JP2991382B2 - Fused tricyclic compounds and salts thereof - Google Patents

Description

The present invention relates to a novel condensed tricyclic compound exhibiting excellent antibacterial activity and a salt thereof.

[Prior Art] As this kind of tricyclic compound, a compound described in JP-A-62-187472 is known. However, there is no known compound having a structure like the compound of the present invention.

[Problems to be Solved by the Invention] An object of the present invention is to provide a novel condensed tricyclic compound exhibiting excellent antibacterial activity and a salt thereof.

[Means for Solving the Problems] The compound of the present invention is a novel compound not described in the literature and has the following general formula (Wherein X ₁ represents a halogen atom, R ₁ represents a lower alkyl group, a halogeno lower alkyl group, a hydroxy lower alkyl group, a lower alkenyl group, a cycloalkyl group or a phenyl group which may have a substituent. R ₂ represents a hydrogen atom, a halogen atom, an amino group, a hydroxyl group or a methyl group, and R ₃ represents a halogen atom, a lower alkyloxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an arylthio group. Group, an arylsulfinyl group or an arylsulfonyl group, or a group represented by the following formula (a), (b) or (c) Wherein R ₄ and R ₉ represent a hydrogen atom, a lower alkyl group or an acyl group, and R ₅ , R ₆ and R ₁₀ are the same or different and represent a hydrogen atom, a lower alkyl group or a halogeno lower alkyl group. R ₇ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a hydroxy lower alkyl group, an amino group, a mono- or di-lower-alkylamino group, an amino-lower-alkyl group, or a mono- or di-lower-alkylamino-lower-alkyl group R ₈ represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkyloxy group, n represents 3, 4 or 5, A represents C—X ₂ or a nitrogen atom. X ₂ represents a hydrogen atom, a halogen atom, a methyl group, a cyano group or a lower alkyloxy group, and B represents the following formula (a), (b), (c) or Group represented by (d) Wherein Y represents an oxygen atom or a sulfur atom, R ₁₁ , R ₁₃ and R ₁₄ represent a hydrogen atom or a lower alkyl group, and R ₁₂ represents a hydrogen atom, a lower alkyl group, a lower alkyloxy group A mercapto group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an arylthio group, an arylsulfinyl group, an arylsulfonyl group, an amino group, a mono- or di-lower alkylamino group or a cyclic amino group which may be substituted. means. And a salt thereof.

Compound (I) of the present invention can be produced by a production method represented by the following reaction formula.

Production method 1 (substitution reaction) Production method 2 (oxidation reaction) Production method 3 (alkylation reaction) Production method 4 (ring closure reaction) Production method 5 (ring closure reaction) Production method 6 (ring closure reaction) Production method 7 (alkylation reaction) Production method 8 (oxidation reaction) Production method 9 (substitution reaction) Production method 10 (ring closure reaction) (Wherein X ₃ represents a halogen atom, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an arylsulfinyl group or an arylsulfonyl group, X ₄ represents a hydrogen atom or a halogen atom, and Z ₁ , Z ₂ and Z ₃ represents a protecting group, Z ₄ represents a hydrogen atom or a protecting group, R represents a lower alkyl group or a benzyl group which may have a substituent, and R ′ represents a lower alkyl group or an aryl group. R ″ represents a lower alkyl group, R ₁ ′ represents a lower alkyl group, a hydroxy lower alkyl group or a halogeno lower alkyl group, and R ₃ ′ represents a halogen atom or a lower alkyl group in the definition of R ₃ above. a sulfinyl group, a lower alkylsulfonyl group means an aryl sulfinyl group or an arylsulfonyl group other than group, R ₁₂ 'is a hydrogen atom or a lower a Refers Kill group, R ₁₂ "means a lower alkyl group, amino group, mono- or di-lower alkylamino group or an optionally substituted cyclic amino group, k denotes 1 or 2, m is X ₁ , Y, R ₁ , R ₂ , R ₃ , R ₁₁ , R ₁₃ , R ₁₄ , A and B are the same as those described above.) In the present specification, “halogen atom” Examples include fluorine, chlorine or bromine. "Lower alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. "Lower alkenyl" includes, for example, vinyl, allyl, 1-propenyl, isopropenyl and the like. “Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl and the like can be mentioned. Examples of the substituent in "phenyl which may have a substituent" or "benzyl which may have a substituent" include, for example, halogen, hydroxy, nitro, amino, lower alkyl, lower alkyloxy and the like. . “Aryl” includes, for example, phenyl, tolyl, naphthyl and the like. "Acyl" includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, trifluoroacetyl, chloroacetyl and the like. Examples of the “cyclic amino group” include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like. These cyclic amino groups may have a substituent such as hydroxy, halogen, lower alkyl, amino, mono- or di-lower alkylamino, amino lower alkyl or mono- or di-lower alkylamino lower alkyl.

Examples of the salt of the compound of the present invention include salts with inorganic acids such as hydrochloric acid and phosphoric acid; acetic acid, lactic acid, oxalic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid,
Salts with organic acids such as malonic acid and gluconic acid; salts with acidic amino acids such as aspartic acid and glutamic acid.

The compound represented by the general formula (I) may also exist as an enol type, and such tautomers are included in the compounds of the present invention.

The compounds of the present invention may also exist as hydrates. Such forms are of course also encompassed by the compounds of the present invention.

The compounds of the present invention include those having asymmetric carbon atoms, which may exist as optically active forms. Therefore,
These optically active substances are included in the compound of the present invention.

Furthermore, some of the compounds of the present invention have multiple asymmetric carbon atoms, which can 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 described in detail below.

Production Method 1 In the formula (I), R ₃ is a lower alkyloxy group, a lower alkylthio group, an arylthio group or (a),
Compound (I-1) of the present invention which is (B) or (C)
Can be produced by reacting the compound (II) with a compound represented by the following formula R ₃ ′ -H (III) (wherein R ₃ ′ is the same as described above).

This reaction can be carried out by stirring the starting compounds (II) and (III) for 10 minutes to 24 hours in an inert solvent at 10 to 180 ° C.

Examples of the solvent include dimethylformamide, dimethylsulfoxide, ethanol, methanol, acetonitrile, water, chloroform, pyridine and the like. These solvents may be used alone or as a mixture.

This reaction is generally carried out in the presence of a base as an acid acceptor using the starting compound (III) in an equivalent amount or a slightly excessive amount relative to the starting compound (II).
When I) is an amine, it may be used in excess to double as an acid acceptor.

Examples of the base include organic bases such as triethylamine, dimethylaniline, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine, and hydroxides such as sodium hydroxide and potassium hydroxide; Carbonates such as sodium carbonate and potassium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate; sodium, potassium, sodium hydride and the like.

This reaction can also be carried out by reacting with a compound (II) using a reagent in which the starting compound (III) and a base are bound, for example, sodium methoxide, sodium ethoxide, sodium methanethiolate and the like.

The starting compound (II) can be produced by any of the following production methods (2) to (10).

Production method 2 In the formula (I), R ₃ is a lower alkylsulfinyl group,
The compound of the present invention which is a lower alkylsulfonyl group, an arylsulfinyl group or an arylsulfonyl group (I-
2) can be produced by oxidizing compound (IV).

This reaction can be carried out in the same manner as in Production Method 8 described later.

Starting compound (IV) can be produced by any one of production methods (1) and (3) to (10).

Production Method 3 The compound (I-3) of the present invention wherein R ₁ is a lower alkyl group, a hydroxy lower alkyl group or a halogeno lower alkyl group in the formula (I) may be produced by alkylating the compound (V). Can be.

This reaction can be carried out in the same manner as in Production Method 7 described below.

The starting compound (V) is produced according to the production methods (1), (2) and (4).
To (10).

Production method 4 In formula (I) The compound (I-4) of the present invention wherein is (a) can be produced by reacting the compound (VI) with s-triazine in the presence of a base.

This reaction can be carried out by stirring the starting compound (IV) and s-triazine at 50 to 150 ° C for 1 to 24 hours in an inert solvent in the presence of a base.

Examples of the solvent include benzene, toluene, xylene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like. Examples of the base include a strong base such as sodium hydride.

The starting compound (VI) can be produced by the method described in Reference Examples 1 to 15 or a method analogous thereto.

Production method 5 In formula (I) Is (b), and R ₁₂ is a hydrogen atom or a lower alkyl group, and the compound (I-5) of the present invention is produced by reacting the compound (VII) with a carboxylic acid anhydride and a carboxylic acid orthoester. be able to.

In this reaction, the starting compound (VII) is reacted with a carboxylic anhydride such as acetic anhydride and a carboxylic acid orthoester such as ethyl orthoformate or ethyl orthoacetate at 100 to 180 ° C for 1 hour.
It can be carried out by stirring for 1010 hours.

Starting compound (VII) can be produced by the method described in Reference Examples 16 to 19 or a method analogous thereto.

Production method 6 In formula (I) The compound (I-6) of the present invention wherein is (c) can be produced by reacting the compound (VIII) with an isocyanate compound or an isothiocyanate compound.

In the reaction of the step [6-1], the compound (VIII) and an isocyanic acid compound such as ethoxycarbonyl isocyanate or an isothiocyanic acid compound such as 3,4-dimethoxybenzyl isothiocyanate are reacted in a solvent such as trahydrofuran or toluene. It can be carried out by stirring at 0 to 150 ° C. for 5 minutes to 2 hours.

The reaction in the step [6-2] is performed by converting the compound (IX) from 0 to
It can be carried out by treating with a base at 150 ° C. for 5 minutes to 24 hours. Specific examples of the solvent include tetrahydrofuran, toluene, ethanol, and water, and examples of the base include sodium hydride and potassium carbonate.

The reaction of the step [6-3] includes hydrochloric acid, sulfuric acid, hydrobromic acid,
Acids such as formic acid and trifluoroacetic acid or alkali hydroxides;
It can be carried out by hydrolyzing compound (X) in the presence of a base such as alkali carbonate. When trifluoroacetic acid is used, the reaction is promoted by adding an ion scavenger such as anisole.

In this production method, each step can be carried out stepwise, or can be carried out without isolation of intermediate compounds (IX) and (X), by appropriately selecting reaction reagents and reaction conditions. is there.

The starting compound (VIII) can be produced by the method described in Reference Examples 20 to 21 or a method analogous thereto.

Production method 7 In formula (I) Is (b) and R ₁₂ is a lower alkylthio group, and the compound (I-7) of the present invention can be produced by alkylating compound (XI).

This reaction can be carried out by stirring the compound (XI) and the alkylating agent at 0 to 150 ° C for 30 minutes to 5 hours in a solvent in the presence of a base. Examples of the solvent include tetrahydrofuran, dioxane, ethanol, dimethylformamide, dimethylsulfoxide, and water, and examples of the base include sodium hydride, alkali hydroxide, alkali carbonate, alkali metal alkoxide, and triethylamine. Examples of the alkylating agent include methyl iodide, ethyl iodide, dimethyl sulfate and diethyl sulfate.

Starting compound (XI) can be produced by Production Method 6.

Production method 8 In formula (I) Is (b) and R ₁₂ is a lower alkylsulfinyl group,
The compound of the present invention which is a lower alkylsulfonyl group, an arylsulfinyl group or an arylsulfonyl group (I-
8) can be produced by oxidizing compound (XII).

This reaction can be carried out by stirring the compound (XII) and the oxidizing agent in a solvent such as chloroform, acetone, acetic acid and water at −10 to 100 ° C. for 5 minutes to 10 hours. Examples of the oxidizing agent include aqueous hydrogen peroxide, peracetic acid, and m-chloroperbenzoic acid.

Starting compound (XII) can be produced by Production Method 7.

Production method 9 In formula (I) Is (b) and R ₁₂ is a lower alkyloxy group, an amino group, a mono- or di-lower alkylamino group or an optionally substituted cyclic amino group (I)
-9) can be produced by reacting compound (XIII) with a compound represented by the following general formula R ₁₂ ″ -H (XIV) (wherein R ₁₂ ″ is the same as described above).

This reaction can be carried out in the same manner as in Production Method 1.

Starting compound (XIII) can be produced by Production Method 7 or 8.

Production method 10 In formula (I) The compound (I-10) of the present invention wherein is (d) can be produced by reacting the compound (XV) with an azo compound or a hydrazine compound.

The reaction of step [10-1] is carried out in a solvent in the presence of a base with X ₄
Is a hydrogen atom and the azo compound is 0 to
It can be carried out by stirring at 150 ° C. for 10 minutes to 2 hours.
Specific examples of the solvent include tetrahydrofuran and the like, examples of the base include sodium hydride and the like, and examples of the azo compound include diethyl azodicarboxylate.

The reaction of the step [10-2] is carried out in a solvent in the presence of a base with X ₄
Is a halogen atom, and the hydrazine compound is stirred at 0 to 150 ° C. for 10 minutes to 2 hours. Specific examples of the solvent include tetrahydrofuran and the like, potassium hydroxide and the like as the base, and N-acetyl-N'-t-butoxycarbonylhydrazine and the like as the hydrazine compound.

In the reaction of step [10-3], compound (XVI) is treated with 0 in a solvent.
It can be carried out by treating with an acid or a base at 〜150 ° C. for 5 minutes to 24 hours. Examples of the acid include hydrochloric acid, sulfuric acid, and trifluoroacetic acid. As the solvent and the base, for example, the same ones as described in Step [6-2] of Production Method 6 can be used.

The reaction of the step [10-4] is performed in the same manner as the step [6-] of the production method 6.
In the same manner as in [3], hydrolysis can be carried out.

In the present production method, each step can be carried out stepwise, or the intermediate compounds (XVI) and (XVII) can be carried out without isolation, by appropriately selecting reaction reagents and reaction conditions. is there.

The starting compound (XV) can be produced by the method described in Reference Examples 22 to 23 or a method analogous thereto.

If possible, each starting compound used in each of the above-mentioned production methods may be used in a form where amino groups not involved in the reaction are protected, and after the reaction, the protecting group may be removed by a conventional method. As the protecting group, any protecting group can 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 acid, nucleic acid, or β-
A protective group usually used as a protective group in the field of lactam compound chemistry is used. Preferred protecting groups include, for example, easily hydrolyzable groups such as formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, t-butoxycarbonyl, and benzyl groups.

The compound of the present invention thus produced is isolated and purified according to a conventional method. Depending on the conditions for isolation and purification, the compound of the present invention can be obtained in the form of a salt or in a free form, and these are mutually converted according to the purpose to produce the desired form of the compound of the present invention.

The stereoisomers of the compound of the present invention can be separated from each other by a usual method, for example, fractional crystallization, chromatographic separation and the like. In addition, using the starting compound having a specific configuration, the compound of the present invention having the corresponding specific configuration can also be produced by each of the above production methods.

The optical isomers of the compound of the present invention can be separated by applying a known method.

[Effect of the Invention] The compound (I) and its salt thus obtained are both novel compounds and exhibit excellent antibacterial activity, and are therefore valuable as antibacterial agents. The compound (I) or a salt thereof can be used not only as pharmaceuticals for humans and animals but also as fish disease drugs, agricultural chemicals, food preservatives, and the like.

Next, data on the antibacterial activity of the compound of the present invention will be described below.

^{* 1} Minimum growth inhibitory concentration (MIC: μg / ml) is Chemotherap
y, 29 (1), measured according to the method described in 76 (1981),
The results are shown in the above table. ^{* 2} A: Staphylococcus aureus 209P JC-1 (S. aureus 209P JC-1). B: E. coli NIHJ JC-2. C: E. coli P-51208 D: P. aeruginosa12. E: Pseudomonas aeruginosa 1011-1 (P. aeruginosa 1011-1). ^{* 3} Means the compound of Example 16 (the same applies hereinafter).

Thus, the compounds of the present invention show excellent antibacterial activity and a broad antibacterial spectrum in in vitro tests.

Further, the compound of the present invention shows an excellent in vivo infection protective effect against infections caused by various bacteria, and shows good safety in toxicity tests on animals.

When the compound of the present invention is used as an antibacterial agent in humans,
The dosage varies depending on age, body weight, symptoms, administration route, etc., but it is recommended to administer 5 mg to 5 g per day in one or several divided doses. The administration route may be oral or parenteral.

The compounds of the present invention may be in bulk, but are usually administered in a form prepared with a pharmaceutical carrier. Specific examples include tablets, liquids, capsules, granules, fine granules, powders, syrups, injections, ointments and the like. These preparations are prepared according to a conventional method. Oral pharmaceutical carriers include starch, mannitol, microcrystalline cellulose, CMC, N
a, Substances that are commonly used in the field of pharmaceuticals such as water and ethanol and do not react with the compound of the present invention are used. Injectable carriers include carriers commonly used in the field of injectables, such as water, physiological saline, glucose solutions, and infusions.

Further, the above-mentioned liquid preparations and ointments can also be used for treatment in otolaryngology and ophthalmology.

[Examples] Next, the production method of the compound of the present invention will be described more specifically with reference to Examples and Reference Examples.

Reference Example 1 Ethyl 1-cyclopropyl-6,7,8-trifluoro-2-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate: (1) 1-cyclopropyl-6,7, 8-trifluoro-1,4
-Dihydro-4-oxoquinoline-3-carboxylate (10 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was stirred under ice-cooling and stirred under a methylmagnesium bromide ether solution (3.
12.9 ml of mol /) are added dropwise over 1.5 hours. The reaction solution is stirred at room temperature for 1 hour and concentrated to dryness under reduced pressure. Water is added to the residue, neutralized with 10% hydrochloric acid, and extracted with chloroform.
The extract was dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with chloroform) to give 1-cyclopropyl-6,7,8-trifluoro-4-.
Hydroxy-2-methyl-1,2-dihydroquinoline-3
9.27 g of ethyl carboxylate are obtained. mp 81-82 ° C. (2) Dissolve 4.58 g of the above compound in 50 ml of toluene, and add 3.18 g of dichlorodicyanoquinone (DDQ) to the solution.
For 3 hours. After cooling, the reaction mixture is washed with 20% aqueous sodium hydrogen carbonate and concentrated under reduced pressure. The precipitated crystals were collected by filtration and recrystallized from chloroform-n-hexane to give the desired product 3.35.
get g. mp 167-171 ° C. The following compounds are obtained by subjecting the corresponding starting compounds to a reaction treatment in the same manner as in Reference Example 1.

Reference Example 21 ethyl 1-cyclopropyl-2-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate: mp 121-122 ° C (recrystallized from ethanol). Reference Example 31-cyclopropyl-6-fluoro-2-methyl-7-
Ethyl phenylthio-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate: mp 159 ° -161 ° C. (recrystallized from ethanol). Reference Example 4 1-cyclopropyl-7-chloro-6-fluoro-2-
Ethyl methyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate: mp 147-148 ° C (recrystallized from ethanol). Reference Example 5 1-cyclopropyl-6,7-difluoro-2-methyl-
Ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate: (1) 8.5% ethyl β-cyclopropylaminoacrylate
g, diisopropylethylamine 9.6 ml and toluene 50 m
The mixture of 1 was cooled on ice and 9.7 g of 2,4,5-trifluorobenzoic acid chloride was added dropwise thereto over 10 minutes. After stirring for 30 minutes under ice-cooling and 3.5 hours at room temperature, water is added to the reaction solution, and the organic layer is separated. After drying the organic layer, it was concentrated to dryness under reduced pressure, and α-
Ethyl (2,4,5-trifluorobenzoyl) -β-cyclopropylaminoacrylate is obtained.

(2) Dissolve the above compound in 50 ml of tetrahydrofuran,
Under ice cooling, 5.6 g of potassium t-butoxide was added thereto. The reaction solution is stirred at room temperature for 8 hours, concentrated to dryness under reduced pressure, ice water is added to the residue, and neutralized with a 10% aqueous acetic acid solution. The precipitated crystals are collected by filtration, washed with water and dried to obtain 12.2 g of the desired product.
mp 185-186 ° C. Reference Example 6 7- (3-t-butoxycarbonylamino-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-2
-Methyl-1,4-dihydro-4-oxoquinoline-3-
Ethyl carboxylate: 1-cyclopropyl-6,7,8-trifluoro-2-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate 2.0 g, 3-t-butoxycarbonylaminopyrrolidine 2.86 g and 10 ml of dimethyl sulfoxide are heated and stirred at 90-95 ° C for 2 hours. After cooling, water was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from acetonitrile to obtain 2.56 g of the desired product. mp 189-190 ° C. Using the corresponding starting compounds, the reaction is carried out in the same manner as in Reference Example 6 to obtain the following compounds.

Reference Example 7 7- (3-t-butoxycarbonylaminomethyl-1-
Ethyl (pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-2-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate: mp 127-128 ° C (recrystallized from n-hexane-ether). Reference Example 8 7- (3-t-butoxycarbonylamino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-2-methyl-1,4-dihydro-4-oxoquinoline-3 -Ethyl carboxylate: mp 190-191 ° C (recrystallized from acetonitrile-isopropyl ether). Reference Example 9 7- (trans-3-t-butoxycarbonylamino-
4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-2-methyl-1,4-dihydro-4-
Ethyl oxoquinoline-3-carboxylate: mp 170-171
° C (recrystallized from acetonitrile-isopropyl ether). Reference Example 10 1-Cyclopropyl-6,8-difluoro-7- (4-formyl-1-piperazinyl) -2-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate ethyl: m.p.
196-198 ° C (recrystallized from ethyl acetate). Reference Example 11 1-cyclopropyl-6,8-difluoro-2-methyl-
Ethyl 7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate: mp1
44 ° C (recrystallized from ethyl acetate). Reference Example 12 1-cyclopropyl-2-ethyl-6,8-difluoro-
Ethyl 7- (4-formyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate: m.p.
p.195-196 ° C (recrystallized from ethanol). Reference Example 13 1-cyclopropyl-2-ethyl-6,8-difluoro-
Ethyl 7- (4-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate: mp1
64-165 ° C (recrystallized from ethanol). Reference Example 14 7- (3-t-butoxycarbonylamino-1-pyrrolidinyl) -1-cyclopropyl-2-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-
Ethyl carboxylate: mp 157-158 ° C (recrystallized from ether). Reference Example 15 ethyl 1-cyclopropyl-6-fluoro-7- (4-formyl-1-piperazinyl) -2-methyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate: mp 227 ° C (recrystallized from ethanol). Example 1 5-cyclopropyl-6,7,8-trifluoro-pyrido [4,3-b] quinoline-1,10 (2H, 5H) -dione: 1-cyclopropyl-6,7,8-trione A mixture of 9 g of ethyl fluoro-2-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, 4.48 g of s-triazine and 90 ml of dry tetrahydrofuran was treated with 1.66 sodium hydrogen hydride (1.66).
Add g and heat to reflux for 12 hours. 400 ml of ice water is carefully added to the reaction solution, and the precipitated crystals are collected by filtration and dried to obtain the desired product 3.
Get 4g. mp300 ℃ or more. Example 2 10-Cyclopropyl-3-fluoro-2-phenylthiopyrido [2,3-b] [1,6] naphthyridine-5,6 (7H, 10
H) -Dione: 1.38 g of ethyl 1-cyclopropyl-6-fluoro-7-phenylthio-2-methyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, 560 mg of s-triazine And 60% hydrogenated sodium hydroxide 2 in a mixture of 30 ml of a mixed solvent of dry dimethylformamide-toluene (1: 4).
Add 10 mg and heat and stir at 95 ° C for 1.5 hours. The reaction solution is concentrated under reduced pressure, and the residue is acidified by adding water and a 10% aqueous acetic acid solution. The precipitated crystals are collected by filtration and recrystallized from chloroform-ethanol to obtain 840 mg of the desired product. mp300 ℃ or more. Example 3 5-Cyclopropyl-6,8-difluoro-7- (1-piperazinyl) pyrido [4,3-b] quinoline-1,10 (2H, 5
H) -dione: (1) 1-cyclopropyl-6,8-difluoro-7-
(4-formyl-1-piperazinyl) -2-methyl-1,
To a mixture of 390 mg of ethyl 4-dihydro-4-oxoquinoline-3-carboxylate, 150 mg of s-triazine and 10 ml of a mixed solvent of dry dimethylformamide-toluene (1: 4) was added 60
Then, 60 mg of sodium hydride was added thereto, and the mixture was heated and stirred at 95 ° C for 2.5 hours. The reaction solution is concentrated under reduced pressure, and water and a 10% aqueous acetic acid solution are added to the residue to adjust the pH to 6. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 5-cyclopropyl-6,8-
Difluoro-7- (4-formyl-1-piperazinyl)
Pyrido [4,3-b] quinoline-1,10 (2H, 5H) -dione 26
Obtain 0 mg. mp 265-268 ° C. (2) A mixture of 610 mg of the above compound and 6 ml of 10% hydrochloric acid was heated at 110 ° C.
For 6 hours. After cooling, the reaction solution is neutralized with a 10% aqueous sodium hydroxide solution and extracted with chloroform. The extract is concentrated, and the residue is recrystallized from ethanol to obtain 260 mg of the desired product. mp 269-271 ° C. Using the corresponding starting compounds, the reaction is carried out in the same manner as in Example 3 to obtain the following compounds.

Example 4 5-Cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) pyrido [4,3-b] quinoline-1,10 (2H, 5H) -dione: mp 241-242 ° C. (Recrystallized from ethanol). Example 5 5-Cyclopropyl-6,8-difluoro-4-methyl-
7- (4-methyl-1-piperazinyl) pyrido [4,3-
b] Quinoline-1,10 (2H, 5H) -dione: mp 247-248 ° C
(Recrystallized from ethanol). Example 6 5-cyclopropyl-6,8-difluoro-7- (4-formyl-1-piperazinyl) -4-methylpyrido [4,3
-B] quinoline-1,10 (2H, 5H) -dione: mp 248 to 249
° C (recrystallized from chloroform). Example 7 (1) 10-cyclopropyl-3-fluoro-2- (4-
Formyl-1-piperazinyl) pyrido [2,3-b] [1,
6] Naphthyridine-5,6 (7H, 10H) -dione: mp 300 ° C or higher (recrystallized from chloroform-ethanol). (2) 10-cyclopropyl-3-fluoro-2- (1-
Piperazinyl) pyrido [2,3-b] [1,6] naphthyridine-5,6 (7H, 10H) -dione: mp 260-265 ° C. Example 8 7- (3-Amino-3-methyl-1-pyrrolidinyl)-
5-cyclopropyl-6,8-difluoropyrido [4,3-
b] Quinoline-1,10 (2H, 5H) -dione: (1) 7- (3-t-butoxycarbonylamino-3-
Methyl-1-pyrrolidinyl) -1-cyclopropyl-6,
To a mixture of 600 mg of ethyl 8-difluoro-2-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, 190 mg of s-triazine and 12 ml of dry tetrahydrofuran was added 6
70% of 0% sodium hydride is added, and the mixture is heated and stirred at 70 ° C. for 4 hours. After cooling, 40 ml of ice water was carefully added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from chloroform-n-hexane to give 7- (3-t-butoxycarbonylamino-3
-Methyl-1-pyrrolidinyl) -5-cyclopropyl-
6,8-difluoropyrido [4,3-b] quinoline-1,10 (2
330 mg of (H, 5H) -dione are obtained. mp264-265 ° C. (2) A mixture of the above compound (400 mg) and trifluoroacetic acid (2 ml) is stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure, water is added to the residue, and the mixture is neutralized with a 1N aqueous sodium hydroxide solution and extracted with chloroform. The extract is dried and concentrated, and the precipitated crystals are recrystallized from methanol-isopropyl ether to obtain 230 mg of the desired product. mp 221-223 ° C. The following starting compounds are obtained by reacting the corresponding starting compounds in the same manner as in Example 8.

Example 9 (1) 7- (3-t-butoxycarbonylamino-1-
(Pyrrolidinyl) -5-cyclopropyl-6,8-difluoropyrido [4,3-b] quinoline-1,10 (2H, 5H) -dione: mp 246-266 ° C (decomposition). (2) 7- (3-Amino-1-pyrrolidinyl) -5-cyclopropyl-6,8-difluoropyrido [4,3-b] quinoline-1,10 (2H, 5H) -dione: mp 213-215 ° C. Example 10 (1) 7- (trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl) -5-cyclopropyl-6,8-difluoropyrido [4,3-b] quinoline-
1,10 (2H, 5H) -dione: mp 257-259 ° C (recrystallized from chloroform). (2) 7- (trans-3-amino-4-methyl-1-
(Pyrrolidinyl) -5-cyclopropyl-6,8-difluoropyrido [4,3-b] quinoline-1,10 (2H, 5H) -dione: mp 160-161 ° C. Example 11 (1) 7- (3-t-butoxycarbonylamino-methyl-1-pyrrolidinyl) -5-cyclopropyl-6,8-
Difluoropyrido [4,3-b] quinoline-1,10 (2H, 5H)
-Dione: mp 210-212 ° C (recrystallized from chloroform-acetonitrile). (2) 7- (3-aminomethyl-1-pyrrolidinyl)-
5-cyclopropyl-6,8-difluoropyrido [4,3-
b] Quinoline-1,10 (2H, 5H) -dione: mp 156-158
° C. Example 12 (1) 7- (3-t-butoxycarbonylamino-1-
Pyrrolidinyl) -5-cyclopropyl-6,8-difluoro-4-methylpyrido [4,3-b] quinoline-1,10 (2H,
5H) -dione: mp 166-168 ° C (recrystallized from ethanol). (2) 7- (3-amino-1-pyrrolidinyl) -5-cyclopropyl-6,8-difluoro-4-methylpyrido [4,3-b] quinoline-1,10 (2H, 5H) -dione: mp242
~ 243 ° C (recrystallized from ethanol). Example 13 7- (3-Amino-1-pyrrolidinyl) -5-cyclopropyl-6,8-difluoropyrido [4,3-b] quinoline-
1,10 (2H, 5H) -dione: 5-cyclopropyl-6,7,8-trifluoropyrido [4,3-b] quinoline-1,10 (2H, 5H) -dione 200 mg, 3
-225 mg of aminopyrrolidine and dimethyl sulfoxide 2
The mixture of ml is heated and stirred at 90 ° C. for 20 minutes. The reaction solution is concentrated to dryness under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. The extract is dried and concentrated, and the precipitated crystals are recrystallized from methanol to obtain 110 mg of the desired product. mp213 ~ 21
5 ° C. Using the corresponding starting compounds, a reaction treatment was conducted in the same manner as in Example 13 to obtain the following compounds.

Example 14 7- (Trans-3-amino-4-methyl-1-pyrrolidinyl) -5-cyclopropyl-6,8-difluoropyrido [4,3-b] quinoline-1,10 (2H, 5H) − Zeon: mp1
60-161 ° C. Example 15 7- (3-Amino-3-methyl-1-pyrrolidinyl)-
5-cyclopropyl-6,8-difluoropyrido [4,3-
b] Quinoline-1,10 (2H, 5H) -dione: mp 221-223
° C. Example 16 7- (3-Aminomethyl-1-pyrrolidinyl) -5-cyclopropyl-6,8-difluoropyrido [4,3-b] quinoline-1,10 (2H, 5H) -dione: mp156- 158 ° C. Example 17 5-cyclopropyl-6,8-difluoro-7- (1-piperazinyl) pyrido [4,3-b] quinoline-1,10 (2H, 5
H) -Dione: mp 269-271 ° C. Example 18 2- (3-amino-1-pyrrolidinyl) -10-cyclopropyl-3-fluoropyrido [2,3-b] [1,6] naphthyridine-5,6 (7H, 10H) -dione: (1 ) 10-Cyclopropyl-3-fluoro-2-phenylthiopyrido [2,3-b] [1,6] naphthyridine-5,6 (7
(H, 10H) -dione 540mg dissolved in chloroform 150ml,
Under ice-cooling, 360% of 80% m-chloroperbenzoic acid was added thereto, followed by stirring at room temperature for 2 hours. The precipitated crystals are collected by filtration to give 2-
490 mg of a mixture of a phenylsulfinyl compound and a 2-phenylsulfonyl compound is obtained.

(2) A mixture of 400 mg of the above mixture, 200 mg of 3-aminopyrrolidine, 230 ml of triethylamine and 30 ml of acetonitrile is heated under reflux for 2.5 hours. After cooling, the precipitated crystals are collected by filtration, dissolved in a 30% aqueous acetic acid solution, and treated with activated carbon. The solution
Neutralize with a 20% aqueous sodium hydroxide solution, precipitate the crystals, filter, wash with water and recrystallize from ethanol to obtain 140 mg of the desired product. mp 277-280 ° C. Reference Example 16 2-amino-1-cyclopropyl-6-fluoro-7-
(P-tolylthio) -1,4-dihydro-4-oxo-1,8
-Naphthyridine-3-carboxamide: (1) 6 g of ethyl 2,5-difluoro-6- (p-tolylthio) nicotinate was dissolved in 30 ml of toluene, 4 ml of cyclopropylamine was added, and the mixture was heated under reflux for 3 hours. 3.6 g of ethyl cyclopropylamino-5-fluoro-6- (p-tolylthio) nicotinate are obtained. mp 117 ° C. This compound is hydrolyzed with an alkali to give 2-cyclopropylamino-5-fluoro-6- (p-tolylthio)
2.16 g of nicotinic acid are obtained. mp 215 to 126 ° C (decomposition) (recrystallized from ethanol). (2) 1.3 g of the above compound was dissolved in 10 ml of dioxane, and 1.0 ml of trichloromethyl chloroformate was added thereto. The mixture was heated under reflux for 6 hours, and 1-cyclopropyl-6-fluoro-7- was added.
1.28 g of (p-tolylthio) -2H-pyrido [2,3-d] [1,3] oxazine-2,4 (1H) -dione are obtained. mp161〜1
63 ° C (recrystallized from ethanol). This compound was heated to reflux with malononitrile sodium salt in dimethylformamide for 12 hours to give 2-amino-
1-Cyclopropyl-6-fluoro-7- (p-tolylthio) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbonitrile is obtained. mp 269-271 ° C (recrystallized from ethanol-chloroform). (3) A mixture of 1.4 g of the above compound and 5 ml of concentrated sulfuric acid was added at 65 ° C.
Heat and stir for hours. After cooling, ice water was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from chloroform-ethanol to give 1.28 g of the desired product. mp 246-248 ° C. Reference Example 17 2-amino-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxamide: (1) 6,7-difluoro-2H-3,1-benzoxazine-
Dissolve 20.4 g of 2,4 (1H) -dione in dimethylformamide and react with ethyl iodide at room temperature in the presence of sodium hydride to give 1-ethyl-6,7-difluoro-2H-3,1-
16.5 g of benzoxazine-2,4 (1H) -dione are obtained.

(2) 15 g of the above compound was dissolved in dimethylformamide, and sodium salt of malononitrile was added thereto. The mixture was heated under reflux for 10 hours to give 2-amino-1-cyclopropyl-6,7.
-Difluoro-1,4-dihydro-4-oxoquinoline-
13.65 g of 3-carbonitrile are obtained. mp 300 ° C or higher (recrystallized from chloroform-ethanol). (3) The above compound (7.5 g) was treated in the same manner as in Reference Example 16 (3) to obtain the desired product (6.7 g). mp 300 ° C or higher (recrystallized from chloroform-ethanol). Reference Example 18 2-amino-1-cyclopropyl-6,7-difluoro-
1,4-dihydro-4-oxoquinoline-3-carboxamide: (1) 2,4,5-trifluorobenzoylacetonitrile 1
0 g is dissolved in 250 ml of dioxane, 6.2 g of potassium t-butoxide is added thereto, and the mixture is heated and stirred at 60 ° C. for 1 hour. Add 5.5 g of cyclopropyl isothiocyanate at room temperature
Heat and stir at 60 ° C for 1 hour. The reaction solution is returned to room temperature, 3.4 ml of methyl iodide is added thereto, and the mixture is stirred at room temperature for 17 hours and at 60 ° C. for 1 hour. Next, 7.6 g of potassium carbonate is added to the reaction solution, and the mixture is heated under reflux for 2 hours. The reaction solution is concentrated to dryness under reduced pressure, ice water is added to the residue, and the precipitated crystals are collected by filtration. The crystals are washed with water and ethanol and dried to give 1-cyclopropyl-6,7-difluoro-2-methylthio-1,4-
Dihydro-4-oxoquinoline-3-carbonitrile 9.
Get 3g. mp 212-214 ° C (recrystallized from chloroform-ethanol). (2) The above compound (6.0 g) was dissolved in chloroform and oxidized with m-chloroperbenzoic acid to give 1-cyclopropyl-6,7.
5.7 g of -difluoro-2-methylsulfinyl-1,4-dihydro-4-oxoquinoline-3-carbonitrile are obtained. mp 230-231 ° C (recrystallized from chloroform-ethanol). (3) Dissolve 5.5 g of the above compound in 250 ml of ethanol, saturate with ammonia gas, stopper tightly, and leave overnight. The precipitated crystals are collected by filtration to obtain 3.2 g of 2-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carbonitrile. mp 300 ° C or higher (recrystallized from chloroform-ethanol). (4) The above compound (3.0 g) was treated in the same manner as in Reference Example 16 (3) to obtain the desired product (2.4 g). mp 294 to 295 ° C (recrystallized from chloroform-ethanol). Reference Example 19 2-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxamide: using 2,3,4,5-tetrafluorobenzoylacetonitrile The reaction product is treated in the same manner as in Reference Example 18 to obtain the desired product.
mp 256-259 ° C (recrystallized from chloroform-ethanol). Example 19 10-Cyclopropyl-7,8-difluoropyrimido [4,5-
b] Quinoline-4,5 (3H, 10H) -dione: 2-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxamide 1.48 g, ethyl orthoformate 2.6 ml and acetic anhydride 15m
The mixture of l is heated to reflux for 7 hours. After cooling, the precipitated crystals are collected by filtration and recrystallized from chloroform-ethanol to give 1.3 g of the desired product. mp300 ℃ or more. The following starting compounds are obtained by reacting the corresponding starting compounds in the same manner as in Example 19.

Example 20 10-ethyl-7,8-difluoropyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione: mp 300 ° C. or higher (recrystallized from chloroform-ethanol). Example 21 10-Cyclopropyl-7,8,9-trifluoropyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione: mp300
℃ or more (recrystallized from chloroform-ethanol). Example 22 10-ethyl-7,8-difluoro-2-methylpyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione: 2-amino-1-ethyl-6,7-difluoro- 1,4-dihydro-4-oxoquinoline-3-carboxamide 1.0
g, ethyl orthoacetate (2.1 ml) and acetic anhydride (10 ml) were reacted in the same manner as in Example 19 to obtain 0.9 g of the desired product.
Recrystallize from chloroform-ethanol. mp300 ℃
that's all. Example 23 10-Cyclopropyl-7-fluoro-8- (p-tolylthio) pyrimido [4,5-b] [1,8] naphthyridine-4,5
(3H, 10H) -dione: 1-cyclopropyl-6-fluoro-7- (p-tolylthio) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxamide 500 mg, ethyl orthoformate 0.8 m
l and 5 ml of acetic anhydride are heated and stirred at 120 ° C for 2 hours. After cooling, the precipitated crystals are collected by filtration and recrystallized from chloroform-ethanol to give 410 mg of the desired product. mp300 ℃
that's all. Example 24 10-Cyclopropyl-7-fluoro-8- (1-piperazinyl) pyrimido [4,5-b] quinoline-4,5 (3H, 10H)
-Dione: 10-cyclopropyl-7,8-difluoropyrimido [4,5
-B] A mixture of 300 mg of quinoline-4,5 (3H, 10H) -dione, 360 mg of anhydrous piperazine and 6 ml of dimethyl sulfoxide is heated and stirred at 110 ° C. for 1.5 hours. After cooling, the precipitated crystals are collected by filtration, dissolved in a 10% aqueous acetic acid solution, and treated with activated carbon. The solution is made weakly alkaline with a 10% aqueous ammonia solution, and the precipitated crystals are collected by filtration and dried to obtain 280 mg of the desired product. mp281〜
284 ° C (decomposition). Example 25 10-Cyclopropyl-7-fluoro-8- (4-methyl-1-piperazinyl) pyrimido [4,5-b] quinoline-
4,5 (3H, 10H) -dione: 10-cyclopropyl-7,8-difluoropyrimido [4,5
-B] A mixture of 300 mg of quinoline-4,5 (3H, 10H) -dione, 0.42 g of N-methylpiperazine and 6 ml of dimethylsulfoxide is heated and stirred at 110 ° C. for 1.5 hours. After cooling, the precipitated crystals are collected by filtration and recrystallized from chloroform-ethanol to give 240 mg of the desired product. mp 284-288 ° C (decomposition). Using the corresponding starting compounds, the reaction is carried out in the same manner as in Examples 24 and 25 to give the following compounds.

Example 26 8- (3-amino-1-pyrrolidinyl) -10-cyclopropyl-7-fluoropyrimido [4,5-b] quinoline-
4,5 (3H, 10H) -dione: mp 259-265 ° C (decomposition). Example 27 10-Cyclopropyl-7,9-difluoro-8- (1-piperazinyl) pyrimido [4,5-b] quinoline-4,5 (3H, 1
0H) -dione: mp 300 ° C or higher. Example 28 10-Cyclopropyl-7,9-difluoro-8- (4-methyl-1-piperazinyl) pyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione: mp 250 ° -261 ° C. (Disassembly). Example 29 8- (3-Amino-1-pyrrolidinyl) -10-cyclopropyl-7,9-difluoropyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione: mp 269-271 ° C. Example 30 10-ethyl-7-fluoro-8- (1-piperazinyl)
Pyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione: mp 278-289 ° C (decomposition) (recrystallized from chloroform-ethanol). Example 31 10-ethyl-7-fluoro-8- (4-methyl-1-piperazinyl) pyrimido [4,5-b] quinoline-4,5 (3H, 1
0H) -dione: mp 300 ° C or higher (recrystallized from chloroform-ethanol). Example 32 8- (3-Amino-1-pyrrolidinyl) -10-ethyl-
7-Fluoropyrimido [4,5-b] quinoline-4,5 (3H, 1
0H) -dione: mp 300 ° C or higher (recrystallized from chloroform-ethanol). Example 33 10-ethyl-7-fluoro-2-methyl-8- (1-piperazinyl) pyrimido [4,5-b] quinoline-4,5 (3H, 1
0H) -dione: mp 288-293 ° C (decomposition) (recrystallized from chloroform-ethanol). Example 34 10-Ethyl-7-fluoro-2-methyl-8- (4-methyl-1-piperazinyl) pyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione: mp 278-282 ° C (decomposition)
(Recrystallized from chloroform-ethanol). Example 35 8- (3-amino-1-pyrrolidinyl) -10-ethyl-
7-Fluoro-2-methylpyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione: mp 251-255 ° C (decomposition). Example 36 10-cyclopropyl-7-fluoro-8- (1-piperazinyl) pyrimido [4,5-b] [1,8] naphthyridine-4,
5 (3H, 10H) -dione: (1) 10-cyclopropyl-7-fluoro-8- (p-
Torylthio) pyrimido [4,5-b] [1,8] naphthyridine-4,5 (3H, 10H) -dione (350 mg) was dissolved in chloroform (300 ml), m-chloroperbenzoic acid (374 mg) was added, and the mixture was added at room temperature for 30 minutes. Stir. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were cooled and collected by filtration to give 8- (p-toluenesulfinyl).
Mixture of isomer and 8- (p-toluenesulfonyl) isomer 34
Obtain 0 mg.

(2) A mixture of 100 mg of the above mixture, 60 mg of anhydrous piperazine and 2 ml of dimethyl sulfoxide is heated and stirred at 110 ° C. for 1 hour. After cooling, the precipitated crystals are collected by filtration, dissolved in a 10% aqueous acetic acid solution and treated with activated carbon. The solution is made weakly alkaline with 10% aqueous ammonia, and the precipitated crystals are collected by filtration, washed with water and dried to obtain 70 mg of the desired product. mp 275-278 ° C (decomposition). Example 37 10-Cyclopropyl-7-fluoro-8- (4-methyl-1-piperazinyl) pyrimido [4,5-b] [1,8] naphthyridine-4,5 (3H, 10H) -dione: N Using -methylpiperazine, the desired product is obtained in the same manner as in Example 36 (2). mp 291-295 ° C (decomposition). Reference Example 20 Ethyl 2-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate: 1-cyclopropyl-6,7,8-triethyl A mixture of 8.5 g of ethyl fluoro-2-methylsulfinyl-1,4-dihydro-4-oxoquinoline-3-carboxylate and 250 ml of 11% ethanolic ammonia is left at room temperature for 4 days. The reaction solution is concentrated to dryness under reduced pressure, water and ether are added to the residue, and the precipitated crystals are collected by filtration and dried to obtain 6.5 g of the desired product. mp18
6-187 ° C. Reference Example 21 Ethyl 1-cyclopropyl-6,7-difluoro-2-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate: 1-cyclopropyl-6,7-difluoro-2-methyl Sulfinyl-1,4-dihydro-4-oxoquinoline-
3.04 g of ethyl 3-carboxylate is dissolved in 40 ml of ethanol, 10 ml of a 40% aqueous solution of methylamine is added thereto, and the mixture is left for 2 days. The reaction solution is concentrated to dryness under reduced pressure, water is added to the residue, and the precipitated crystals are collected by filtration and dried to obtain 2.5 g of the desired product.
mp 165-166 ° C. Example 38 10-Cyclopropyl-7,8,9-trifluoropyrimido [4,5-b] quinoline-2,4,5 (1H, 3H, 10H) -trione: (1) 2-amino-1 -Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-
Ethyl carboxylate 6g, ethoxycarbonyl isocyanate
A mixture of 4.5 g and 100 ml of toluene is heated and stirred at 100 ° C. for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [chloroform-methanol (20:
1) and purified by 1-cyclopropyl-2
-(3-ethoxycarbonylureido) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-
4 g of ethyl carboxylate are obtained. mp 181-184 ° C. (2) 3.55 g of the above compound, 3.5 g of potassium carbonate, ethanol 7
A mixture of 0 ml and 70 ml of water is stirred for 30 minutes at room temperature and then left overnight. The ethanol is distilled off under reduced pressure and the solution is acidified with 10% hydrochloric acid. The precipitated crystals are collected by filtration, washed with water, and dried to give 10-cyclopropyl-3-ethoxycarbonyl-7,
8,9-trifluoropyrimido [4,5-b] quinoline-2,4,
3.12 g of 5 (1H, 3H, 10H) -trione are obtained. mp260-262
° C (decomposition). (3) A mixture of 520 ml of the above compound and 15 ml of a 1N aqueous solution of sodium hydroxide is heated and stirred at 100 ° C. for 1 hour. 20% after cooling
The mixture is acidified with hydrochloric acid, and the precipitated crystals are collected by filtration, washed with water and dried to obtain 330 mg of the desired product. mp300 ℃ or more. Example 39 10-Cyclopropyl-7,8-difluoro-1-methylpyrimido [4,5-b] quinoline-2,4,5 (1H, 3H, 10H) -trione: 1-cyclopropyl-6,7- Difluoro-2-methylamino-1,4-dihydro-4-oxo-quinoline-3-
A mixture of 1.84 g of ethyl carboxylate, 3.94 g of ethoxycarbonyl isocyanate and 30 ml of toluene is heated and stirred at 100 ° C. for 20 minutes. The reaction solution was concentrated under reduced pressure, and potassium carbonate was added to the residue.
1.2 g, 35 ml of ethanol and 35 ml of water are added and left overnight at room temperature. The reaction solution is acidified with 10% hydrochloric acid and extracted with chloroform. The extract is dried and concentrated, and ethyl acetate is added to the residue. The precipitated crystals are collected by filtration to obtain 140 mg of the desired product. mp300 ℃ or more. Example 40 8- (3-Amino-1-pyrrolidinyl) -10-cyclopropyl-7,9-difluoropyrimido [4,5-b] quinoline-2,4,5 (1H, 3H, 10H) -trione : 10-cyclopropyl-7,8,9-trifluoropyrimido [4,5-b] quinoline-2,4,5 (1H, 3H, 10H) -trione 3
A mixture of 00 mg, 320 mg of 3-aminopyrrolidine and 5 ml of dimethyl sulfoxide is heated and stirred at 120 ° C. for 5 hours. After cooling, the precipitated crystals are collected by filtration. Dissolve these crystals in glacial acetic acid,
The solution is treated with activated carbon and then made alkaline with 10% aqueous ammonia. The precipitated crystals are collected by filtration, washed with water and dried to obtain 230 mg of the desired product. mp300 ℃ or more. The following starting compounds are obtained by carrying out the reaction treatment in the same manner as in Example 40 using the corresponding starting compounds.

Example 41 10-Cyclopropyl-7,9-difluoro-8- (1-piperazinyl) pyrimido [4,5-b] quinoline-2,4,5 (1
H, 3H, 10H) -trione: mp 296-299 ° C (decomposition). Example 42 10-Cyclopropyl-7,9-difluoro-8- (4-methyl-1-piperazinyl) pyrimido [4,5-b] quinoline-2,4,5 (1H, 3H, 10H) -trione: mp300 ℃ or more. Example 43 10-Cyclopropyl-7,9-difluoro-8- (cis-
3,5-Dimethyl-1-piperazinyl) pyrimido [4,5-
b] Quinoline-2,4,5 (1H, 3H, 10H) -trione: mp300
Over ℃. Example 44 10-cyclopropyl-7-fluoro-1-methyl-8-
(4-methyl-1-piperazinyl) pyrimido [4,5-
b] Quinoline-2,4,5 (1H, 3H, 10H) -trione: mp288
~ 290 ° C (decomposition). Example 45 10-Cyclopropyl-7,9-difluoro-8-methoxypyrimido [4,5-b] quinoline-2,4,5 (1H, 2H, 10H)-
Trione: 1-cyclopropyl-2- (3-ethoxycarbonylureido) -6,7,8-trifluoro-1,4-dihydro-4
A mixture of 100 mg of ethyl-oxoquinoline-3-carboxylate, 100 mg of potassium carbonate and 7 ml of methanol is heated and stirred at 70 ° C. for 1 hour. The reaction solution is concentrated to dryness under reduced pressure, water is added to the residue, and the mixture is acidified with 10% hydrochloric acid. The precipitated crystals are collected by filtration and recrystallized from chloroform-methanol to give the desired product 40.
get mg. mp 305-307 ° C (decomposition). Example 46 10-cyclopropyl-7,8-difluoro-2-methylthiopyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione: (1) 2-amino-1-cyclopropyl Dissolve 5.0 g of ethyl 6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate in 20 ml of tetrahydrofuran,
To this is added 780 mg of 60% sodium hydride, and after a further 5 minutes, a solution of 5.1 g of 3,4-dimethoxybenzyl isothiocyanate in 20 ml of tetrahydrofuran is added. After stirring the reaction solution for 1 hour, 3 ml of methyl iodide was added thereto, and
Stir for hours. After concentrating the reaction solution and acidifying it with a dilute acetic acid aqueous solution, the precipitated crystals are collected by filtration, washed successively with water and ethanol, and 10-cyclopropyl-7,8-difluoro-2-methylthio-3- ( 3,4-dimethoxybenzyl)
Pyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione
Get 7g. mp 255-258 ° C. (2) 7 g of the above compound, trifluoromethanesulfonic acid 2.6
A mixture of ml, anisole 4.3 ml and trifluoroacetic acid 100 ml is left for 5.5 hours at room temperature. The reaction mixture is concentrated, water is added to the residue, and the mixture is neutralized with 28% aqueous ammonia. The precipitated crystals are collected by filtration and washed successively with water and ethanol to obtain 4.5 g of the desired product. mp 250-253 ° C. Example 47 10-Cyclopropyl-7-fluoro-2-methylthio-
8- (1-piperazinyl) pyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione: 10-cyclopropyl-7,8-difluoro-2-methylthiopyrimido [4,5-b ] A mixture of 3.28 g of quinoline-4,5 (3H, 10H) -dione, 1.1 g of anhydrous piperazine and 100 ml of pyridine is heated and stirred at 80 to 85 ° C for 4 hours. The reaction solution was concentrated to dryness, ethanol was added to the residue, and the precipitated crystals were collected by filtration and washed with ethanol and ether to give the desired product (3.74).
get g. mp 288-289 ° C (decomposition). Example 48 10-Cyclopropyl-7-fluoro-2-methylthio-
8- (4-methyl-1-piperazinyl) pyrimido [4,5
-B] Quinoline-4,5 (3H, 10H) -dione: The desired product is obtained in the same manner as in Example 47 using N-methylpiperazine. mp 253-254 ° C (decomposition). Example 49 10-Cyclopropyl-7-fluoro-2- (1-piperazinyl) -8- (1-piperazinyl) pyrimido [4,5-
b] Quinoline-4,5 (3H, 10H) -dione: 10-cyclopropyl-7-fluoro-2-methylthio-8- (1-piperazinyl) pyrimido [4,5-b] quinoline-4,5 (3H A mixture of 100 mg of (10H) -dione, 0.2 ml of pyrrolidine and 3 ml of pyridine is heated and stirred at 115 ° C. for 17 hours. The reaction solution is concentrated to dryness under reduced pressure, ethanol is added to the residue, and the precipitated crystals are collected by filtration. 5m of ethanol on this crystal
l and 3 ml of 28% aqueous ammonia are added, and the mixture is heated under reflux at 85 to 90 ° C for 2 hours. Water was added to the reaction solution, and the crystals were collected by filtration.
Washing with ethanol and ether gives 40 mg of the desired product. mp 231-235 ° C (decomposition). Example 50 10-Cyclopropyl-7-fluoro-8- (4-trifluoroacetyl-1-piperazinyl) -2-methylsulfinylpyrimido [4,5-b] quinoline-4,5 (3H, 10H)
-Dione: (1) 10-cyclopropyl-7-fluoro-2-methylthio-8- (1-piperazinyl) pyrimido [4,5-b]
3.44 g of quinoline-4,5 (3H, 10H) -dione in chloroform
Dissolve in 150 ml, add 20 ml of triethylamine and 10 ml of trifluoroacetic anhydride under ice-cooling, and stir at room temperature for 30 minutes. The reaction solution is concentrated to dryness under reduced pressure, and water is added to the residue.
The precipitated crystals are collected by filtration, washed with water and ethanol, and washed with 10-cyclopropyl-7-fluoro-8- (4-trifluoroacetyl-1-piperazinyl) -2-methylthiopyrimido [4,5-b 3.8 g of quinoline-4,5 (3H, 10H) -dione are obtained. mp 274-279 ° C (decomposition). (2) Dissolve 3.7 g of the above compound in a mixed solvent of 400 ml of chloroform and 120 ml of methanol, and add 1.97 g of 80% m-chloroperbenzoic acid under ice cooling. After stirring at room temperature for 1.5 hours, the reaction solution is concentrated under reduced pressure, and ethanol is added to the residue.
The precipitated crystals are collected by filtration and washed with chloroform to give 3.19 g of the desired product. mp 235-243 ° C (decomposition). Example 51 10-Cyclopropyl-7-fluoro-2-methoxy-8
-(1-Piperazinyl) pyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione: 10-cyclopropyl-7-fluoro-8- (4-trifluoroacetyl-1-piperazinyl)- 2-methylsulfinylpyrimido [4,5-b] quinoline-4,5 (3H, 10
A mixture of 300 mg of H) -dione and 20 ml of a 28% methanol solution of sodium methoxide is heated under reflux for 1.5 hours. The reaction mixture is treated with activated carbon by adding hydrochloric acid and then made alkaline with 28% aqueous ammonia. The precipitated crystals are collected by filtration and washed with water and ethanol to obtain 140 mg of the desired product. mp300 ℃ or more. Example 52 10-Cyclopropyl-7-fluoro-2-dimethylamino-8- (1-piperazinyl) pyrimido [4,5-b] quinoline-4,5 (3H, 10H) -dione: 10-cyclopropyl- 7-fluoro-8- (4-trifluoroacetyl-1-piperazinyl) -2-methylsulfinylpyrimido [4,5-b] quinoline-4,5 (3H, 10
A mixture of 300 mg of H) -dione, 3 ml of a 50% aqueous solution of dimethylamine and 10 ml of ethanol is heated and stirred at 60 ° C. for 2.5 hours. After cooling, the precipitated crystals are collected by filtration. The crystals are dissolved in a 30% aqueous acetic acid solution, treated with activated carbon, and then made alkaline with 28% aqueous ammonia. The precipitated crystals are collected by filtration and washed with water and ethanol to obtain 105 mg of the desired product. mp282-28
3 ° C (decomposition). Example 53 5-Cyclopropyl-6,7,8-trifluoropyridazino [4,5-b] quinoline-1,10 (2H, 5H) -dione: 1-cyclopropyl-6,7,8- 1.86 g of ethyl trifluoro-2-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate was dissolved in 60 ml of tetrahydrofuran, 340 mg of 60% sodium hydride was added, and 1.3 g of diethyl azodicarboxylate was further added. Tetrahydrofuran 20
Add the solution dissolved in ml. The reaction solution is heated under reflux for 40 minutes and concentrated to dryness under reduced pressure. Water is added to the residue, acidified with 10% hydrochloric acid, and extracted with chloroform. After the extract is dried and concentrated, chloroform and ethanol are added to the residue. The precipitated crystals are collected by filtration and washed with ethanol to obtain 80 mg of the desired product. mp300 ℃ or more. The above-mentioned filtrate was concentrated, and ethanol and ether were added, and the precipitated crystals were collected by filtration, washed with ether, and dried.
Cyclopropyl-2,3-diethoxycarbonyl-6,7,8-
810 mg of trifluoro-3,4-dihydropyridazino [4,5-b] quinoline-1,10 (2H, 5H) -dione are obtained. mp214
~ 217 ° C. Example 54 5-Cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) pyridazino [4,5-b] quinoline-1,10 (2H, 5H) -dione: 5-cyclopropyl -2,3-diethoxycarbonyl-
6,7,8-trifluoro-3,4-dihydropyridazino [4,5
-B] a mixture of 400 mg of quinoline-1,10 (2H, 5H) -dione, 0.4 ml of N-methylpiperazine and 7 ml of pyridine at 70 ° C.
Heat and stir for 10 hours. The reaction solution is concentrated to dryness under reduced pressure, and ethanol is added to the residue. The precipitated crystals are collected by filtration and washed with water and ethanol to obtain 104 mg of the desired product. mp300
Over ℃. Reference Example 22 Ethyl 2-bromomethyl-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate: 1-cyclopropyl-6,7-difluoro-2-methyl- 4.1 g of ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate was dissolved in 65 ml of carbon tetrachloride, and 2.58 g of N-bromosuccinimide and 17 mg of dibenzoyl peroxide were added thereto.
And refluxed at 80 ° C. for 20 hours. Water is added to the reaction solution, and extracted with chloroform. The extract is dried and concentrated under reduced pressure, and the residue is purified by silica gel column chromatography. After elution with chloroform and concentration under reduced pressure, n-hexane is added to the residue. The precipitated crystals are collected by filtration and dried to obtain 3.81 g of the desired product. mp 135-136 ° C. Reference Example 23 2-bromomethyl-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-
Ethyl carboxylate: Using ethyl 1-cyclopropyl-6,7,8-trifluoro-2-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate as in Reference Example 22, the target compound Get. mp 161-162 ° C. Example 55 5-Cyclopropyl-8-fluoro-7- (4-methyl-1-piperazinyl) pyridazino [4,5-b] quinoline-1,10 (2H, 5H) -dione: (1) 2-bromomethyl -1-cyclopropyl-6,7-
Difluoro-1,4-dihydro-4-oxoquinoline-3
3.8 g of ethyl carboxylate, 1.88 g of N-acetyl-N'-tert-butoxycarbonylhydrazine, 90 of tetrahydrofuran
30 ml of a mixture of 0.5 ml of a 0.5N aqueous solution of sodium hydroxide at 70 ° C.
Stir for minutes. The reaction solution is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. After drying the extract, it is concentrated under reduced pressure, and n-hexane is added to the residue. The precipitated crystals are collected by filtration and dried to give 2-[(N-acetyl-N'-t-
0.55 g of ethyl butoxycarbonylhydrazino) methyl] -1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate are obtained. mp1
09-113 ° C. (2) 2 ml of trifluoroacetic acid was added to 550 mg of the above compound,
Stir at room temperature for 40 minutes. The reaction solution is concentrated to dryness under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. The extract is dried and concentrated, and isopropyl ether is added to the residue. The precipitated crystals are collected by filtration, washed with isopropyl ether and dried, and 3-acetyl-5-cyclopropyl-7,8-difluoro-3,4-dihydropyridazino [4,5-b] quinoline-1 350 mg of 10,10 (2H, 5H) -dione are obtained. mp300 ℃ or more. (3) A mixture of 333 mg of the above compound, 500 mg of N-methylpiperazine and 20 ml of pyridine is heated and stirred at 90 ° C. for 6 hours.
The reaction solution is concentrated to dryness under reduced pressure, ether is added to the residue, and the precipitated crystals are collected by filtration. The crystals are dissolved in a 5% aqueous acetic acid solution, treated with activated carbon, and then neutralized with 28% aqueous ammonia. The precipitated crystals are collected by filtration, washed with water, and dried to obtain the target compound 90.
get mg. mp300 ℃ or more. Example 56 5-Cyclopropyl-6,8-difluoro-7- (1-piperazinyl) pyridazino [4,5-b] quinoline-1,10 (2
(H, 5H) -dione: (1) 2-bromomethyl-1-cyclopropyl-6,7,8
Using ethyl-trifluoro-1,4-dihydro-4-oxoquinoline-3carboxylate, the reaction was carried out in the same manner as in Example 55 (1) to give 2-[(N-acetyl-N'-t-butoxy). Carbonylhydrazino) methyl] -1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate. mp176-1
80 ° C. (2) Using 100 mg of the above compound, a reaction treatment was carried out in the same manner as in Example 55 (2) to give 3-acetyl-5-cyclopropyl-
6,7,8-trifluoro-3,4-dihydropyridazino [4,5
-B] 70 mg of quinoline-1,10 (2H, 5H) -dione are obtained.
mp 186-191 ° C. (3) A mixture of 212 mg of the above compound, 258 mg of anhydrous piperazine and 12 ml of pyridine is heated and stirred at 80 ° C. for 2.5 hours. The reaction solution is concentrated to dryness under reduced pressure, and isopropyl ether and ethanol are added to the residue. The precipitated crystals are collected by filtration, washed with ethanol and dried to obtain 97 mg of the desired product. mp283-2
88 ° C (decomposition). Example 57 5-Cyclopropyl-6,8-difluoro-7- (4-methyl-1-piperazinyl) pyridazino [4,5-b] quinoline-1,10 (2H, 5H) -dione: 5-cyclopropyl 65 mg of -6,7,8-trifluoropyridazino [4,5-b] quinoline-1,10 (2H, 5H) -dione and 84 mg of N-methylpiperazine were treated in the same manner as in Example 13, 34 mg of the desired product are obtained. mp300 ℃ or more.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // A61K 31/00 631 A61K 31/00 631C 31/435 606 31/435 606 31/47 610 31/47 610 31/495 601 31/495 601 31/50 603 31/50 603 31/505 606 31/505 606 31/535 606 31/535 606 (72) Inventor Hiroyuki Miyamoto 704, Kanaokacho, Sakai-shi, Osaka 2 Ever Grin Kanaoka No. 6 Room 108 (72) Inventor Junji Nakano 3-6-6 Kanodai Higashi, Ikoma City, Nara Prefecture (72) Inventor Junichi Matsumoto 2-15-15 Kanodai Higashi, Ikoma City Nara Prefecture 3 (72) Shinichi Nakamura Takatsuki City, Osaka Prefecture 1-12-12 Tsukawaki (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 471/04 C07D 471/14 CAPLUS (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula (Wherein X ₁ represents a halogen atom, R ₁ represents a lower alkyl group, a halogeno lower alkyl group, a hydroxy lower alkyl group, a lower alkenyl group, a cycloalkyl group or a phenyl group which may have a substituent. R ₂ represents a hydrogen atom, a halogen atom, an amino group, a hydroxyl group or a methyl group, and R ₃ represents a halogen atom, a lower alkyloxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an arylthio group. Group, an arylsulfinyl group or an arylsulfonyl group, or a group represented by the following formula (a), (b) or (c) Wherein R ₄ and R ₉ represent a hydrogen atom, a lower alkyl group or an acyl group, and R ₅ , R ₆ and R ₁₀ are the same or different and represent a hydrogen atom, a lower alkyl group or a halogeno lower alkyl group. R ₇ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a hydroxy lower alkyl group, an amino group, a mono- or di-lower-alkylamino group, an amino-lower-alkyl group, or a mono- or di-lower-alkylamino-lower-alkyl group R ₈ represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkyloxy group, n represents 3, 4 or 5, A represents C—X ₂ or a nitrogen atom. X ₂ represents a hydrogen atom, a halogen atom, a methyl group, a cyano group or a lower alkyloxy group, and B represents the following formula (a), (b), (c) or Group represented by (d) Wherein Y represents an oxygen atom or a sulfur atom, R ₁₁ , R ₁₃ and R ₁₄ represent a hydrogen atom or a lower alkyl group, and R ₁₂ represents a hydrogen atom, a lower alkyl group, a lower alkyloxy group A mercapto group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an arylthio group, an arylsulfinyl group, an arylsulfonyl group, an amino group, a mono- or di-lower alkylamino group or a cyclic amino group which may be substituted. means. A) a fused tricyclic compound represented by the formula: or a salt thereof.