WO1996033992A1

WO1996033992A1 - Optically active quinolinecarboxylic acid derivatives and salts thereof

Info

Publication number: WO1996033992A1
Application number: PCT/JP1996/001120
Authority: WO
Inventors: Tetsuo Shibata; Hideto Fukui; Takanobu Naito; Jun Nakano; Tetsuro Maejima; Yoshiyuki Tatsumi; Tadashi Arika
Original assignee: Kaken Pharmaceutical Co., Ltd.
Priority date: 1995-04-27
Filing date: 1996-04-24
Publication date: 1996-10-31
Also published as: AU6181296A

Abstract

Optically active trans-quinolinecarboxylic acid derivatives represented by general formula (I), having potent antibacterial activities against gram-positive bacteria and MRSA, and salts thereof, antibacterial agents containing the same as the active ingredient; and optically active pyrrolidine derivatives represented by general formula (II) and salts thereof, serving as intermediates for the synthesis of the above quinolinecarboxylic acid derivatives.

Description

Spectroscopy Optically active quinoline carboxylate derivative and salt technology

The present invention relates to a novel optically active quinol having antibacterial activity that is useful as a pharmaceutical, veterinary drug, aquatic medicine, pesticide, preservative, industrial bactericide, etc. Linkonic acid derivatives and their salts, antibacterial agents containing them as active ingredients, and optically active quinolincarbons It relates to an optically active pyrrolidine derivative and a salt thereof, which are intermediates of the synthesis of an acid derivative. Technology

To date, various antibacterial compounds have been developed and used for the treatment of bacterial infections. However, due to the general use of antibacterial compounds, the emergence of drug-resistant bacteria such as MRSA (methicillin-resistant yellow staphylococcus aureus) has recently become clinically significant. Is a serious problem. Therefore, the development of a new antibacterial compound having sufficient antibacterial activity against drug-resistant bacteria such as MRSA is desired. .

Accordingly, the applicant has filed 7- (Sys or Trans-13A as an excellent antibacterial compound having a sufficient antibacterial activity. No. 4 No. 1 No. 1 No. 1 port No. 1 — Piro-Rigid No. 1 1 No. No. 6 No. 6 No. 1 No. 1, 4 No. Draw 8—Methoxy 4—Oxoquinoline 13—Patented for a patent for carboxylic acid and its salt first (International Publication W 0 95 5/1 1 9 0 2). Such quinoline carboxylate derivatives have a broad spectrum of antimicrobial spiking properties, and It has strong antibacterial activity against positive bacteria and drug-resistant bacteria, especially MRSA.

7-(Circuit or Transformer 1-3-Amino Memories 4-1 Trifnorem Ornaments 1-1 Pyrrolidine) 1-1-Cycrop Lopinole 6 — phenol 1, 4-dihydro 1 8 — methoxy 4 — oxoquinoline 3 — power oleonic acid and its salts Is an asymmetric carbon atom at the 3rd and 4th carbon atoms of the 7-position pyrrolidine in the quinoline skeleton, and the normal reaction is a racemic body ((±) body, specific rotation [α] 0). However, both the (+) and (1) optical isomers of the oleonic acid inducer have stronger antibacterial activity. Or it was not known. Disclosure of invention

Under such circumstances, the present inventors obtained an optically active form of this compound, and the optically active form having a specific rotation (+) was about twice that of the (±) form. They have antibacterial activity and found that the (Soil) body is less toxic than the body, thus completing the present invention.

That is, the present invention provides a compound of the general formula (I):

(In the formula, R ¹ may be substituted, and may be an alkyl group having 1 to 6 carbon atoms, an alkyl group having 2 to 6 carbon atoms, or 3 to 7 carbon atoms. R ² is a hydrogen atom; a halogen atom; an optionally protected hydroxyl group; Amino group or alkynoleamino group having 1 to 6 carbon atoms; diaminoquinole amino group having 1 to 6 carbon atoms in each alkynole group: Represents an alkyl group having 1 to 6 carbon atoms, R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and A represents a nitrogen atom or a nitrogen atom. Is

(In the formula, A 'is a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms: an alkyl group having 1 to 6 carbon atoms which may be substituted. Group: a cyano group: or a nitro group, or A 'may form a ring together with R ¹ , and the ring may further be an oxygen atom, a nitrogen atom Or a sulfur atom may be included as a constituent atom, or may be replaced by an alkyl group having 1 to 6 carbon atoms). R ⁴ represents a hydrogen atom or an amino protecting group, and * 1 and * 2 represent an asymmetric carbon atom having a trans-substituted substituent. And a salt thereof, which is an optically active quinoline carboxylate derivative represented by the formula:

This onset Ming in is al, Ri Ah in shea click B A Le key Le group R ¹ 3 carbon atoms but it may also be substituted is 1-7, Ri Oh R ² is water atom, A is

(In the formula, A 'is a hydrogen atom; a halogen atom: an alkyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms which may be substituted. An optically active quinoline carboxylate derivative or salt thereof, which is a cyano group or a cyano group or a nitro group). And R ^{1 is a} power mouth profile, R ² is a hydrogen atom and A is

(Logen atom in the formula: represents an phenolic quinotolo group having 1 to 6 carbon atoms, which may be a phenol having 1 to 6 carbon atoms).

The present invention relates to an acid derivative or a salt thereof.

In addition, the present invention is based on (+)-7-((3R.4S))-translation 1-amino-methylation 4-trino-methylation 1 (1 opening mouth) 1 1 1 Cyclo bropinol 1 6 — Fluoro π-1,4 ジ P P-8-METHOXY 4 1 oxoquinoline 131-Carbonic acid or a salt thereof.

Further, the present invention relates to an antibacterial agent containing the above-mentioned optically active quinoline carboxylic acid derivative or a salt thereof as an active ingredient.

Furthermore, the present invention relates to a method for treating bacterial infection using the above-mentioned optically active quinolincanolevonic acid derivative or a salt thereof.

Further, the present invention provides a compound of the general formula (（)

(In the formula, R ⁴ represents a hydrogen atom or an amino protecting group, and * 1 and * 2 each have a substitution group for a transgenic bond.) Optically active pillory represented by an asymmetric carbon atom) Related to derivatives or salts thereof.

In addition, the present invention is based on (1) -1 (3R, 4S) -1trans 13-1 Or about its salt.

The compound of the present invention is an optically active compound in which the aminoamino group at position 3 and the trifluoromethyl group at position 4 are in the trans configuration. The pyrrolidine residue is bonded to the carbon atom at position 7 of the quinoline carboxylate derivative. The compound of the present invention is characterized in that the optically active substance having a specific rotation (+) has about twice the antibacterial activity of the (±) form, and has a higher activity than the (soil) form. It is less toxic. Best mode for carrying out the invention — In general formula (I), the substituted C ¹ to C 6 carbon atoms represented by R ¹ Alkyl residues of a alkyl group include, for example, a methylene group, an ethyl group, an isopropyl group and a tert-butyl group. Examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a methoxy group, an ethoxy group, and an iso group. (B) Alkoxy groups having 1 to 6 carbon atoms, such as a poxy group and a tert-butoxy group, are obtained. Specific examples of the alkyl group having 1 to 6 carbon atoms which may be replaced include, for example, a methyl group, an ethyl group, and an isopro group. Pinole group, tert-butyl group, diphenyl olemethyl group, 2 — phenol oleno group, 2 — hydroxyethyl group and 2 — methoxy Such as a stil group is removed. Examples of the optionally substituted alkenyl group having 2 to 6 carbon atoms include, for example, an isopropioninole group and 2 —fluoroiso Pronyl group etc. are required. Replaced Examples of the cycloalkyl group having 3 to 7 carbon atoms include a cyclopropynole group, a cyclopropyl group, and a 2-phenylphenylene group. For example, there is a group of phenolic groups. Examples of the aryl group which may be replaced include halogen atoms such as fluorine atoms, chlorine atoms, and bromine atoms, and methoxy groups. , An ethoxy group, an isopropoxy group, a tert-butoxy group, etc., an ethoxy group having 1 to 6 carbon atoms, a methyl group, an ethyl group, A group consisting of an alkyl group having 1 to 6 carbon atoms, such as an isopropyl group and a tert-butyl group, a hydroxyl group, an amino group and a nitro group It may be replaced by one to three groups selected from the above, and phenyl groups and the like may be replaced. 2, 2, 4, 4, 4, 5, 6, 5, 6, 5, 6, 5, 6, 7 2,4-methoxyphenyl group, 41-methylbenzoyl group, 42-nitrovinyl group, and 2.4-ginitole There are many different groups, such as a robinole group. In particular, from the viewpoint of antibacterial activity, R ¹ may be substituted with a C 3 to C 7 cycloanolequinolene group, particularly a cyclopropyl group Is preferred o

As a c b gain down atoms in R ² Ru is I table, it was example, if full Tsu crowd atom, chlorine atom is Ru is Oh-up et al. Protecting groups for hydroxyl groups that may be protected include, for example, acetyl groups and tetrahydrovinyl benzoyl groups. Protecting groups for the amino group and the alkylamino group having 1 to 6 carbon atoms which may be used include, for example, an acetyl group and a tert- group. Butoxycarbonyl and benzyloxycarbonyl groups are available. Protected alkylamino groups with 1 to 6 carbon atoms, each with an alkyl group of 1 to 6 carbon atoms that may be protected Examples of the alkylamino group of the alkylamino group and the alkyl group having 1 to 6 carbon atoms include, for example, a methyl group and an ethyl group. It is.

As the alkyl group having 1 to 6 carbon atoms represented by R ³ , for example, a methyl group, an ethyl group, an isopropynole group, a tert-butynole group The basics etc. will be excreted.

The halogen atom represented by A 'is, for example, a fluorine atom, a chlorine atom, or a bromine atom. As the phenol group having 1 to 6 carbon atoms, for example, a methyl group, a methyl group and the like can be mentioned. Examples of the anoreoxy group having 1 to 6 carbon atoms which may be substituted include, for example, a methoxy group, a fluoromethyoxy group, and a difluoro group. There are various types of melody, ethoxy, 1-noreth ethoxy, 2 phenol, etc.

The tricyclic quinoline skeleton in which A 'forms a ring with R ¹ is, for example, 2,3-dihydro 7 7 H — pyrido [1,2,3-de] [1,4] benzoxazines, 2.3 — dihydro 17-oxo 17 H — Pylori K [1,2,3-de] [1,4] Benzothiazines

Examples of the amino-protecting group represented by R ⁴ include an acetate group, a tert-butoxycarbonyl group, a benzyloxy group, and a benzyloxy group. Bonyl groups are required.

In general formula (I), R ¹ is a cyclopropyl, R ² is a hydrogen atom, and A is

(In the formula, A 'is a hydrogen atom; a halogen atom: an alkyl group having 1 to 6 carbon atoms; a 1-6 carbon atom which may be substituted. (A cyano group or a nitro group) are preferred in terms of antibacterial activity.

The optically active quinoline carboxylic acid derivative of the present invention represented by the general formula (I) has been described above, but specific examples will be given. Speaking of (+) — 7-((3R.4S)) 1-1-1-4-1-1-1-1-4- (Ninole) 1-Cyclopropinole 6-Function 1-4, 4-Hydrogen 8-Metric machine 4-1-1-Power Norebonic acid, (I) -I7-((3R, 4S)-Trans-I3-(tert-butoxyquinone-boninole-Amino-methino-) Ref. 1-Cyclopropinole 1-1-Cyclopropinole 6-Ref. 1, 4-Ref. Sea 4 — OkiSokino 1-3-carboxylic acid, 7-((3R, 4 S)-Trans-3-Acetaminoamine 4-1 -1-Chromo-Pin-N-O) 1-Cyclo-Pin-No-Ray 6-H-N-O-R-H- 1.4-------------------------------------------------------------------------------------- NORIN 3 — Force oleonic acid, 7 — ((3R, 4 S) — TRANS 1 3 — BENGE ORENO C Tri-Finore-No-I-No-Ray 1-Pyro-Ri-Jin-No-Re) 1 1-Cycloprop-No-Ray 6-Fin-Role-No. Toxicone 4 — Oxoquinoline 3 — Power such as oleonic acid. In particular, because of its excellent antibacterial activity, (+) — 7 — ((3R, 4S)-1-3- (Pinoret 11) Pyrole 6 1 — Cyclic opening 1 — 4-Hole 1 — 4, 4-Hydrogen 8 — Methoxy 4 1 Oxoquinoline 3 — phenolic acid is preferred.

The optically active quinoline carboxylic acid derivative of the present invention can form an acid or a base and an acid addition salt or a base addition salt. Examples of acid addition salts include salts with mineral acids such as hydrochloric acid, sulfuric acid, etc., acetic acid, trifenorole acetic acid, p-toluenesolenoic acid, and meta-acid. Salts with organic acids such as sulfonate may be removed. Examples of the base addition salt include salts with an anolycal metal such as sodium and potassium, magnesium salt, potassium salt and the like. Salt with alkaline earth metal, ammonium salt, trimethylaminoamine, pyridin, N-methylolive velidine, N-methinolemo Salts with nitrogen-containing organic bases such as noreholin, genenoreamin, benzylinoremine, N, N-dimethylaminoethanol You can do it.

Next, a method for producing an optically active quinolincarboxylic acid derivative represented by the general formula (I) of the present invention will be described. As for the production method of the compound of the present invention, an appropriate method should be selected according to the type of the substitution group and the like, and a preferable production method should be selected. An example is shown below.

Manufacturing method 1

(I)

(Wherein, RRR 3 R ⁴ , A, * 1 and * 2 are the same as described above, and Y represents a halogen atom or a snolephonate ester residue.) )

The optically active quinoline carboxylate derivative (I) is capable of condensing the quinoline derivative (III) with the optically active pyrrolidine derivative (II). It is manufactured. The raw material of the optically active pyrrolidine derivative (II) can be obtained by the following production method 5 or

6, the quinoline derivative (III) is a known substance, and is disclosed in Japanese Patent Application Laid-Open No. Sho 59-212474, Japanese Patent Publication No. Production by a method described in, for example, JP-A-81-181, JP-A-62-252772, JP-A-62-277362, etc., or a method analogous thereto. can do .

Examples of the halogen atom represented by Y include a fluorine atom and a chlorine atom, and examples of the sulfonate ester residue include methane. Sulfonate residue, P-Tonolenesulfonate residue, 2,4,6 — Triisopropynolebenzensulfonate residue Etc. are exterminated.

Condensation reactions include aromatic carbohydrates such as benzene, tonolene or xylene, methanol, ethanol or ethanol. Alcohols having 1 to 4 carbon atoms, such as propanol, d-tetrahydrofuran, dioxan or monoglyme, etc. -Non-protons such as tenorene, acetonitrile, dimethyl alcohol, amide methyl sulfonide, or dimethyl alcohol It is performed in a polar solvent. The reaction temperature is usually from 0 ^eC to 200 ° C, and the reaction time is usually from 10 minutes to 24 hours.

The condensation reaction usually involves the use of 1 to 5 equivalents of a pyrrolidine derivative (III) per 1 equivalent of a quinoline derivative (III) in the presence of a deoxidizing agent. It is done using. Examples of the deoxidizing agent include anolyte metal hydroxide such as sodium hydroxide or hydroxide hydroxide, magnesium hydroxide or water. Alkaline earth metal hydroxides such as oxidized canoledium, sodium carbonate, sodium carbonate, sodium carbonate, sodium carbonate or carbonated water Alkali metal carbonates, such as common potassium, tri-tin oleamine, pyridin, N-methyl mono-ole or 1,8- diaza Organic bases such as bicyclo [5,4,0] decane 7-ene (DBU) can be removed. The amount of the deoxidizing agent used varies depending on the amount of the pyrrolidine derivative (II), and is usually 1 to 7 equivalents to 1 equivalent of the quinoline derivative (III). .

Production Method 2 Compound of the general formula (I) wherein R ³ is a hydrogen atom (I

-a) The manufacturing method

R4HNCH ₂

(Ι ')

R ⁴ HNCH ₂

(I-a)

(Wherein, R ¹ R ² , R ⁴ , A, * 1 and * 2 are the same as described above, and R ³ represents an alkyl group having 1 to 6 carbon atoms.) The compound of the formula (Ia) is produced by subjecting the compound (1 ′) of the general formula (I) in which R is an alkyl group having 1 to 6 carbon atoms to a hydrolytic decomposition. It can be used under both anodic and acid conditions.

Examples of the alkyl group having 1 to 6 carbon atoms represented by R ³ include a methyl group, an ethyl group, an isopropyl group and the like. If the reaction is carried out under the alkaline conditions, sodium hydroxide, potassium hydroxide, magnesium hydroxide, or hydroxylate may be used as the basic reactant. Hydrolysis is performed using barium or ammonia water, etc., and using methanol, ethanol or water as the solvent. . The reaction temperature is usually 0 to 100 ° C, and the reaction time is usually 10 minutes to 5 hours.

If the reaction is carried out under acidic conditions, the acidic reactant may be hydrochloric acid, sulfuric acid, formic acid, acetic acid or trifluoroacetic acid, or a mixture thereof. Usually used as a solvent, methanol, Hydrolysis is carried out using alcohol such as ethanol, isobrono, 'nonore', etc. with 1 to 4 charcoals or water. The reaction temperature is usually 0 to 13 (TC, and the reaction time is usually 10 minutes to 10 hours.

When hydrolysis is carried out under acidic conditions, an acid addition salt of the compound of the general formula (Ia) in which R ⁴ is a hydrogen atom may be directly attached. .

Production method 3 Production method of compound (Ia) of general formula (I) in which R ^J is a hydrogen atom

(I-a)

(Where RRRRA, Y, * 1 and * 2 Is the same as the above, and L represents a fluorine atom or an acetoxy group. )

The compound represented by the general formula (Ia) is converted into a boron chelate compound (IV) by adding a boron reagent to the quinoline derivative (III). After condensing with a pyrrolidine derivative (II) to form a boron chelate (V), the boron reagent is removed using a salt group. It can be manufactured by

The borination reaction of the quinoline derivative (III) can be carried out by using boron trifluoride, boron trifluoride, a diethyl ether complex, and boron as a boron reagent. A mixture of an acid and anhydrous acetic acid is used in excess of 1.2 equivalents to 1 equivalent of the quinoline derivative (III). In ethereal solvents such as ether ether, tetrahydrofuran or dioxan, at 20 ° C power, if necessary, 100 ° C The heating is performed up to the heating. The reaction time is usually 30 minutes to 24 hours.

The condensation reaction between the home chelate compound (IV) and the pyrrolidine derivative (II) can be carried out by a metanole, an ethanole or an isopropane. Acetanols such as phenols with 1 to 4 carbon atoms, such as phenols, ethers such as tetrahydrofuran or monogram, acetonitrile Deoxidizers in non-protonic polar solvents such as nore, dimethyl norm amide, dimethyl nore foxide or snore holane In the presence of the compound, 1 to 5 equivalents of the pyrrolidine derivative (II) is used per 1 equivalent of the boron chelate compound (IV). The reaction temperature is usually from 0 to 100 ° C, and the reaction time is usually from 30 minutes to 24 hours. Examples of the deoxidizing agent include anolyte metal hydroxide such as sodium hydroxide or hydroxylate, magnesium hydroxide or water. Alkaline earth metal hydroxides, such as calcium oxide, sodium carbonate, Metals such as sodium hydrogen carbonate, potassium carbonate, or sodium hydrogen carbonate, metal carbonates, triethylamines, pi Resin, N—Methyl phenol or 1,8-diazabicyclo [5,4,0] Organic base is exposed. The amount of the deoxidizing agent to be used is usually 1 to 7 equivalents to 1 equivalent of the boron chelate compound (IV).

The base used for removing the boron reagent from the boron chelate form (V) is sodium hydroxide, calcium hydroxide, or the like. Alkali metal hydroxides, such as rubber, hydroxide magnesium, magnesium hydroxide, etc., etc. Earth metal hydroxides, carbonic acid, etc. Metals such as sodium, sodium carbonate, sodium carbonate, potassium carbonate, etc., triethylamine, trimethylamine, etc. , N—Can be used to remove third-order amides such as methyl morpholine. The amount of the base used is from 2 equivalents to a large excess with respect to 1 equivalent of the boron chelate (V) o This reaction is usually carried out using a lower alcohol containing water as a solvent. As a rule, the reaction is usually carried out at 20 to 100 times and at a reaction time of 30 minutes to 12 hours.

R ^{1 is a} cyclopropyl, R ² is a hydrogen atom, and A is

(In the formula, A 'is a hydrogen atom; a halogen atom: an alkyl group having 1 to 6 carbon atoms; an alkyl group having 1 to 6 carbon atoms which may be substituted. A cyano group or a nitro group).

—In the compound of the general formula (I), R ¹ is a cyclopropyl group, 0, R ² is a hydrogen atom, and A is

(In the formula, A 'is a hydrogen atom: a halogen atom: an alkyl group having 1 to 6 carbon atoms: an alkyl group having 1 to 6 carbon atoms which may be substituted. The above reaction is carried out using a quinoline derivative (III), which is a xyl group (which represents a cyano group or a nitro group) as a starting compound. It is manufactured by this method.

Production Method 4 Production Method of Compound (I-b) of Formula (I) wherein R ⁴ is a hydrogen atom

(In the formula, R R RA, * 1 and * 2 are the same as described above, and R represents an amino protecting group.)

The compound represented by the general formula (I-b) is a compound represented by the general formula (1), (2) or (3), wherein R ⁴ is an amino protecting group R ^4. The compound (I) can be produced by removing the protecting group of the compound (1 ").

Examples of the amino-protecting group represented by R ⁴ include an acetyl group, a tert-butoxycarbonyl group, a benzyloxy group and the like. Poinole groups are exposed.

Removal of the protecting group is not routinely performed according to the protecting group used, for example, when the protecting group is tert-butoxycarbonyl. (Ii) In the case of a group, treatment with an acid such as hydrochloric acid or trifluoroacetic acid, and the protecting group is a benzyloxy group In the case of the cannylboninole group, this can be achieved by hydrogenation in the presence of a catalyst such as palladium carbon.

On the other hand, the optically active quinoline carboxylate derivative of the present invention

General formula (I I), which is a compound intermediate of (I):

(Wherein, R ⁴ , * 1 and * 2 are the same as above). The optically active pyrrolidine derivative represented by the formula: is a novel compound. Examples of the amino-protecting group represented by R ⁴ include an acetyl group, a tert-butoxycarbonyl group, a benzyloxy group, and a benzyloxy group. Boninole groups are exposed.

— An example of the optically active pyrrolidine derivative represented by the general formula (II) is, for example, (1) one (3R, 4S) one trans. 1 3 — Amino Methylinole 4 1 Trifluoromethylpyrrolidin, (1) 1 (3S, 4S) — Trans 1 3 — (tert 1 (4,1S)-Trans 3-------------------------------------------------------With Tri-norramino-pyrrolidine, (3S, 4S) -trans-r3 3 — benzene Noreboninorea Minorenori No.4, etc. Mole-pyrrolidine, etc. By using an optically active pyrrolidine derivative appropriately selected from these, the optically active quinoline carboxylate derivative of the present invention can be obtained. The conductor is; Also, the optically active pyrrolidine derivative (II) can form an acid and an acid addition salt. Examples of the above-mentioned acid addition salts include salts with mineral acids such as hydrochloric acid, sulfuric acid, etc., acetic acid, trifluoroacetic acid, and P-tonolene sulphonic acid. And salts with organic acids such as methanophoric acid.

Next, a method for producing an optically active pyrrolidine derivative represented by the general formula (II) of the present invention will be described.

Production method 5 Production method of compound (II-a) of general formula (II) wherein R ^{4 is an} amino protecting group

(VI) (vm)

(K) (X)

(XI)

H

(Π— a)

(In the formula, R ⁴ ′, * 1 and * 2 are the same as 刖 iri.) Departure substance (Sat)-Trans -Methoxy canine bottles 41-Trifolene oleometin pyrrolidine (VI) can be found, for example, in the literature (Tetrahedron Letters). (Tet rahedr on Letters), Vol.34, o.20, P.3279-3282, 1993) can be produced.

The compound (VI) is hydrolyzed by a conventional method to give a (Sat) 1 trans 1 1 benzene 1 4 1 trifluoromethyl pyrrolidine 3 — After obtaining carboxylic acid (VII), the optically active compound is subjected to optical separation by an ordinary method using an optically active amine to obtain an optically active compound.

(VI II). Next, the compound (IX) is obtained by allowing the compound (VI II) to act with a reducing agent such as hydrogen hydride or the like. The compound (X) is obtained by allowing the compound (IX) to act on phthalenoimide. The compound (X) is treated with hydrazine or the like to give the compound (XI). Ru compound an equivalent of § Mi Roh protecting group R ^¾ introduced Ri by the conventional method (XI I) e. After that, the benzyl group of compound (XII) can be removed by a conventional method to produce compound (II-a).

Examples of optically active amines for use in optical resolution include, for example, 1-phenyleneamine, siliconconidin, and 11-naphthyl. ) Ethylamine etc. (+) body, (1) physical strength is increased.

In addition, using the obtained optically active carboxylic acid (VI II), the compound can be converted to the compound (II-a) by the following method.

(VB) (XI) (ΗΓ)

(In the formula, R ⁴ ′, * 1 and * 2 are the same as described above.) The compound (VIII) was converted into the compound (XIII) by a conventional method, The compound (XIV) is obtained by reacting the compound (XIII) with ammonia. The compound (XIV) is reduced by a conventional method to give the compound (XI) Four

After obtaining the compound, a suitable amino-protecting group R is introduced by a conventional method to obtain the compound (XII). After that, the benzyl group of the compound (XII) can be removed by a conventional method to produce the compound (IIa).

Production Method 6 Production Method of Compound (II-b) of Formula (II) wherein R ⁴ is a hydrogen atom

H H

(Π— a) (Π-b)

(In the formula, R ⁴ , * 1 and * 2 are the same as described above.)-The compound represented by the general formula (II-b) is a compound obtained by the production method 5 (II- a) that Ki § Mi Roh protecting group R ⁴ and out and this you Concrete made Ri by the and the child you divided Ri by the conventional method.

Since the optically active quinoline carboxylate derivative (I) of the present invention has strong antibacterial activity, it can be used for medicines, animals and marine medicines. It can then be used as a food preservative or as a pesticide.

When the compound of the present invention is used as a medicament, the dosage usually varies depending on the administration method and the dosage form, but is 10 mg per day for an adult. ~ Lg. The 1 dose should be administered in one or several divided doses. In addition, the above-mentioned dose may not be over-administered if necessary. The dosage to be used as a veterinary drug will vary depending on the type and size of the animal and the type of the infectious agent, but usually it will be different. , 1 mg / kg to 200 rag / kg / day It is an enclosure.

For an antibacterial preparation containing the compound of the present invention, select an appropriate preparation method according to the administration method, and use excipients, binders, diluents, and other pharmaceutical additives. It is prepared by the preparation method of each type of drug which is usually performed using Antibacterial preparations include oral preparations such as tablets, powders, granules, capsules, capsules, solutions and syrups, as well as injections, external preparations, and solid preparations. Medicines, eye drops, nasal drops, etc.

Next, the present invention will be described concretely with working examples and reference examples. Na us, ¹ H - NMR scan Bae click DOO Honoré is, d 6 _ di main switch Honoré scan Honoré scion sheet de - (. CDC 1) (DMS 0 d 6) or other heavy click B B E Honoré beam soluble Using a liquid, tetramethyl silane (TMS) is used as the internal standard, and a JNM-EX270-type disc outlet meter (270 MHz, Japan Electronics Co., Ltd.) Δ value was shown in ppm. The mass spectrometer was measured with a QP100 0 X-type spectrometer (manufactured by Shimadzu Corporation). The melting point was measured with an uncorrected trace melting point analyzer (Yanagimoto Seisakusho). The specific rotation [a] D was measured with a 241-type polarimeter (PerkinElmer). The absolute configuration was determined by X-ray structural analysis. Reference Example 1

(Sat) 1-transition 1 1 1 pengino-lei 4 1-no-reno-methylol-pyrrolidin 13-force olenoic acid

F ₃ C C0 ₂ H

(Sat) 1-transition 1 1 1-Penzinole 4-Trif-Noreo Mouth-methyl pyrrolidin 1- 3 — Force oleic acid methyl benzoyl ester 601 g ( (1.86 mol) was dissolved in 2 liters of methanol, and 564 ml of a 10 N aqueous sodium hydroxide solution was added thereto under ice cooling, followed by stirring at 0 ° C. for 1 hour. In consideration of the precipitated crystals, add 3.5 liters of distilled water to the depleted liquid, concentrate under reduced pressure until the liquid volume is reduced to half, and wash the residual liquid with diethyl ether. It was purified. Under ice cooling, the pH of the aqueous layer was adjusted to 3 by adding concentrated hydrochloric acid, and taking the precipitated crystals into consideration, 449.5 g of the target substance was obtained as a white powder ( Yield 88.5%).

MS (M / Z); 272 (M ⁺ ), 182, 91.

^{1 H - NMR δ (CDC 1} 3); 2.62~ 2.76 (lH, m), 2.90 (IH, t, J = 9Hz), 3.09~ 3. 18 (1 H, m), 3.41 (IH, t, J = 9Hz), 3.67 (IH, d, J = 13Hz), 3.78 to 3.92 (IH, m), 4.06 (IH, d, J = 10Hz), 4.46 (lH, d, J = 13Hz) ), 7.33 to 7.46 (5H, m), 10.99 (lH, bs)

Reference Example 2

(1) 1 (3S, 4S) 1 Trans 1 1 1 Pengeorin 4 1 Trifolene oleometinol pyrrolidine 13 — Force olevonic acid

(Sat) obtained in Reference Example 1 1 Trans 1-1-Benzyl 1-4 1 Trif-N-O-L-Methyl-N-Pyrro-L-I- 13-P-olenoic acid 445 g (1.63 mol) was dissolved in 1.34 liters of methanol with heating, and R (+)-1-phenyleneamine 197.5 g (1.63raol) Was added. After standing at room temperature overnight, the precipitated crystals were taken into consideration to obtain 196 g of crude crystals. After dissolving the crystals in 0.9 liters of methanol with heating, leaving them to stand at room temperature overnight, take the crystals that have precipitated out into account. (1) -(3 S. 4 S)-Trans-1-1-Benzinol-1-41-Trifnorrenol-O-methylol-Pyrrolidin-3-Carbonic acid 'R (+) -96.2 g of phenyleneamine salt was obtained.

The obtained optically active salt was dissolved in 244 ml of a 2N aqueous solution of sodium hydroxide and washed with diethyl ether. Under ice-cooling, add 40.7 ml of pus-hydrochloric acid to the aqueous layer, extract with ethyl acetate, dry with magnesium sulfate, and reduce the pressure of the ethyl acetate layer. Shrunk. 200 ml of n-hexane was added to the residue, and the precipitated crystals were collected. 56 g of the target substance was obtained with an optical purity of 98% or more (yield 12.6%).

(The optical purity was determined by the following equation: trans-1-1-penta-phenol-4-trifluoro-meth-i-pyrrolidin-13--force-olevonic acid. R (+)- After using a condensing agent to make the aminoamine salt into its amide, the high-speed liquid chromatograph is mixed with a diastereomer. The ratio was measured.)

[a] _D -22.9 ° (c = l, 0, M e 0 H)

R (+)-1-The same operation as above was performed using S (-) 11 1-phenylamine instead of phenylamine. More (+)-(3R, 4R) 1-1-1-1-Benzolene 4-1-Trifolene olefin-Pyrrolidin 1-3-Force oleonic acid I got it.

[] _D + 22.5 ° (c = 1.0, Me OH)

Reference Example 3

(1) 1 (3S, 4S) 1 Trans. 1 1 1 Page 4 3 — Hydroxy memory 4 1 gin

Hydrogenated lithium medium (700 mg, 18.4 mniol) was suspended in anhydrous tetrahydrofuran (100 ml), and the suspension was cooled under ice cooling in Reference Example 2. (1) 1 (3 S. 4 S) 1 Trans 1 1 1 Benzino 1 4-Trifolene Oromethylmethylpyrrolidin 13 3-Force A solution of 5 g (18.3 mmol) of the acid in 150 ml of anhydrous tetrahydrofuran was added dropwise over 10 minutes. After stirring at room temperature for 2 hours, excess reagent was decomposed by adding 10 g of sodium sulfate decahydrate. The insoluble matter is removed by suction, the concentration of the concentrated solution is reduced, and the residue is purified by silica gel chromatography chromatography (elution solvent ethyl acetate). : N-hexane = 1: 2) to obtain 3.9 g of the target compound (yield: 77.0%).

1 H - NMR δ (CDC 1 3); 2.31~ 2.49 (2H, m), 2.56 (1H, t, J = 9Hz), 2.76~ 2. 97 (3H, π), 3 · 10 (1H, t, J = 9Hz), 3.54 to 3.64 (lH, m), 3.61 (2H, s), 3.71 to 3.78 (lH, m), 7.19 to 7.38 (5H, m)

_{[A] D - 29. 0 (} c = 1.0, CHC 1 3)

(+) — (3 R, 4 R) 1-transition- 1- 1-Penzinole 4-trif-nor-e-methyl-pyrrolidine 13-force olevonic acid In the same operation as above, I got a (+)-(3R, 4R) form.

[] _D + 28.8 ° (c = 1.0, CHC 13) Reference Example 4

(+)-(3 S, 4 S) 1 Transist 1 1 1 Peng rail 3 — Endless rail 4 — Trifnorre rail gin

(1)-(3S, 4S) obtained in Reference Example 3-Trans 1-1 Page 3-Hydroxyme 4-Tri-free Dissolve 3.4 g (13.Ommol) of olefin resin in 50 ml of anhydrous tetrahydrofuran, and prepare 1.91 g (16.9 mmol) of phthalanolamide and triflic acid. To the mixture was added 4. lg (15.6 mmol) of ethanol, and 2.71 g (15.6 mmol) of getyl azodicarbonate was added dropwise under ice-cooling. After stirring the mixture at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and diethyl ether was added. The precipitated precipitate was removed by filtration, and the pressure of the concentrated solution was reduced. The obtained residue was purified by silica gel chromatography chromatography (eluting solvent: ethyl acetate: n-hexane = 1: 5) for the purpose. 4.4 _g of the product was obtained as a white powder (yield: 87.2%).

^{(. CDC 1) - 1 H} NMR <5; 2.46~ 2.54 (lH, m), 2.56 ~ 2. 68 (lH, m), 2.70~ 2.86 (2H, m), 2. 93 (1H, t, J = 8 Hz), 3 58 (1Η, dd, J = 13 and 15 Hz), 3 68 to 3 78 (1Η, in), 3.82 to

3 98 (1Η, πι), 7 19 to 7.36 (5Η, πι), 7.70 to 7 78 (2Η, ιη), 7.84 to 7.92 (2H, m) [a] + 5.2 (c = 1.0, CHC

(+) — (3 R, 4 R) 1 Transistor 1 1 1 Page 4 3 — Hydrodynamic 4 4 1 Trifore 4 4 (1) One (3R, 4R) body was obtained by the same operation as described above, except for using the above-mentioned method.

[] - 5. 5 (c = 1.0, CHC 1 3)

Reference Example 5

(1) 1 (3 R, 4 S) — Trans

3 — (t er t — Butt cann o bonin oa n o a n a n o n) 4 4

(Wherein, Boc represents a tert-butoxycarbonyl group) (1) (1) -1 (3R.4S) 1-transition 11 1 3 — Amino-methylo 4-Tri-no-methyl

(+)-(3 S, 4 S) obtained in Reference Example 4-Trans-1-Page 1 3-3-1-4- Dissolve 4.2 g (10.8 mm 01) of fluoromethylpyrrolidin in 150 ml of methanol and add 5 ml of hydrazine monohydrate for 12 hours at room temperature. It was stirred. The precipitated precipitate was removed by filtration, the solution was reduced in pressure and concentrated, the residue was dissolved in a cross-section hologram, washed with water, and dried over sodium sulfate. Then, the mixture was concentrated under reduced pressure to obtain 2.7 g of a crude product as a target substance.

(2) (-) 1 (3 R, 4 S)-Transform 1 1 1 Benzil 1 3-(tert-1-1-1-Benzyl 1-4) 1 Tri-Following Chromosome

(1)-(3R, 4S) -transition 11-1 1-1---------------------tri-tri-obtained from (1) above 2.7 g of crude product of o-methylpyrrolidin is dissolved in 100 ml of jig-mouth rometan, and 4.71 g (21.6 mmol) of di-tert-butyrene resin carbonate is dissolved. And the mixture was stirred at room temperature for 18 hours. The reaction solution is concentrated under reduced pressure, and the obtained residue is purified by silica gel chromatography chromatography (elution solvent: ethyl acetate: _n -hexane). 1: 5), and 3.2 g of the target compound was obtained as a slightly yellow powder (yield: 82.8%).

MS (M / Z); 358 (M ⁺ ), 301, 240, 150, 91

^{. 1 H - NMR δ (CDC} 1 3): 1.45 (9 H, s), 2.38 ~ 2.74 (5H, m), 2.94~ 3.06 (lH, m), 3 11~ 3.34 (2H, ra), 3.59 ( 2H. Dd, J = 12 and 15 Hz), 5.30 (lH, bs), 7.22 to 7.38 (5H, m) [a] D-5.7. (C = 1.0, CHC 13)

(-) 1 (3 R, 4 R) 1 Trans. 1 1 1 Benzino 1 3 — Trino 4 im (+) — (3 S, 4 R) 1 Trans 1 1 1 Benzuru 3 — Aminomethyl 1 4 1 Trifluoromethyl After obtaining the mouth ring, perform the same operation as above (+) I got a body (3 S. 4 R)

C α] + 5.7 ° (c = 1.0, C Η C 13)

Example 1

(1) 1 (3 S, 4 S) 1 Trans 3 (tert-Bacterial boninole Amino Mori) 4 Trifolone Oro Methylin N

F ₃ C CH ₂ NHBoc ヽ N

H

(Where Boc is the same as above)

(1) -1 (3R, 4S) obtained in Reference Example 5-Trans-1-Penzinole 3-(tert-Butoxycanole Bonyl Aminome Dissolve 26.0 g (72.5 mmol) of trifluoromethyl pyridine in 260 ml of methanol, and add 10% 、, ジ radium. Hydrogenation was performed at 50 ^eC and 1 atm with the addition of 2.6 g of carbon. After 60 hours, the catalyst was separated and the filtrate was concentrated under reduced pressure. 100 ml of n-hexane was added to the residue, and the precipitated crystals were collected by filtration to give 29.7 g of the target substance as a white powder (yield: 76.3%). MS (MZZ); 268 (M ⁺ ), 211, 138, 57

... 1 H - NMR 6 (CDC 1 3); l "(9H, s), 2. 33~ 2. 57 (2H, m), 2 64~ 2.74 (lH, m), 3 05~ 3. 28 (5H, m), 4.82 (lH, bs)

[α] _D -24.4 ° (c = 1.0, CHC 13)

(+) — (3 S, 4 R) Trans

3 — (t er t — BT)

4—Similar operation using trifluoromethyl pyrrolidine The (+)-(3 R. 4 R) body was obtained by performing.

_{[Α] D + 21. 0 °} (c = 1. 0, CHC 1 3)

Reference Example 6

(1) 1 (3S, 4S) 1 Trans 1 1 1 Benzyl 4-Trifnorolemethyropyrrolidin 1 3 — Power '

(1) -1 (3S, 4S) obtained in Reference Example 2 Trans 1 1 1 benzene 4 1 -Dissolve 56 g (205.lmmol) of phenolic acid in 220 ml of methylene chloride, and add 73.2 g (615.4πππιο1) of titanium chloride under ice-cooling. . After stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure. The residue was dissolved in 600 ml of methylene chloride. This solution was dropped into a 28% aqueous ammonia solution under ice cooling over 2 hours. After the dropwise addition, the methylene chloride layer is separated, dried over sodium sulfate, and the methylene chloride is distilled off under reduced pressure to obtain 54.2 g of the intended substance. (Yield 97.0%). Melting point: 88-91 C

MS (M / Z); 272 (M ⁺ ), 228, 200, 91

1H-NMR δ (CDC 13); 2.58 to 2.68 (lH, m), 2.63 to 2.79 (lH, m), 2.84 to 3.02 (3H, m), 3.09 to 3.3.0 (lH, m m), 3.66 (2H, s), 5.57 (lH, bs), 6, 28 (lH, bs), 7.24 to 7.39 (5H, m) [] _D -27.0 ° (c = 1.0, e OH)

Reference Example 7

(1)-(3R, 4S) 1 Trans 1 1 1 Benzyl 3-(tert-butanol) Boninole Amino Metinole 4) 1 Trif Oro-methyl pyridine

(Wherein, Boc represents a tert-butoxycarbonyl group) (1) (1) -C3R, 4S) 1- 1-benzyl-3 -Amino Methylone 4 1 Trifluoromethyl Pyrolysine 2

Suspended lithium aluminum (11.4 g, 0.3 nol) was suspended in 300 ml of water-free tetrahydrofuran, and obtained in Reference Example 6 under ice-cooling ( 1) 1 (3S, 4S) 1 Trans-1-Benzyl 4-1 Trifluoromethylpyrrolidin 13-Power amide A solution of 53.2 g (195.6 mmol) of anhydrous tetrahydrofuran (200 ml) was added dropwise over 10 minutes. After stirring at 50 for 1 hour, the mixture was allowed to cool, and sodium sulfate decahydrate 32 g and 10N Excess reagent was decomposed by adding 5 ml of aqueous solution of sodium hydroxide. The insolubles were removed by suction filtration, and the solution was concentrated under reduced pressure to obtain a crude product of the intended product.

(2) (—) 1 (3 R, 4 S) 1 Trans 1 1 1 Benzinol 1 3 — (tert 1 Butoxyn cane Boninore Amino Metinole)-4 -Tri-fringe pills

H

(1) 1 (3R, 4S) obtained in the above (1) 1 Trans 1 1 Peng No 3-Amino Methyl 4 4-Trino 4 Dissolve 48 g of the crude product of methylpyrrolidine in 200 ml of jig-mouth lum and add 46.9 g of di-tert-butylisocarbonate (46.9 g). 215.2 mmol), and the mixture was stirred at room temperature for 18 hours. The reaction solution is concentrated under reduced pressure, and the obtained residue is purified by silica gel chromatography with a liquid chromatography (eluting solvent ethyl acetate: n-hexane = 1: 2), and the target substance 53. O g was obtained as a slightly yellow powder (yield 75.7%).

MS (M / Z); 358 (+), 301, 240, 150, 91 1 H - NR δ (CDC 1 Q); 1.45 (9H, s), 2.38~ 2.74 (5H, m), 2.94~ 3.06 ( lH, m), 3.11 to 3.34 (2H, m), 3.59 (2H, dd, J = 12 and 15Hz), 5.30 (1H, bs), 7.22 to 7.38 (5H, m) [a] _D -7.1 ° (c = 1.0, Me 0 H)

Example 2

(I)-(3R, 4S) I Trans I 3-Aminomethyl 4-Trif-N-O-L-O-I-M

(1) One (3S, 4S) ton obtained in Example 1 Sue 3 — (tert-butoxy-boninore-a-mino-m-in-no-re)-4-Trif-no-re-or-o-m-in-no-re-pyrrolidine 202 mg (0.754 mmo 1) It was dissolved in 1 ml of lorometan, and 1 ml of acetic acid at the mouth of trifonole was added under ice cooling, followed by stirring at 0 ° C for 1 hour. 0.19 ml of concentrated hydrochloric acid was added to the reaction solution, and the mixture was concentrated under reduced pressure to obtain 161 mg of the target substance as a slightly yellow powder (yield: 88.6¾).

Melting point: 193-200. C

MS (M / Z); 168 (M ⁺ ), 151, 138, 82

¹ H-NMR δ (DMS 0-d ₆ ); 2.76 to 2.89 (lH, m),

3.01-3.15 (2H, m) 3.26-3.64 (5H, m), 8.45 (2H, bs),

8.48 (1H, bs)

[a] _D — 17.2 ° (c = 1.0, e 0 H)

Reference Example 8

1 — Pin opening 6, 7-Circular opening 1, 4-1 Hidro 8-Methoxy 4-1 oxoquinoline 1-3- Boronic acid chelate body

1-Cycloprop-1, 6-7-Dihydro 1, 4-Dihydro 8-Methoxy-4-Oxokinoline 1 3-Power 590 mg (2 mmol) of boric acid was suspended in 13 ml of 42% hydrofluoric acid, stirred at 100 ° C for 3 hours, poured into water, and the deposited precipitate was collected by filtration. This precipitate is dissolved in acetone and the insoluble material is dissolved. After separation of acetate, the acetate was distilled off, the residue was added with diethyl ether, and the crystals precipitated were collected, and 432 mg of the title boron chelate body was obtained. Was obtained as a white powder (yield 63.0%).

Mp; 220 to 225 ^o C

MS (M / Z); 344 ( ^Mτ ), 299, 250

¹ H-NMR δ (DMS 0-d ₆ ); 1.28 to 1.38 (4H, m),

4.17 (3H, s), 4.49 to 4.56 (lH.m), 8.24 to 8.31 (lH, dd, J =

8.25, 9.90Hz), 9.19 (1H, s)

Example 3

(+)-7-((3 R. 4 S) 1-Trans-3-Amino-Methyl-1-4-Trif-Or-M-1-1-Pyrrolidinol 1-1 Cyclic mouth pill 1-6-Folding 1.4-Dihydro 8-Methoxy 4-1

* ½u

(1) (1) 1 7-((3R.4S)-Trans-1 3-(tert-1-1-1-1-1-1-1-1-1-1-4-1-1 1 1 Cyclopropinole 6-Fluoro 1, 4-Hydro 8-Methoxy 4-oxoquinoline 1-force oleonic acid C0 ₂ H

Boc

(Wherein, BOC is the same as above)

31.0 g (90.Immol) of the boron chelate obtained in Reference Example 8 was dissolved in 300ral dimethyl phenol noreoxylate, and (1)-(3S, 4S) -1 Trans 13-4 (tert-butanol) 21.4 g (108. Immol) And Trietinoreamin 12.5ml

(90. Immol) was 8:00 Ma撹stirred at pressurized example by 40 ^e C. The reaction solution was poured into water, the pH was adjusted to 3.8 with 10% citric acid, and the precipitated yellow precipitate was collected. The obtained precipitate was suspended in a mixed solution of 80% ethanol, 1.9 liters of triethanolamine and 400 ml of triamine, and refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was added with isopropanol, and the yellow crystals precipitated were collected. The resulting crystals were separated into isobrono, 'no-no-no-re and After washing with ethyl ether, 44.lg of crude product was obtained.

(2) (+) _ 7-((3 R. 4 S)-Trans-1 3-Amino-methylo-4 4 2 1) 1-cyclone mouth Pinole 6-Phno-leo mouth 1,4,1-Hydrogen 8—Methoxy 4—Oxoquinoline 13—Power Rubonic acid hydrochloride

(1) -17-((3R, 4S) -1trans-13- (tert-butoxycarbonyl) obtained in the above (1) 1 4 1 Trifluoromethyl 1 1 1) Cyclopropine 6 — Phenoole 1, 4 — Dihydro 8 — Methoxy 4 — oxoquinoline 1 3 — Call 43 g of a crude product of boric acid was suspended in 120 ml of a methyl chloride solution, and 120 ml of trifluoroacetic acid was added thereto under ice cooling, followed by stirring for 1 hour. The reaction solution was concentrated under reduced pressure, and 500 ml of dimethyl ether was added to the residue, and the precipitated crystals were collected. The obtained crystals were suspended in 350 ml of methanol, 100 ml of concentrated hydrochloric acid was added to dissolve the crystals, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in methanol lOOinl, and the precipitate was added with diethyl ether. The precipitate was collected by filtration, and 20.5 g of the target substance was converted to a slightly yellow powder. (Yield 47.4%).

Melting point: 192 to 194 ° C (decomposition)

MS (M / Z); 443 (M ⁺ ), 426, 399, 382

1H-NMR δ (DMS 0-dg); 1.04 to 1.15 (4H, m), 2.77 to 2.82 (lH, m), 2.94 to 3.12 (2H, m), 3.37 to 3.40 (lH, m ), 3.50 to 3.56 (lH, m), 3.64 (3H, s), 3, 68 (lH, dd, J = 4.5,

11. lHz), 3.86 to 3.95 (2H, m), 4.16 to 4.17 (1H, m), 7.75 (1H, d, J = 13.2Hz), 8.33 (3H, bs), 8.70 (lH, m s), 14.94 (lH, bs) [a] D + 9.2. (C = 1.0, MeOH)

(+)-(3 R. 4 R) as a raw material-3-(tert-butoxy boninole boninole aminomethyl). The same operation as above is used for the method using the Romenopyrrolidin. (1) — 7 — ((3S, 4R) — Trans 3 — Amino Mori No. 4-Tri-no-Ri-no-Minore 1-1-Pyro Rigino-no-Ire 1-1-Cyclopropinole 6-Fno-Rio Mouth 1, 4- Dihydro 8-Methoxy 4-One year old Kisoquinoline 3-Power oleonic acid and hydrochloride.

[] D-10.6. (C = 1.0, M e O H)

Reference Example 9 (Sat) 1 7 — (Transform 1 3 — Amino Methyl 4 — Trif Mole Ole Methyl 1 1 Pyrrolidine) 1 1 Cyclopro Pinole 6 — Phenoole 1, 4-Hydro 1 8 — Methoxy — 4 — Oxoquinoline 3 — Power oleonic acid 'HCl

(1) (±)-7-(trans-1-3-(tert-butoxy boninole amino-chin-no) 1-4 1-trifluoromethyl-1 -1-Cyclopro pino 6-Fluoro 1.4-4-Hydro 8-Methoxy 14- 1-3 — carboxylic acid

21.5 g (62.6 mmol) of the boron chelate obtained in Reference Example 8 was dissolved in 214 ml of dimethylsolephoxyside, and (Sat) 3 — (tert-butoxycarbonyl-ino-amino-methyl)-4 1-trif-nor-e-methyl-pyrrolidin 20.1 g (75.lmmol) and Add 8.7 ml (62.6 mmol) of tritinoleamine and add 40. The mixture was stirred with C for 20 hours. The reaction solution was poured into water, adjusted to pH 3.5 with 10% citric acid, and the precipitated yellow precipitate was taken into consideration. The obtained precipitate is suspended in a mixture of 80% ethanol, 1.6 liters and 400 ml of triethylamine, and is returned for 1.5 hours. I washed away. The reaction solution is concentrated under reduced pressure, isopropanol is added to the residue, and the pale yellow crystals precipitated are collected. The isopropanol is added to the residue. After washing with ethyl ether, 29.8 g of a crude product of the intended product was obtained.

(2) (Sat) 1 7-(Translation 1 3 — Amino Methyl No. 4 1 Mouth prop pinole 6-Fluoro 1,4 -Hydroxy 8 -Methoxy 4 -oxo quinoline 3-Power olevonic acid / hydrochloride (±)-7-(trans-1-3-(tert-butoxycarbonyl bonyl amino-methyl) obtained in (1) above. Tri-Finore-No-I-No-R 1 1-Pi-Ro-Pi-No-R 1 6-Fin-No-Role 1, 4-Di-Hydrogen 8-Met Quinoquinoline-3-19.3 g of crude product of carboxylic acid is suspended in 88 ml of methylene chloride, and the mixture is cooled under ice cooling. (2) 88 ml of acetic acid was added and stirred for 2 hours. The reaction solution was depressurized and concentrated, and 200 ml of diethyl ether was added to the residue, and the crystals that had precipitated out were taken into account. The obtained crystals were suspended in 220 ml of methanol, dissolved in 17 ml of concentrated hydrochloric acid, and the reaction solution was concentrated under reduced pressure. The residue was heated and dissolved in 650 ml of isopropropyl alcohol, and after cooling, the precipitated crystals were collected and 24.6 g of the target substance was obtained as a pale yellow powder. (Yield 97%).

Melting point: 218-221 ° C

— NMR data was the same as that of the (+) field.

[Antibacterial activity test]

The antibacterial activity of the (+) form and the (1) form of the optically active form obtained in Example 3 was compared with the racemic form (Sat) form obtained in Reference Example 9. And compared. The antibacterial activity is shown in Table 1 below as the minimum inhibitory concentration. The test method was measured by the agar plate dilution method according to the standard method specified by the Japanese Society of Chemotherapy. Inoculum volume was 1 0 ⁴ CFUZ scan pop Bok, use the medium had use of the sensitivity disk medium one N (Japan made this made medicine).

Minimum growth inhibitory concentration (gZm 1)

Test bacteria

(+) Body (±) body (-) body Staphylococcus 7 ureus-≤ 0.006 ≤ 0.006 ≤ 0.006 Smith

(Staphylococcus aureus Smith)

Stretch coccus' Viogenes · 0.0125 0.025 0.025

(Streptococcus pyogenes Cook)

Enterococcus faecalis 0.025 (Enterococcus faecalis) 1373 Escherichia coli 0.025 0.1 0.2 (Escherichia coli) NIHJ JC-2

o

Starfish Lococus 《Aura Reus O

≤, 0.006 0.0 o C

125 0.0125 (staphylococcus aureus;

JS-1 (MRSA)

Souyu Rococos * Aau Reus 0.39 0.39 0.78 KP-90-3 (MRSA)

Klebsiella pneumoniae 0.12 0.39 (Proteus vulgaris) No.33 Proteus mirabilis . 2 (Proteus mirabilis) JY-10

Serratia, Manoessessence 0.39 0.78 (aerratia marcescens)

No.16-2

[Acute toxicity test]

The acute toxicity of the (+) form of the optically active substance obtained in Example 3 and the (Sat) form obtained in Reference 9 were compared. Male ICR A single dose in a vein using a mouse (5 weeks old), LD

50 values were calculated by the probit (pr0 bit) method. Test compound LD ₅₀ (mg / kg)

(+) Body 1 1.7

(±) body 1 7 9.5

[Formulation Example 1]

Compound ((+) form) obtained in Example 3 100 g Conta start 40 g Avisenole 30 g Magnesium stearate 3 g The compound obtained in Example 3 ((+)-isomer), Consort, Abicell (trade name, manufactured by Asahi Kasei Corporation) and stearic acid Tablets containing 100 mg of the above compound per tablet were produced by mixing magnesium in the amount described above and tableting.

[Formulation Example 2]

Compound obtained in Example 3 ((+)-isomer) 200 mg Body sugar 250 mg Distilled water for injection 200 ml Compound obtained in Example 3 in distilled water for injection ( After dissolving (+)-form) and glucose in the amount described above, pour into the sample, replace with nitrogen, and pressurize at 121 C for 15 minutes after replacing with nitrogen. Then, an injection having the composition described above was obtained. Industrial applicability

The optically active quinoline carboxylate derivatives and salts thereof in the trans configuration of the present invention have a broad antibacterial spectrum, and It has strong antibacterial activity against ram-positive bacteria, especially drug-resistant bacteria, especially MRSA, and has low mutagenicity. Therefore, it is useful for pharmaceuticals and the like.

In addition, the optically active quinoline carboxylate derivative of the present invention has about twice the antibacterial activity of its racemic form, and is toxic. Due to the low tilting power, the dosage is reduced and the side effects can be reduced.

The optically active pyrrolidine derivative, which is another invention, is an intermediate for the production of the optically active quinoline carboxylic acid derivative of the present invention. It is useful as such.

Claims

The scope of the claims

1. General formula (I)

(In the formula, R ¹ may be substituted, and may be an alkyl group having 1 to 6 carbon atoms, an alkyl group having 2 to 6 carbon atoms, or a cycle having 3 to 7 carbon atoms. Represents a lower alkyl group or a aryl group, and R ² is a hydrogen atom; a halogen atom; a hydroxyl group or an amino group which may be protected. Represents an alkylamino group having 1 to 6 carbon atoms; a dialkylamino group having 1 to 6 carbon atoms in each alkyl group: or 1 to 6 carbon atoms. R ³ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and A represents a nitrogen atom or

(In the formula, A 'is a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms which may be substituted. A cyano group or a nitro group, or A 'may form a ring with R ¹ , and the ring may further be an oxygen atom or a nitrogen atom. Alkyl groups having 1 to 6 carbon atoms, which may contain sulfur atoms as constituent atoms. And R ⁴ represents a hydrogen atom or an amino protecting group, and * 1 and * 2 represent trans to each other. An optically active quinoline carboxylate derivative or a salt thereof, which is represented by an asymmetric carbon atom having a substituent having a steric configuration.

2. R ¹ is a cycloalkyl group having 3 to 7 carbon atoms which may be ^replaced , R ^ώ is a hydrogen atom, and Α is

(In the formula, A 'represents a hydrogen atom: a halogen atom: an alkylene group having 1 to 6 carbon atoms: an alkoxy group having 1 to 6 carbon atoms which may be substituted. The optically active quinolino canoleic acid derivative or a salt thereof according to claim 1, wherein the group represents a cyano group or a nitro group).

3. R ¹ is cyclopropyl, R ² is a hydrogen atom, and A is

(In the formula, A 'is a water atom; a halogen atom: an alkyl group having 1 to 6 carbon atoms; an alcohol group having 1 to 6 carbon atoms which may be S-substituted. (The group represents a cyano group or a nitro group.) The optically active quinolinol olenoic acid derivative or the optically active quinolinol olenoic acid derivative described in claim 1 which is a claim Salt.

4 (+) — 7 — ((3 R. 4 S) 1-Trans 1-3-Aluminum 4-1 1) Cyclo-Pinole 6- 1-Hole-Role 1.4-Hydrogen- 8-Methoxy- 4 One-sided oleic acid

The optically active quinoline canolevonic acid derivative or a salt thereof according to claim 1, which is a salt thereof.

5. — General formula (II):

FoC CH NHR ⁴

(Π)

H

(In the formula, R ⁴ represents a hydrogen atom or an amino protecting group, and * 1 and * 2 represent an asymmetric carbon having a trans-substituted substituent. An optically active pyrrolidine derivative or a salt thereof represented by the following formula:

6. (I)-(3R, 4S)-Trans-13-Amino-methylo 4-Trino

H

6. The optically active pyrrolidine derivative or a salt thereof according to claim 5, which is a salt thereof.

7. An anti-microbial compound containing the optically active quinoline carboxylic acid derivative or its salt described in claim 1 as an active ingredient. Fungicides.

8. An antibacterial agent containing, as an active ingredient, the optically active quinoline carboxylic acid derivative or a salt thereof according to claim 2.

9. An antibacterial agent comprising, as an active ingredient, the optically active quinoline carboxylic acid derivative or a salt thereof according to claim 3.

10. An antibacterial agent containing the optically active quinolincarboxylic acid derivative or a salt thereof according to claim 4 as an active ingredient.

11.A method for treating bacterial infections using the optically active quinoline carboxylate derivative or a salt thereof described in claim 1.

12. A method for treating bacterial infectious diseases using the optically active quinoline carboxylic acid derivative or a salt thereof according to claim 2.

13. A method for treating bacterial infection using the optically active quinoline carboxylic acid derivative or a salt thereof according to claim 3.

14.Method of treating bacterial infectious diseases using the optically active quinoline carboxylic acid derivative or its salt described in Paragraph 4 of the Claims o.