JPH06199834A - Optically active 8-methoxyquinoline-3-carboxylic acid derivative - Google Patents

Abstract

(57) [Summary] [Structure] The following formula [Chemical formula 1] 7-((S) -7-amino-5-azaspiro [2,4] heptan-5-yl) -8-methoxyquinoline-3-carboxylic acid derivative and a salt thereof. [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
((S) -7-Amino-5-azaspiro [2,4] heptan-5-yl) -8-methoxyquinoline-3-carboxylic acid derivative and a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art A quinoline-3-carboxylic acid derivative having a (S) -7-amino-5-azaspiro [2,4] heptyl group at the 7-position and a methoxy group at the 8-position at the same time according to the present invention has hitherto been available. Not known at all.

[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 is 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-
It was found that a ((S) -7-amino-5-azaspiro [2,4] heptan-5-yl) -8-methoxyquinoline-3-carboxylic acid derivative is an excellent compound that solves these problems, The present invention has been completed.

That is, the present invention provides the following formula (I)

[Chemical 2] A 7-((S) -7-amino-5-azaspiro [2,4] heptan-5-yl) -8-methoxyquinoline-3-carboxylic acid derivative and a pharmaceutically acceptable salt thereof It is a thing.

The compound of the above formula (I) of the present invention can be converted into a pharmaceutically 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 above formula (I) of the present invention include acid addition salts and alkali addition salts. Examples of the acid addition salts include hydrochloric acid and bromide. Hydrochloric 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-toluenesulfonic acid, mandelic acid , 10- Organic acid salts such as camphorsulfonic acid and tartaric acid are examples of alkali addition salts 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 novel 7 represented by the above formula (I) of the present invention
The-((S) -7-amino-5-azaspiro [2,4] heptan-5-yl) -8-methoxyquinoline-3-carboxylic acid derivative can be produced by the following method. The manufacturing method 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 formula (I) has the following formula (II):

[Chemical 3] (Wherein, X represents a halogen atom) and a 7-halogenoquinoline-3-carboxylic acid derivative represented by the following general formula
(III)

[Chemical 4] (In the formula, R ¹ represents a hydrogen atom or a protective group such as a lower alkanoyl group or a halogeno lower alkanoyl group ester type residue.) (S) -7-amino-5-azaspiro [2,4] heptane The derivative can be produced by reacting with a derivative in a solvent in the presence or absence of a base, and optionally deprotecting an amino group by hydrolysis.

Any solvent may be used in the present production method 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.

Hydrolysis of the amino-protecting group is carried out by a method known per se using an acid or an alkali. Acids such as hydrochloric acid and sulfuric acid are used for acidic hydrolysis and hydroxylation is used for alkaline hydrolysis. An alkali such as sodium or potassium hydroxide is used, and these acids or alkalis are used in the reaction as an aqueous solution or a solution of an organic solvent such as methanol, ethanol, n-butanol, sec-butanol, tert-butanol, or a water-containing organic solvent. The reaction can be carried out at room temperature 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 above formula (I) has the following general formula (IV):

[Chemical 5] (In the formula, X has the same meaning as described above, and R ² represents a halogen atom, an aliphatic acyloxy group, an aliphatic acyloxy group optionally substituted with a halogen atom, or an aromatic acyloxy group.) Derivatives and the general formula (II
(S) -7-amino-5-azaspiro [2,4] heptane derivative represented by I) is reacted in the presence or absence of a base in a solvent, and then, if necessary, a base. It can be produced by deprotecting an amino group by dechelation and hydrolysis by treatment with a protic polar solvent in the presence or absence of.

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. Alcoholic 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.

Further, as the protic polar solvent used in the dechelation reaction, 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.

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

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 novel 7-((S) -7-amino-5-azaspiro [2,4] heptan-5-yl) -8-methoxyquinoline represented by the above formula (I) thus produced. A drug containing a 3-carboxylic acid derivative and a pharmacologically acceptable salt thereof as an active ingredient is usually an oral administration agent such as capsule, tablet, fine granule, granule, powder, syrup, or injection. It is administered as a drug, suppository, eye drop, eye ointment, ear drop or integument. 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) Methylcellulose, polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, etc.), coating agents (hydroxypropylmethylcellulose, sucrose,
Ingredients such as titanium oxide) and bases (polyethylene glycol, hard fat, etc.) are water-soluble or soluble when used in injections, eye drops, and ear drops Pharmaceutical components such as auxiliary agents (distilled water for injection, physiological saline, propylene glycol, etc.), pH regulators (inorganic or organic acids or bases), isotonic agents (salt, glucose, glycerin, etc.), stabilizers, etc. However, in the case of ophthalmic ointments and skin agents, formulation components (white petrolatum, macrogol, glycerin, cotton cloth, etc.) suitable for ointments, creams and patches 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. .

[0023]

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

Example 1 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 / hydrochloride (1) [1-Cyclopropyl-6-fluoro -1,4
-Dihydro-8-methoxy-4-oxo-7-((S)
-5 -7 trifluoroacetyl-amino-5-azaspiro [2,4] heptane-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 3.00 g,
(S) -7-Trifluoroacetylamino-5-azaspiro [2,4] heptane hydrochloride [[α] _D ²⁰ + 54.9 °
(c = 0.1, H ₂ O)] 2.72 g, triethylamine 4.0 ml
And a mixture of 12 ml of dimethyl sulfoxide and 40 ml at room temperature.
Stir for 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-diethyl ether to obtain yellow crystals (5.15 g). NMR spectrum δ (CDCl ₃ ) ppm: 0.70-1.35 (8H,
m), 3.37 (1H, d, J = 10.5Hz), 3.67 (3H, s), 3.93 (1H, d, J = 12H
z), 4.10-4.40 (4H, m), 7.45 (1H, d, J = 13.5Hz), 7.79 (1H, d, J
= 6.5Hz), 8.91 (1H, s) (2) 1-Cyclopropyl-6-
Fluoro-1,4-dihydro-8-methoxy-4-oxo-7-((S) -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-((S) -7-Trifluoroacetylamino-5-azaspiro [2,4]
Heptan-5-yl) quinoline-3-carboxylic acid-
A mixture of 4.64 g of O ³ , O ⁴ ] difluoroboron, 4.6 ml of triethylamine and 200 ml of methanol was heated under reflux for 15 hours. The reaction mixture was concentrated under reduced pressure to give residual crystals of 10
% Hydrochloric acid was added to make the solution acidic, and the precipitated crystals were collected by suction filtration and washed successively with water and ether to obtain 3.44 g of pale yellow crystals. Recrystallization from acetonitrile gave pale yellow prism crystals having a melting point of 190 to 192 ° C. Elemental analysis _{C 22 H 21 F 4 N 3} O 5 theory _{C, 54.66; H, 4.38;} N, 8.69 Found _{C, 54.67; H, 4.27;} N, 8.72 ratio optical rotation [α] _D ²⁰ - 153.4 ° (c = 0.1, MeOH) (3) 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 / hydrochloride 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-((S) -7-trifluoroacetylamino-5- Azaspiro [2,4] heptan-5-yl) quinoline-3-carboxylic acid 3.10
1 g of a mixture of 13 g of 10% aqueous sodium hydroxide solution
Stir at room temperature for hours. The reaction solution was adjusted to pH 8 with 10% hydrochloric acid, the precipitated crystals were collected by suction filtration, and then converted into the hydrochloride by a conventional method. Recrystallization from ethanol gave 1.20 g of light brown columnar crystals having a melting point of 199 to 203 ° C. (decomposition). Elemental analysis value C ₂₀ H ₂₂ FN ₃ O ₄ · HCl · 1 / 2H ₂
O theory _{C, 55.49; H, 5.59;} N, 9.71 Found _{C, 55.59; H, 5.78;} N, 9.76 ratio optical rotation [α] ^{_{D 20 - 132.5 ° (c =}} 0.1, DMF)

[0025]

INDUSTRIAL APPLICABILITY The novel 7-((S) -7-amino-5-azaspiro [2,4] heptan-5-yl) -8- represented by the above formula (I) thus produced A methoxyquinoline-3-carboxylic acid derivative and a pharmacologically acceptable salt thereof have excellent antibacterial activity, antitumor activity and anti-AIDS virus activity, and are therefore extremely useful as pharmaceuticals.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI technical display location C07D 207: 00 215: 00) (72) Inventor Masayuki Uejima 16- Mitsumata Town, Takefu City, Fukui Prefecture Two

Claims (1)

[Claims] 1. The following formula: 7-((S) -7-amino-5-azaspiro [2,4] heptan-5-yl) -8-methoxyquinoline-3-carboxylic acid derivative and a pharmaceutically acceptable salt thereof.