JPH02255687A - Tricyclic compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I {R1 is (halogeno) lower alkyl, lower alkenyl, (substituted) phenyl, etc.; R2 is H, halogen, cyano or lower alkyloxy; R3 is halogen or group shown by formula II to formula IV [R5 and R10 are H, lower alkyl, etc.; R6, R7 and R11 are H, (halogeno) lower alkyl, etc.; R8 is H, halogen, lower alkyl, etc.; R9 is H, halogen, lower alkyl, etc.; n is 3-5]; R4 is halogen, -OR12, -SR13 or -NR14R15 (R12 to R15 are H, lower alkyl, etc..; R15 is H or lower alkyl); X is S or O}. EXAMPLE:5-Amino-9-cyclopropyl-6,7-dirluoro-2,3,4,9-tetrahydroisothiazo lo[5,4- b]quinoline-3,4-dione. USE:An antimicrobial agent. PREPARATION:A 2-mercaptoquinolone derivative shown by formula V (R is lower alkyl) is reacted with an electrophilic aminating agent in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel tricyclic compounds, namely 5-1 substituted inthazoloquinolines or inxazoloquinolines/derivatives and salts thereof, which exhibit excellent antibacterial activity.

Prior Art Japanese Patent Application Laid-Open No. 187472/1987 discloses various inthazoloquinoline/and inxazoloquinoline derivatives. However, these compounds do not have a substituent at the 5-position.

OBJECTS OF THE INVENTION The present invention provides novel 6-substituted inthazoloquinolines and inxazoloquinoline derivatives that exhibit excellent antibacterial activity.

Structure of the Invention The compound of the present invention has the following general formula (I) [wherein R+ is a lower alkyl group, a herogeno lower alkyl group, a lower alkenyl group, a cycloalkyl group, or a phenyl group which may have a substituent] R2 means a hydrogen atom, a halogen atom, a cyano group or a lower alkyloxy group, R3 means a halogen atom or a group represented by the following formula, where R11 and Rho are hydrogen Atom, lower alkyl group or acyl IA (the acyl group may be substituted with a halogen atom), and Re, R7 and RII are the same or different and represent a hydrogen atom, a lower alkyl group or a halogen lower alkyl group. or R6 and R7 may be combined to form a direct bond or -(CH2)m-, where m means 1 or 2, and Rs is a hydrogen atom, a halogen atom, a lower atom, , a kill group, a hydroxy lower alkyl group, a water M group, a mono- or di-lower alkylamino-7 group, an amino-lower furkyl group, or a mono- or di-lower alkylamino lower alkyl group, R9 is a hydrogen atom, a halogen atom, means a lower alkyl group or a lower alkyloxy group, n means an integer of 3.4 or 5, R4 is a halogen atom, -. Rat, SR+3 or NR+aRIs, where RII1 R13 and R14 mean a hydrogen atom, a lower alkyl group, a benzyl group which may have a disubstituted group, or an acyl group which may be substituted with a halogen atom; RII means a hydrogen atom or a lower alkyl group, and X means a sulfur atom or an oxygen atom. ] and salts thereof.

In this specification, examples of the halogen atom include fluorine, chlorine, and bromine. Examples of lower alkyl include methyl, ethyl, propyl, butyl, inbutyl, t-butyl, pentyl, neopentyl, and the like. Examples of the lower alkenyl group include vinyl, allyl, 1-propenyl, impropenyl, and the like.

Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the substituent on the phenyl group or benzyl group which may have a substituent include halogen, lower alkyl, lower alkyloxy, halogeno lower alkyl, and hydroquine.

Examples include nitro amide 7. Examples of the acyl group optionally substituted with a halogen atom include tolumyl, acetyl, propionyl, and butyryl.

Examples include imbutyryl, pivaloyl, trifluoroacetyl, chloroacetyl, and the like.

Salts of the compounds of the present invention include salts with inorganic acids such as hydrochloric acid and phosphoric acid; acetic acid, lactic acid, oxalic acid, succinic acid, meta/sulfo7 rll, maleic acid! [I Maron Wi, salts with amyl acids such as glufonic acid, asparagic acid, salts with acidic amino acids such as glutamic acid/rI&.

The compound represented by the general formula (Ri) is the compound represented by the following formula (wherein, Ra
t R21R31Ra and X are the same as above. ) These tautomers are also included in the compounds of the present invention.

Compounds of the invention may also exist as hydrates. Therefore, such forms are naturally included in the compounds of the present invention.

The compounds of the present invention include those that have asymmetric carbon atoms, and may exist as optically active forms. Therefore, these optically active substances are included in the compounds of the present invention.

Furthermore, some of the compounds of the present invention have multiple asymmetric carbon atoms and may exist as different stereoisomers. These stereoisomers are also included in the compounds of the present invention.

The method for producing the compound of the present invention will be explained below.

(1) The compound of the present invention in which X is a sulfur atom has the following general formula (■) (wherein, R means a lower alkyl group, R1゜R2,R
3 and R4 are the same as above. It can be produced by reacting a 2-mercaptoquinolone derivative represented by ) with an electrophilic aminating agent in the presence of a base, and isolating the product by a conventional method.

In this reaction, the starting material compound (II) is an alcohol such as methanol, ether, or 1,2-jethoxyethane.

Tetrahydroxide, dioxa/l, hydroxides such as sodium hydroxide and potassium hydroxide, sodium carbonate and potassium carbonate in an inert solvent such as dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, or a mixed solvent of these and water. Carbonates such as 1 m carbonates such as sodium bicarbonate and potassium bicarbonate, potassium heptadide, and sodium hydride.

Sodium ethoxide, potassium t-butoxide.

carried out by stirring with an electrophilic aminating agent in the presence of a base such as butyllithium, triethylamine 7.1.8-diazabicyclo[a4.0]-7-undecene (DIIU), preferably under a nitrogen stream. The reaction temperature that can be achieved is usually in the range of -20 to 150°C, preferably in the range of -10 to 00°C.

Examples of electrophilic aminating agents include O-alkylhydroxylamines, O-arylhydroxylamines I
O-amylhydroxylamine, hydroxylamine-
Known hydroxylamines such as 0-sulfonoic acid, 0-diphenylphosphinylhydroxylamine, chlorami 7, etc. can be mentioned.

The raw material compound (■) used in this reaction is, if possible,
The amine 7 group that does not participate in the reaction may be used in a protected form, and the protecting group may be removed by the reaction method. Any protecting group may be used as long as it can be removed without destroying the structure of the compound of the present invention formed by the reaction, such as peptide, amino sugar, PAm, or β-
Protective FJ, which is commonly used as a protecting group in the field of chemistry of lactam compounds! is used. Preferred protecting groups include, for example, acetyl and trifluoroacetyl.

Easily hydrolyzable groups such as ethoxycarbonyl, or
Examples include easily hydrolyzable groups such as zyl groups.

■ The compound of the present invention in which X is an oxygen atom has the following general formula (Ill) (wherein R'' means a lower alkyl group, k means 1 or 2, R1, R2, R3, Ra and R is the same as above.) It can be produced by reacting the quinophyl derivative 4 represented by (R is the same as above) with droxyurea in the presence of a base, and isolating the product by a conventional method.

This reaction can be carried out under the same conditions as in reaction (1) above.

If possible, the raw material compound (III) used in this reaction is used in a protected form with the amine 7 group that does not participate in the reaction as described in (1) above, and after the completion of the reaction, the FJ is protected by a conventional method. Groups may be removed.

Starting compounds (■) and (III) are new compounds and can be produced according to the following reaction formula.

(Left below) ↓ (In the formula, 2 means a halogen atom, R'' means a lower alkyl group, a lower alkylokynemethyl group or a substituted benzyl group, R1, R2, R3, Ra
, R, R' and k are the same as above.) According to this reaction formula, carboxylic acid (1) is converted into acid chloride by a conventional method, and the resulting compound is condensed with malonic acid ester in the presence of a base. The compound is deesterified to β-ketoester' (2). This is reacted with a substituted inthiocyanate and an optionally substituted alkyl halide in the presence of a base to obtain anaminoketoester (3).

This is then cyclized in the presence of a base to give a chimeron derivative (4). The starting compound (■) can be produced by treating the compound (4) in which R'' is a lower alkyloxymethyl group or a substituted benzyl group with an acid.

Further, the starting compound (I[I) can be produced by treating the compound (4) in which R'' is a lower alkyl group with an oxidizing agent such as metachloroperbenzoic acid in a solvent.

(The compound of the present invention in which 311L+ is a group other than a halogen atom has the following general formula (mV) (wherein, Z means a halogen atom, R1, R2゜R4
and It can be produced by isolating the product using conventional methods.

This reaction is carried out in an inert solvent at 10-180°C, preferably at 2
This can be carried out by stirring the starting compounds (IV) and (V) at 0 to 130°C for 10 minutes to 24 hours, preferably 30 minutes to 15 hours.

As a solvent, for example, dimethylformamide.

Ethanol, methanol, acetonitrile, water.

Examples include chloroform and pyridine. These solvents may be used alone or in combination.

This reaction is generally carried out in the presence of an acid acceptor using the starting compound (V) in an equivalent or excess amount relative to the starting compound (IV); It may also be used to serve as an acid receptor.

Examples of acid acceptors include triethylamine.

Dimethylanili7. N,N-diisopropylethylamine, 1,8-diazabicyclo[5,4,O coma-undecene (DI3U), secondary bases such as pyridine, hydroxides such as sodium hydroxide and potassium hydroxide, sodium carbonate and potassium carbonate. and carbonates such as sodium bicarbonate and potassium bicarbonate.

If possible, the starting materials/compounds (IV) and/or (V) used in this reaction are used in a form with the amine 7 group that does not participate in the reaction protected, as described in reaction (1) above. After completion of the reaction, the protecting group may be removed by a conventional method.

Starting compound (IV) can be produced by the reaction (1) or 2).

(4) The compound of the present invention in which Ra is a group other than a halogen atom has the following general formula (Vl) (wherein, Z means a halogen atom, and R11R2゜R3
and It can be produced by isolation according to a method.

This reaction is carried out in fI medium in the presence or absence of a base as an acid acceptor at 10-180°C, preferably 20-130°C.
At ℃, the raw material compound (Vl) and (■) are 109~
This can be carried out by stirring for 24 hours.

Examples of solvents include alcohols such as methanol and ethanol, Tricrete, and chloroform.

Examples include toluene, xylene, dioxane, acetonitrile, dimethylformamide, and water.

These solvents may be used alone or in combination.

Examples of bases include sodium and potassium.

Examples include sodium hydride and the acid acceptor described in reaction (3) above. Further, when the raw material compound (■) is an amine, it may be used in excess to also serve as a base.

Note that this reaction uses a reagent in which the starting compound (■) is bound to a base (for example, sodium methoxide).

It can also be carried out by using sodium ethoxide, sodium methanethiolate, etc.) and reacting it with compound (Vl).

The compound (Vl) and/or (■) used in this reaction is used, if possible, in a form with the amine group that does not participate in the reaction protected, as described in reaction fl) above, and after the completion of the reaction, The N group may be removed by conventional methods.

The compound of the present invention produced in this manner is isolated and purified according to conventional methods. tIlrIi, depending on the purification conditions,
Although it can be obtained in the form of a salt or a free form, these can be mutually converted depending on the purpose to obtain the desired form of the compound f1 of the present invention.
1 will be manufactured.

Stereoisomers of the compounds of the invention can be separated from each other by conventional methods, such as fractional crystallization, chromatographic separation, and the like. Note that the compound of the present invention having a corresponding specific configuration can also be produced by the above method using a starting compound having a specific configuration.

Optically active forms of the compounds of the present invention can be separated by applying known methods.

Effects of the Invention The compound (1) thus obtained and its salts are both new compounds, and since they exhibit extremely excellent antibacterial activity, they are valuable as antibacterial agents. Compound (I
) or its salts can be used not only as human and veterinary medicines, but also as fish disease medicines, agricultural chemicals, food preservatives, and the like.

Next, data regarding the antibacterial activity of the compounds of the present invention are listed below.

(Left below) Antibacterial action in vitro “1 Shiyu 02 A: Staphylococcus T. ureus
209P JC-1 (S, aureus 20
9P JC-1).

B: Enoerishi 7 Cori NIIIJ JC-
2 (E, coleoptera NIIIJ JC-2>.

C: Niji I Rishi 7・] Ri P-51208 (E,
colt P-51208) D ゛ Shoe F
tnas elgi l-i! 2(P, aerug+n
osa +2>.

13 C means the compound of Example 3 (the same applies below).

”It small WFfl stop 1GN1t (MrC: u
g/ml) CtChemotherapy,
29(1), 76(+11181) according to the method of Kiga, and the results are shown in the table above.The compound of the present invention exhibits extremely excellent antibacterial activity and a broad antibacterial spectrum in the Ura Vrtro test.

Furthermore, the compounds of the present invention exhibit excellent in ViVO infection protective effects against local or systemic infections caused by various bacteria, and also exhibit good safety in general toxicity tests in animals.

When the compound of the present invention is used as an antibacterial agent in humans, the dosage varies depending on the patient's age, symptoms, route of administration, etc.; It is recommended that you do so.

The route of administration may be either oral or parenteral.

Although the compound of the present invention may be administered as a bulk powder, it is usually administered in a prepared form together with a pharmaceutical carrier. Specific examples include tablets, liquids, capsules, tt granules, fine granules, powders, syrups, injections, ointments, and the like. These formulations are prepared according to conventional methods. u Starch as a carrier for daily preparations.

Mannitol, crystalline cellulose, CMCNa, water, eta/
Substances that are commonly used in the field of pharmaceutical preparation, such as alcohols, and which do not react with the compound of the present invention are used. Examples of the carrier for injection include carriers commonly used in the field of injections such as water, physiological saline, glucose solution, and infusion preparations.

The above solutions and ointments can also be used in otorhinolaryngology and ophthalmology treatments.

EXAMPLES Next, the method for producing the compounds of the present invention will be explained in more detail with reference to Examples and Reference Examples.

Reference example 1 5-(N-acetylbenzylamino)-1-cyclopropyl-a7-difluoro-2-mercap)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester: (1) 2, 3,4.6-Tetrafluorobenzoic acid 19.
4g.

Dioxa 7200■1 and benzylamine 35.3
ml of the mixture was refluxed for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, water was added to the residue, the pH was adjusted to 3 with hydrochloric acid, and the mixture was extracted with ethyl acetate. After drying the extract, it is treated with activated carbon and compressed into bags. Ether and n-hex 7 were added to the residue, the crystals were collected by filtration, and 2-benzylamino-&4. 20.2 g of B-trifluorobenzoic acid are obtained. m, 9.140~1
41”C.

(2) 21.7 g of the above compound, 1B acetic anhydride, 8■1
A mixture of 200 parts and 1 part of chloroform is heated under reflux for 9 hours, and the reaction mixture is extracted with an aqueous solution of caustic soda having a pH of 9 to IO. The extract is adjusted to pH 3-4 with hydrochloric acid, and then extracted with ethyl acetate. After drying the extract, it was concentrated under reduced pressure, and the residue was treated with isopropyl ether. The crystals were collected by filtration, and 2-(N-
17.0 g of acetylbenzylamino)-46-dolifluorobenzoic acid are obtained. m, 9.150-153℃
.

(3) 1.6 g of the above compound, ) 70.
A mixture of 991 and toluene 1011 was cooled with water, and a toluene solution 31 of 0.62 g of ethyl chlorocarbonate was added dropwise thereto over 10 minutes. After stirring for 1 hour, the precipitate is filtered off. Separately, 780 g of 92% sodium ethoxide was added to a toluene solution of 1.67 g of diethyl malonate, and the mixture was stirred at room temperature for 1 hour, and the resulting ethanol was distilled off. The above solution is added dropwise to this solution at room temperature and stirred for 2 hours. The reaction solution is extracted with an aqueous solution of caustic soda having a pH of 10 to 10H, and the extract is adjusted to pH 3 to 4 with hydrochloric acid and then extracted with ethyl acetate. After drying the extract, it was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (eluent: chloroform) to obtain 2-
2.3 g of diethyl (N-acetylbenzylamine)-14,6-)lifluorobenzoylmalonate is obtained. To this, add lOl of water and p-toluenesulfo/fil-permanent 4
Add 80 mg and heat under reflux for 1 hour. Next, extract with ethyl acetate, dry the extract and concentrate under reduced pressure to obtain 2-(N-
1.9 g of ethyl acetylbenzylamine/)-3,4,8-trifluorobenzoylacetate is obtained.

4) Dissolve 20 g of the above compound in 720 o 1 of dioxa, add 3.8 g of powdered potassium hydroxide, and dissolve at room temperature.
The reaction mixture was stirred for an hour and concentrated under reduced pressure, and to the residue was added n-beef starch, and the glassy solid was collected by filtration. This was added to a mixture of 5.3 g of cyclopropyl thiocyanate and 1.8 ml of p-methoxybenzyl chloride, and 0 ml of toluene was added and stirred for 15 hours. To this reaction solution was added 7.0 g of potassium carbonate and 200 g of dioxane. add 1
The reaction solution was heated and stirred at θO'C for 2 hours, concentrated under reduced pressure, acidified with dilute hydrochloric acid, and then extracted with chloroform. Chloroform was distilled off to give 5-(N-acetylbenzylamino)-1-cyclopropyl-6,7-difluoro-2
-(p-methoxybenzylthio)-1,4-dihydro-
1 g of ethyl 4-oxoquinoline-3-carboxylate I is obtained as colorless crystals.

m, 9.188-174°C.

(1) Dissolve 10.3 g of the above compound in 7°1 of trifluoroacetic acid, and add 5.21 g of anisole and F-trifluorometa7 sulfo7 ill 3. The reaction solution was concentrated under reduced pressure, ether was added to the residue, and the mixture was extracted with 5% aqueous sodium hydroxide solution. After making the extract acidic with dilute hydrochloric acid, add chloroform! Extract. Chloroform is distilled off to obtain 8.1 g of the desired product.

Reference example 2 5-amino-1-cyclopropyl-&7.8-)lifluoro-a-2-mercapto-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester: (1) Known compound pentafluoroben Ethyl acetate was reacted in the same manner as in Reference Example 1 (to) to obtain 1-cyclopropyl-5,a 7.8-tetrafluoro-2-(p-
m-9 to obtain ethyl methoxybenzylthio)-1,4-dihydro-4-oxoquinoline-3-carboxylate,
No. 1 6-153℃.

■ A mixture of 36.3 g of the above compound, 18.9 g of &4-dimethoxybenzylamide and 380 g of toluene was refluxed for 2.5 hours at 111A to give 1-cyclopropyl-a7.8-)refluoro-5-( 44.5 g of ethyl 3,4-dimethoxybenzylamino)-2-(P-methoxybenzylthio)-1,4-dihydro-4-okinki/su/-3-carboxylate is obtained as pale yellow crystals.
m, P, 120-121°C.

(3) The above compound is subjected to reaction treatment in the same manner as in Reference Example 15) to obtain the desired product. m, P, 102-104°C.

Reference Example 3 1-Cyclopavir-5,6,7,8-tetrafluoro-2-mercapto-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester: Reference Example 2 (1)
! The obtained 1-cyclopropyl-5,6,7°8-tetrahydrog-2-(p-methoxybenzylthio)-1,4-
21.2 g of ethyl dihydro a-4-oxoquinoline-3-carboxylate was dissolved in 1001 of trifluoroacetic acid, and 1004 g of anisole and trifluorometa/sulfo/
Add 7.29 g of acid while stirring with water cooling, and leave at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, ether was added to the residue, and the mixture was extracted with dilute aqueous sodium hydroxide solution. The extract was acidified with diluted hydrochloric acid, extracted with chloroform, dried, and the chloroform was distilled off to obtain 15.8 g of the desired product.

m, f), 126-128°C.

Example 1 5-amino-9-cyclopropyl-a7-difluoro-
2,149-tetrahydrointhiazolo[he4-b]quinoline-3,4-dione: (1) Sodium hydrogen carbonate 9
．． Dissolve 5g in 300ml of water and dissolve hydroxylamine-
Add 5.1 g of 〇-sulfonic acid. Add to this 5-(N-
Acetylbenzylamino)-1-cyclopropyl-a7
-difluoro-2-mercapto-1,4-dihydro-4
A solution of 8.1 g of ethyl -oxoquinoline-3-carboxylate in 80 ml of tetrahydrofuran is added dropwise under a nitrogen stream. After stirring at room temperature for 2 hours, the reaction solution was made acidic with dilute hydrochloric acid, and the precipitated crystals were collected by filtration to give 5-(N-acetylbenzylamino)-9-cyclopropyl-7-difluoro-2,3, 4,9-tetrahydroisothiazo” [1l
75.2 g of b4-b]quinoline-to-4-dio are obtained as v11 colored crystals.

m, 9.275-27B”C.

(2) Add 4.6 g of the above compound to 40 μl of trifluoroacetic acid.
To this was added 4.7 ml of anisole and 3.7 ml of trifluoromethanesulfo/acid.
6. Heat and reflux the reaction solution for 6 hours under reduced pressure! After condensation, water is added to the residue and the precipitated crystals are collected by filtration to obtain the desired product 2.53.
g is obtained as slightly brown crystals.

m, 9.275-276°C (decomposition) Example 2 5-benzylamino-9-7 clop avir-a7-cyfluorost ■-tetrahydroisothiazo0 [a4-
bl+/! 77-a4-di#y: 6-(N-acetylbenzylamino)-9-cyclopropyl-mitsu-difluoro-'I,9-tetra and droisothiazolo[5,4-
b] Quinoline-3,4-dione f, 35ga, :acetic acid-
Add 20 ml of water-sulfuric acid (8:6:1) mixture and heat and stir at 100°C for 2 hours.

After cooling, water is added to the reaction solution, and the precipitated crystals are taken out and washed with water to obtain 1.0 g of the desired product.

m, 9.227-230°C Example 3 5-amino-7-(3-amino-1-pyrrolidinyl)-
9-Cyclopropyl-6-fluoro. -su a 4,9-tetrahydroisothiazolo[5,4-bl quinoline-a4
-dio/: 5-amino-9-cyclopropyl-a7-difluoro-
2,3,4,9-tetrahydroisothiazolo[to 4-b
] A mixture of 309 g of quinoline-4-dione, 7430 mg of 3-aminopyrrolidi, and 7151 mg of pyridine was heated and stirred at 90°C for 15 hours. 1. Concentrate the reaction solution under reduced pressure, add ether to the residue, and filter the precipitated crystals. take.

The crystals are suspended in 28% aqueous ammonia and stirred at room temperature for 1 hour. The crystals are collected by filtration, washed successively with water and ethanol, and then dried to obtain 323 g of the desired product.

m, 9.250-255°C (decomposition).

The following compounds of Examples 4 to 8 are obtained in the same manner as in Example 3 using the corresponding starting compounds.

Example 4 5-amino-7-(trans-3-amino-4-methyl-1-pyrrolidinyl)-9-cyclopropyl-6-fluorose 3.4.9-tetrahydrothiazolo[5,
4-bl quinoli/-λ4-dione: m, P, 270
~27°C (decomposition).

Example 5 5-amino-9-cyclopropyl-6-fluoro-7-
(1-piperazinyl)-2,&49-tetrahydrothiazolo[a4-b]quinoline-he4-dione: m
, p, 269-273°C (decomposed).

Example 6 5-amino-9-cyclopropyl-6-fluoro-7-
(3-Methyl-1-piperazinyl)-4&49-tetrahydroisothiazolo[5,4-b]quinoline-he4-dio7: m, 9.270-273°C (decomposition).

Example 7 5-amino-8-cyclopropyl-6-fluoro-7-
(cis&5-dimethyl-1-piperazinyl)-1L4
．． 9-tetrahydrothiazolo[5,4-bl quinoline-3,4-dione: m, p, 300°C or higher.

Example 8 5-7 minnow 9-cyclopropyl-6-fluoro C1-7
-(3-hydroxy-1-pyrrolidinyl)-λ14,9
-tetrahydrothiazolo[he4-b]ki/su7-3
．． 4-? ) Off: m, 9.300℃ or higher.

Example 9 5-amino-9-cyclopropyl-a7.8-)rifluor”-2,3,4,9-tetrahydroisothiazolo[5
,4-b]quinoline-3,4-dione:5-amino-1
-cyclopropyl-6,7,8-trifluoro-2-mercapto-1,4-dihydro-4-oxoquinoline-3
- Carbo/ethyl acid is reacted in the same manner as in Example 1 to obtain the desired product.

m, 9.275-280°C (decomposition).

Example 10 5-benzylamino-9-cyclopropyl-a7.8-
trifluoro'-2-3,4,9-f) Rahido a inthiazolo c to 4-b] Quinoli7-3,4-dione: (Otori) In Reference Example 2■, &4-dimethoxybenzylamine was replaced with benzylamine By using 5-be/zylami/-1-cyclopropyl-a7.8-)lifluoro-2-mercapto-1,4-dihydro-4-oxoquinoline-3-carbo/ethyl acid. m, p
, 102-104°C.

(2) The above compound is subjected to reaction treatment in the same manner as in Example 1 to obtain the desired product.

Example 11 5-amino-8-cyclopropyl-a8-difluto-
7-(1-pibe5di-l)-Z3,4.0-tetrahydrothiazolo[5,4-b]quinoline-&4-dionedi5-7minor8-cyclopropyl-&7.8- ) Refluoro-2Tλ49-tetrahydrothiazolo[翫4-
b] A mixture of 300 g of quinoline-3,4-dione and 394 g of anhydrous piperazine and 3 g of pyridine is heated and stirred at 90° C. for 6 hours. After cooling, add 1 cup of ether and collect the precipitated crystals by filtration. Add these crystals to 1 liter of 28% ammonia water.
-1 and stirred at room temperature for 1 hour. Filter the crystals,
After sequentially washing with water and ethanol, 305 m of the target material was removed.
get g.

m, P, 295-296°C (decomposition).

The following compounds of Examples 12 and 13 are obtained in the same manner as in Example 11 using the corresponding η material compounds.

Example 12 5-amino-9-cyclopropyl-a8-difluoro-
7-(3-methyl-1-piperazinyl)-Z3,4.9
-tetrahydrothiazooc5.4-b]quinoline-
3,4-dione: m, p, 294-296°C (decomposition).

Example 13 5-amino-9-cyclopropyl-a8-difluoro-
7-(cis-3,5-dimethyl-1-piperazinyl)-
2,3,4,9-tetrahydrothiazolo[to 4-b
]quinoline-a4-dio/: m, p, 274-27
7°C (decomposition).

Example 14 5-amino-9-cyclopropyl-a8-difluoro-
7-(4-methyl-1-piperazinyl)-2,3,4,
9-tetrahydrothiazolo[5,4-b]ky/phosphorus-he4-dione: 5-amino-9-cyclopropyl-6,7,8-)lifluoro-& 3.4.9-tetrahydrothiazoO [
5,4-bl +/! J-3.4-city 300m
g.

A mixture of 917 g of N-methylbiperazine and 3 parts of acetonitrile is heated under reflux for 11 hours. The crystals are then collected by filtration and washed with acetonitrile. Recrystallization is performed from a mixed solvent of chloroform-ethanol-acetonitrile to obtain the desired product 204-g as a slightly yellowish-green prism product. m,
9.225-227°C.

Example 15 5-amino-7-(3-amino-1-pyrrolidinyl)-
9-cyclopropyl-a8-difluoro-2,a49-
Tetrahydroisothiazolo[5,4-b]+7phosphorus-4-dione: 5-amino-9-cyclopropyl-7,8-)difluoro-2,a4,9-tetrahydroithiazo' [a
4-bl +/su/-'a, 4-dione 300 mg
.

3-7 A mixture of 396 g of minopyrrolidine layer and 31 g of pyridine was heated at 80°C, heated and stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and 10 x 1 of ether was added to the residue to form crystals.
! Fire a gun. The product is washed successively with 28% ammonia water, water and ethanol to obtain 325 μg of the desired product as a pale yellow powder.

m, 9.250-253°C (decomposition).

The following compounds of Examples 16 to 20 are obtained in the same manner as in Example 15 using the corresponding starting compounds.

Example 16 5-amino-7-(trans-3-ami/-4-methyl-1-pyrrolidinyl)-9-cyclopropyl-a8-difluoro-2,&49-tetrahydroisothiazolo[5
,4-blquinoline-3,4-dione: m, 9.2
57-259°C (decomposition).

Example 17 5-amino-7-(3-aminomethyl-1-pyrrolidinyl)-9-cyclopropyl-a8-difluoro-2,3
,4,9-tetrahydrothiazolo[翫4-b]quinolino-14-dione: m, P, 2 (14-266°C (decomposition).

Example 18 5-amino-9-7 clobrovir-a8-difluoro-
7-(2-N,N-dimethylaminomethylmorpholy/)
~2.3.4.9-Tetrahydrointhiazo I: +[to4-b]quinoline-3,4-9o/2m, P, 17
3-175℃.

Implementation F419 5-amino-9-cyclopropyl-a8-difluoro-
7-(1-pyrrolidinyl)-43,4,9-tetrahydrothiazo Ej[5,4-b]quinoline-3,4-
Geoy: m, p, 237-238°C.

Example 20 5-amino-e-cyclo-a-pil-a8-difluoro-
7-(3-hydroxy-1-pyrrolidinyl)-2,3,
4,9-Tetrahydrointhiazo D[a4-b]ky/phosphorus-a4-dione: m, p, 276-278°C (decomposition).

Example 21 9-cyclopropyl-5,8,7,8-tetrasulfo
-2,a4,9-tetrahydroisothiazo11 [5,
4-b] Quinoline-3,4-dio/: 1-cyclopropyl-5,8,7,8-tetrahydro
-2-(p-methquine beydylthio)-1,4-dihydro-4-oxoquinoline-3-carbo/ethyl acid is reacted in the same manner as in Example 1 to obtain the desired product. m, 9.
222-224°C (decomposition).

Example 22 9-cyclopropyl-5,8,8-)refluoro-7-
(1-pyrrolidinyl)-'2 & 49-tetrahydroinchazolo[5,4-b]quinoly-3,4-dio/: 9-cyclopropyl-% flll, 49-tetrahydroinch to 7.8-tetrafluoro-4 Azolo [5,4
-blquinoline-3,4-dione 1. A mixture of 538-g of Og, pyrrolisif and 10 ml of pyridine was heated and stirred at 90°C for 2 hours.The reaction solution was concentrated under reduced pressure.
Add acetonitrile to the residue and collect the crystals by filtration.

Recrystallized from chloroform-ethane to obtain target compound 19
2-g is obtained as colorless needles.

m, 9.288-289°C.

Example 23 5-amino-9-cyclopropyl-8,7,8-)lifluoro-2,3,4,9-tetrahydrothiazolo[
4-b] Bovine Norin-&4-dione: (1) 9-Cyclopavir-5,6,7,8-tetrafluoro-2,3,
72.35 g of 49-tetrahydroinchazolo[he4-b]quinoline-he4-dio, 1.31 g of 3°4-dimethoxybenzylamine, anhydrous potassium carbonate 1. Of
and 50 μl of toluene and the U compound were heated and stirred at 120°C for 3 hours. The reaction solution was concentrated under reduced pressure, ethanol was added to the residue, and the precipitated crystals were collected by filtration and washed with water to obtain 9-7 cloprovir-a7,8. 1.2 g of quinoli-7-he4-dione are obtained.

(2) Add 900 g of this compound to 1 portion of trifluoro vinegar! l
10■ Dissolve in 1 and add 0.4 ml of anisole to this.
and trifluoromethanesulfo/acid 0.21 and stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the precipitated crystals were collected by filtration and washed with water to obtain the desired product 2.
Obtain 3-g.

m, p, 275-280°C (decomposition).

Example 24 5-7 minnow 9-cyclopropyl-a8-difluoro-
7-(1-pyrrolidinyl)-2,&4,9-tetrahydrothiazoloC5,4-b]quinoli/-&4-dione: (1) 9-cyclopropyl-11-trifluoroCl-7
-(1-pyrrolidinyl)-1-49-tetrahydrothiazolo[a4-b]quinori/-λ4-dio/2.4
A mixture of 25g of 2g, &4-dimethoxybenzylamine and 241g of toluene was heated under reflux for 21 hours. Insoluble materials are removed by filtration, chloroform is added to the filtrate, and the filtrate is washed with dilute hydrochloric acid and concentrated under reduced pressure. Inpropyl ether and chloroform were added to the residue and warmed, and the crystals were collected by filtration to give 9-cyclopropyl-6&-difluoro-5=(
&4-Tumethoxybenzylamino)-7-(1-pyrrolidinyl)-2,&4,9-tetrahydrothiazolo[
4-b] quinoliy-3,4-dio/B43-g is obtained as light yellow needles. Recrystallize from chloroform-ethanol.

m, 9.178 = 177°C.

■616 mg of the above compound was mixed with 5.01 mg of trifluoroacetic acid.
To this was added 413 g of anisole and 780.185 ml of trifluorometa/sulfo, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, ice water was added to the residue, and the mixture was made alkaline with 10% aqueous sodium hydroxide solution. After that, acidify with dilute hydrochloric acid. Discard the aqueous layer, wash the residue with water, add ethanol, and stir.

The formed crystals were collected by filtration and washed successively with ethanol and inpropyl ether to obtain the desired product 111302 mg as pale yellow needles. Recrystallize from chloroform-ethane. m, I), 235-237°C.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a cycloalkyl group, or even if it has a substituent R_2 means a hydrogen atom, halogen atom, cyano group or lower alkyloxy group, R_3 means a halogen atom or a group represented by the following formula ▲ Numerical formula, chemical formula, table, etc. ▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, where R_5 and R_1_0 mean a hydrogen atom, a lower alkyl group, or an acyl group (the acyl group may be substituted with a halogen atom), R_6, R_7 and R_1_1 are the same or different and mean a hydrogen atom, a lower alkyl group or a halogeno lower alkyl group, or R_6 and R_7 may be combined to form a direct bond or -(CH_2)_m-, Here, m means 1 or 2, and R_8 is a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy lower alkyl group, a hydroxyl group, an amino group, a mono- or di-lower alkylamino group, an amino-lower alkyl group, or a mono- or di-lower alkyl group. means an alkylamino lower alkyl group, R_9 means a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyloxy group, and n is 3, 4 or 5
R_4 is a halogen atom, -OR_1_2, -SR_1_
3 or -NR_1_4R_1_5, where R
_1_2, R_1_3 and R_1_4 mean a hydrogen atom, a lower alkyl group, a benzyl group which may have a substituent or an acyl group which may be substituted with a halogen atom, and R_1_5 means a hydrogen atom or a lower alkyl group. However, X means a sulfur atom or an oxygen atom. ] and its salts.