JPS63166876A - Pyridonecarboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [Ra and Rb are H or lower alkyl; Rc is lower alkyl or Rb together with Ra or Rc may form methylene chain; Rd is ethyl, 2-fluoroethyl, vinyl, cyclopropyl, mono-(or di-)fluorophenyl, etc.; Q is CH, C-F, C-Cl or N] and salt thereof. EXAMPLE:(-)-7-[3-(1-Aminoethyl)-1-pyrrolidinyl]-1-ethyl-6,8-difluoro-1 ,4-dihydro-4- oxoquinoline-3-carboxylic acid. USE:A remedy for microbism. PREPARATION:A compound expressed by formula II (Xs is a substituent group nucleophilically substitutive with an amine, e.g. halogen or methanesulfonyl, etc.) is reacted with a pyrrolidine derivative expressed by formula III in the presence of an unreactive solvent, e.g. THF, ethanol, DMSO, DMF, water, etc., at 20-150 deg.C to afford the aimed compound expressed by formula I.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a compound having extremely strong antibacterial activity and excellent pharmacokinetics.

[Prior Art] Various studies have been conducted on compounds having antibacterial properties, and Japanese Patent Application Laid-Open Nos. 59-67269 and 60-214773 disclose compounds having antibacterial properties. A wide group of compounds belonging to the pyridone carboxylic acid derivatives are claimed. As preferred compounds, compounds in which X is N, CH, or CF, Y is fluorine, and R1 is ethyl, 2-fluoroethyl, or cyclopropyl are described as preferred compounds.

However, among the basic substituents 2 that greatly influence antibacterial activity and physicochemical properties, those having a pyrrolidine group as the most preferable one are disclosed in JP-A No. 59-67279.
No. 11 (compound code name Cl-934) and Examples 43 to 47 (compound hjP+ of Example 44)-111558 of JP-A-60-214773 (see the 26th I CAAC abstract). In the formula, R2 and B represent a compound having a group represented by hydrogen or lower alkyl. However, Cl
-934 has antibacterial activity against Durham-negative bacteria compared to PD-11.
7558 has insufficient antibacterial activity against Pseudomonas aeruginosa and is still far from satisfactory.

[Object of the invention] The present invention has excellent antibacterial activity against aerobic bacteria as well as anaerobic bacteria, and has high solubility in water.
The purpose of the present invention is to provide a compound with excellent intestinal absorption and metabolic stability.

[Means for achieving the object] The present inventor has discovered that a pyridonecarboxylic acid derivative has a group represented by the general formula: In this formula, at least Rb or R
Compounds in which either one of c is a lower alkyl group, especially the combination of this substituent, the type of substituent at the 1-position, and the type of the atom at the 8-position, give a roughly levorotatory optically active substance with strong antibacterial activity. It was discovered that the compound has good water solubility, and the object of the present invention was achieved.

[Structure of the Invention] The present invention is based on the general formula (wherein Ra and Rb each represent hydrogen or lower alkyl, Rc represents lower alkyl, and Rb represents R
a or Rc may form a methylene chain (n is 2 to 5) represented by (CH2)ll, Rd is ethyl, 2
- means fluoroethyl, vinyl, isopropyl, isopropenyl, cyclopropyl, monofluorophenyl or difluorophenyl. q is CHlC-F, C
-Cl or N) and salts thereof.

Here, the lower alkyl group has 1 to 6 carbon atoms,
Particularly suitable are methyl and ethyl.

Also preferred are those in which Rb and Rc form a methylene chain having 2 to 5 carbon atoms, and those in which Ra and Rb form a methylene chain having 2 to 4 carbon atoms; Rd is ethyl;
Cyclopropyl and 2,4-difluorophenyl are preferred, and q is preferably C-H%C-F, C-Cl or N.

Examples of the salts of the compounds of the present invention include salts with inorganic or organic acids such as hydrochloric acid, sulfuric acid, and methanesulfonic acid, and alkali metal salts or alkaline earth metal salts such as sodium salts and calcium salts of carboxylic acids. be done. Furthermore, the compounds of the present invention may also exist as hydrates.

The compound of the present invention can be synthesized by the method exemplified below. That is, a compound represented by the general formula [11]: (wherein Rd and Q are the same as above, and Xs means a substituent that can be nucleophilically substituted with an amine, such as a halogen, methanesulfonyl group, etc.) Formula [HI3: (wherein, Ra
%Rb and Rc are the same as above).

This reaction consists of acetonitrile, tetrahydrofuran (
T)IF), ethanol, chloroform, dimethyl sulfoxide (DMSO), dimethylformamide (DM
F) is preferably carried out at a temperature of about 20 DEG to about 150 DEG C. in the presence of a non-reactive solvent such as pyridine, picoline, water, etc.

The pyrrolidine derivative represented by the general formula [III] can be synthesized, for example, by the following method.

That is, the known compound 1-benzyl-4-carboxy-2-pyrrolidone is treated with thionyl chloride to form an acid chloride, which is further reacted with Meldrum's acid, and then decarboxylated to derive a 4-acetyl form. The ketone moiety of the acetyl group was made into an oxime with hydroxylamine, and then catalytically reduced with Raney nickel to 4-(l-aminoethyl it-
Benzyl-2-pyrrolidone is obtained. This was tertiary-butoxycarbonylated (Boc-formed) with 2-[tert-butoxycarbonyloxyimino]-2-phenylacetonitrile (hereinafter abbreviated as Boc-ON), and this compound was
It is separated into two stereoisomers by high performance liquid chromatography (HPLC) or fractional recrystallization. One of them is treated with trifluoroacetic acid (TF^) to remove Boc. The obtained primary amino compound is treated with acid chloride of N-balatoluenesulfonylproline, and then optically resolved by column chromatography. After treating the obtained optically active substance with a base to remove tosylproline, the amide of the pyrrolidine ring was reduced with lithium aluminum hydride, the primary amine moiety was protected by Boc conversion, and palladium-
Debenzylation with carbon or the like yields optically active 3-(1-tert-butoxycarbonylamino)ethylpyrrolidine.

In addition, in the manufacturing method of the present invention described above, general formula [II
The amino group of the pyrrolidine derivative represented by I] may be protected so as to be substantially inert to the reaction. Such protecting groups include acyl groups such as formyl, acetyl, trifluoroacetyl; ethoxycarbonyl,
2 or more carbon atoms such as tertiary butoxycarbonyl (Boc)
Alkoxycarbonyl group of 6: Aryloxycarbonyl such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, phenoxycarbonyl: Silyl group such as trimethylsilyl, nitrityl, tetrahydropyranyl, vinyloxycarbonyl, 0-nitrophenylsulfenyl, diphenylphos Examples include groups such as finyl, p-toluenesulfonyl and benzyl. These protecting groups can be removed by known methods such as acid or base hydrolysis after the reaction, if desired.

Next, the present invention will be explained using reference examples and examples, but the present invention is not limited thereto.

1: 4-acetyl-1-benzyl-2-pyrrolidone (1) l-benzyl-4-carboxy-2-pyrrolidone 4.4
g and 10 ml of thionyl chloride. After adding 30 ml of dioxane and heating and stirring at 90 to 100°C for 30 minutes, the solvent and excess thionyl chloride are distilled off under reduced pressure to obtain a residue of acid chloride.

Magnesium ethoxide 2 in 40+ al of anhydrous ether
．． 5 g and 3.5 g of ethyl malonate were added, and the mixture was refluxed for 1.5 hours. While stirring the resulting solution under water cooling, the above ether solution of acid chloride was added dropwise. After dropping, the mixture is refluxed for 1 hour, and while cooling with water, an excess of dilute sulfuric acid is added to make it weakly acidic, followed by extraction with ether and drying.

After evaporating the solvent, 10a+1 acetic acid, 45 ml of water, and 1 ml of concentrated sulfuric acid were added to the residue, and after 5 hours of rapid flow, the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, washed successively with 10* hydrochloric acid and saturated sodium bicarbonate, dried, and the solvent was distilled off to obtain 3.3 g of the above compound (1) as an oil.

NMR (CDC13) δppm: 2.2 (3H,
s) 2.66 (2H, d, J-7, 2Hz), 3.0
~3.6 (3H, n) 4.32, 4.52 (IH
, d, J=14Hx, AB-q), 7.29 (5
H,s) Pyridine 15o+1 was added to 3.3 g of compound (1) and 2.5 g of hydroxylamine hydrochloride, and the mixture was heated at 90°C.
Heat for 5 hours. Add water and acidify with hydrochloric acid, then extract with dichloromethane. Dichloromethane was distilled off, and the resulting residue was subjected to column chromatography using 30 g of silica gel and eluted with methanol-chloroform (1:20) to obtain 2.6 g of the above compound (2) as a powder.

NMR (CDC13) δppm: 1.8 (3H, s
)2.62 (2)1. d, J-7, 2H1), 2.9
~3.6 (3)1. m) 4.44 (2H, S), 7.
69.3 g of 28(5H,s) oxime (2), 20 ml of Raney nickel and 700 ml of methanol were mixed and stirred for 8 hours under a hydrogen stream. The catalyst was filtered off and methanol was distilled off under reduced pressure to obtain 84 g of pale yellow oil (3).

JINMR (CDCH3) δppm: 0.09
(3H, d, J-7Hz), 1.08 (3H, d, J
-7Hz), 1.96 (3H, s), 2.0 to 2.6
(3)1. m), 2.6 to 3.5 (3H, m),
4.42 (2H, s), 7.28 (5) 1. S) Amino body (3) 84.0g in tetrahydrofuran 600m
1, add 72.2 g of Boc-ON, and stir for 70 minutes. The solvent was distilled off, and the residue was dissolved in 1λ of ethyl acetate.

After washing with 0.2N sodium hydroxide solution and saturated brine, the organic layer was dried with sodium sulfate. When the solvent is distilled off and n-hexane is added to the residue, it solidifies. After filtering, wash with petroleum ether67
．． 0 g of powder was obtained.

Recrystallization from ether gave 23.7 g of isomer 4A as colorless needles with a melting point of 138°C. Repeated recrystallization of the mother liquor with ether yielded 12.9 g of isomer 4B with a melting point of 139.
~141t: Obtained as colorless prism crystals. 4A and 4B show black peaks in HPLC.

Column: Nucleosil 50-5 20X 250mm Solvent: Ethyl acetate-THF (95:5), Flow rate: 5a+
l/min holding time: 4A 4B, 5 min 4B 52.5 min'H
-NMR (CDC1a) δppm: 4A 1.
06 (3H, d, J-7H2), 1.42 (9H, S)
2.2-2.7 (2H, l11), 2.9-3.5
(2Lm), 3.5-3.9 (IH, IB), 4.
3-4.5 (1)1. m), 4.46 (2H, 80-
q, J-16) 1z), 7.35 (58, m) 4B
1.09 (3H, d, J-7H2), 1.42 (9
H, s) 2.1-2.6 (2H, m), 2.8-3.
4 (2H, m), 3.4-3.8 (LH, l), 4
．． L ~4.4 (18, l), 4.48 (2B, AB
-q, J-16Hz), 7.37 (5H, m) Boc form (4B) 8.0 g was added to 50 ml of trifluoroacetic acid under water cooling, and then stirred at room temperature for 1 hour. Trifluoroacetic acid is distilled off under reduced pressure. Add 50ml of water to the residue and neutralize with NaHCO. After extraction with chloroform, Na, SO, and drying, the solvent was distilled off to obtain 5.5 g of colorless oil (5B).

'11-NMR (CDCH,) δppm: 1.
05 (3H, d, J-7) 1z), 1.24 (2H, S
), 2.0-2.5 (3H, m), 2.6-3.
0 (IH, m), 3.0-3.5 (2H, m)
, 4.45 (2H, s), 7.211 (5H, 5)
(S) -? 1-p-toluenesulfonylproline2.
5g, thionyl chloride 2.1ff11 and benzene 20
Mix m1 and heat under reflux for 5 hours. Benzene is distilled off, benzene is added to the residue, and the distillation is repeated three times) to obtain acid chloride as an oil.

4-aminoethyl compound (5B) 3.55g and pyridine 1
．． Dissolve 1 ml in 15 ml of dichloromethane, and add the above acid chloride to 15 ffl of dichloromethane while stirring at room temperature.
! Dissolve and drip. After 24 hours, the reaction solution was washed with 2N hydrochloric acid, water, 2N sodium hydroxide, and water in this order, dried over sodium sulfate, and the solvent was distilled off to obtain a yellow oil. This one is silica gel TL
Since it was found to be a 1:1 mixture (Rf O, 29 and Rf O, 26) with C (ethyl acetate-methanol 95:5), it was applied to a column of 100 g of silica gel.
Each isomer obtained by elution with ethyl acetate-methanol (95:5) was recrystallized from ethyl acetate-〇-hexane.

Isomer 6a 870 mg, melting point 96-98°C TLC
Rf-0,29, [α] D-91,3° (c-0,5
15, chloroform) isomer 6b 820 mg, melting point 1
26-132°C TLCRf-0,26[α]D-
136,0" (c-0,350, chloroform)'
H-NMR (CDCh) δppIIl:6a 1.1
9 (3H, d, J=7Hz), 1.4-1.8 (3H,
m) 1.8-2.2 (2H, m), 2.44 (3H,
m), 2.28-2.8 (2H, a+), 3.0-3
．． 4 (3H, m), 3.4-3.7 (ill, m)
, 3.9-4.2 (2H, m), 4.50 (2H, 8B
-q, J=16Hz), 6.88 (IH, d, J-
8) 1z) 7.28 (5H, s), 7.44 (2H,
d, J-7Hz), 7.70 (2H, d, J=7Hz) 6b 1.15 (3H, d, J-782), 1.4~
1.9 (41 (, m) 2.0 to 2.8 (3H, m),
2.45 (3H, s), 3.0-3.4 (2H, m)
, 3.4-3.8 (2H, m), 4.45 (2H, ^
B-q, J-16Hx), 6.138 (IH, d,
J-8) IZ) 7.39 (5)1. s), 7.44
(2H, d, J-7Hz), 7.89 (2H, d, J
-78x) Reference example 7: (-)-4-(1-aminoethyl)-1
-benziisomer (6b) 1.08g, 15 mixed with 10ml of sodium hydroxide and 30111 ethanol 3
Heat fast for days.

Ethanol was concentrated, extracted with chloroform, dried over Glauber's salt, and the solvent was distilled off to obtain 480 mg of a colorless oil (7b).

[α], -4,6″″ (c-2,0, chloroform) isomer (8a) t, og, 8 sodium hydroxide 10
ml and 30 ml of ethanol were mixed and reacted in the same manner as above to obtain colorless oil (7a) 430B.

[al o + 4.4” (c-2, o, chloroform)'H-NMR (CDCHs) δppm Near a
, 7b 1.05 (3H, d, J-7) 1z), 1.2
4 (2H, S) 2.0 to 2.6 (3H, a+), 2
．． 6-3.0 (IH, m) 3.0-3.5 (2H, m)
, 4.45 (2H, s), 7.28 (5H, s) (+) 345 mg of amino body (7a) in THF 30 m
1 and 389 mg of Boc-ON was added thereto and left for 3 days. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (50%).
Dissolve in m1.

After washing with 0.5N sodium hydroxide and water and drying with sodium sulfate, the solvent was distilled off. It was applied to a column of 30 g of silica gel and eluted with chloroform-methanol (98:2) to obtain 340 mg of colorless crystals (8a). Melting point 129-130℃ [α coro + 31.9° (C-0,295, chloroform) (
-) Amino compound (7b) 406mg in THF 20a+
Dissolve in 1 and add 530mg of Boc-ON to it and add 24
Stir for an hour. After THF was distilled off, the residue was treated in the same manner as above to obtain 410 mg of colorless crystals (8b) with a melting point of 129-131°C.

[α] D-32,5@(C-0,30, chloroform)' H-NMR was consistent with 4B.

(-) Amino form (7b) 480111g in THF
The mixture was dissolved in 30 ml of water, 4500 mg of LiAlH was added thereto, and the mixture was heated under reflux for 2 hours. Add 2 ml of water-cooled sewage dropwise and remove insoluble matter by filtration. Boc-ON 540n+g was added to the filtrate and stirred for 12 hours. The solvent was distilled off, and the residue was dissolved in 50 ml of ethyl acetate, washed with 0.5N sodium hydroxide and water, and dried over Glauber's salt. Column chromatography using 30 g of silica gel and elution with ethyl acetate-benzene (2:1)
0 mg of colorless oil (9b) was obtained.

IQ] D-9,80" (c-2,0, chloroform)
'H-NMR (CDCHs) δ11p■:
1.10 (3H, d, J-7Hz) 1.44 (9)
1. S), 1.6-3.0 (Parrot, 2H) 3.60 (2
H, AB-q, J-16Hz), 7.30 (5
)1,5) 460 mg of 1-benzyl compound (9b) 5X
Using 800I1g of Pd-C (moisture 52,5!k) as a catalyst, 20ml of ethanol was irradiated with a tungsten lamp under a 4-atmosphere hydrogen stream and shaken for 4 hours.

The catalyst was removed by filtration and the filtrate was concentrated to dryness to obtain 320 mg of colorless oil (10b). If you leave it for a while, it will partially solidify.

Hydro-4-oxoquinoline-3-carboxylic photobenzylic compound (obtained by catalytic reduction of 04 g of 9bH (-) -
3-(1-tert-butoxycarbonylaminoethyl)pyrrolidine (10b) and 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-
3-Carboxylic acid 800B is heated under reflux with 2 ml of triethylamine in 20 ml of acetonitrile for 2 hours.

The crystals precipitated by concentration are collected by filtration and washed with ether.

Add this to 0ml of TF8 and stir for 20 minutes. T.F.A.
is distilled off and 150 ml of water is added to precipitate crystals. Add concentrated hydrochloric acid to this to make a solution, and extract with chloroform.

The aqueous layer was concentrated to 100 ml, and the mixture was cooled with water and adjusted to pH 12 with sodium hydroxide solution and adjusted to pH 7.20 with hydrochloric acid. After extraction with chloroform and drying with Glauber's salt, the solvent was distilled off. The residue was recrystallized from ethanol to give 608m colorless crystals with a melting point of 218°C.
I got g.

[αlo -221,0@(C-0,428,0,I
N-hydrochloric acid) elemental analysis value C+ah+hNsOs・%H20
Calculated value as C57,7515,92N 11.22
Analysis value C58,13H5,90N 11.14')I
-NMR (NaOD): 1.12 (3) 1. d,
J-7) 1z), 1.44 (3H, t, J-7H1)
1.4-1.7 (kl (, m) 1.9-2.2 (
2H, m), 2.7-2.9 (IH, m) 3.4-4
．． 0 (4Lm), 4.3-4.6 (2H, m) 7.7
2 (IHdd, J-2Hz, 15Hz), 8.
32 (IH,S) Pyrrolidine derivative (10b) obtained by catalytic reduction of 1.10 g of benzylic compound (9b) and 1-cyclopropyl-6,7,8-trifluoro-1
, 750 mg of 4-dihydro-4-oxoquinoline-3-carboxylic acid and 2 ml of triethylamine were heated under reflux in 20 ml of acetonitrile for 4 hours to precipitate crystals.

After 6 days, the crystals were collected by filtration to obtain 1.07 g of yellow needle-like crystals with a melting point of 233-236°C. Add 1.04 g of this to 20 ml of TFA and stir for 20 minutes. 150ml of water after distilling off TFA
After adding, adjust the pH to 12 with 2N sodium hydroxide solution under water cooling.
shall be. Adjust the pH to 7.20 with hydrochloric acid and extract with chloroform. After drying the organic layer with Glauber's salt, the solvent was distilled off. The residue was recrystallized from ethanol-ammonia water to give a melting point of 217-229°C.
86 Oa+g of colorless needle crystals were obtained.

[α], -250, Q@ (C-〇, 49K, Q,
IN Hydrochloric acid) Elemental analysis value Calculated value as C+eHz+FJ30s C60,47H5,61N 11.13 Analysis value
C60,37H5,69N 11.11'H-NMR (
NaOD): 1.12 (3H,d,y-yox
), 1.0-1.3 (41 (, m), 1.4-1.7
(1) 1st part), 1.9-2.2 (2H, m), 2.
7-2.9 (IH, m), 3.4-3.9 (2)1
．． l11), 3.9-4.0 (IH, m), 7.65
(IH, dd J-ISHHz, 2Hz), 8.4
7(IH,5)7-chloro-1-(2,4-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid 200m
50 ml of acetonitrile and 250 mg of 3-[1-tert-butoxycarbonylaminoethylcopyrowazine were added to the solution, and the mixture was allowed to flow rapidly for 1.5 hours. After 6 days, the solvent was distilled off under reduced pressure, and 5 ml of ethanol was added to the residue to crystallize it, collected by filtration, and washed with ether.

5 ml of trifluoroacetic acid was added to the obtained crude crystals, stirred at room temperature for 10 minutes to remove Boc, the solvent was distilled off under reduced pressure, 10 ml of IN sodium hydroxide was added to the residue, and after dissolution, 0.0 ml of trifluoroacetic acid was added and stirred at room temperature for 10 minutes to remove Boc.
Neutralize with 05N hydrochloric acid and collect the precipitated crystals by filtration. The crude crystals were recrystallized from concentrated ammonia-ethanol to give a melting point of 213-214.
70 mg of the title compound was obtained at .

Elemental analysis value C□HsJsNa03・%1 (calculated value as 20: C60,86H6,32N 10.14 analysis value: C60,65H5,99N to.07') I-N
MR (NaOD): 1.04 (3) 1. d J-7
) IZ), 1.35-1.6 (1) 1. m), 1.8~
2.1 (IH, m), 1.70. (IH, m), 3.0
~4.0 (4H, m), 7.25 (2H, m)7.
45 (IH, m), 7.90 (IH, d, J = 12) 1
z), 8.34 (IH, s) layer side 4 near-3-(1-
aminoethyl)-1-pyrosadi-1-benzyl-3-(1
-Tertiary butoxycarbonylaminoethyl)-pyrrolidine (270 mg) is reduced in 40 ml of ethanol using 54 kPd-C (500 mg) as a catalyst.
-chloro-1-cyclopropyl-6,7-difluoro-
1,4-dihydroquinoline-3-carboxylic acid 150mg
% triethylamine and 20 ml of acetonitrile were mixed and heated under reflux for 12 hours.

After 6, reduce the pressure of acetonitrile? The crystals precipitated by UIi are collected by filtration and dissolved in 10 ml of TF. After stirring for 30 minutes, concentrate under reduced pressure. Add 20 ml of water to the residue, adjust the pH to 12 with 2N sodium hydroxide solution, and adjust the pH to 7.2 with hydrochloric acid. After extraction with chloroform and drying of Glauber's salt, the solvent was distilled off and the residue was evaporated with ethanol.
Pale yellow crystals with a melting point of 131'e recrystallized from aqueous ammonia 5
5IIIg was obtained.

Elemental analysis value C + gHztFCHNs03・%H20 Calculated value: C56,02H5,77N l0J2 analysis value: C56,19) 15.18 N 10.35
'H-NMRδ (DMSO-d,): 1. Q9
(3H, d J-7Hz), 0.8-1.3 (411
, m), 1.4~1.8 (IH, m), 1.13~
2.2 (2H, m), 2.8-2.9 (IH, m),
3.2-4.0 (4H, m), 4.1-4.5 (IH,
m), 7.118 (IH, d J-15Hz), 8.8
7 (LH,s) ヱヱ韮! -benzy-3-(1-tert-butoxycarbonylaminoethyl)pyrrolidine (9b) 410 mg to 596
The debenzylated product obtained by passing through 50 ml of ethanol using 1.0 g of Pd-C as a catalyst and 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-
150 mg of dihydroquinoline-3-carboxylic acid, 1 ml of triethylamine.

The mixture was mixed with 30 ml of acetonitrile and heated under reflux for 12 hours. Acetonitrile is distilled off under reduced pressure and the residue is dissolved in chloroform. The organic layer was washed with mirabilite acid and water, dried with sodium chloride, and the solvent was distilled off. Add 20ml of water to the residue, adjust the pH to 11 with IN sodium hydroxide, and then adjust to pH 7.2 with hydrochloric acid.
5. After extraction with chloroform, Na25O, and drying, the solvent was distilled off. Recrystallized from ethanol, melting point 198-2
118 mg of colorless crystalline powder at 00°C was obtained.

[α]D-163,7° (c-0,430,0,IN
Hydrochloric acid) elemental analysis value C1eH*+CHFN30s/station 8
Calculated value as 20 C56, 65H5, 50N 10.
43 analysis value C56, 58H5, 59N 10.41'
H-NMR (NaOD): o, oa ~1.10 (
28, m), 1.16 (3H, d, J-7Hz), 1
．． 1-1.35 (2H, m) 1.5-1.9 (IH, m
), 2.0-2.3 (2H, m), 2.8-3.0 (
01,m), 3.4-3.7(4)1. m) 3.7~
4.0(IH,m), 4.2-4.4(II(,[
0)7.82 (1)1. d, J-15H2),
8.61 (IH,s) [Effects of the Invention] According to the present invention, strong antibacterial activity is maintained by introducing a lower alkyl group into at least one of the substituents Rb or Rc in the compound [I]. At the same time, water solubility can be improved, and a compound with excellent intestinal absorption and metabolic stability can be obtained.

In other words, the compounds of the present invention are expected to exhibit good pharmacokinetics, have low toxicity, and can be expected to be highly useful as pharmaceuticals.

Accordingly, the compounds of the present invention can be widely used as antibacterial agents, for example in the form of oral, parenteral and topical administration to humans and other mammals. In other words, it is suitable for treating various infections of the respiratory system, urinary system, intestinal tract, etc., and is effective against lower respiratory tract infections such as pneumonia, as well as bronchitis, nephritis, cystitis, prostatitis, urethritis, etc. It has a particularly good effect
≧You can expect it.

The dosage for adults is 50 mg to 2 g per day, usually 100 to 800 mg, administered orally in 1 to 3 divided doses. It can also be administered parenterally, for example, by intravenous infusion of 50 to 150 mg per dose for adults, or externally as suppositories, ointments, creams, eye drops, etc.

As for formulations, it is possible to manufacture tablets, capsules, powders, granules, syrups, and other injections by appropriately using excipients, disintegrants, solubilizing agents, stabilizers, etc. For example, for 100 mg of the compound of the present invention, 2
3mg, CMC-Na 22.5mg, hydroxypropyl cellulose 3B, magnesium stearate 1.5
It can be mixed to make a capsule.

The toxicity of the compound of the present invention is weak; for example, when 200 mg of the compound of Example 1 was intravenously injected into 5 mice, none of them died, and 1.0.0 is considered to be more than 1 g of 2QQl.

Next, we will discuss the antibacterial activity (MIC) of representative examples of the compounds of the present invention.
μg/ml).

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ I (In the formula, Ra and Rb each mean hydrogen or lower alkyl, Rc means lower alkyl, and Rb means R
a or Rc may form a methylene chain represented by (CH_2)_n (n is 2 to 5). Rd is ethyl, 2
- means fluoroethyl, vinyl, isopropyl, isopropenyl, cyclopropyl, monofluorophenyl or difluorophenyl. Q is CH, C-F, C-
Cl or N) and its salts (2) In the general formula [I], Ra is hydrogen or methyl, Rb is hydrogen or methyl, Rc is methyl or ethyl, Rd is ethyl or cyclopropyl, 4- Fluorophenyl, 2,4-difluorophenyl, the compound (3) according to claim 1, wherein Q is CH or N. In the general formula [I], Ra and Rb are hydrogen, Rc is methyl or ethyl, Rd Compound (4) according to claim 1, wherein is ethyl or cyclopropyl, and Q is C-F Claim 1, wherein the compound represented by general formula [I] is an optically active compound Compound (5) Compound (6) according to Claim 4, in which the optically active form is levorotatory A therapeutic agent for infectious diseases containing the compound according to Claim 1 as an active ingredient