JPS6219594A - Cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [X is H or OH; Z is OH, (substituted)lower alkoxy, cycloalkyloxy or chain or cyclic amino] and its salt. EXAMPLE:Sodium 7beta-D-phenylglycylamido-3-methoxycarbonylmethyloxy-3-ceph em-4-carboxylate shown by the formula II. USE:An antibacterial agent for oral administration having high blood concentra tion (2-3 times as much as that of cephalexn). PREPARATION:For example, a compound shown by the formula III (Y is H, OH or protected OH; R<1> is amino-protecting group; R<2> is H or COOH protecting group) is reacted with a halogenoacetic acid derivative shown by the formula IV (W is halogen) to give a compound shown by the formula V. Then the sulfoxide group of the compound shown by the formula V is reduced and further deprotected to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel oral cephalosporin derivative,
More specifically, the present invention relates to oral cephalosporin derivatives having excellent antibacterial activity and non-toxic salts thereof.

BACKGROUND OF THE INVENTION Cephalosporins are widely used in the treatment and prevention of various infections caused by pathogenic bacteria.

Among these, oral cephalosporin agents, typified by cephalexin-7, are currently most widely used because they can be administered more easily than injectable cephalosporin agents.

However, the antibacterial activity and antibacterial spectrum of existing oral cephalosporin agents are significantly inferior to that of the injectable topical agent Allopolita, and the significant increase in resistant bacteria has recently become a problem. .

Against this background, there is a desire for the emergence of an oral cephalosporin agent that has better antibacterial activity, a broader antibacterial spectrum, and an effective blood concentration.

The inventors of the present invention have developed a novel method that has strong antibacterial activity and a broad antibacterial spectrum.
As a result of extensive research aimed at finding an oral heptafurosporin derivative that provides high blood concentrations, we found that it has superior antibacterial activity and antibacterial spectrum to cephalexin.
The inventors also discovered a cephalosporin derivative that exhibits a blood concentration 2 to 3 times that of cephalexin, and completed the present invention.

The present invention will be explained below.

The present invention is based on the general formula (1), (wherein,
Indicates a chloroalkyloxy group or a chain or cyclic amine group. ) and their non-toxic salts.

In the present invention, an unsubstituted lower alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methquine group, an ethoxy group, an n-propoxy group, and an inpropoxy group. , n-butoxy group, imbutquin group, pentyloxy group, and the like.

The lower alkoxy group having a substituent means an alkoxy group substituted with a phenyl group, a substituted phenyl group, a pyrrolidino group, or a piperidino group, such as a benzyloxy group, a nitrobenzyloxy group, a methoxybenzyloxy group,
-piperidinoethoxy group, 4-piperidinomethoxy group, etc.

A cycloalkyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group.

In addition, the chain or cyclic amine group refers to a monomethylamine group, a monoethylamino group, a dimethylamino group, a diethylamino group, a morpholino group, a pyrrolidino group, a piperidino group, etc., and these are substituted with a carboxyl group, etc. It's okay.

The non-toxic salt of the compound represented by the general formula (1) of the present invention means a pharmacologically acceptable salt, for example, an alkali metal salt such as sodium or potassium, an alkali salt such as calcium or magnesium Salts with inorganic bases such as earth metals, ammonia, triethylamine, cyclohexylamine,
Salts with organic bases and basic amino acids such as arginine and lysine, and sulfuric acid.

Salts with mineral acids such as hydrochloric acid and phosphoric acid, or acetic acid, lactic acid, tartaric acid,
Examples include salts with organic acids such as fumaric acid, maleic acid, trifluoroacetic acid, and methanesulfonic acid.

Furthermore, the compound of the present invention has D-form, 5-form and DL-form which are optical isomers resulting from the asymmetric carbon atom in the 7-position side chain, and the present invention encompasses all of them.

The compound (r) of the present invention can be obtained, for example, by the following production method.

Compounds represented by general formula (II) (wherein, Y represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, R1 represents a protecting group for an amine group, and R2 represents a hydrogen atom or a protective group for a carboxyl group) and general formula (II) W-CH2-C-Z
('') (in the formula, W represents a halogen atom, and 2 has the same meaning as above) is reacted to form a derivative of the general formula (IV) (in the formula, Y, Z , R1 and R2 have the same meanings as above).

Subsequently, the sulfokide group of compound (IV) is reduced by a conventional method, and the protecting group is removed by a method frequently used in the field of β-lactam chemistry to obtain the compound (1) of the present invention. is obtained.

The protected hydroxyl group represented by Y in the above general formulas (II) and (IV) means a hydroxyl group protected with a benzyl group, paramethoxypenzyl group, varanitrobenzyl group, or tetrahydropyranyl group, The protecting group for the amine group represented by R1 is t-butoxycarbonyl group, halamethoxybenzylox7carbonyl group, 2,2,2-t')
It means a chloroethoxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a trityl group, a phthaloyl group, etc. The carboxyl protecting group represented by R2 includes a benzhydryl group, a hensyl group, a paranitrobenzyl group,
It means those frequently used in the field of β-lactam chemistry, such as para-methoxybenzyl group, 2,2,2-tri1chloroethyl group, and trimethylsilyl group.

Compound (IV) can be produced from compound (II) and compound ([[) under the following reaction conditions.

That is, compound (If) is dissolved in an organic solvent that does not participate in the reaction, and compound ('III) is dissolved in 1. in the presence of a base.
Add 0 to 2.5 equivalents. Reaction temperature is -20℃~100℃
Although it can be carried out at a temperature of 0°C to 60°C, it is usually suitable. The reaction time is 0.5 to 40 hours, preferably 4 to 20 hours. Suitable solvents include NlN-
Dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide.

Examples include hexamethylphosphoric triamide, tetrahydrofuran, acetonitrile, dioxane, and the like.

Preferred bases include organic bases such as diisopropylethylamine, triethylamine, dimethylaminopyridine, and dimethylaniline, and the optimum amount used is 0.9 to 2.5 equivalents.

The reaction conditions for obtaining the compound (1) of the present invention from the compound (F/) may be those commonly used in the field of β-lactam chemistry. For example, the reduction of the sulfoxide of the compound (IV) is performed using N, It can be carried out under conditions using phosphorus tribromide in N-dimethylformamide.

Moreover, the removal of the protecting group can be carried out under conditions such as trifluoroacetic acid-anisole, zinc-acetic acid or catalytic reduction.

When the compounds of this invention are administered orally, conventional bulking agents,
It can be used by making it into oral preparations such as tablets, capsules, and granules by using additives such as binders, disintegrants, excipients, pH regulators, and solubilizers.

Effects of the Invention The compound of the present invention does not exhibit strong antibacterial activity equivalent to or stronger than cephalexin, a commercially available oral cephalosporin agent, and its blood concentration is 2 to 3 times higher than that of cephalexin. It showed good oral absorption.

The compounds obtained in Example 4 and Example 5 are listed below as typical examples.1. The results of a test comparing the minimum inhibitory concentration (MIC value) against various bacteria and maintenance of blood concentration during oral administration with cephalexin are shown.

Test Example 1 Antibacterial tests against Staphylococcus aureus and Escherichia coli were conducted using the agar plate dilution method (inoculum amount: 106 cells/d).
), the results shown in Table 1 below were obtained.

Table 1 MIC value (pg/mt) Test Example 2 Changes in blood concentration over time by oral administration to male Wistar rats (7 weeks old) were investigated.

Drug dosage: 50■/K9 Quantitative method: bioassay method (Test bacteria 2 E. coli 5C507) The results are shown in Table 2.

Table 2 Blood Concentration (μg/-) Examples Next, the present invention will be explained in more detail with reference to Examples, but they are not intended to limit the present invention. 4xycarbonyl group.

Bh represents a benzhydryl group, and PMB represents a p-methoxybenzyl group).

Example 1 o2Bh door β-(N-(t-)carbonyl)-D-phenylclinolamide]-3-(1-methyltetrazol-5-yl-thiomethyl)-3=cephem-4- Carboxylic acid benzhydryl ester-1-oxide 7.2
9 (9,69mM) of N.

Ammonium chloride 1.305 ? in N-dimethylformamide 51- solution? (24.4mM) and water were added and stirred for 40 minutes to dissolve ammonium chloride. This was cooled to -10°C, and zinc powder 1.9
Add 059 (29.1mM) and incubate at -5°C to 0°C.
Stir for hours. After the reaction, the zinc dust was removed several times, the lachrymal fluid was extracted with ethyl acetate (200ml), and the ethyl acetate layer was washed with saturated saline (10mg x 2) and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (benzene:acetone=10
: 1 to 8:1) and 7β-(N-(t-but*≠xycarbonyl)
-D-phenylcridylamin)')-3-diquinomethylene cepham 4-carboxylic acid benzhydryl ester-
1-Oxide was 5.1f4.

m, p, 201-205℃ (decomposition) Engineering Rv,,”,”r,cm’: 3320, 2
960.1780.173 Shiro 60.1490°11
6O NMR (CDCl2) δ (ppm); 1.42 (9H
18), 3.32 (IH, d, J=j4Hz).

3.70 (IH, d, J = 14Hz), 4.71 (IH
, d, J=4Hz).

526 (1u, a, J==sHz), 5.36 (IH
, 8).

5.43 (IH, be), 568 (IH, d, J=5H
z).

5.82 (IH, s), 5.88 (IH, dd, J-1
0Hz, 4Hz).

6.85 (IH, s), 7.20-7.46 (15H,
m).

7.78 (IH, d, J = 10 Hz) Cb) 7β-(N-(t-carbonyl)-D-7enylgly/ruami)",) -3- Exomethylene cepham-4-carboxylic acid benzhydryl ester-1-oxide 4.35P (6,92mM
) was dissolved in a mixture of 150 ml of acetonitrile and 2.1 ml of acetic acid, cooled to -30°C, and ozone was introduced over a period of about 1 hour until the reaction solution turned blue.

Next, excess ozone was removed with nitrogen gas, dimethyl sulfide 3- was added at the same temperature, and the temperature was raised to 10°C over 1 hour. Extracted with. The ethyl acetate layer was washed with saturated brine (100 d) and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (benzene:acetone=8:1-5:
1) 7β-[N-(t-butyl-mixicarbonyl)
3.39 Pint of -3-hydroxy-3-cephem-4-carboxylic acid benzhydryl ester-1-oxide.

Engineering RνKBr −+ ・ max '''' ・ 3440.2960.1785.1665~1690°1490.116O NMR (CDC43) δ (ppm); 1.44 (9H, bs), 3.34 (IH, d, J ==
18Hz).

366 (IH, d, J = 18H2), 4.49 (IH,
d, J=5Hz).

5.20 (IH, d,, r=5H2) 15.63 (IH
, d, J=5Hz).

5.98 (IH, da, J=10Hz, 5Hz).

6.92 (IH, s), 7.22-7.66 (16H,
m).

11.64 (IH, bs) (C) Door β-(N-(t-)≠-φoxycarbonyl)-D
-Phenylglycylamide 6-hydroxy-3-cephem-4-carboxylic acid benzhydryl ester-1-
To a solution of oxide 535W (0.85mM) in anhydrous dimethyl sulfoxide 6, were added bromoacetic acid methyl ester 156cm (1.7mM) and tosiisopropylethylamine 165cm (1,287FIM), and the mixture was stirred at room temperature for 4 hours. The mixture was extracted with ethyl acetate (50me), and the ethyl acetate layer was washed with saturated brine (3-Oix3) and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to 7 silica gel column chromatography (benzene:
7β-(N-(t-booxycarbonyl)-D-phenylglycylamido)-5-methoxycarbonylmethyloxy-3-cephem-4 -Carboxylic acid benzhydryl ester--1-oxide 2
I got 40 mf.

m, p, 1138-190℃ (decomposition) (recrystallization from methanol-chloroform)
cm-'; max 3370.2960, 1785.1680~1720
.

1490.1165 NMR (CDCl2) δ (ppm); t42 (9H, bs), 3.34 (IH, d, J==1
9Hz).

3.66 (5H, s), 3.78 (IH, d, J=19
Hz).

4.35 (IH, d, , T=16Hz).

4.42 (1H, a, J=sHz).

4.49 (IH, d, , T = 16H2).

5.19 (IH, d, J=6Hz), 5.70 (IH,
d, J=6Hz).

5.96 (IH, ad, J=9H2,5H2), 6.9
3 (IH, S).

7.2CI-744 (15H, m).

748 (IH, d, J = 9Hz) (d) Door β-(N-(t-butene; beef 7carponyl)-D-phenylglycylamidocou 3-methquincarbonylmethyloxy-3-cephem- 4-Carboxylic acid benzhydryl ester-1-oquinodo 240'rllf (0,
34mM) of anhydrous N,N-dimethylformamide 3
- Add 93μ (0.34mM) of phosphorus tribromide to the solution under water cooling.
was added and stirred for 50 minutes. After extraction with ethyl acetate (50-), the ethyl acetate layer was washed with saturated brine (30m7!X3) and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography to obtain 163 quartz of benzhydryl ester of benzeneniacerglycylamide-3-methoxycarbonylmethyloxy-6-cephem-4-carboxylic acid.

Engineering RνKBrcm-'; aX 3200~'5400, 1775.1670~1720
゜1490.116O NMR (CDC43) δ (ppm); 1.41 (9
a, s), 3.23 (2H, bs).

3.70 (3H, S), 4.39 (IH, d,, T=1
6Hz).

4.49 (IH, d, J=16Hz).

4.97 (IH, d, J=5Hz), 5.23 (+H
, a, J=9Hz).

5.67 (+H, dd, J = 9Hz, 5Hz).

5.70 (IH, a, J = 5H2), 5.79 (II (
, a, J=51Th).

5.91 (IH, 8), 7.25-7.48 (1
5H, m) Trifluoroacetic acid 2.5- and anisole 0
．． 57! 7β-(N-(t-Boo-oxycarbonyl)-D-phenylglycylamidocou-5-methoxy/carbonylmethyloxy-6-cephem-4-carboxylic acid benzhydryl resteryl 16 omy(0,23
) was added and stirred for 60 minutes. The reaction mixture was slowly added dropwise to a mixture of ether and n-hexane (1:2.30), and trifluoroacetate (white crystals) was precipitated, yielding 120 μl (0.22 mM). Next, after dissolving these crystals and 40 μm (0.47 mM) of sodium hydrogen carbonate in 4 μl of water, the solution was subjected to Cefazo, Cus LH-20 columnarography (water), and the eluate was freeze-dried.
90 quarts of sodium salt of β-D-phenylglycylamide-3-methoxycarbonylmethyloxy-3-cephem-4-carboxylic acid was obtained.

Br IRv cm-': ax 3200~3400, 1755, 1595° 1650~
1365 NMR (D20) δ (ppm); 3.23 (IH, d, T = 17Hz), 3.56
(IH, d, J=17H2).

3.78 (3H, s), 4.56 (IH, d, J=17
H2).

4.66 (IH, d, , T = 17Hz), 5.07 (I
H, dj = 5Hz).

5.59 (IH, d, J=5Hz), 7.48-7.5
6 (5H, m).

Based on the operation and reaction conditions disclosed in Example 1 above, the compounds exemplified below were produced. (Table 3) Table 3 Table 5 (continued) Example 4 (a) 02Bh 7β-(4-(4-methoxybenzyl)oxy, t-N-(t-fu-ioxycarbonyl)-D-phenyl glycylamide)-3-(1-methyltetrazole-5
-yl-thiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester-1-oxide 14.342
(16.5mM) in tetrahydrofuran 94.5d
and N,N-dimethylborumamide 273-dissolved in a mixture of zinc powder 11. /+1 Zinc dust was removed by several times, the filtrate was neutralized with sodium bicarbonate powder, and ethyl acetate (5
00m/). The ethyl acetate layer was diluted with saturated brine (1
50dX2) and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (CHCl3:MeOH=200
: 1 to 150 : 1) and 7β-(4-(4
-methoxybenzyl)odokin-N-(t-p≠==ki7-benzyl)-D-phenylglycylamide]-6-exomethylene cepham-
9342 of 4-carboxylic acid benzhydryl ester-1-oxide was obtained.

m, p, 104-108℃
ct3) δ (ppm); 1.42 (9H, S), 3.32 (IH, d, J = 14
H2).

3,66 (I H, d T J = 14 Hz)
+3.80 (3H, s).

t72 (1H, d, J=saz), t96 (2a, s)
.

5.14 (IH, d, J = 5H2), 5.34 (IH,
8).

5.43 (IH, bs), 5.56 (IH, d, J: 5
H2).

5.81 (IH, s), 5.86 (IH, dd, J
==10Hz, 5&).

6.86 (2H, d, J=8Hz), 6.92 (IH,
s).

6.94 (2H, d, J=8Hz), 7.22-7.
38 (14H, m).

7.63 (IH, d, J = 10H2) C○2Bh 7β-(4-(4-methoxybenzyl)oxide-N-(t-boomy-dicarbonyl)-D-phenylcrysylamide co-3-exomethylene Cepham-4-
Carboxylic acid benzhydryl ester-1-oxide 5
f (6,35mM) in dichloromethane 600-
and methanol 1.24- dissolved in a mixture of -30℃
Ozone was introduced for about 30 minutes until the reaction solution turned blue. Next, excess ozone was removed with thiazine gas, dimethyl sulfide 4- was added at the same temperature, and the mixture was heated for 1 hour.
It was raised to ℃. The reaction solution was concentrated to half volume using an evaporator, washed with saturated brine (200 mJ), and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (benzene:acetone=
10:1 to 1:1) to give 7β-[4-(4-methoxybenzyl)oxy-N-(t-dobu mixicarbonyl)-D-phenylculinylamide]-3-hydroxy-3- 5852 pieces of cephem-4-carboxylic acid benzhydryl ester-1-oxide were obtained.

Engineering RvKBr, -1; ax 3350.2950, 1785.1650 ~ 1720° 1610.1490.1235 NMR (CDC43) δ (ppm); 1.46 (9
H, 8)tA36(IHldd, J=18H2,2H2
).

3.69 (IH, d, J = 18Hz), 3.82 (3
H,s).

4.50 (jH, dd, J=5H2, 2Hz).

5.00 (2H, s), 5.14 (IH, d, J=5H
z).

5.49 (IH, d,, r=5H2).

6.01 (IH, dd, J=10H2, 5H2).

6.92 (IH, s), 6.93 (2H, d, J=9
Hz).

6.99 (2H, d, J=9Hz), 7.28-7.4
8 (14H, m).

7.63 (IH, d, J = 10 Hz) (c) n 7β-(a-(4-methoxybenzyl)oxide-N-(t-bu≠=#ki/carbonyl)-D-phenylcrysylamidecou 3-hydroxy-3-cephem-4
-Carboxylic acid benzhydryl ester-1-oquinodo
4.37? Bromoacetic acid ethyl ester 1 in anhydrous dimethyl sulfoxide 7-(5,70mM) solution
．． 90? (11.4mM) and diinopropylethylamine (8.54mM) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate (150me).
The ethyl acetate layer was extracted with saturated brine (1oo7!x3
) and dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (
benzene:acetone=:30:1~7:1), 7
β-[4-(4-Methoquinobenzyl)oxy-N-(wo-bu≠grave #quinocarbonyl)-D-phenylcrysylamide-3-ethoxycarbonylmethyloxy-3-cephemu 4-carboxylic acid benzhydrin ester-1-
1.7 q y'4 of oxide.

m, p, 206-208℃ (decomposition) (recrystallization from methanol-chloroform) Engineering Rv KB
rcm-': ax 3280. 1780.1690~1710°1655
．． 1500.1220-1240°116 O NMR (cDct,) δ (ppm); 1.23 (3H
, t, J=7Hz), 1.43(9H,s).

3.40 (1H, d, J=18Hz), 182 (3H,
s).

583(II(, d, J=18I(Z).

a, 16 (2a, q, J=7az).

4.36 (IH, d, J: 17Hz).

4.46 (IH, d, J+ = 4Hz).

4.51 (IH, d, J=17H2).

4.99 (2H, s ), 5.13 (IH, cl, J =
6Hz)”.

5.53 (IHla, J=6Hz).

6.00 (IH, dd, J=10Hz, 4-Hz).

6.92 (2H, d, J=8Hz), 6.95 (IH,
s).

6.98 (2H, d, J=8Hz).

Z3o ~ Zso (1sa, m) (d) 02Bh 7β-(4-(4-methoxybenzyl)oxide-N-(t-potato=≠xycarbonyl)-D-7enylgly/lamide]-3-ethoxycarbonyl To a 15-solution of methyloxy-3-cephem-4-carboxylic acid benzhydryl ester-1-oxide (2,1 mM) in anhydrous 1'LN-dimethylformamide was added 568 μm of phosphorus tribromide (2,1 mmol) on water-cooling. 1??IM) and 3
Stirred for 0 minutes. The mixture was extracted with ethyl acetate (150-), and the ethyl acetate layer was washed with saturated brine (100-x3) and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (benzene:acet/=sa:1-25:1) to obtain 7β-(4-(4
t I got 15 f.

Br Engineering Rν sub-1; ax 1690-1720, . 1510 'A' 17 D
.

NMR (CDCl3) δ (ppm); 1.24 (
3H,t, J=7Hz), 1.42(9H,s).

3.26 (IH, d, J=16Hz).

3.40 (IH, d, J = 16Hz), 3.82 (3H
,s).

4.18 (2H, q, Jl Near H2), 4.46 (
2H,'s).

4.98 (2H, s), 4.99 (IH, d, J=5H
z).

668 (IH, dd, J=9Hz, 5Hz).

6.92 (2H, a, y-=9Hz), 6.93 (1H
,s).

6.1 (2H, a, J=aHz).

7.30-7.50 (14H, m).

(e) Mixed diyl of trifluoroacetic acid 15 and anisole 3)oxy-N-(t-butyloxycarbonyl)-D-phenylglycylamide)-3-ethoxy/carbonylmethyloxy-6-cephem -4-Carboxylic acid benzhydryl ester≠tlsr (1,55mM) was added and stirred for 50 minutes. The reaction solution was mixed with ether and n-hexane (1:2゜12
0rnI! , ) was slowly added dropwise, and 7111 nq of precipitated trifluoroacetate crystals were collected.

Next, this crystal and sodium hydrogen carbonate 227■ (2,6
cefazo after dissolving 10 mM) in water.

7β-4-hydroxy-D-phenylglyfuramido-3-ethoquinocarbonylmethyloquino-6-cephem-4-carboxylic acid was subjected to column chromatography (water) on LH-20, and the eluate was lyophilized to obtain 7β-4-hydroxy-D-phenylglyfuramido-3-ethoquinocarbonylmethyloquino-6-cephem-4-carboxylic acid. 350 μ of the sodium salt of was obtained.

I R'LI KB"cm-": ax 3340~5400.+750.1670°1590~
1610,1505.120ONMR(D20)δ(p
pm); 1.27 (3H, t, J=7Hz), 4.
26 (2H,q, J=7H2).

3.27(1) (, d, J=17Hz).

! L56 (IH, d, J=17Hz).

4.56 (IH, d, J=16Hz).

4.67 (IH, d, J=16Hz), 5.06 (I
H, d, J=5)Lz).

5.54 (IH, d, , T = 5H2), 6.91 (
2H, d, J = 9Hz).

7.43 (2H, d, J=9Hz).

In accordance with the operating and reaction conditions disclosed in Example 4 above,
The compounds illustrated below were produced.

(Table 4) Table 4 02Na Table 4 (continued) Table 4 (continued) Table 4 (continued) Table 4 (continued)

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, or a cyclic amino group) and non-toxic salts thereof.