JPH01100165A - Oxime or hydroxylamine derivative based antimicrobial agent - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R is halogen; R<1> is alkyl, cycloalkyl, phenyl or thienyl; R<2> is H or alkyl; Q is N or NH; X is CH, N, CF or CCl; Y is H, amino, etc., m is 3-7; n is 0, 1 or 2, provided that n is 0 when Q is N]. EXAMPLE:1-Cyclopropyl-6, 8-difluoro-1, 4-dihydro-7- ( 3-hydroxyamino-1-pyrrolidi nyl)-4-oxo-3-quinolinecarboxylic acid. USE:An antimicrobial agent. PREPARATION:A compound expressed by formula II (L is leaving group) is reacted with a compound expressed by formula III (Y<1> is H, protected amino or substituent group) to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an oxime or hydroxyamine derivative antibacterial agent useful as an antibacterial agent.

As a quinolone carboxylic acid-based antibacterial agent similar to Tomooka Niyoshi oxime or hydroxyamine derivative-based antibacterial agent, JP-A-49-
14240.57-46986.60-228479.
Compounds described in publications such as No. 80-64979.61-225181 are known.

Some of these conventional products have problems such as causing side effects such as convulsions when administered to the human body. Therefore, an object of the present invention is to provide an antibacterial agent that has strong antibacterial activity and has reduced convulsions and other central side effects.

The present invention is based on the general formula (wherein R is halogen, R' is alkyl, cycloalkyl, optionally substituted phenyl or thienyl, R'' is hydrogen or alkino, Q is -N- or -NH -1X is CH, N, CF or CC1°Y is hydrogen, an optionally protected amine or substituent, m is an integer from 3 to 7, n is 0.
represents 1 or 2, respectively, provided that when Q is -N-, n is 0. ) or a salt thereof.

The terms used in the definition of the above general formula will be explained below.

Halogens include fluorine, chlorine, bromine, and iodine; alkyls include C, -C, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and pentyl; cycloalkyls include cyclopropyl, cyclobutyl, Examples of C, -C, cycloalkyl such as cyclopentyl, cyclohexyl, and cycloheptyl, and substituents include hydroxy, halogen, alkyl, and alkoxy. Examples of alkoxy include C, -C, and alkoxy such as methoxy, ethoxy, propoxy, and butoxy. Protecting groups include common amine protecting groups such as carbobenzoxy. As a free radical,
Halogen, tosyloxy, etc. are used.

The compound (I) of the present invention is a compound represented by the general formula % (in the formula, L is a leaving group, and R and R'%X have the same meanings as above). , 0% R2, m, n have the same meanings as above, yl
represents hydrogen, a protected amine group or a substituent) to form a compound represented by the general formula (wherein Q, R%R', X, Y', and m have the same meanings as above). ) and when Y is an amine protecting group, further! It is obtained by subjecting a to a deprotection reaction.

That is, the method for producing compound (I) is shown by the following formula.

(Left below) (In the formula, L, Q, R, R', R', X, Y', m are front -
(Y3 represents hydrogen, amino or a substituent).

Each step will be explained below.

Kamee 1 The compound (I&) of the present invention is obtained by adding an amine (I) to the raw material (I).
The zero reaction obtained by reacting [[) is
The reaction temperature can be carried out in a solvent such as water, alcohols, acetonitrile, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), etc.
It is suitable to heat the mixture to 200°C, preferably 80 to 120°C, or about the boiling point of the solvent, and react for 1 to several hours.

In order to accelerate the reaction, a base such as triethylamine, pyridine, DBU, etc. may be added by a conventional method.

Kameshiko 1 Compounds in which yl is a protected amine in formula (Ia) are carefully selected and subjected to a deprotection reaction to form other target compounds (r
b). In other words, the deprotection reaction is performed using a base such as sodium hydroxide or potassium hydroxide, or an acid such as hydrochloric acid or acetic acid, in a solution such as water, a water-alcohol mixture, or a water-acetic acid mixture, at a temperature between room temperature and the boiling point of the solvent. It can be easily carried out by a conventional method at a temperature of . The compound represented by the general formula (It), which is a starting material of the present invention, can be synthesized, for example, by the following route.

(Margin below) (Refer to Japanese Patent Application Laid-Open No. 61-2252) (In the formula, Xi and X2 each represent a halogen, and R1
has the same meaning as above. ) The compound represented by formula (I) can then be converted into an acid addition salt according to conventional methods, if desired. Examples of the acid include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and salts with organic acids such as methanesulfonic acid, lactic acid, oxalic acid, and acetic acid.

Moreover, the compound (1) of the present invention can be administered to humans or mammals by oral or parenteral administration. They can be formulated into tablets, capsules, large portions, granules, injections, suppositories, and syrups by conventional pharmaceutical methods. Examples of pharmaceutically acceptable carriers, diluents, and excipients include lactose, sucrose, wheat starch, potato starch, magnesium stearate, gelatin, methylcellulose, agar, and water. If necessary, stabilizers, emulsifiers,
Wetting agents, buffering agents, and other formulation aids may be added.
The appropriate daily dose is 1-500 mg for oral administration and 0.1-300 mg for injection.

Examples, reference examples, and formulation examples are shown below to clarify this embodiment.

Abbreviations used in Examples, Reference Examples, and Tables have the following meanings.

cti, ct,: methylene chloride, EtOH: ethanol, HBr: hydrogen bromide, Et: ethyl, AcOH:
Acetic acid, MeO: methoxy, Ts: p-toluenesulfonyl + Ac'acetyl* Cbz: hensyloxycarbonyllupon (Ia-1 1-cyclopropyl-6, 7.8-1 refluoro-1.
4-dihydro-4-oxo-3-quinolinecarboxylic acid (
! [-1) 401 mg, 3-hydroxyaminopyrrolidine.2HCl (III-1) 446 mg.

1,8-diazabicyclo[5.4.0]undecene-1 (DBU) was added to a suspension consisting of 15 ml of acetonitrile.
Add 776 mg, reflux and stir for 5 minutes.

After cooling the reaction solution, the precipitated crystals were collected by filtration and mixed with methanol,
If washed sequentially with chloroform, the melting point is 225-227℃ (
122 mg of the target product (Ia-1) was obtained (decomposition point).

Elemental analysis value (X)'C+ tH+ tN*o-F* *
0. Theoretical value + C. as 3H*0. 55.07i H. 4.79;N. 1
1.33; F. 10.25 Experimental value: C. 54.87
;H. 4.78; N. 11.70; F, 9.85
IR (Nujol): 1375. 1470
．． 1610 am-' (blank below) Example 2 Monooxo-3-quinolinecarvone (Ia-2) 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarvone Acid (I[-
1) 250mg, 3-methoxyaminopyrrolidine
2HC1(II[-2) 360mg acetonitrile 5
Add 72 ml of DBUo to the ml solution and reflux for 1 hour. Concentrate under reduced pressure, dissolve the residue in water, and neutralize with acetic acid.
Next, it is extracted with methylene chloride, and the extract is washed with water and concentrated. The residue was recrystallized from methylene chloride/ethanol,
Target product (Ia-2) with melting point 184-187°C 0.13
Obtain 1g.

IR(Nujol)+3260.1732.1632.
1600 am-'.

-4-oxo-3-quinolinecarvone Ia1-
cyclopropyl-6,7,8-trifluoro-1,4-
Dihydro-4-oxo-3-quinolinecarboxylic acid (I[
-1) 1.2g (4.24mM) of anhydrous acetonitrile 30ml, crude 3-methoxyaminomethylpyrrolidine.2
- Add 2.28 g (6.36 mM) of trifluoroacetate and 3 ml of DBU sequentially and reflux for 30 minutes. After neutralization by adding 1.28 ml of acetic acid under ice cooling, the precipitated crystals are collected by filtration and washed with methanol to obtain 0.68 g of a yellowish white target product (I a-3) with a melting point of 158-160°C.

IR(Nujol)' 1720.1620 cm-
'NMR (CF, C00H) (1) pIII) 14
．． 7 (bs, 18), 8.59 (s, IH)
, 7.83.7.67 (dd, IH, J=2Hz,
15Hz), 4.2-3.5 (m, 5H)3.
55 (s, 38), 3.02 (d, 2H,T
=6Hz>, 3.0-1.5 (m, 3)1),
1.5-1.0 (m, 4H) (blank below) So-3-quinolinecarvone Ia-4 (ll-1)
(1l-5) (isomer of m-4) 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-year-old xo-3-quinolinecarboxylic acid <If-
1) 640 mg, 3-benzyloxycarbonylamino-4-methoxyaminopyrrolidine (III-4) 1.0
DB in a suspension consisting of 9 g and 20 ml of acetonitrile.
After adding 3 g of Ul and refluxing for 2 hours, acetonitrile was distilled off under reduced pressure from the reaction solution, and water was added to the residue to precipitate crystals. The crystals are collected by filtration and recrystallized from methanol/methylene chloride to obtain the desired product (Ia-
Obtain 16 g of 4N.

Elemental analysis value (X): C**H**NhOsF*t
, [Theoretical value: C,59,01H,4,96+N,1
0.60; F, 7.19 Experimental value: C, 58,94;
H, 5,02; N, 10.50; F, 7.36I
R(CHCIs> 1310.1440.1619.
1710 cm-' and 10'' (I a-4 isomer) (I a-5) (I a-4 isomer) (Ib-1) (
Isomers) (I b-2) (Isomers of I b-1) Example 4(a)
19% HBr/500 mg of compound (Ia-4) obtained in
Add 10 ml of CHsCOOH solution and stir for 30 minutes at room temperature. Acetic acid is distilled off from the reaction mixture under reduced pressure, the residue is dissolved in water, and then neutralized with 28% aqueous ammonia. If the precipitated crystals are filtered and recrystallized from chloroform, the melting point is 176-1.
Obtain the desired product (Ib-1>0.13 g at 79°C.

Elemental analysis value (X)'C+aH*. NaO4Fm・1:
Theoretical value as 3H,0: C,51,74i H,5,45i N,1
3.41+F, 9.10 Experimental value: C, 51,65;
H, 5,25; N, 13.38i F, 8.94I
R(CHCIm> 1460. 1620 am”1
-cyclopropyl-6,7,8-trifluoro-1,4
-dihydro-4-year-old xo-3-quinolinecarboxylic acid (I
[-1) 0.59 g, compound (I[[-5) 1.05
g, DBUo in 20 ml suspension of acetonitrile, 96
g and reflux for 2 hours. By the same post-treatment as in Example 4(a), the desired product (Ia-5
) 1.05g is obtained.

Elemental analysis value (X)' Theoretical value as C**Ha-N-OJ*: C, 59,08; H, 4,96; N, 10
．． 60; F, 7.19 Experimental value: C, 59,23;
H, 4,99; N, 10.72F F, 7.29I
R(CHCIm) 1320.1450.1624.1
720 am"b) Hypothesis (I b-2 If 500 mg of the compound (Ia-5) obtained in Example 5(a) is used and treated in the same manner as in Example 4(b), the melting point is 218.
Obtain the target product (I b-2>0.11 g at -220°C.

Elemental analysis value (X) 'C+aHmaNaOaFx ・
Theoretical value as 0.25HtO: C,54,20i H,5,18; N,1
4.05; F, 9.53 experimental value + C, 53,94:
u, s, as; N, 14.35i F, 9.70I
R (Nujol) 1455. 1605
am"LLL2" (blank below) 1-cyclopropyl-8-chloro-6,7-cyfluoroyl, 4-dihydro-4-oxo-3-quinoline carboxylic acid (II-2) 490 mg, 3-hydroxyaminopyrrolidine・DBU749n+ was added to a suspension consisting of 430 mg of 2HC1 (III-1) and 20 ml of acetonitrile.
Then, acetonitrile was distilled off under reduced pressure from the reaction mixture, water was added to the residue, and the mixture was extracted with dichloromethane. After drying, the dichloromethane layer is distilled off and the residue is recrystallized from methanol to give a melting point of 190-192°C.
116 mg of the desired product (Ia-6) was obtained.

I R (Nujol) 1455.1605 cm-
'Elemental analysis value (X)? CI? H,tN104FC1
Theoretical value F C,52,73 as -0,3HIO; H,4,58i N,1
0.85i F, 4.91 experimental value: C, 52, 63:
H, 4,50i N, 10.65; F, 5.09-
(Ia-7>1-cy')lopropyl-8-chloro-6,7-cyfluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (II-2) 120 mg, 3-methoxyamino Pyrrolidine (If[-1) 400mg, DBUO,,
60 ml of the mixture are refluxed for 1 hour in 7 ml of acetonitrile. Concentrate under reduced pressure, dissolve the residue in water, neutralize with acetic acid, and extract with CHtC1*. Concentrate the extract and remove the residue with E.
Recrystallized from tOH/CH*C1*, melting point 159-16
78 ■ of the target product (Ia-7) was obtained at 1°C.

Elemental analysis value (%): CI#HtsNj04FCITot, Te theoretical value: C, 54, 62 薯H, 4, 84; N
, 10.63i F, 4.80 Experimental value: C, 54, 42
; H, 4,92; N, 10.62; F, 5.15
I R (CIC1,) 3275.1720.1618
．． 1600 cm-'Kanhai ■1 Kumarishini' U-1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-year-old xo-3-quinolinecarboxylic acid ( II-3) 150, 3-methoxyaminopyrrolidine (II-2) 400mg% DBU0.7
0 ml of the mixture is refluxed in acetonitrile for 1 hour.

Concentrate under reduced pressure, dissolve the residue in water, neutralize with acetic acid, and dilute with CH,
Extract with C1. Concentrate the extract and convert the residue to CH*C1
Recrystallization from t/EtO)i yields 0.127 g of the desired product (Ia-8) with a melting point of 204-205°C.

Elemental analysis value (X)' Theoretical value as Cm+H3,N5O4Fa: C, 55,88; H, 3,80; N, 9
．． 31; F, 16.84 Experimental value: C, 55,85;
H, 3,88i N, 9.30i F, 16.76I
R(CHCl,) 3250.1725.1620
am” (blank below) 1-thienyl-6,7-difluoro-4-oxo-3-
162 mg of quinoline carboxylic acid (ll-4).

80 μm of 3-methoxyiminopyrrolidine (II[-6) was dissolved in 5 mL of DMSO and stirred at 70° C. for 2 hours. The precipitated crystals are collected by filtration and washed with methanol to reduce the decomposition point to 2.
The desired product (Ia-9) 71m& is obtained at 64-266°C.

In addition, the filtrate was concentrated under reduced pressure and washed with methanol (Ia-
9) Obtain 103 mg.

Elemental analysis value (X) 'C+eHtJsOaFS theoretical value F C,56,85i H,4,02j N,1
0.47i F, 4.735, 7.99 Experimental values: C, 56,85; H, 4,07; N, 1
0.42i F, 5.11s, a, os NMR (CFsCOOH) (ppm) 3.13 (
2H, m), 3.63-4.05 (2B, m),
4.05 (38,s), 4.56-4.66 (2
H, m), 6.63 (IH.

dd), 7.22-7.73 (3L m), 8.
17 (IH, dd).

9.15 (IH, 5) -3-quinolinecarboxylic acid (I a-10) 1-thienyl-6,7-difluoro-4-year-old xo-3-quinolinecarboxylic acid (If -4) 14-0 mg, 3-hydroxy Iminopyrrolidine (III-7) 55 DMSOfl
ml and heated and stirred at 70°C for 2.5 hours. The reaction solution was concentrated under reduced pressure and washed with methanol to obtain the desired product (Ia-
10) After obtaining 173 mg, recrystallize from DMF to obtain 68 mg of crystals of the target product (Ia-10) having a decomposition point of 277-280°C.

Elemental analysis value (X)'C+mH+aNsOaFS theoretical value: C,55,81i 1(,3,64i N,1
0.85i F, 4.9O5,8,28 Experimental value: C, 55,56i H, 3,84; N, 1
0.90; F, 5.0O5,8,30 (blank space below) -5)13
9mg13-methoxyiminopyrrolidi■-5) 13-
9 mg, 3-methoxyiminopyrrolidine (I-8) 7
Dissolve 1 mg in 4 ml of DMSO and stir vigorously at 70° C. for 2 hours. After concentrating under reduced pressure, the mixture was washed with methanol to obtain 161 mg of crystals. If this is recrystallized from DMF, the target product (Ia-11) with a decomposition point of 290°C or higher is 91m
get g.

Elemental analysis value (%): C! @H,, Theoretical value as NIO&F: c, ao, ts; H, 4,54; N, 1
0.52; F, 4.76 Experimental value: C, 60,90;
u, a, s; N, 10.01i F, 4.64 (blank below) Tue JtL main ■ 1-(4-hydroxyphenyl)-6,7-difluoro 4-oxo 3-quinoline carbon #(π-5 )151
mg, 66 mg of 3-hydroxyiminopyrrolidine in DM
Dissolve in 6 ml of S0, stir at 70°C for 2 hours, concentrate under reduced pressure, wash with methanol, and obtain the desired product (Ia-1).
2) After obtaining 189 mg, recrystallization is performed from DMF to obtain 39 mg of (Ia-12) having a decomposition point of 290° C. or higher.

Elemental analysis value (X): Theoretical value as C*J+aNsOsF (・IH*O):
C,57,83: H,4,37i N,10.12
; F, 4.57 Experimental value: C, 58,27; H, 4
,47i N, 10.68i F, 4.64N M R
(CFnCOOH) ppm3.31 (2H, m)
, 3.90 (2H, m), 4.91 (2H, m
>6.53 (H, d), 7.28 (21, d),
7.42 (2H, d) 8.33 (IH, d),
9.10 (IH, s) (hereinafter referred to as the margin)
6) 134mg, 3-methoxyiminopyrrolidine 84m
Dissolve g in 2 ml of DMSO and heat and stir at 70°C for 2.5 hours. The precipitated crystals were collected by filtration and washed with methanol to obtain 112 mg of the target product (Ia-13).
Recrystallization is performed from the following to obtain 79 mg of the target product (Ia-13) having a decomposition point of 259-261°C.

Elemental analysis value (X) 'C*tHI@N5OJs as theoretical value F C,58,47+ )1.3.74i N,
9.74; F, 13.21 experimental value: C, 58, 54:
H, 3,71; N, 9.72; F, 13.23N
MR (d-DMSO) ppm3.08 (2B
, m), 3.79 (21, m), 4.13 (
3H, s) 4.53 (28, m), 6.33 (1
)1. d), 7.70-8.40 (4H, m),
9. Ll (IH, s) (hereinafter blank) 1-(2,4-difluorophenyl)-6,7-di upper μ
Yuri 1-(2,4-difluorophenyl)-6,7-difluoro-4-year-old xo-3-quinolinecarboxylic acid (W 6
) 116 mg, 3-hydroxyaminopyrrolidine (DI
-7) Dissolve 41mg in 04ml of DMS, 15 hours for 2 hours.
Heat and stir for 1 minute. After concentration with reduced EE, the residue is washed with acetone to obtain 99 mg of the target product (Ia-14). This is recrystallized from methanol to obtain 78 mg of the target product (Ia-14) having a decomposition point of 260-262°C.

Elemental analysis value (X): cm. Theoretical value as HIJsOJs: C, 57,56; H, 3,38F N, 10
．． 07+ F, 13.66 Experimental value: C, 57,33;
H, 3,46; N, 9. s9+ F, L3.82
NMR (d7DMso) ppm 3.05 (2H, m), 3.85 (2H, m),
4.47 (21, m)6.33 (tH, d),
7.20-8.42 (4H, m), 9.11 (L
H, s) (blank below) Large 11L1 3-quinoline carbon (Ia-151-cyclopropyl-6,7-difluoro-4-year-old xo 3-quinolone carbon fl (II-7) 107 mg, 3-methoxy Iminopyrrolidine (I[-6) 80mg in DMS03
ml, heated and stirred at 70"C for 2 hours. The precipitated crystals were collected by filtration and washed with methanol to obtain the desired product (Ia-1
5) Obtain 93 mg. Recrystallization is performed from DMF to obtain 62 mg of the target product (Ia-15) having a decomposition point of 278-280°C.

Elemental analysis value <%>'C = aHr 5NsoaF as theoretical value: C, 60, 16; H, 5, 05i N, 1
1.69i F, 5.29 Experimental values: c, so, zo;
H, 5,09; N, 11.73; F, 5.55I
R (Nujol) 1720.1618 (C=0
) cm-' (blank space below) oxo-3-quinolinecarvone I a-16) 1-
Cyclopropyl-6,7-cyclohydro-4-oxo-3-
48+ng of quinolinecarboxylic acid (II-7), 24mg of 3-hydroxyiminopyrrolidine (III-7) in DM
Heat and stir at 70'C with 2 ml of S0 for 2 hours. After concentration under reduced pressure, the residue was washed with methanol to obtain the target product (Ia
-16) Obtain 54 mg.

Recrystallization is performed from DMF to obtain 18 mg of the target product (Ia 1B) having a decomposition point of 290° C. or higher.

Elemental analysis value (X)? CI? H1@N,O,FtL,
-1: Theoretical value: C, 59,12; H, 4,67i
N, 12.17i F, 5.50 Experimental value: c, ss,
7s; H, 4,81; N, 12.09; F, 5.
48NMR (NaOD) ppm 1.36-1.76 (4H, m), 3.23 (2
1, m), 3.70 (IH.

m), 3.96 (2H, m), 4.60 (2H
, m), 7.16 (IH.

t), 7.95 (1)1. dd), 8.81
(1)1. s) (blank below) 1-ethyl-8,7,8-1-lifluoro-4-year-old xo-3-quinolinecarboxylic acid (If-8) 138 mg, 3-methoxy 70 mg of iminopyrrolidine and 02 ml of DMS are heated and stirred at 100° C. for 2 hours. After concentration under reduced pressure, the residue was washed with acetone to obtain the target product (Ia-17) 155
get. Recrystallization from acetic acid yields a decomposition point of 250-252.
Obtain 90 mg of the target product (Ia-17) at °C.

Elemental analysis value (X) ' C + tHttNaOaFm and theoretical value: C, 55, 89i H, 4, 69; N,
11.50; F, 10.40 Experimental values: c, ss, os
; H, 4,67; N, 11.44+ F, 10.4
7I R (Nujol) 1718.1622 (C
=o) am-' (blank below) 3-quinoline carbon (Ia-18) (g8)
.

1-ethyl-6,7,8-)lifluoro-4-oxo-
3-quinolinecarboxylic acid (It-8) 143”gs
69 mg of 3-hydroxyiminopyrrolidine was added to DMSO0
Dissolve in 4 ml and heat and stir at 70°C for 4 hours. g to obtain 137 mg of the target product (Ia-18). DM
Recrystallized from SO/methanol with decomposition point 24B-251
91 mg of the target product (I a -18) was obtained at .

Elemental analysis value (z) = C1, HI6N, 04F, theoretical value: C, 54,70; H, 4,30; N, 10
．． 63; F, 10.82 Experimental value: C, 54,60;
H, 4,36; N, 11.72; F, 10.76
I R (Nujol) 1720.1630 (C
=o) am-'NMR (NaOD> ppm 1.85 (3H, t), 3.15 (2H, m),
4.19 (2H, m) 4.69 (2H, q),
4.78 (2H, m>, 8.09 (IH, d)8
．． 74 (IL s) (blank below) υExample 19 Oxo-3-quinoline carbon I a-19>1-
cyclopropyl-6,7,8-trifluoro-1,4-
Dihydro-4-year-old xo-3-quinolinecarboxylic acid (I[
-1) 0.677 g, 3-benzyloxycarbonylamino-nopyrrolidine (I[[-7) 1.141 g, DMF25
DBUl. Add 0 36 g and stir at 100°C for 1 hour. The solvent is distilled off from the reaction solution under reduced pressure, and water is added to the residue to precipitate crystals. If the crystals are filtered and recrystallized from methanol, the melting point is 180-18.
Obtain 1,096 g of the desired product (Ia-19) at 2°C.

Elemental analysis value (X) 'C*iH*-N-OaF*ToshiY-Theoretical value: C. 58.36;H. 4.70: N
．． 10.89; F. 7.39 Experimental value: C, 58.3
1;H. 4.78; N. 10.75; F. 7.2
0I R (Nujol) 1630. 1705.
1720 cm” (blank below) b) 1-cyclopropyl-6,8-difluoro-
・Compound (Ia-19) obtained in Example L9(a) 54
Add 5 ml of 19% HBr/AcOH solution to 6 mg,
Stir for 30 minutes at room temperature. Acetic acid is distilled off from the reaction solution under reduced pressure, and the residue is dissolved in water and then neutralized with 28% aqueous ammonia. If the precipitated crystals are collected by filtration and recrystallized from DMSO-methanol, the target product (I
b-3) Obtain 175 mg.

Elemental analysis value (y,): C+J+J404F, theoretical value as 0.3H,0:
C, 52,93; H, 4,86; N, 14.52i
F, 9.85 Experimental value: C, 52,94; H, 4,
89; N, 14.38; F, 9.67I R (Nuj
ol) 1465.1620 cm" (blank space below) λ52 left ball test example (antibacterial spectrum) Antibacterial activity was measured by minimum inhibitory concentration according to the method specified by the Japanese Society of Chemotherapy. The results are shown in Table 1. .

In the table, A, B, C, and D represent the following meanings.

A: Staphylococcus aureus SM
ITH) B: Staphylococcus aureus 5R
77) C: Big! 11111 (Escherichia coli EC-14)D
:Escherichia coli 5R377(R
)) The concentration of the test microorganism used was 10B bacteria/ml.

Table 1 From the above, it was revealed that the compound of the present invention exhibits particularly strong anti-Gram-positive bacterial activity.

Patent applicant: Shionogi & Co., Ltd.

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R is halogen, R^1 is alkyl, cycloalkyl, optionally substituted phenyl or thienyl, R^
2 is hydrogen or alkyl, Q is -N= or -NH-,
X represents CH, N, CF or CCl, Y represents hydrogen, optionally protected amino or a substituent, m represents an integer of 3 to 7, and n represents 0, 1 or 2, respectively. However, Q is −N=
When , n is 0. ) or its salt. (2) An antibacterial agent containing the compound according to claim 1.