JPS58154589A - Cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:A cephalosporin derivative of formulaI X is CNCH2SCH2-, group of formula II (R1 is lower alkyl), formula III; Y is H, lower alkoxy; Z is H, lower alkyl, group of formula IV; W is O, imino; R2 is hydroxyl, lower alkoxy; R2 is H, phenyl . EXAMPLE:4'-Glycylamino-2-oxy-benzoic methyl-(6R,7S)-7- 2-(cyanomethylthio)- acetamide -7-methoxy-3- ( 1-methyl-1H-tetrazol-5-yl )thio methyl -3-cephem-4- carboxylic acid hydrochloride. USE:An antibacterial that can be given orally and is excellent in keeping its concentration in blood for hours. PREPARATION:For example, the reaction of a compound of formula V or its reactive derivative with a compound of formula VI (A is group or atom reactive with carboxylic acid; R4 is H, protecting group) gives the compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (however, kr Fi is a low-alkyl alkyl group and JiIF is not included); i, R, is a hydroxyl group or a lower alkoxy group; ks Fi is a water-bulky polymer or a substituent-optionally substituted Fe2A/group; Tamedakasio FC@Shiru.

-tNoarosborins generally have poor absorption from the gastrointestinal tract and are administered by injection.

Considering this situation, the users of this book went to the Hinoki Kenshiki Kuraho in order to get some rest from the oral administration 4-healing Seven-F Rosvorin #4# general formula (in the formula, R, 13 and %11tf6i1doden 1ft
) We succeeded in creating the th standard calfone M which can be treated with TjE, and also succeeded in creating a conductor (IVI4rn+, which has the function of cepheme product in the order of t phalosborin, by converting the refoxyl group into The new charcoal cephalosporin blocker is a long-lasting product.The cephalosporin rays in the body have excellent absorbability from the digestive tract, and when inhaled, T7M is easily absorbed by in vivo enzymes. The ester moiety of the substituent at the 4-position is hydrolyzed to form a 4(I
Compounds in which Z is a free carboquine group) are converted into K, that is, by oral administration in the cephalosporin #s4 body, a high blood chain degree of the non-ester form with excellent anti-activity can be obtained. , Moreover, this high blood agitation persists for a long time. Furthermore, by forming the cephalosporin enzyme into its acid addition salt, the absorption efficiency is improved, and at the same time, the stability of the cephalosporin ta conductor is improved. They discovered that the invention could be easily synthesized, isolated, and formulated for oral administration, leading to a complete defeat of the invention.

Throughout this specification, lower class a! A Lechire group has 1 or more carbon atoms.
4, specifically methyl, ethyl, n-propyl, 1so-propyl, n-
Buchi I, 1so-7chi? and tert-glutyl are listed. The most preferred among such lower alkyl groups is methyl. In addition, a lower alkoxy group refers to a carbon number of 1 to 4.
I! It refers to L-shaped and branched ones, specifically methoxy, ethoxy, n-□ globoxy, 1so-globoxy, and n-gutoxy.

1so-Gutoki 7, Lert-7) Chrysanthemums are listed.

As such lower alkoxy group, methoxy is preferable.

- t = 77o sphorin # conductor (IJ fl, it is likely that the amino group forms a late addition salt, and the acid for forming such an acid addition salt 1- is formed with an amine group and a pigeon). There is no particular restriction as long as it is an acid that can be obtained and medicinally tolerated. Examples of such acids include hydrochloric acid, phosphoric acid, mineral acids such as 614#, and oxalic acid.

Humare translation, maleic acid, citric acid, tartaric acid, mekunsulehon! l! ,) oals such as luenesulfonic acid -
14< will be done.

Cephalosporin v5 (oxyimino &
In the oxidized portion of the monomer which has 44, there are geometric isomers of Shin-Nashi and Ike-Anti, and it is preferable to use Shin-Nashi in the present invention.

Among the cephalosborin product conductors (1), those with aminothiazole kji, aminethiazole neutral
the! The existence of the L-friendly isomer as an iminothian phosphorus compound is also known, or the form in which it occurs is derived from this book l#, l4, i'
Needless to say, among the cephalosporin disruptors (1), α-oxybenzi!
It is preferable that the asymmetric carbon at the α-position of a compound having a group is 0.

A cephalosporin body can be produced, for example, by the following method. Also, the general formula (in the formula, x, y, zr;
Takashi Wai! compound or its t51Ji5 #S conductor and the general formula (where W, R□ and Rs are 1 and t01
It is false, AFi force r Lebon shaman and reactive group may be friends, R4t'i water chart original atom t is protecting group Mugiwa °r, l
) is produced by reacting the compound represented by K with ib.

General formula UIV) AK# in K! Examples of the group or system f reactive with ML, carboxylic acid, include halogen f, H5(h-(&&, Brt low d 71L/4
The 7L/ group and the box ^ represent substituted allyl Jk. ) etc. can be opened. Preferred examples of the di-converted groups include p-tri-I and the like. In addition, the above halogen source f
Specifically, chlor, brome, and iodine can be used. Also, it is a must for Hajime Hokuma who gets defeated in R6! IK
Depending on the situation, the amine group may be restored as long as it can be restored to the original amine group. , chloroacetyl group, trithiyl group, etc.

In addition, in Futan Jb, if X in compound 0 is an amino group, the amine group is also lI
It is better to keep it safe with the same one as in Book J.

Compound 1m(1) may be subjected to the reaction as it is, but it is preferable to react it after converting it into a warped brocade.

Compounds (button-containing compounds), which are bLb compound in the I levoxy group and are commonly used in esterification reactions, are exemplified.・Sex-
The calyx is a light, like thorium. Jl & 41 with Calirum Nato and Alkali Metal Nato! ．． ) ethylamine.
Organic salts with organic amines such as dicyclohexylamine are used.

The reaction between the salt of the compound (Otori) and the compound (2) is preferably carried out under cooling in order to avoid the lifetime of the Δ1-isomer.

The reaction consists of dimethylformamide, dimethylacetamide, hexamethyldriamide phosphate, acetone,
The reaction can be easily carried out in the presence of am, which does not inhibit reactions such as acetonitrile. After the esterification reaction, the cephalosporin (1) is preserved by removing the protective group from the amine group by a method known per se, depending on the rearrangement.

Compound (g) is produced, for example, as follows.

(Left below) (In the formula, all and R are reddish colors as above) 1 When compound (V) is an ester, the hydrolysis pII is used (in the formula, W.R, , R, and The details of steps 1 and 2 are as follows.

[Step 1]

Examples of reactive derivatives of compound 11 (Vl) include salts of sodium, potassium, tritylamine, etc., acid halides (acid chlorides, etc.), acid anhydrides, mixed acid anhydrides [alkyl carbonates (monoethyl carbonates, etc.), etc.], Active amide (
Examples include amides with imidazole, etc., and esters (cyanomethyl esters, etc.).

When compound (Vl) is used in the form of a free acid or salt, it is preferable to use a suitable condensing agent, such as N, N'- such as N, N'-dicyclohexylcarbodiimide Disubstituted carbodiimide, %1
4, N, N' - Lebeau imidazole, N, f'
The Q reaction in which a dehydrating agent such as an azolide compound such as l'-naonyldiimidazole is used is usually carried out in an inert #I medium. Specific examples of the solvent include organic solvents such as water, acetone, dioxane, acetonitrile, chloroform, benzene, ethylene chloride, ethylene chloride, tetrahydrofura, and pyridine, and mixtures thereof.

This reaction is preferably carried out at room temperature or under cooling (-20°C to θ
℃).

The hydrolysis treatment of the ester form of compound (V) may be carried out by means known per se.

[Step 2] This reaction is preferably carried out under cooling in order to avoid the production of the Δ8-isomer as a by-product.

Further, the reaction can be easily carried out in the presence of a solvent that does not inhibit the reaction, such as dimethylformamide, dimethylacetamide, hexamenaltria ξ-dophosphate, acetone, acetonitrile, methylene chloride, and benzene.

(Left below) Cephalosporin-conductor (1) U can be made into its acid addition salt by a method known per se.

Pharosvorin fermentation compound (1) and its acid addition salt are:
It can be isolated and purified according to conventional methods.

By diluting the 9M cephalosporin conductor or the forging process thereof with a pharmaceutical excipient according to a method known per se, a micro-infectious disease therapeutic agent for oral administration is prepared.
-Can be intense. Dilution is carried out by means known per se, such as mixing. Examples of excipients include starch. Lactose, sand.

Calcium carbonate, phosphorus power! One example is the Rhesium fly.

Upper IE! The anti-infectious disease agent may further contain other additives, if desired, such as binders (e.g., denone, etc.).
gum arabic, calhoki dimethyl cellulose, hydroxypropyl cellulose, crystalline cerelace, etc.), lubricants (e.g., magnesium stearin, kurukunato), oxidation agents (e.g. calhoquine dimethyl cellulose, hydroxypropyl cellulose, crystalline cerelace, etc.); ) are listed as preferred additives. t
After mixing the mixture, the mixture is formulated into dosage forms suitable for oral administration, such as capsules, powders, fine granules, granules, dry syrup, etc., according to methods known per se.

When the above-mentioned infectious disease treatment agent is orally administered, the active ingredient, cephalosporin derivative (1) or its salt, is rapidly absorbed from the gastrointestinal tract, and immediately hydrolyzed by enzymes in the body after absorption. It is converted into the corresponding non-esterified form or its acid addition salt.

By the way, this non-ester form and its salt have excellent antibacterial activity, and Staphylococcus aureus (5tiphylococcus 5lur-
Klebsiella pneumonia containing Escberichia coli (Klebsiella pneumonia)
oniie L Prote 9 tatami Vulgaris (Prote
us vulgaris)% Proteus mirabilis, Proteus morganii
It has excellent anti-activity against gram-based anti-inflammatory drugs such as phthalate. In addition, the non-esterified form and its salt Fi are of low toxicity.

Therefore, the thin plane infection of the present invention! IE/8 contaminants include, for example, food preparations containing humans (dogs, cats, cows, horses, rats.

It can be used as a therapeutic agent for diseases caused by microscopic diseases of mice (e.g., purulent spasms, absorptive tract infections, biliary tract infections, urinary tract infections, etc.).

The administration of cephalosporin A4 (1) and its acid addition salts may differ depending on the subject of administration, symptoms, etc. For example, when administering to an adult with purulent disease, the dosage of cephalosporin In terms of the corresponding non-ester form,
For example, about 1 to 20 ~ / IiL per day, about 8
Administer orally about 4 times.

(Left below) Reference Example 1 4-(N-notoxycarphoniaglycyl)ami/
-Synthesis of 2-oxybenzoic acid (reaction A) Synthesis of methyl 4-(Nt-7toxycarbonylglycyl)amino-2-ox7benzoate N-t-butoxycarbonyl-glycine 15F in methylene chloride 160 - to 1
74%, dicyclohexyl carbonimide 17.67
f and p-aminosalicyl methyl ester 14.81
ft-added and stirred simultaneously at θ-6'C, then Wa
Leave it in X overnight.

Thereafter, methylene chloride was removed under reduced pressure, and ethyl acetate was added to the residue to remove unbaked substances. Fluid F with saturated hydrogen carbonate)
Wash sequentially with IJum ssb Japanese saline solution and dry with Glauber's salt. Thereafter, ethyl acetate is concentrated under reduced pressure and ethyl ether is added to obtain the title compound 189 (yield 468%).

1, R(Nujol, ('1m-'): 88
60, 81300, 16801610.1596 NMR ((C1)@LCO+PI)m)! 1
42 (s, 9H, CH, x8) 888 (d, J-6,5Hz, 2H, -(,:mu1
．． -)8.9 (1(s, 8H, -C)i3)5
．． 9O-640 (br, 1)1. -NH-)? ,07
(dXd, J=8.5.8.0Hz, IH,
Hc”) 7.88 (d, J = 8.0Hz,
IH, Ha rice) 7.71 (d, J-8, 5Hz, IH,
Hc town 9.40 (bs, lh, -NH-) 1075 (s, IH, -0H) (reaction b) 4-(N-L-1 toxycarbonylreuglycyl)'r
Synthesis of minnow 2-oxygynozoic acid - Compound borrowed from Ame A 8.5f, sodium hydroxide 0.96ft-/X 10
- In addition, stir at 60'C for 1.6 hours. that bond,
The reaction mixture was diluted twice with σ ethyl chloride, made acidic with a phosphoric acid bath, and then used once with enoic acid. The first chilled layer was dried with fc#L in salt water and dried with sodium chloride. The jar was filled with a lot of heat under reduced pressure.
The title compound 2 t (yield: 601 s) is obtained by treating the residue with ether.

Nujol (m'): 8B80.
168G, 160ONMR ((CD, ) t SO,
ppm): 1.4! (s,9H,CH,x8)
8.86 (d, J = 6.6) 1 wealth, 2H, -C) i,
-) 7.09 (dXd, J=8.6.8.0Hz, IH
, Hb") 7.89 (d, J=8.0Hz, IH, Ha
”)7-78(d,J-8,6Hz,1)1.Hc”
)600-8.00(br,8H,-NH+,-0)1
, -()048)9,86 (bs, IH, -N
) 1-) Reference Example 2 Synthesis of 4-(N-t-butoxycarbonyl-glycyl)amino-2-methoxybenzoic acid (IX Me A) 4-(N-1-7toxycarbonyl-glycyl)amino-2 - Combination of ethyl methoxybenzoate and potassium hydroxide 1
．． 1f was heated and dissolved in anhydrous inglobil alcohol 25-, the compound of reaction A of Reference Example 1, 189'tlt, and water inpropyl alcohol-I was heated to 50 wj. . 9 crystals obtained by handling V, washing with black water inglobil alcohol and then ethyl acetate, 5°26? and 2.97 t of methyl p-toluenesulfonate in anhydrous dimethylformamide 4
0- and stirred at 50-60°C for 2 hours. Thereafter, ethyl butyrate was added to the reaction bath liquid, and the mixture was thoroughly washed with a 2N sodium hydroxide solution and then with saturated saline, and dried over Glauber's salt. Ethyl acetate was removed under reduced pressure and the residue was crystallized from inpropyl ether to yield the title compound 8.4.
5t (yield 70s) is obtained.

1R (Nujol, cI11'): 84g0.88
80.1720°1700.1675.160O NmN((CDhC'J, 9pm)' 1.42(s, 9H, CH, X8) 176(s, 8H, -OCH,) 8,'l(s, ilH, -CHg)8.92 (d
, J-6,5)1g, 2H, -CHg-)6
．． 00-6.46 (br, IH, -NB-)7.11
1(dxd, J-8,6,8,0Hz, 1B,
Wbmine) 7.66 (d, J=8.0Hz, 11
．． 8a) 7.69 (d, J=8.5Hz, 1) 1
．． Hc') 9.86 (bs, 18.-Nu-) 4-(Nt-7toxycarponylglycyl)amino-2-methoxyrii: Synthesis of J# acid, water 6-, methyl alcohol 6 mO 1.98 of the compound of fi6A in the solution
f & sodium hydroxide 0.28 f Jl, 60
Stir 2I#- at ~60°C. After that, I added methyl alcohol to sardines, added ethyl acetate to the enemy, and turned the original into 6-Quen 4! Extract with EK L and ethyl acetate. ) Thoroughly wash with mw% & salt water, dry with Glauber's salt, and remove ethyl acetate under reduced pressure. The residue was crystallized from isopropyl ether to give the title compound 1.66
f (yield 86.7%).

IR (Nujol, ffi'): 8B70.17
2G, 1680°605 NMM ((CDs)! SO, ppm)'
1.42 (s, 9H, CH, X8) 8.85 (d, J-6, 6Hz, 2H, -CI, -) 8
．． 87 (s, 8H, -OCH,) 6.20-6.70 (br, 2H, -NH-, -
CO, H) 7.18 (dXd, J-8,5,8,0Hz
, '18. Hb') 7.69 (d, J-8,0Hz, l
H, Ha')7.75 (d, J=8.5Hz, lH,
Hc'' ) 9.89 (bs, th, -NH-) Reference Example 8 Synthesis of 4-(N-4-7)xysulfonyl-phenylglyfur)amino-benzoic acid (anti-6A) 4-(N- Synthesis of t-butoxy(phenylglycyl)amino-ethyl benzoate t-1 Toxica was dissolved in 20-methylene chloride of Bonyl-glycine Stt;
Cool to -20°C. Then triethylamine 1.7
m, then add ethyl chlorocarbonate 114-, -16~
Stir for 20 minutes at -10°C. Then methylene chloride 10
At the same temperature, add 197 f of ethyl p-aminobenzoate dissolved in m and stir at 0° C. or below, and leave overnight at room temperature. Methylene chloride was removed under reduced pressure, and ethyl acetate was added to the residue, which was thoroughly washed with a 6% citric acid solution and then with saturated brine, and dried over Glauber's salt. Thereafter, ethyl acetate was distilled off under reduced pressure, and the residue was crystallized from benzene-n-hexane to give the title compound 86f (yield 7b-).

IR (KBr, tx-'): 8g80, 16
90, 1660.

69O NMM ((CDs)ISO, ppm): 1.80
(t, J=6.6Hz, 8B, -Cki
, ) 1.88 (s, 9H, CH, x8 ) 4.28 (q, J=6.511z, 2H, -CH*
)5.84 (d, J=91(z, 18, -
CH-)7.05-7.60 (m, ?H,C,H,
, -NH-X2)? ,64,7.88 (d,
d, J=9Hz, 4H, -C,H4-) (Rehearsal T
oB) Synthesis of 4-(N-t-1 toxysulfonyl-phenyleclycyl)ami7-benzoic acid 1.5f of the compound of reaction A was added to a mixture of 2N-sodium hydroxide bath Q2.0m and ethyl alcohol 5-. Add 70
Stir at °C for 8 hours. Thereafter, ethyl alcohol was poured under reduced pressure, ethyl acetate was added, and the mixture was washed with a 5% citric solution and then with saturated saline.

Dry with Glauber's salt. After that, ethyl acetate was removed under reduced pressure.
The title compound 1.2f (yield 88g) is obtained.

NMR ((CDs), SO, ppm)'1.88 (
s, 9 H, (H3X 8)5&2 (d,
J=9Hz, l)i, -Cti-)7.05~
7.60 (m, 7H, C, H, +, -NH-X2)y
, 62.7.86 (d, d, J=9H small, 41-1.-
C, H, -) 10.46 (br, 1B, -CO, H) Reference Example 4 Synthesis of 2-(N-t-1 toxycarbonyl-glycyl)amino-benzoic acid N-t-butquincarbonyl- 6T of glycine is dissolved in 50-methylene chloride and cooled to -20°C. Then 4 mg of triethylamine, then 2.
Add 75 Mtt and stir at -15°C to -io'eK for 20 minutes. Then, 892 t of O-aminobenzoic acid was mixed with 50 m of dimethylformamide, )! Dissolved in a mixture of J ethylamine 4d and 9#! Drop the pot at a temperature of li1, and drop it at a temperature of 1
Stir for a while and leave at room humidity overnight. Thereafter, methylene chloride was distilled off under reduced pressure, ethyl acetate was added to the residue, and IQ
Wash with S citric aS solution and then saturated saline solution for f minutes, and dry with a #IK awn. Thereafter, the ethyl buttonate was removed under reduced pressure and the residue was washed with methylene chloride to obtain the title compound 8.62.
(Yield 68-) is obtained.

1k (Nujol, E'): 8280, 1710, 16
80°1660.1605 NMk (C1), OD, ppm): 1.45 (s, 9H, CH, x8) 8.88 (s, 28, -CH, -) 7.06 (
txa, J=6.5, 2.0Hz, IH, Hcmine)7.
60 (tXd, J=6.5.2.011z, IH, Hb
) 801 (dxd, J=6.5.2.0Hz, IH
, Hc") 8.68 (dXd, J=6.6.2.0Hz
, IH, Hd') 8-(N-t-butoxyluponylglucide I) A) Synthesis of No-Bansha Aya &-M Obtained in a yield of 55% by the same method as in Example 4.

NMk ((CD, ), SO, ppm): 1.48 (s
, 9H, CH, x8) 8.78 (d, J-
6,5Hz, 28, -CI, -)650-7.10
(br, 2H, -NH-, -CO,H) 7.25-8.
BO(4H,-C,H,-)10.05(bs,if
(, -NH-) Reference Example 6 Synthesis of 4-(N-i-1 toxycarbonylglycyl)amino-benzoic acid Obtained in the same manner as in Reference Example 4 in a yield of 48-.

Summer R (Nujol, 3'): 8B
6G, 8260.1680°60O NMR ((C1's)*SO,ppm): 1.4
0(s,9H,C)1. x 8 ) 1.86 (d, J=
6.5Hz, 2H, -CI, -)6.80~7.05(
br, 2H, -NH+, -co, n)7.62.7
．． 8B (dd, J-9Hz, 4H, -C, H, -) 11
．． 0(bs, IH, -NH-) Reference Example 7 4-(N-t-1 toxycarbonyl-glycyloxy)
Synthesis of Benzoic Acid N-t-butoxycarbonyl-glycine is dissolved in 6 fl liters of methylene chloride and cooled to -20°C. Triethylamine 4-1 and then chlorR#ethyl 275- were added,
Stir for 20 minutes at -15°C to -1θ°C. That servant, p-
Hydroquine benzoic acid, 894 ml, methylene chloride 50 d,
A solution of triethylamine 4- dissolved in a mixed solution was added dropwise at the same time, and the mixture was stirred at 0° C. or lower for 1 hour. After 7 hours, the reaction solution was thoroughly washed with 11# of 10 citric acid and then with a saline solution, and dried with Glauber's salt. V) I, methylene chloride 5
When it is decompressed and recrystallized using a fkt pen nanano,
Title V compound 4.9F (yield 68%) is obtained.

1R (Nujol, Qll-): 8420.8B
40, IT'IO.

1720.168O NkR ((CD)), CO, ppm): 1.48(s,
9H, CH, x8) 4.18 (d, J=6.5Hz, 2H, -CH!-)6
．． 15-6.66 (br, IH, -N)i-)7.26
．． 8.08 (dd, J-9Hz, 4H, -C,)i,)
8.15 (bs, lH, -CO!H) Reference Example 8 Synthesized water of 4-(N-t-1-toxychloride glycyl)amide 7-2-oxyaminocarboxylic acid chlormethic acid, 2
0.2 mol of 4-(N-1-7) quincarpol-glycyl)amino-2-oxybenzoic acid #0.76 and 0.76 mol of sodium bicarbonate were added to 001 and stirred for a while. After that, 200m of methylene chloride! .

0.02 mol of tetra-n-7 tylammonium bisulfate and 0.28 mol of chloromethyl chlorosulfate are sequentially added, and the mixture is vigorously stirred at room temperature for 2 to 3 hours. Thereafter, the two phases are separated, and the aqueous layer is extracted with methylene chloride, combined with the previous methylene chloride layer, and removed under pressure. Add ethyl acetate to the residue, wash thoroughly with saturated noble brine, and dry over magnesium sulfate. After that, ethyl acetate is placed under reduced pressure to obtain the target compound in a yield of 61'j.

IR (Nujol, (x'): 887
0.1710.1686°61O NMR ((CDI)ICO291)m ) '1.48
(s, 9H, CH, x8) 8.91 (d, J=6.9Hz, 2H, -CH!-)6
．． 08 (s, 2H, -CH,CL)5.87-
6.46 (br, IH, -NH-)7.09 (d
Xd, J=8.5, 8Hz, IH, Hb'
)7.42(d, J-BHz, 18.Ha')7
．． 7B (d, J4.5Hz, IH, Hc”)9
．． 46(bs, IH, -N)i-)+025(s,
141. -0H) - Compounds of Reference Examples 9-14 in Example 8 can be converted into gold by removing the force in the same manner as Example 8. Methoxybenzoic acid dilormethyl Ik (Nujo
l, CIII'): 8B40.8260.17B
0゜1670.161O NkR(((1)s)t(-〇,ppm)'1
．． 42 (s, 9H, CH, x8) 882 (s, Bki, (J(-Hs) 8
．． 91 (d, J 6.6Hz, 2H, -(J
l! -)b! j4(8,2M,-C)i,Ct)58(
J-6,40 (br, IH, -NH-)7.14 (d
Xd, J=8.5.8kit, IH, Hb”
) 7.61 (d, J-8Hz, lH, H-→7.7
6 (d, J-8, 514z, lH, Hc”) 9.46 (
bs, IH, -NH-) 4-(tho1-7toxycarbonylphenylglyfur)amino-chloromethylbenzoate IR (KBr, am-
'): 8800.1780.168ONMR (CD,
OD, ppm): 1.42 (s, 9H, CH, x8) 6.29 (s, IH, -CB-) 6.87 (s
, 2h, -CH,C1,)? , 207.50 (I
n, 5H, -CaHs) 7.6 &, 7.98 (d
d, J-9Hz, 4h, c, n4) & Example 11 2-(N-t-7) Levonylglycyl) Acrylic acid chloromethyl 1k (Nujol, 011-') + 8876
, 8840, 1766.

1700.1680.164O NbsK < CD (near, ppm): 8th (s, 9
H, CH, X8) 8.87 (d, J=6.5Hz, 2H,=C)1. −)
5.10-5.60 (br, IH, -NH-)5
．． 87(s,2H,-CH,CL)7.07(tX
d, J=66.2Hz, IH, Hc rice) 7, b4 (tX
d, J=65.2Hz, 1B, Hb rice) 8.00 (dX
d, J=6.5.2Hz, IH, Ha”)8.69(
dXd, J=6.5.2Hz, if(,lid')1
1.20 (br, lh, -NH-)8-(N- is -butoxycarbonyl-glycyl)amino-chloromethylbenzoate NMW (LbCls, ppm): 1.54 (+s, 9H, CH, x8 )8su9(d, J
=6.51-1, 21-4. -CH,-)5.88(
s, 2H, -C)i, Ct) 9.70-6. )0(b
r, IH, -N)i-)7.10-8.20(4)1.
-C, H, -)9.12 (bs, IH, -NH-) Reference ell l B 4-(Nt-ptoxysulfonylglycyl)ami7
- Alalmethyl benzoate JR (Nujol, tM-”): 8800,
1780, 167ONMR ((CD,), CO, pp
m): 1.48 (s, 9H, CH, x! 1) 896 (d, J-6, 5Hz, 2) 1. -Cl, -)6
．． 06 (s, 2H, -CH, C1) 6.00-6.48 (br, 1) 1. -NH-)7
．． 80.8.04 (dd, J=9Hz, 4B, -CHH
,-)9.58(bs,l)i,-NH-) Reference-14 4-(N-t-7)xycarbonyl a-glycyloxy)almethylbenzoate 1k (74lA, am' ):8Bg0.177
0.174ONMM(<LL)y)ICU,ppm)
:1.48(s, 9H1)1. x8) 4.15 (d, J=6.5Hz, 2H, -C
)1. -)6.02(s,2H,-CH,Ct)6
．． 05-6.70 (br, IH, -NH-)7.
27.8. o6 (dd, J=9Hz, 4)1. −
C, H4-) Production example! 4'-Crycylamino-2-oxy-benzoic acid methyl-(6R,7S)-7-[2-('yl/l-f-ruthio)-acetamido]-7-medoxy8-[methyl-methyl- 18-tetran-ru 5-i? I
(6k,7S)-7-[2-(Noah/methylthio)-anadamide]-7 without isolating the crude iodomethyl ester obtained by reacting with 3 ommol of Jium by a known method. -Medki7-8-[((
Methyl-IH-7) Raf-5-yl)thiocomethyl)-8-cephem-4-carbon late sodium 4mmol of 4(ld dimethylformamide #!) was added at -20"C and stirred for 10 minutes to 1 hour. Then, add ethyl acetate, wash thoroughly with dilute bulk sodium carbonate IV solution and then saturated brine, and dry on a stove.Then, ethyl acetate is removed under reduced pressure and crystallized with isopropyl ether. 4'-(N-(-butoxycarbonyl-glycyl)amino-2-oxy-benzoic acid methyl-(6R,78)tetrazolumih-rol)thio]methyl]-8- obtained from Cephemu 4 ~ carboquine rate Q,
By treating the 5 mm leakage according to method 1 of the following method 1.1 for decomposition group reaction, compound No. 4Ii was obtained in a yield of 5.
Get it for 4 chi.

1 R(Nu 3 o I * ”-' N:
2250.1780.1740°68O NMR (CD30D, ppm): 8.48 (s, 8H, C, -QC town) 8.48
, 8.62 (s, s, 4H, -CH, SCH, -
)8.60 (2H,C,-H*) 8.91(s,6H,N-(:H,,-C:H,-)4
．． 18.4.68 (d, d, J-18Hz, 2)
1. -C)i, 5-)5.08 (s, l)i,c
, -H) 6.05, 6.21 (dd, J=5.
6Hz, 2ki, -CO,Ckll-)7.04(
dXd, J-8, 6, 8Hz, lH, Hbmine) 7.86
(d, J-8Hz, li (, Ha rice) 7.80 (d, J
= 8.6Hz, IH, Hc') (1st) 0.5 mmol of the compound was dissolved in γ-ninol, and 2N
- Uniform water dioxane bath 2.5~5.0 go (10~2
Add 1J times mole) k and leave it at room temperature for 30 minutes to 1 hour P#1
4'1. After that, add ethyl acetate, remove the precipitated crystals, and remove the crystals with ethyl acetate.
! Borrow l.

(Setting 6 () 1#S stand @ u, bm mole is aged 8 to 610 times, M
The title compound is superior to K by adding phase-polarized water X1 and 2 to 4 liters of water, washing with a vine, collecting the precipitated crystals, and washing with ethyl acetate.

Production Example 2-16 Production gA+ The compounds shown in the following table were produced according to the method of 1.

In addition, in the production example number - in the table, (I) means that the above (method →, ! & process of (1 method) has been applied, respectively)◇Also, all of these compounds are hydrochlorides. be.

(The following is a blank space) Formulation Example 1 According to the following composition, an aqueous solution of hydroxypropylcellulose is added to a mixture of the compound of Production Example 1 and starch kh, kneaded, and then sized by drying and pulverizing. To this sized powder, a portion of starch and a generous amount of magnesium stearate are added and mixed, and tablets are prepared.

Compound of Production Example 1 62.5 titer Magnesium stearate 2 Dahytroxyglobil cellulose 2. Preparation Example 2: Total fi of 200 or higher by adding Oq starch Tablets having the following composition are manufactured according to the method of Preparation Example 1.

Compound of Production Example 4 or 5 62.5allp titer stearin cough magnesium 2m? Hydroxyprobyl cellulose 2hθ■ Lactose is added to make a total amount of 2001v Preparation Example 3 Starch and the compound of Production Example 1O are added and mixed to the mixture of magnesium phosphate, and capsules are produced according to the usual capsule filling method. .

Compound of Production Example 1O 62-5 titer Magnesium stearate III & starch added to total amount 1509 Salmon oral administration accident cephalosporin agent of the present invention Recovery of non-ester form in urine when administered orally to humans The rate results are as follows.

Administration subjects: 2 healthy adults (3 subjects) Administration method: A formulation with a potency of 62.5 mg was orally administered as the 2 non-esters.

Quantification method: B. subtilis (B, aubtilis)
ia) All test bacteria were placed using the vapor disk method.

(Margin below) Note) The above urinary recovery rate is the average of 3 cases. .

Claims (1)

[Claims] cephalosporin derivatives or acid addition salts thereof represented by Coxy group, R3 is a hydrogen atom or a phenyl group which may have a substituent.