m / z): 254 ( M +) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 3.91 (2H, s), 4.34 (2H, s),
7.06 (1H, s), 7.19-7.22 (1H,
m), 7.63 (1H, s), 7.90 (1H, d),
8.45-8.47 (1H, m) Example 4 2- (4-Imidazolylmethyl) -4,5-dihydrothiazolo [5,4-h] quinoline Raw material compound: 7-Bromo-5,6,6 7,8-Tetrahydroquinolin-8-one hydrobromide, 4-imidazolylmethylthioacetamide hydrochloride Melting point 198-200 ° C Ethyl acetate-methanol Elemental analysis value (as C ₁₄ H ₁₂ N ₄ S.0.1H ₂ O ) C (%) H (%) N (%) S (%) Theoretical value 62.25 4.55 20.74 11.87 Experimental value 62.55 4.55 20.55 11.97 Mass spec value (m / Z): 268 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.96-3.06 (4H, m), 4.23 (2)
H, s), 7.03 (1H, s), 7.19 (1H, d
d), 7.61-7.65 (2H, m), 8.40 (1
H, dd), 12.01 (1H, br) Example 5 a) 1-Benzoyl-5-bromo-4,5,6,7-
0.52 g of tetrahydroindol-4-one and 0.29 g of 4-imidazolylthioacetamide hydrochloride were dissolved in 15 ml of ethanol with heating, and the mixture was heated under reflux for 15 hours.
The reaction solution was cooled, the solvent was evaporated under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was extracted with 1N hydrochloric acid. The aqueous layer was neutralized with aqueous sodium hydrogen carbonate solution and extracted with chloroform.
It was dried over anhydrous magnesium sulfate. Evaporate the solvent,
0.21 g of 6-benzoyl-2- (4-imidazolylmethyl) -4,5-dihydro-6H-pyrrolo [3,2-
d] Benzothiazole was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ: 3.13 (2H, t), 4.19 (2H, s),
6.50 (1H, d), 6.90 (1H, d), 7.0
1 (1H, s), 7.6-7.9 (6H, m) b) The compound obtained in a) was dissolved in 4 ml of methanol and 0.2 ml of 5N sodium hydroxide aqueous solution was added for 20 minutes. It was stirred. Methanol-chloroform (5: 1) was added to the residue obtained by distilling off the solvent, the insoluble material was filtered off, and the residue obtained by distilling off the solvent was subjected to silica gel column chromatography (chloroform: methanol: 29%). Ammonia water = 200: 10: 1) and then crystallized from 2-propanol-acetonitrile to give 0.0
54 g of 2- (4-imidazolylmethyl) -4,5-dihydro-6H-pyrrolo [3,2-d] benzothiazole were obtained.

Melting point 192-195 ° C. 2-propanol-acetonitrile Elemental analysis value (as C ₁₃ H ₁₂ N ₄ S.0.1H ₂ O) C (%) H (%) N (%) S (%) theoretical value 60.49 4.76 21.70 12.42 Experimental value 60.34 4.75 21.77 12.39 Mass spectrum (m / z): 256 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.83 (2H, t), 2.94 (2H, t),
4.15 (2H, s), 6.16 (1H, d), 6.5
9 (1H, d), 6.96 (1H, brs), 7.57
(1H, s), 10.78 (1H, brs), 11.9
3 (1H, br) Example 6 0.63 g of 9-benzoyl-3-bromo-1,2,3,4-tetrahydrocarbazol-4-one and 4-imidazolylthioacetamide hydrochloride were prepared in the same manner as in Example 5a). From 0.30 g, 0.21 g of 6-benzoyl-2- (4-imidazolylmethyl) -4,5-dihydro-6H-thiazolo [5,4-c] carbazole was isolated.

B) Using 0.21 g of the compound obtained in a) and treating in the same manner as in Example 5b), 2- (4-imidazolylmethyl) -4,5-dihydro-6H-thiazolo [5 , 4-c] Carbazole acetonitrile solvate was obtained.

Melting point 117-119 ° C. 2-propanol-acetonitrile Elemental analysis value (as C ₁₇ H ₁₄ N ₄ S.CH ₃ CN) C (%) H (%) N (%) S (%) theoretical value 65. 68 4.93 20.16 9.23 Experimental value 65.55 5.00 20.11 9.00 Mass spectrum value (m / z): 306 (M ⁺ ) Nuclear magnetic resonance spectrum (DMSO-d ₆ , inside TMS) Standard) δ: 2.07 (3H, s), 3.07 (6H, s),
4.25 (2H, s), 7.02-7.05 (3H,
m), 7.32-7.35 (1H, m), 7.60 (1
H, s), 7.89-7.91 (1H, m), 11.2
5 (1H, s), 11.97 (1H, br) Example 7 2- (4-imidazolylmethyl) -4,5 of Example 4
0.10 g of m-chloroperbenzoic acid (80%) was added to a solution of 0.10 g of dihydrothiazolo [5,4-h] quinoline in 20 ml of dichloromethane, and the mixture was stirred at room temperature for 3 hours.
The solvent was distilled off and the residue was subjected to alumina column chromatography (chloroform: methanol = 100: 1), silica gel column chromatography (chloroform: methanol: 29% ammonia water = 200: 10: 1),
Further purification by thin layer chromatography (chloroform: methanol: 29% aqueous ammonia = 100: 10: 1), crystallization from ethyl acetate-methanol, and 0.0
27 g of 2- (4-imidazolylmethyl) -4,5-dihydrothiazolo [5,4-h] quinoline 9-oxide was obtained.

Melting point 197-200 ° C. (dec.) Ethyl acetate-methanol Mass spec (m / z): 285 (M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 2.95 (4H, s), 4.22 (2H, s),
7.07 (1H, brs), 7.17-7.22 (2
H, m), 7.62 (1H, s), 8.12 (1H, d
d), 11.98 (1H, br) Table 1 below shows the structures of the example compounds.

[0068]

[Table 1]

In addition to the exemplified compounds described above, other compounds of the present invention will be shown using the format of the table below. These compounds can be synthesized using the synthetic routes and methods described in the above-mentioned flow charts and examples, and their variations known to those of ordinary skill in the art, and require special experimentation. is not.

[0070]

[Table 2]

[0071]

[Table 3]

[0072]

[Table 4]

[0073]

[Table 5]

[0074]

[Table 6]

[0075]

[Table 7]

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 31/425 ACL 9454-4C AEN 9454-4C 31/435 AAE 9454-4C ACP 9454-4C // (C07D 513 / 04 277: 00 333: 00) (72) Keiji Miyata, 5 Pastoral Life 101, 4-15 Azuma, Tsukuba, Ibaraki Prefecture (72) Inventor Mitsuaki Ota, 3-9 Kinindai, Taniwahara Village, Tsukuba-gun, Ibaraki Prefecture 11

Claims (1)

[Claims] 1. General formula (I) (Chemical formula 1) (The symbols in the formulas have the following meanings: A ring: thiophene ring, benzothiophene ring, pyrrole ring, N-benzoylpyrrole ring, pyridine ring, pyridine-N-oxide ring, indole ring, N-benzoylindole ring, Quinoline ring or quinoline-N-oxide ring L and La: same or different, lower alkylene group, Im: imidazole ring, provided that Im is bonded to L at a carbon atom on the ring) Or a pharmaceutically acceptable salt thereof.