JPH0649059A - 7-@(3754/24)5-azaspiro(2,4)heptan-5-yl)-8-alkoxyquinoline-3-carboxylic acid derivative - Google Patents

Abstract

(57) [Summary] [Structure] The following general formula: (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a halogeno lower alkanoyl group or an ester-type protecting group, R ³
Represents a hydrogen atom or a lower alkyl group, and R ⁴ represents a lower alkyl group. ) 7- (5-azaspiro [2,
4] heptan-5-yl) -8-alkoxyquinoline-
3-carboxylic acid derivative. [Effect] The compound of the present invention is useful as an antibacterial agent and the like.

Description

Detailed Description of the Invention

[0001]

INDUSTRIAL APPLICABILITY The present invention has a novel antibacterial action, antitumor action and anti-AIDS virus action, and is useful as an antibacterial agent, antitumor agent and AIDS therapeutic agent.
The present invention relates to an azaspiro [2,4] heptan-5-yl) -8-alkoxyquinoline-3-carboxylic acid derivative and a pharmacologically acceptable salt thereof.

[0002]

2. Description of the Related Art A quinoline-3-carboxylic acid derivative according to the present invention having a 5-azaspiro [2,4] heptyl group at the 7-position and an alkoxy group at the 8-position at the same time has never been known.

[0003]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention Pyridonecarboxylic acid synthetic antibacterial agents have made epoch-making progress since the discovery of norfloxacin, and their indications are expanded to various infectious diseases in addition to urinary tract infections. Since then, many pyridonecarboxylic acid synthetic antibacterial agents have come to be used clinically.

However, in clinical practice, the number of bacteria that are insensitive to these drugs has been increasing in recent years, and as a side effect, compounds that induce convulsions and compounds that have phototoxicity when used in combination with certain anti-inflammatory agents are also present. Has been known.
In addition, among the pyridonecarboxylic acid-based synthetic antibacterial agents, there are compounds that do not show the expected in vivo antibacterial activity or clinical effects despite their strong in vitro antibacterial activity due to their low absorption rate. Is recognized.

From these facts, it is hard to say that existing synthetic antibacterial agents are completed drugs, and they are effective against non-susceptible bacteria isolated clinically, and have high safety and excellent in v
There has been a strong demand for the development of synthetic antibacterial agents having ivo antibacterial activity.

[0006]

DISCLOSURE OF THE INVENTION As a result of intensive research conducted by the present inventors in view of the above-mentioned circumstances, a novel 7-
(5-Azaspiro [2,4] heptan-5-yl) -8
It has been found that an -alkoxyquinoline-3-carboxylic acid derivative is an excellent compound that solves these problems. Furthermore, they have also found that these compounds have excellent antitumor activity and anti-AIDS virus activity, and completed the present invention.

That is, the present invention has the following general formula (I)

[Chemical 2] (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a halogeno lower alkanoyl group or an ester-type protecting group, R ³
Represents a hydrogen atom or a lower alkyl group, and R ⁴ represents a lower alkyl group. ) 7- (5-azaspiro [2,
4] heptan-5-yl) -8-alkoxyquinoline-
The present invention relates to a 3-carboxylic acid derivative and a pharmacologically acceptable salt thereof.

In the general formula (I) of the present invention, R ¹ , R ² , R
Examples of the lower alkyl group represented by ³ and R ⁴ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-
Examples of the lower alkanoyl group represented by R ² include a formyl group, an acetyl group, a propanoyl group, a butyroyl group, and a trimethylacetyl group. Examples of the halogeno lower alkanoyl group include a fluoroacetyl group. , A difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, and the like. Examples of the ester type protecting group include, for example, benzyloxycarbonyl group, ethoxycarbonyl group, methoxycarbonyl group, tert-butoxycarbonyl group. Groups and the like.

The compound represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt, or a base or an acid can be liberated from the produced salt, if desired. .

Examples of the pharmaceutically acceptable salt of the compound represented by the general formula (I) of the present invention include acid addition salts and alkali addition salts. Examples of the acid addition salt include:
Hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and other mineral salts, or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, methanesulfonic acid, p-toluene sulfone Organic acid salts such as acids, mandelic acid, 10-camphorsulfonic acid, tartaric acid, etc., such as sodium, potassium, calcium, silver,
Examples thereof include inorganic alkali salts such as zinc, lead and ammonium, and salts of organic bases such as ethanolamine and N, N-dialkylethanolamine.

The compound represented by the general formula (I) of the present invention has an asymmetric carbon atom, and optical isomers may exist, but the present invention also includes these isomers and mixtures thereof. It

The 7- (5-azaspiro [2,4] of the present invention
Heptan-5-yl) -8-alkoxyquinoline-3-
The following compounds may be mentioned as preferred embodiments of the carboxylic acid derivative, but the present invention is not limited to these examples. (1) 7- (7-Amino-5-azaspiro [2,4] heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3 -Carboxylic acid (2) 7-((S) -7-amino-5-azaspiro [2,4] heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy -4
-Oxoquinoline-3-carboxylic acid (3) 7-((R) -7-amino-5-azaspiro [2,4] heptan-5-yl) -1-cyclopropyl-6-fluoro-1,4- Dihydro-8-methoxy-4
-Oxoquinoline-3-carboxylic acid (4) 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (7-methylamino-5-azaspiro [2,4] heptan-5-yl) -8 -Methoxy-4-
Oxoquinoline-3-carboxylic acid (5) 1-cyclopropyl-6-fluoro-1,4-dihydro-7-((S) -7-methylamino-5-azaspiro [2,4] heptan-5-yl ) -8-Methoxy-
4-oxoquinoline-3-carboxylic acid (6) 1-cyclopropyl-6-fluoro-1,4-dihydro-7-((R) -7-methylamino-5-azaspiro [2,4] heptane-5 -Yl) -8-methoxy-
4-oxoquinoline-3-carboxylic acid (7) 1-cyclopropyl-7- (7-dimethylamino-5-azaspiro [2,4] heptan-5-yl) -6
-Fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (8) 1-cyclopropyl-7-((S) -7-dimethylamino-5-azaspiro [2,4] Heptan-5-yl) -6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (9) 1-cyclopropyl-7-((R) -7-dimethylamino- 5-Azaspiro [2,4] heptan-5-yl) -6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

The novel 7- (5-azaspiro [2,4] heptan-5-yl) -8-alkoxyquinoline-3-carboxylic acid derivative represented by the general formula (I) of the present invention is prepared by the following method. Although it can be produced, the production method of the compound is not limited to these methods.

According to the first mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) has the following general formula (II):

[Chemical 3] (In the formula, R ¹ and R ⁴ have the same meanings as described above, and X represents a halogen atom.) 7-halogenoquinoline-
3-carboxylic acid derivative and the following general formula (III)

[Chemical 4] (Wherein R ² and R ³ have the same meanings as described above) and the 7-amino-5-azaspiro [2,4] heptane derivative is reacted in a solvent in the presence or absence of a base. It can be manufactured by

The solvent used in the present production method may be any solvent as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, N, N. -Aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide and hexamethylphosphoric triamide, aromatic hydrocarbon solvents such as benzene and toluene, pyridine, picoline, lutidine, collidine, etc. Examples of the organic bases, mixed solvents thereof, and the like.

Examples of the base used in the present production method include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5,4,0] -7-
Undecene, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like can be mentioned, and the reaction is carried out in the range from under ice cooling to the reflux temperature of the solvent.

According to the second mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) has the following general formula (IV):

[Chemical 5] (In the formula, R ⁴ and X have the same meanings as described above, and R ⁵ represents a halogen atom, an aliphatic acyloxy group, an aliphatic acyloxy group optionally substituted with a halogen atom, or an aromatic acyloxy group.). Boric acid derivative and 7-amino-5-azaspiro [2,3
4] After the reaction with a heptane derivative in the presence or absence of a base in a solvent, further dechelation by treatment with a protic polar solvent in the presence or absence of a base, if necessary. It can be manufactured by performing

In the present production method, the solvent used for the reaction between the compound represented by the general formula (IV) and the compound represented by the general formula (III) may be any solvent as long as it does not inhibit the reaction. Alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, aprotons such as acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, hexamethylphosphoric triamide, etc. Polar solvents, aromatic hydrocarbon solvents such as benzene and toluene, organic bases such as pyridine, picoline, lutidine and collidine, halogen-containing hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane and chloroform, or mixed solvents thereof. Etc.

Examples of the base used in the present production method include triethylamine, diisopropylamine, 1,8-diazabicyclo [5,4,0] -7-undecene, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and hydrogencarbonate. Examples thereof include potassium, and the reaction is carried out in the range from under ice cooling to the reflux temperature of the solvent.

The protic polar solvent used in the dechelation reaction is, for example, methanol,
Alcohol solvents such as ethanol, n-propanol, isopropanol, n-butanol, etc., or water, and mixed solvents thereof, or acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphine. For example, a mixed solvent of a solvent such as folic triamide, benzene, toluene, pyridine, picoline, lutidine, collidine, dichloromethane, 1,2-dichloroethane, chloroform and methanol or water may be used. It is carried out up to the reflux temperature.

According to the third mode of the method for producing a compound according to the present invention, among the compounds represented by the general formula (I), the compound in which R ¹ is a hydrogen atom is represented by the general formula (I). It can be produced by hydrolyzing a compound in which R ¹ is a lower alkyl group among the compounds described above.

This hydrolysis is carried out by a method known per se using an acid or an alkali. For the acidic hydrolysis, hydrochloric acid,
Acids such as sulfuric acid are used for alkaline hydrolysis, and alkalis such as sodium hydroxide and potassium hydroxide are used. These acids or alkalis are aqueous solutions or methanol, ethanol, n-butanol, sec-butanol, tert-butanol, etc. It can be used in the reaction as a solution in an organic solvent or a water-containing organic solvent, and the reaction is carried out from room temperature to the reflux temperature of the solvent.

According to the fourth mode of the method for producing a compound according to the present invention, among the compounds represented by the general formula (I), the compound represented by the general formula (I) in which R ² is a hydrogen atom is
Of the compounds represented by R ² are hydrolyzed compounds in which R ² is a lower alkanoyl group or halogeno lower alkanoyl group, or compounds in which R ² is an ester-type protecting group are solvent-free or in the presence or absence of a cationic scavenger in a solvent. It can be produced by treating with acid and deprotecting under the following conditions.

This hydrolysis is carried out by a method known per se using an acid or an alkali. For acidic hydrolysis, hydrochloric acid,
Acids such as sulfuric acid are used for alkaline hydrolysis, and alkalis such as sodium hydroxide and potassium hydroxide are used. These acids or alkalis are aqueous solutions or methanol, ethanol, n-butanol, sec-butanol, tert-butanol, etc. It can be used in the reaction as a solution in an organic solvent or a water-containing organic solvent, and the reaction is carried out from room temperature to the reflux temperature of the solvent.

Further, examples of the solvent used in the deprotection reaction of the ester type protecting group include acetic acid, ethyl acetate, dioxane, water, methanol, ethanol or a mixed solvent thereof. As the cation scavenger, Examples thereof include anisole and thioanisole, and examples of the acid include hydrochloric acid, hydrobromic acid, trifluoroacetic acid, and the like, and the reaction is carried out in the temperature range from under ice cooling to room temperature.

According to the fifth mode of the method for producing a compound of the present invention, among the compounds represented by the general formula (I), the compound in which R ² and / or R ³ is a lower alkyl group is
In the above general formula (I), a compound in which R ² or / and R ³ is a hydrogen atom is reacted with a halogeno lower alkyl in a solvent in the presence or absence of a base, or (V)

[Chemical 6] (In the formula, R ⁶ represents a hydrogen atom or a lower alkyl group.)
It can be produced by reacting with an aldehyde compound represented by: in the presence of formic acid.

As the solvent when halogeno lower alkyl is used in the present production method, for example, N, N-dimethylformamide, acetone, ethanol, tetrahydrofuran, benzene, chloroform and the like can be mentioned, and as the base, for example, triethylamine, Examples thereof include potassium carbonate.

The aldehyde compound represented by the general formula (V) when an aldehyde compound is used in the present production method includes formaldehyde, acetaldehyde,
Propionaldehyde and the like can be mentioned. Formaldehyde is preferably used as an aqueous formaldehyde solution (formalin), and when acetaldehyde and propionaldehyde are used, nitrobenzene is preferably used as a solvent.

Any reaction is carried out in the temperature range from room temperature to the reflux temperature of the solvent.

According to the sixth mode of the method for producing a compound according to the present invention, the compound represented by the general formula (I) is a compound represented by the following general formula (VI):

[Chemical 7] (In the formula, R ¹ , R ² and R ³ have the same meanings as described above and Y represents a halogen atom.) By reacting an 8-halogenoquinoline-3-carboxylic acid derivative with an alcoholate in a solvent, It can be manufactured.

The solvent used in the present production method may be any solvent as long as it does not inhibit the reaction, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, N, N-dimethylformamide, N-methyl. Solvents such as 2-pyrrolidone, dimethyl sulfoxide, hexamethylphosphoric triamide, benzene, toluene, pyridine, picoline, lutidine, collidine, dichloromethane, 1,2-dichloroethane, chloroform and the like can be mentioned. The reaction is carried out under ice-cooling to an outer temperature of 300 ° C. in a sealed tube.

In the present production method, among the compounds used as starting materials, the compounds represented by the general formulas (II) and (IV) are described in JP-A-62-252772 and JP-A-63-297.
366, JP-A-64-16746, JP-A-2-12
4873, JP-A-3-95176, JP-A-4-69
It is a known compound disclosed in JP-A No. 388, JP-A-4-149174 and the like.

The above-mentioned general formula (I) produced in this manner
A novel 7- (5-azaspiro [2,4] heptan-5-yl) -8-alkoxyquinoline-3-carboxylic acid derivative represented by: and a pharmacologically acceptable salt thereof as an active ingredient Is usually capsules, tablets, fine granules,
It is administered as an oral administration agent such as granules, powders, syrups, etc., or as an injection, a suppository, an eye drop, an eye ointment, an ear drop or an external skin preparation. These preparations can be manufactured by a conventional method by adding pharmacologically and pharmaceutically acceptable additives. That is, for oral agents and suppositories, excipients (lactose, D-mannitol, corn starch, crystalline cellulose, etc.), disintegrants (carboxymethyl cellulose, carboxymethyl cellulose calcium, etc.), binders (hydroxypropyl cellulose, hydroxypropyl) Pharmaceutical ingredients such as methylcellulose, polyvinylpyrrolidone, etc., lubricants (magnesium stearate, talc, etc.), coating agents (hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.), bases (polyethylene glycol, hard fat, etc.), For injections, eye drops, and ear drops, solubilizers or solubilizers (water for injection, physiological saline, propylene glycol, etc.) that can form a water-based or dissolution-in-use dosage form, pH adjusters (inorganic) Or organic acids or bases), isotonic Formulation components such as agents (salt, glucose, glycerin, etc.), stabilizers, etc. are suitable for ointments, skin preparations, ointments, creams, and patches (white petrolatum). , Macrogol, glycerin, cotton cloth, etc.) are used.

The dose of this drug to a treated patient depends on the patient's symptoms, but in the case of an adult, the daily dose is usually about 10 to 1000 mg by oral administration and about 1 to 500 mg by parenteral administration. .

[0035]

EXAMPLES The present invention will be described below with reference to examples.
The invention is not limited to these examples.

Example 1 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7- (7-trifluoroacetylamino-5-azaspiro [2,4] heptane-
5-yl) quinoline-3-carboxylic acid (1) [1-cyclopropyl-6-fluoro-1,4
-Dihydro-8-methoxy-4-oxo-7- (7-trifluoroacetylamino-5-azaspiro [2,4]]
Heptan-5-yl) quinoline-3-carboxylic acid-
O ^3, O ^4] difluoro-boron [1-cyclopropyl-6,7-difluoro-1,4
Dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid -O ^3, O ^4] difluoro boron 2.00 g,
A mixture of 1.81 g of 7-trifluoroacetylamino-5-azaspiro [2,4] heptane hydrochloride, 2.6 ml of triethylamine and 10 ml of dimethyl sulfoxide was stirred at room temperature for 7.5 hours. 50 ml of diethyl ether was added to the reaction solution, and the precipitated crystals were collected by suction filtration and washed with ethyl acetate to give yellow crystals [1] having a melting point of 267 to 270 ° C (decomposition).
-Cyclopropyl-6-fluoro-1,4-dihydro-
8-Methoxy-4-oxo-7- (7-trifluoroacetylamino-5-azaspiro [2,4] heptane-5
- yl) quinoline-3-carboxylic acid O ^3, O ^4] to give the difluoro boron 3.04 g. NMR spectrum δ (DMSO-d ₆ ) ppm: 0.68-0.92 (4
H, m), 1.02-1.28 (4H, m), 3.47-4.27 (5H, m), 3.63 (3H, s), 4.
35-4.42 (1H, m), 7.83 (1H, d, J = 14Hz), 8.98 (1H, s), 9.65 (1
(H, d, J = 7.5Hz) (2) 1-cyclopropyl-6-fluoro-1,4-
Dihydro-8-methoxy-4-oxo-7- (7-trifluoroacetylamino-5-azaspiro [2,4] heptan-5-yl) quinoline-3-carboxylic acid [1-cyclopropyl-6-fluoro- 1,4-dihydro-8-methoxy-4-oxo-7- (7-trifluoromethyl-acetylamino-5-azaspiro [2,4] heptane-5-yl) quinoline-3-carboxylic acid -O ^3, O ⁴ ]
Difluoroboron 2.86 g, triethylamine 2.8
A mixture of 3 ml and 110 ml of methanol was heated under reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, 10% hydrochloric acid was added to the residual crystals, and the crystals were collected by suction filtration and washed successively with water, ethanol and ether to obtain 1.78 g of pale yellow crystals. Recrystallization from acetonitrile gave pale yellow prism crystals having a melting point of 236 to 239 ° C. Elemental analysis value C ₂₂ H ₂₁ F ₄ N ₃ O ₅ theoretical value C _, 54.66; H, 4.38; N, 8.69 experimental value C _, 54.69; H, 4.34; N, 8.66

Example 2 7- (7-Amino-5-azaspiro [2,4] heptan-5-yl) -1-cyclopropyl-6-fluoro-
1,4-Dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7- (7-trifluoroacetyl Amino-5-azaspiro [2,4] heptane-
1-yl) quinoline-3-carboxylic acid 1.58 g, 10
A mixture of 38% aqueous sodium hydroxide solution was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 8 with 10% hydrochloric acid, and the precipitated crystals were collected by suction filtration and dissolved in a 10% aqueous sodium hydroxide solution.
After natural filtration, the pH was adjusted to 8 with 10% hydrochloric acid. The precipitated crystals were collected by suction filtration and colorless crystals having a melting point of 228 to 232 ° C (decomposition) 1.
02 g was obtained. Elemental analysis value C ₂₀ H ₂₂ FN ₃ O ₄ ¼H ₂ O theoretical value C _, 61.29; H, 5.79; N, 10.72 experimental value C _, 61.35; H, 5.66; N, 10.80

The above-mentioned general formula (I) produced in this manner
The novel 7- (5-azaspiro [2,4] heptan-5-yl) -8-alkoxyquinoline-3-carboxylic acid derivative represented by and its pharmacologically acceptable salt show excellent antibacterial activity. Since it has antitumor action and anti-AIDS virus action, it is extremely useful as a medicine.

Continuation of front page (51) Int.Cl. ⁵ Identification number Office reference number FI technology display location C07D 209: 00 215: 00) 7019-4C (72) Inventor Masayuki Uejima 16- Mitsumata Town, Takefu City, Fukui Prefecture Two

Claims (1)

[Claims] 1. The following general formula: (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group, a halogeno lower alkanoyl group or an ester-type protecting group, R ³
Represents a hydrogen atom or a lower alkyl group, and R ⁴ represents a lower alkyl group. ) 7- (5-azaspiro [2,
4] heptan-5-yl) -8-alkoxyquinoline-
3-carboxylic acid derivatives and pharmaceutically acceptable salts thereof.