US 5,049,665 AGrant
Cephalosporin Derivatives
Issue Date:1991-09-17
•2 Claims
Abstract
A cephalosporin derivative having the formula: ##STR1## wherein R.sup.1 is a substituted amino group, X is an alkylene group, R.sup.2 is an aryl or heterocyclic group which may be substituted and R.sup.3 is a hydrogen atom, a negative charge or a residue of an ester which can form a pharmaceutically acceptable ester hydrolyzable in a living body; or a pharmaceutically acceptable salt thereof.
Metadata
Assignee
- Banyu Pharmaceutical Co., Ltd.
Inventors
- Susumu Nakagawa
- Hiroshi Fukatsu
- Yoshiaki Katoh
- Satoshi Murase
Application Information
Application Number:US 4143892
Filing Date:1989-09-29
Priority Date:1987-02-27
Art Unit:122
Classifications
IPC:
C07D50159A61K 31545
Field of Search:
540221;222;225
Patent Drawings
This patent does not have any drawings.
Description
EXAMPLE 1
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-pyridyl methoxy) -3-cephem-4-carboxylate
2.29 g (3.01 mmol) of p-methoxybenzyl 7.beta.-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-hydr oxy-3-cephem-4-carboxylate and 982 mg (3.75 mmol) of triphenylphosphine were dissolved in 48 ml of tetrahydrofuran, and a solution of 408 mg (3.74 mmol) of 4-pyridinemethanol in 24 ml of tetrahydrofuran was added thereto at room temperature under nitrogen atmosphere. Then, a solution of 0.58 ml (3.67 mmol) of diethylazodicarboxylate in 24 ml of tetrahydrofuran was dropwise added thereto at room temperature, and the mixture was stirred for 2 hours at the same temperature. The solvent was distilled off. The residue was dissolved in ethyl acetate, washed sequentially with water, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (Wakogel C-300, elution with 1% methanol-chloroform) to obtain 1.46 g (yield: 56.9%) of p-methoxybenzyl 7.beta.-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-p yridylmethoxy)-3-cephem-4-carboxylate as a light yellow powder. 660 mg (0.774 mmol) of this powder was dissolved in 4.1 ml of dichloromethane and 0.9 ml of anisole, and 6.6 ml of trifluoroacetic acid was dropwise added thereto under cooling with ice. The mixture was stirred for 1 hour at the same temperature. The solvent was distilled off, and isopropyl ether was added to the residue to obtain the trifluoroacetate of the above-identified compound as a powder. This trifluoroacetate was dissolved in water and adjusted to pH6.5 with a sodium hydrogencarbonate aqueous solution. The solution was purified by reversed phase column chromatography (Chemco LC-SORB, SP-B-ODS, elution with 20% methanol aqueous solution) and freeze-dried to obtain 221 mg (yield: 55.7%) of the above-identified compound.
MP: 175.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1670, 1620, 1540
NMR(DMSO-d.sub.6) .delta.: 3.45(2H, br), 3.86(3H, s), 5.02(1H, d, J=4.5Hz), 5.03(2H, s), 5.5(1H, dd, J=4.5Hz & 8Hz), 6.75(1H, s), 7.22(2H, br), 7.41(2H, d, J=5Hz), 8.5(2H, d, J=5Hz), 9.47(1H, d, J=8Hz)
The following compounds of Examples 2-29 were synthesized in the same manner as in Example 1.
EXAMPLE 2
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-ethoxyiminoacetamido]-3-(4-pyridylm ethoxy)-3-cephem-4-carboxylate
MP: 170.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1640, 1620, 1535
NMR(DMSO-d.sub.6).delta.: 1.2(3H, t, J=7Hz), 4.08(2H, q, J=7Hz), 5.01(3H, bs), 5.50(1H, dd, J=5 & 7Hz), 6.7(1H, s), 7.19(2H, br), 7.39(2H, d, J=5Hz), 8.48(2H, d, J=5Hz), 9.43(1H, d, J=7Hz)
EXAMPLE 3
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxylatomethoxyiminoacetamido-3- (4-pyridylmethoxy) -3-cephem-4-carboxylate
MP: 170.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1610, 1535
NMR(DMSO-d.sub.6).delta.: 4.3(2H, bs), 4.95-5.1(3H, m), 5.51(1H, dd, J=4.5 & 8Hz), 6.81(1H, s), 7.2(2H, br), 7.39(2H, d, J=5Hz), 8.49(2H, d, J=5Hz), 11.71(1H, d, J=8Hz)
EXAMPLE 4
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxylato-1-methylethoxyimino) acetamido]-3-(4-pyridylmethoxy)-3-cephem-4-carboxylate
MP: 180.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1560-1680, 1530
NMR(DMSO-d.sub.6).delta.: 1.38(3H, s), 1.45(3H, s), 5.0(3H, bs), 5.55(1H, dd, J=4.5 & 8Hz), 6.69(1H, s), 7.17(2H, bs), 7.38(2H, d, J=5Hz), 8.48(2H, d, J=5Hz), 11.44(1H, d, J=8Hz)
EXAMPLE 5
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-(z)-2-(1carboxylatovinyloxyimino)acetamid o]-3-(4-pyridyl- methoxy)-3-cephem-4-carboxylate
MP: 175.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1600, 1535
NMR(DMSO-d.sub.6).delta.4.86(1H, bs), 5.01(3H, bs), 5.16(1H, bs), 5.53(1H, m), 6.90(1H, s), 7.26(2H, bs), 7.4(2H, d, J=5Hz), 8.49(2H, d, J=5Hz)
EXAMPLE 6
Sodium 7.beta.-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2ethoxyiminoacetamido]-3-(4 -pyridylmethoxy)-3-cephem-4-carboxylate
MP: 190.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1600, 1530, 1410
NMR(DMSO-d.sub.6).delta.: 1.25(3H, t, J=8Hz), 3.4(2H, bs), 4.16(2H, m), 5.0(3H, bs), 5.55(2H, dd, J=5 & 8Hz), 7.42(2H, d, J=5Hz), 8.2(2H, bs), 8.5(2H, d, J=5Hz), 9.42(1H, d, J=8Hz)
EXAMPLE 7
7.beta.-(D-2-amino-2-phenylacetamido)-3-(4-pyridylmethoxy)-3-cephem-4-carbo xylic acid
MP: 165.degree. C. (decomposed)
IR(KBr)cm .sup.-1 : 3430, 3050, 1755, 1670, 1600, 1410
NMR(DMSO-d6).delta.: 3.45(2H, bs), 4.52(2H, bs), 4.9(1H, d, J=5Hz), 4.99(1H, bs), 5,44(1H, d, J=5Hz), 7.44(7H, m), 8.5(2H, d, J=4Hz), 8.76(1H, br)
EXAMPLE 8 Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(3-pyridyl methoxy)-3-cephem-4-carboxylate
MP: 175.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1580-1680, 1540
NMR(DMSO-d.sub.6 +D.sub.2 O).delta.: 3.39(2H, bs), 3.86(3H, s), 5.0(3H, bs), 5.49(1H, d, J=4Hz), 6.77(1H, s), 7.37(1H, dd, J=4.5 & 8Hz), 7.9(1H, d, J=8Hz), 8.48(1H, d, J=4.5Hz), 8.58(1H, s)
EXAMPLE 9
Sodium 7.beta.-[2-(2-aminothiazol-4-y1)-(Z)-2-methoxyiminoacetamido]-3-(2-pyridyl methoxy)-3-cephem-4-carboxylate
MP: 140.degree. C. (decomposed)
IR(KBr)cm .sup.-1 : 1760, 1600-1680, 1530
NMR(DMSO-D.sub.6 +D.sub.2 O).delta.: 3.08, 3.4(2H, ABq, J=13Hz), 3.88(3H, s), 5.05-5.25(1H, m), 5.4-5.75(3H, m), 6.77(1H, s), 7.8-8.25(2H, m), 8.57(1H, d, J=6.5Hz), 8.99(1H, d, J=6Hz)
EXAMPLE 10
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyimino-acetamido]-3-[2-(2-pyr idyl)ethoxy]-3cephem-4-carboxylate
MP: 180.degree. C. (decomposed)
IR(KBr)cm .sup.-1 : 1760, 1580-1680, 1540
NMR(DMSO-D.sub.6 +D.sub.2 O).delta.: 3.04(2H, t, J=6.5Hz), 3.21(2H, bs), 3.86(3H, s), 4.2(2H, t, J=6.5Hz), 4.97(1H, d, J=5Hz), 5.46(1H, d, J=5Hz), 6.77(1H, s), 7.0-7.5(2H, m), 7.67(1H, d, J=8Hz), 8.45(1H, d, J=5Hz)
EXAMPLE 11
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[1-(4-pyri dyl)ethoxy]-3-cephem-4-carboxylate
MP: 175-180.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1660, 1600, 1530
EXAMPLE 12
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-cyanobe nzyloxy)-3-cephem-4-carboxylate
MP: 175-180.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 2230, 1760, 1610, 1530, 1360
NMR(DMSO-d.sub.6).delta.: 3.4(m), 3.88(3H, s), 4.95-5.1(3H, m), 5.4(1H, dd, J=5 & 8Hz), 6.75(1H, s), 7.27(2H, br), 7.62(2H, d, J=8Hz), 7.79(2H, d, J=8Hz), 9.5(1H, d, J=8Hz)
EXAMPLE 13
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-nitrobe nzyloxy)-3-cephem-4-carboxylate
MP: 165-170.degree. C. (decomposed)
IR(KBr)cm .sup.-1 : 1760, 1600, 1520, 1360
NMR(DMSO-d.sub.6).delta.: 3.4(m), 3.86(3H, s), 5.02(1H, d, J=5Hz), 5.12(2H s) 5.55(1H m) 6.75(1H, s), 7.25(2H, br), 7.72(2H, d, J=9Hz), 8.2(2H, d, J=9Hz), 9.5(1H, bd, J=8Hz)
EXAMPLE 14
Sodium 7.beta.-[2-(2-aminothiazol-4-y1)-(Z)-2-methoxyiminoacetamido]-3-(4-carbamo ylbenzyloxy)-3-cephem-4carboxylate
MP: 190-195.degree. C. (decomposed)
IR(KBr)cm .sup.-1 : 1755, 1660, 1615, 1530
NMR(DMSO-d.sub.6).delta.: 3.4(2H, br), 3.85(3H, s), 4.98(1H, d, J=4Hz), 5.02(2H, bs), 5.5(1H, dd, J=4 & 8Hz), 6.74(1H, s), 7.25(2H, bs), 7.47(2H, d, J=8Hz), 7.85(2H, d, J=8Hz), 7.99(2H, s), 9.4(1H, d, J=8Hz)
EXAMPLE 15
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(thiazol-4 -ylmethoxy)-3-cephem-4carboxylate
MP: 150-155.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1620, 1535, 1415, 1370
NMR(DMSO-d.sub.6).delta.: 3.4(m), 3.82(3H, s), 4.95(1H, d, J=5Hz), 5.08(2H, s), 5,45(1H, dd, J=5 & 9Hz), 6.71(1H, s), 7.18(2H, br), 7.72(1H, s), 9.02(1H, s), 9.45(1H, d, J=9Hz)
EXAMPLE 16
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-methylt hiazol-2-ylmethoxy)-3-cephem-4-carboxylate
MP: 175-180.degree. C. (decomposed)
IR(KBr)cm .sup.-1 : 1760, 1615, 1530, 1365
NMR(DMSO-d.sub.6).delta.: 2.35(3H, s), 3.4(m), 3.85(3H, s), 5.0(1H, d, J=5Hz), 5.21(2H, s), 5.5(1H, m), 6.72(1H, s), 7.22(3H, bs), 9.5(1H, bd, J=8Hz)
EXAMPLE 17
Sodium 7.beta.-[2-(2-aminothiazol-4-y1)-(Z)-2-methoxyiminoacetamido]-3-(2-methylt hiazol-5-ylmethoxy)-3-cephem-4-carboxylate
MP: 170-175.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1615, 1535, 1360
NMR(DMSO-d.sub.6).delta.: 2.62(3H, s), 3.4(m), 3.85(3H, s), 4.97(1H, d, J=5Hz), 5.15(2H, s), 5.5(1H, m), 6.72(1H, s), 7.25(2H, br), 7.55(1H, s), 9.5(1H, bd, J=8Hz)
EXAMPLE 18
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1,2,3-thi adiazol-4-yl)-3-cephem-4carboxylate
MP: 160-165.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1620, 1535, 1370
NMR(DMSO-d.sub.6).delta.: 3.4(m), 3.85(3H, s), 4.98(1H, d, J=5Hz), 5.5(3H, m), 6.72(1H, s), 7.2(2H, br), 9.35(1H, s), 9.46(1H, d, J=9Hz)
EXAMPLE 19
Sodium 7B-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-methylimidaz ol-2-ylmethoxy)-3-cephem-4-carboxylate
MP: 160-165.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1660, 1610, 1535, 1360
NMR(DMSO-d.sub.6).delta.: 3.4(m), 3.72(3H, s), 3.86(3H, s), 4.95-5.05(3H, m), 5.5(1H, m), 6.75(1H, s), 6.82(1H, s), 7.12(1H, s), 7.22(2H, br), 9.5(1H, br)
EXAMPLE 20
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(5S)-(2-p yrrolidon-5-ylmethoxy)]-3-cephem-4-carboxylate
MP: 190-195.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1670, 1530, 1365
NMR(DMSO-d.sub.6).delta.: 1.9-2.3(4H, m), 3.4(m), 3.6(2H, m), 3.88(3H, s), 4.1(1H, m), 5.04(1H, d, J=5Hz), 5.5(1H, dd, J=5 & 8Hz), 6.75(1H, s), 7.25(2H, br), 9.32(1H, br), 9.5(1H, d, J=8Hz)
EXAMPLE 21
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(5RS)-(2- pyrrolidon-5-ylmethoxy)]-3-cephem-4-carboxylate
MP: 185-190.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1670, 1530, 1365
NMR(DMSO-d.sub.6).delta.: 1.9-2.3(4H, m), 3.4(m), 3.5-3.7(2H, m), 3.85(3H, s), 4.0(1H, m), 5.0(1H, d, J=5Hz), 5.45(1H, m), 6.75(1H, s) 7.2(2H, br), 8.8-9.6(2H, m)
EXAMPLE 22
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxylatomethoxyiminoacetamido]-3 -(4-carbamoylbenzyloxy)-3-cephem-4-carboxylate
MP: 185-190.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1755, 1660, 1615, 1530
NMR(DMSO-d.sub.6).delta.: 3.36(2H, br), 4.3(2H, br), 4.98(1H, d, J=4Hz), 5.0(2H, s), 5.5(1H, dd, J=4 & 8Hz), 6.8(1H, s), 7.26(2H, bs), 7.44(2H, d, J=8Hz), 7.85(2H, d, J=8Hz), 8.02(2H, s), 11.57(1H, d, J=8Hz), 6.72(1H, s), 7.3(4H, m), 7.84(2H, d, J=8Hz), 9.45(1H, bd, J=8Hz)
EXAMPLE 23
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2carboxylatomethoxyiminoacetamido]-3- benzyloxy-3-cephem-4-carboxylate
MP: 180-185.degree. C.
IR(KBr)cm.sup.-1 : 1760, 1610, 1540, 1410, 1370
NMR(DMSO-d.sub.6).delta.: 3.4(m), 4.28(2H, s), 4.95(3H, m), 5.5(1H, m), 6.82(1H, s), 7.38(5H, m)
EXAMPLE 24
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2carboxylatomethoxyiminoacetamido]-3- [(5RS)-(2-pyrrolidon-5-yl-methoxy)]-3-cephem-4-carboxylate
MP: 155-160.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1670, 1600, 1530, 1360
NMR(DMSO-d.sub.6).delta.: 1.9-2.2(4H, m), 3.4(m), 3.5-3.7(2H, m), 3.9-4.1(1H, m), 4.3(2H, s), 5.02(1H, d, J=5Hz), 5.5(1H, m), 6.82(1H, s), 7.2(2H, br), 8.8-9.2(1H, m), 11.6(1H, br)
EXAMPLE 25
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2carboxylatomethoxyiminoacetamido]-3- (thiazol-4-ylmethoxy)-3-cephem-4-carboxylate
MP: 70-80.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760 1610 1535 1415 1380
NMR(DMSO-d.sub.6).delta.: 3.4(m), 4.28(2H, s), 4.96(1H, d, J=5Hz), 5.09(2H, br), 5.5(1H, m), 6.82(1H, s), 7.18(2H, br), 7.78(1H, s), 9.06(1H, s)
EXAMPLE 26
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxylatomethoxyiminoacetamido]-3 -(4-methyl-thiazol-2-ylmethoxy)-3-cephem-4-carboxylate
MP: 175-180.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1610, 1530, 1410, 1370
NMR(DMSO-d.sub.6).delta.: 2.34(3H, s), 3.4(m), 4.3(2H, bs), 5.0(1H, d, J=5Hz), 5.2(2H, bs), 5.5(1H, m), 6.82(1H, s), 7.2(3H, bs)
EXAMPLE 27
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2carboxylatomethoxyiminoacetamido]-3- (2-methylthiazol-5-ylmethoxy)-3-cephem-4-carboxylate
MP: 170-175.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1610, 1530, 1410
NMR(DMSO-d ).delta.: 2.62(3H, s), 3.4(m), 4.3(2H, bs), 4.98(1H, d, J=5Hz), 5.14(2H, s), 5.5(1H, m), 6.82(1H, s), 7.25(2H, br), 7.55(1H, s)
EXAMPLE 28
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxylatomethoxyiminoacetamido]-3 -(1,2,3-thiadiazol-4-ylmethoxy)-3-cephem-4-carboxylate
MP: 160-165.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1600, 1535, 1410, 1370
NMR(DMSO-d.sub.6).delta.: 3.4(m), 4.28(2H, s), 4.96(1H, d, J=5Hz), 5.45(3H, m), 6.8((1H, s), 7.18(2H, br), 9.31(1H, s)
EXAMPLE 29
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxymethoxyiminoacetamido]-3-(1- methylimidazol-2-ylmethoxy)-3-cephem-4-carboxylate
MP: 155-160.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1620, 1535, 1410, 1370
NMR(DMSO-d.sub.6).delta.: 3.4(m), 3.7(3H, s), 4.28(2H, s), 4.9-5 1(3H, m), 5.4(1H, m), 6.82(2H, s), 7.12(1H, s), 7.16(2H, br)
EXAMPLE 30
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-carboxy latobenzyloxy)-3-cephem-4-carboxylate
1.14 g (1.5 mmol) of p-methoxybenzyl 7.beta.-[2-(2-trityl-aminothiazol-4-yl) -(Z)-2-methoxyacetamido]-3-hydroxy -3-cephem-4-carboxylate and 472 mg (1.8 mmol) of triphenylphosphine were dissolved in 20 ml of tetrahydrofuran, and a solution of 537.1 mg (1.8 mmol) of benzhydryl p-hydroxymethylbenzoate in 10 ml of tetrahydrofuran was added thereto at -20.degree. C. under nitrogen atmosphere. Then, a tetrahydrofuran solution (10 ml) of 0.28 ml (1.8 mmol) of diethylazodicarboxylate was added thereto at the same temperature, and the mixture was stirred for 20 minutes. Ethyl acetate was added to the reaction solution. The solution was washed sequentially with water, a 1N hydrochloric acid aqueous solution, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent wad distilled off and the residue was purified by silica gel column chromatography (Wakogel C-300, elution with dichloromethane-chloroform) to obtain 1.28 g (yield: 80.5%) of p-methoxybenzyl 7.beta.-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-d iphenylmethoxycarbonyl-benzyloxy)-3-cephem-4-carboxylate as a powder. 1.2 g (1.13 mmol) of this powder was dissolved in 12 ml of anisole. 12 ml of trifluoroacetic acid was added thereto under cooling with ice, and the mixture was stirred for 30 minutes at the same temperature. The solvent was distilled off and isopropyl ether was added to the residue to obtain the trifluoroacetate of the above-identified compound as a powder. This powder was dissolved in water and adjusted to pH7.6 with a sodium hydrogencarbonate aqueous solution. The solution was purified by reversed phase column chromatography (Chemco LC-SORD, SP-.beta.-ODS, elution with 10% methanol aqueous solution) and freeze-dried to obtain 312 mg (yield: 53.8%) of the above-identified compound.
MP: 190-195.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1600, 1540, 1380
NMR(DMSO-d.sub.6).delta.: 3.4(m), 3.82(3H, s), 4.98(3H, m), 5.5(1H, m)
EXAMPLE 31
Trisodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxylatomethoxyiminoacetamido]-3 -(4-carboxylatobenzyloxy)-3-cephem-4-carboxylate
The above-identified compound was synthesized in the same manner as in Example 30.
MP: 160-165.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760 1620 1535, 1380
NMR(DMSO-d.sub.6 +D.sub.2 O).delta.: 3.35(2H, m), 4.48(2H, br), 4.98(3H, m), 5.48(1H, d, J=5Hz), 6.82(1H, s), 7.34(2H, d, J=9Hz), 7.84(2H, d, J=9Hz)
EXAMPLE 32
7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-methyl-4 -pyridiniomethoxy)-3-cephem-4-carboxylate
492 mg (0.577 mmol) of p-methoxybenzyl 7.beta.-[2-(2-tritylaminothizol-4-yl) -(Z)-2-methoxyiminoacetamido]-3-(4-p yridylmethoxy)-3-cephem-4-carboxylate prepared in the same manner as in Example 1 was dissolved in 58 ml of acetone, and 2.1 ml (34 mmol) of methyl iodide was added thereto. The mixture was stirred at room temperature overnight. The solvent was distilled off and triturated with ethyl ether to obtain 541 mg (yield: 94.2%) of p-methoxybenzyl 7.beta.-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-m ethyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate iodide as a yellow powder. 519 mg (0.522 mmol) of this powder was dissolved in 2.9 ml of dichloromethane and 0.92 ml of anisole, and 4.6 ml of trifluoroacetic acid was added thereto under cooling with ice. The mixture was stirred for 1 hour at the same temperature. The solvent was distilled off and isopropyl ether was added to the residue to obtain the trifluoroacetate of the above-identified compound as a powder. This powder was dissolved in water and adjusted to pH6.5 with a sodium hydrogencarbonate aqueous solution. The solution was purified by reversed phase column chromatography (Chemco LC-SORB, SP-.beta.-ODS, elution with 30% methanol aqueous solution), and freeze-dried to obtain 88.5 mg (yield: 33.6%) of the above-identified compound.
MP: 140.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1650, 1610, 1535
NMR(DMSO-d.sub.6).delta.: 3.84(3H, s), 4.33(3H, bs), 5.0(1H, d, J=5Hz), 5.27(2H, bs), 5.5(1H, dd, J=5 & 8Hz), 6.76(1H, s), 7.22(2H, br), 8.16(2H, d, J=4Hz), 9.93(2H, d, J=4Hz), 9.49(1H, d, 8Hz)
The following compounds of Examples 33-49 were synthesized in the same manner as in Example 32.
EXAMPLE 33
7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-ethoxyiminoacetamido]-3-[1-methyl-4- pyridiniomethoxy-3-cephem-4-carboxylate
MP: 150.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1645, 1620, 1530
NMR(DMSO-d.sub.6).delta.: 1.22(3H, t, J=7Hz), 4.09(2H, q, J=7Hz), 4.32(3H, bs), 4.99(1H, d, J=4.5Hz), 5.25(2H, bs), 5.51(1H, dd, J=4.5 & 8Hz), 6.71(1H, s), 7.18(2H, br), 8.13(2H, d, J=5Hz), 8.92(2H, d, J=5Hz), 9.42(1H, d, J=8Hz)
EXAMPLE 34
7.beta.[2-(2-aminothiazol-4-yl)-(Z)-2-benzyloxyiminoacetamido]-3-(1-methyl- 4-pyridiniomethoxy)-3-cephem-4-carboxylate
MP: 165.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1660, 1645, 1610, 1530
NMR(DMSO-d.sub.6).delta.: 4.3(3H, bs), 4.98(1H, d, J=4.5Hz), 5.13(2H, bs), 5.23(2H, bs), 5.5(1H, dd, J=4.5 & 8Hz), 6.72(1H, s), 7.2(2H, br), 7.33(5H, bs), 8.12(2H, d, J=6Hz), 8.9(2H, d, J=6Hz), 9.55(1H, d, J=8Hz)
EXAMPLE 35
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxylatomethoxyiminoacetamido] -3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate
MP: 130.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1600, 1540
NMR(DMSO-d.sub.6).delta.: 3.48, 3.78(2H, ABq, J=17Hz), 4.58(3H, s), 5.23(1H, d, J=4.5Hz), 5.3(2H, s), 5.71(1H, d, J=4.5Hz), 7.03(1H, s), 8.03(2H, d, J=5Hz), 8.71(2H, d, J=5Hz)
EXAMPLE 36
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-(1-carboxylato-1-methylethoxyimino) acetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate
MP: 155.degree. C. (decomposed)
IR(KBr)cm .sup.-1 : 1760, 1640, 1585, 1530
NMR(DMSO-d.sub.6 +D.sub.2 O).delta.: 4.86(1H, bs), 5.01(3H, bs), 5.16(1H, bs), 5.53(1H, m), 6.9(1H, s), 7.26(2H, br), 7.4(2H, d, J=5Hz), 8.49(2H, d, J=5Hz)
EXAMPLE 37
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-(1carboxylatovinyloxyimino)acetamid o]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate
MP: 145.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1640, 1595, 1530
NMR(DMSO-d.sub.6 +D20).delta.: 3.45(2H, bs), 4.29(3H, bs), 4.9(1H, bs), 5.01(1H, d, J=4.5Hz), 5.16(1H, bs), 5.52(1H, d, J=4.5Hz), 6.92(1H, s), 8.1(2H, d, J=6Hz), 8.8(2H d, J=6Hz)
EXAMPLE 38
Sodium 7.delta.-[2-(2-aminothiazol-4-yl)-(Z)-2-(.alpha.-carboxylato-3,4-dihydroxy benzyloxyimino)acetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carbox ylate (diastereisomer A)
MP: 170.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1570, 1530
EXAMPLE 39
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-(.alpha.-carboxylato-3,4-dihydroxyb enzyloxyimino)acetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxy late (diastereisomer B)
MP: 175.degree. C. (decomposed)
IR(KBr)cm .sup.-1 : 1760, 1570, 1530
EXAMPLE 40
Sodium 7.beta.-[2-(2-aminothiazol-4-yl}-(Z)-2-(2carboxylatomethylbenzyloxyimino)a cetamido]-3-(1-methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate
MP: 145.degree. C.
IR(KBr)cm .sup.-1 : 1760, 1645, 1585, 1535
NMR(DMSO-d.sub.6 +D.sub.2 O).delta.: 6 3.34(2H, s), 4.27(3H, s), 4.98(1H, d, J=4.5Hz), 5.23(2H, bs), 5.5(1H, d, J=4.5Hz), 6.73(1H, s), 7.13(4H, br), 8.1(2H, bd, J=5Hz), 8.79(2H, bd, J=5Hz)
EXAMPLE 41
7.beta.-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-ethoxyiminoacetamido]-3-(1 -methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate
MP: 140.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1670, 1640, 1610, 1520
NMR(DMSO-d.sub.6).delta.: 1.25(3H, t, J=8Hz), 3.53(2H, bs), 4.16(2H, m), 4.32(3H, s), 4.98(1H, d, J=5Hz), 5.23(2H, bs), 5.55(1H, dd, J=5 & 8Hz), 8.13(2H, d, J=5Hz), 8.92(2H, d, J=5Hz), 9.43(1H, d, J=9Hz)
EXAMPLE 42
7.beta.-(D-2-amino-2-phenylacetamido)-3-(1-methyl-4-pyridiniomethoxy)-3-cep hem-4-carboxylate
MP: 130.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1665, 1640, 1600
NMR(DMSO-d.sub.6 +D.sub.2 O).delta.: 3.4(2H, bs), 4.3(3H, s), 4.4(2H, bs), 4.9(1H, m), 5.06(1H, s), 5.4(1H, s), 7.32(5H, m). 8.1(2H, m), 8.85(2H, m)
EXAMPLE 43
7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-methyl-3 -pyridiniomethoxy)-3-cephem-4-carboxylate
MP: 155.degree. C. (decomposed)
IR(KBr)cm .sup.-1 : 1760, 1580-1680, 1535
NMR(DMSO-d.sub.6).delta.: 3.82(3H, s), 4.34(3H, s), 4.95(1H, d, J=4.5Hz), 5.13(2H, s), 5.45(1H, dd, J=4.5 & 7.5Hz), 6.71(1H, s), 7.17(2H, br), 7.9-8.2(1H, m), 8.57(1H, d, J=8Hz), 8.89(1H, d, J=5Hz), 9.32(1H, bs), 9.43(1H, d, J=7.5Hz)
EXAMPLE 44
7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-methyl-2 -pyridiniomethoxy)-3-cephem--carboxylate
MP: 150.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1660, 1630, 1600
NMR(DMSO-d.sub.6).delta.: 3.53(2H, bs), 3.84(3H, s), 4.33(3H, bs), 4.97(1H, d, J=4.5Hz), 5.3-5.6(3H, m), 6.74(1H, s), 7.2(2H, br), 7.85-8.15(1H, m), 8.15-8.4(1H, m), 8.4-8.7(1H, m), 8.9-9.2(1H, m), 9.47(1H, bd, J=8Hz)
EXAMPLE 45
7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-(2-fluoroethoxyimino)acetamido]-3-(1 -methyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate
MP:148-151.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1600 1680, 1530
NMR(DMSO-d.sub.6).delta.: 4.00-4.93(7H, m), 4.98(1H, d, J=5Hz), 5.23(2H, bs), 5.50(1H, dd, J=5 & 8Hz), 6.74(1H, s), 7.20(2H, br), 8.11(2H, d, J=5Hz), 8.90(2H, d, J=5Hz), 9.48(1H, d, J=8Hz)
EXAMPLE 46
7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-propyl-4 -pyridiniomethoxy)-3-cephem-4-carboxylate
MP: 128-130.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1560-1700, 1530
NMR(DMSO-d.sub.6).delta.: 0.85(3H, t, J=7Hz), 1.6-2.2(2H, m), 3.83(3H, s), 4.3-4.7(2H, m), 4.9(1H, d, J=4.5Hz), 5.26(2H, bs), 5.46(1H, dd, J=4.5 & 8Hz), 6.72(1H, s), 7.2(2H, bs), 8.16(2H, d, J=5Hz), 9.03(2H, d, J=5Hz), 9.45(1H, d, J=8Hz)
EXAMPLE 47
7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-allyl-4- pyridiniomethoxy)-3-cephem-4-carboxylate
MP: 145-150.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1560-1700, 1530
NMR(DMSO-d.sub.6).delta.: 3.85(3H, s), 5.0(1H, d, J=4.5Hz), 5.1-5.6(7H, m), 5.9 6.4(1H, m), 6.75(1H, s), 7.18(2H, bs), 8.1-8.3(2H, m), 8.8-9.1(2H, m)
EXAMPLE 48
7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[1-(1-methy l-4-pyridinio)ethoxy]-3-cephem-4-carboxylate
MP: 120-122.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1755 1640 1610 1530
EXAMPLE 49
7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1-carbamoy lmethyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate
MP: 130-135.degree. C. (decomposed)
IR(KBr)cm .sup.-1 : 1760, 1560-1720, 1530
NMR(DMSO-d.sub.6 +D.sub.2 O).delta.: 3.1-3.6(2H, m), 5.02(1H, d, J=4.5Hz), 5.35(2H, bs), 5.53(1H, d, J=4.5Hz), 6.78(1H, s), 8.19(2H, d, J=5Hz), 8.83(2H, d, J=5Hz)
EXAMPLE 50
Sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido -3-(1-carboxylatomethyl-4pyridiniomethoxy)-3-cephem-4-carboxylate
800 mg(0.938 mmol) of p-methoxybenzyl 7.beta.-[2-(2tritylaminothiazol-4-yl) -(Z)-2-methoxyiminoacetamido]-3-(4-pyridylmethoxy)-3-cephem-4-carboxylate obtained in the same manner as in Example 1 was dissolved in 93 ml of acetone, and 3.34 g (9.49 mmol) of benzhydryl iodoacetate and a few drops of N,N-dimethylformamide were added thereto. The mixture was stirred overnight at room temperature. The solvent was distilled off, and the residue was triturated with ethyl ether to obtain 1.33 g of a powder. 1.3 g of this powder was dissolved in 6 ml of dichloromethane and 1.3 ml of anisole, and 9 ml of trifluoroacetic acid was added thereto under cooling with ice. The mixture was stirred for 1 hour at the same temperature. The solvent was distilled off and isopropyl ether was added to the residue to obtain the trifluoroacetate of the above-identified compound. The trifluoroacetate was dissolved in water and adjusted to pH7.0 with a sodium hydrogencarbonate aqueous solution. Then, the solution was purified by reversed phase column chromatography (Chemco LC-SORB, SP-.beta.-ODS, elution with 30% methanol aqueous solution), and freeze-dried to obtain 133 mg (yield: 21.8%) of the above-identified compound.
MP: 150.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1640, 1535
NMR(DMSO-d.sub.6).delta.: 3.83(3H, s), 4.93(2H, bs), 5.03(1H, d, J=4.5Hz), 5.27(2H, bs), 5.52(1H, dd, J=4.5 & 8Hz), 6.74(1H, s), 7.22(2H, bs), 8.07(2H, d, J=6Hz), 8.78(2H, d, J=6Hz), 9.53(1H, d, J=8Hz)
The following compounds of Examples 51 and 52 were synthesized in the same manner as in Example 50.
EXAMPLE 51
Sodium 7.beta.-[2-(2-aminothiazol-4-Y1)-(Z)-2-ethoxyiminoacetamido]-3-(1-carboxyl atomethyl-4-pyridiniomethoxy)-3-cephem-4-carboxylate
MP: 150.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1640, 1530
NMR(DMSO-d.sub.6).delta.: 1.22(3H, t, J=7Hz), 4.08(2H, q, J=7Hz), 4.9(2H, bs), 5.01(1H, d, J=4.5Hz), 5.25(2H, bs), 5.52(1H, dd, J=4.5 & 7Hz), 6.71(1H, s), 7.2(2H, bs), 8.05(2H, d, J=5Hz), 8.76(2H, d, J=5Hz), 9.46(1H, d, J=7Hz)
EXAMPLE 52
Disodium 7.beta.-[2-(2-aminothiazol-4-yl)-2-carboxylatomethoxyiminoacetamido]-3-(1- carboxylatomethyl-4-pyridinio-methoxy)-3-cephem-4-carboxylate
MP: 150.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1760, 1580-1700, 1540
NMR(DMSO-d.sub.6).delta.: 3.5, 3.8(2H, ABq, J=18Hz), 4.59(2H, s), 5.18(1H, d, J=4Hz), 5.21(2H, s), 5.35(2H, s), 5.73(1H, d, J=4Hz), 7.06(1H, s), 8.07(2H, d, J=6Hz), 8.7(2H, d, J=6Hz)
EXAMPLE 53
7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(3,4-dihydr oxy-1-methyl-6-pyridiniomethoxy)-3-cephem-4-carboxylate
340 mg (0.446 mmol) of p-methoxybenzyl 7.beta.-[2-(2-tritylaminothiazol-4-yl) -(Z)-2-methoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate and 146 mg (0.557 mmol) of triphenylphosphine were dissolved in 7 ml of tetrahydrofuran, and a solution of tetrahydrofuran (3.5 ml) of 170 mg (0.446 mmol) of 4,5-bis(4-methoxybenzyloxy)-2-hydroxymethylpyridine was added thereto at -20.degree. C. under nitrogen atmosphere. Then, a solution of 0.087 ml (0.55 mmol) of diethylazodicarboxylate in 3.5 ml of tetrahydrofuran was dropwise added to the solution at -20.degree. C., and the mixture was stirred for 1 hour at the same temperature. 30 ml of ethylacetate was added thereto. The solution was washed sequentially with water, a 1N hydrochloric acid aqueous solution, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Wakogel C-300, elution with 1-2% methanol-chloroform) to obtain 325 mg (yield: 64.8%) of p-methoxybenzyl 7.beta.-[2-(2-tritylaminothiazol-4-yl)-(Z) -2-methoxyiminoacetamido]-[3,4-bis(4-methoxybenzyloxy) -6-pyridylmethoxy]-3-cephem-4-carboxylate as a powder. 325 mg (0.289 mmol) of this powder was dissolved in 28 ml of methylene chloride, and a solution of 0.067 ml (0.592 mmol) of methyltrilrate in 2 ml of methylene chloride was dropwise added thereto at -20.degree. C. under nitrogen atmosphere. The mixture was stirred for 1 hour at room temperature. The solvent was distilled off, and the residue was triturated to obtain 355 mg (yield: 95.2%) of p-methoxybenzyl 7.beta.-[2-(2-tritylaminothiazol-4-yl) -(Z)-2-methoxyiminoacetamido]-[3,4-bis(4-methoxybenzyloxy) -1-methyl-6-pyridiniomethoxy]-3-cephem-4-carboxylate trifluoromethanesulfonate as a powder. 355 mg (0.275 mmol) of this powder was dissolved in 429 mg (2.79 mmol) of 3-methyl-4-methylthiophenol, 2 ml of methylene chloride and 0.34 ml (2.5 mmol) of thioanisole, and 2 ml of trifluoroacetic acid was added thereto under cooling with ice. The mixture was stirred for 1 hour at room temperature. The solvent was distilled off, and ethyl ether was added to the residue to obtain the trifluoroacetate of the above-identified compound as a powder. This powder was dissolved in water and insolubles were filtered off. The filtrate was purified by reversed phase column chromatography (Chemco LC-SORB, SP-.beta.-ODS, elution with 30% methanol aqueous solution) and freeze-dried to obtain 28.1 mg (yield: 19%) of the above-identified compound.
MP: 150-160.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 3350, 1760, 1670, 1630, 1560, 1535
NMR(DMSO-d.sub.6).delta.: 3.68(3H, s), 3.86(3H, s), 5.07(2H, s), 5.18(1H, d, J=5Hz), 5.61(1H, dd, J=5 & 8Hz), 6.40(1H, s), 6.84(1H, s), 7.26(2H, br), 7.50(1H, s), 9.60(1H, d, J=8Hz)
EXAMPLE 54
Sodium 7.beta.-[2-(2-aminothiazol-4-y1)-(Z)-2-(1-carboxylato -1-methylethoxyimino)acetamido]-3-(3,4-dihydroxy -1-methyl-6-pyridiniomethoxy)-3-cephem-4-carboxylate
The above-identified compound was synthesized in the same manner as in Example 53.
MP: 170-180.degree. C. (decomposed)
IR(KBr)cm.sup.-1: 3450, 1765, 1670, 1635, 1560
NMR(DMSO-d.sub.6).delta.: 1.44(3H, s), 1.46(3H, s), 3.68(3H, s), 5.07(2H, s), 5.20(1H, d, J=4Hz), 5.68(1H, dd, J=4 & 8Hz), 6.41(1H, s), 6.80(1H, s), 7.33(2H, br), 7.51(1H, s), 9.45(1H, d, J=8Hz)
EXAMPLE 55
Pivaloyloxymethyl 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido-3-(4-cyanoben zyloxy)-3-cephem-4-carboxylate
57.4 mg (0.38 mmol) of chloromethyl pivalate was dissolved in 2 ml of acetone, and 63 mg (0.42 mmol) of sodium iodide was added thereto. The mixture was heated for 30 minutes at 50.degree. C., and 4 ml of ethyl ether was added thereto. Insolubles were filtered off and the solvent was distilled off. Then, the residue was dissolved in 1 ml of N,N-dimethylformamide. 100 mg (0.217 mmol) of sodium 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(4-cyanobe nzyloxy)-3-cephem-4-carboxylate prepared in the same manner as in Example 12 was dissolved in 1 ml of N,N-dimethylformamide. The above solution was added to this solution under cooling with ice and stirred for 30 minutes at room temperature. Water and ethyl acetate was added to the reaction solution, and the ethyl acetate layer was separated and washed sequentially with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off and the residue was triturated with ethyl ether to obtain 24.8 mg (yield: 21.2%) of the above-identified compound.
MP: 120-123.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1780, 1750, 1675, 1620, 1530
NMR(DMSO-d.sub.6).delta.: 1.16(9H, s), 3.78(2H, s), 3.86(3H, s), 5.11(2H, s), 5.23(1H, d, J=4Hz), 5.73(1H, dd, J=4 & 8Hz), 5.79, 5.89(2H, ABq, J=6Hz), 6.81(1H, s), 7.24(2H, br), 9.64(1H, d, J=8Hz)
The following compounds of Examples 56-57 were synthesized in the same manner as in Example 55.
EXAMPLE 56
Pivaloyloxymethyl 7.beta.-[2-(2-aminothiazol-4-yl) -(Z)-2-methoxyiminoacetamido]-3-(4-nitrobenzyloxy) 3-cephem-4-carboxylate
MP: 122-125.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1780, 1750, 1680, 1615, 1520
NMR(DMSO-d.sub.6).delta.: 1.11(9H, s), 3.64-3.94(5H, m), 5.23(1H, d, J=4Hz), 5.40(2H, s), 5.63(1H, dd, J=4 & 8Hz), 5.81, 5.89(2H, ABq, J=6HZ), 6.85(1H, s), 7.28(2H, br), 7.72(2H, d, J=8Hz), 8.29(2H, d, J=8Hz), 9.58(1H, d,J=8Hz)
EXAMPLE 57
Pivaloyloxymethyl 7.beta.-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(1,2,3-thi adiazol-4-yl -methoxy)-3-cephem-4-carboxylate
MP: 115-120.degree. C. (decomposed)
IR(KBr)cm.sup.-1 : 1780, 1750, 1675, 1615, 1535
NMR(DMSO-d.sub.6).delta.: 1.10(9H, s), 3.8-4.0(5H, m), 5.22(1H, d, J=4Hz), 5.6-5.9(5H, m), 6.85(1H, s), 7.3(1H, br), 9.24(1H, s),9.62(1H, d, J=8Hz)
The compounds of the present invention have excellent antibacterial activities and are useful for treatment to bacterial infectiousness of mammal including human.
Claims
What is claimed is:
1. A cephalosporin derivative having the formula: ##STR8## wherein R.sup.1 is a substituted amino group selected from the group consisting of: (i) R.sup.4 --C(.dbd.N OR.sup.5)--CONH-- group, wherein R.sup.4 is a phenyl, naphthyl, furanyl, thienyl, thiazolyl, 1,2,4-thiadiazolyl, pyridyl, isothiazolyl, oxazolyl, pyrimidyl group which may be substituted; R.sup.5 is a hydrogen atom or a C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, phenyl, naphthyl, benzyl, phenethyl, naphthylmethyl, pyridyl, furanyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, isoquinolyl, quinolyl, oxazolyl, isoxazolyl, tetrazolyl group which may be substituted; (ii) R.sup.4 --C(.dbd.C(--R.sup.6)--R.sup.7)--CONH-- group, wherein R.sup.4 is a phenyl, naphthyl, furanyl, thienyl, thiazolyl, 1,2,4-thiadiazolyl, pyridyl, isothiazolyl, oxazolyl, pyrimidyl group which may be substituted; each of R.sup.6 and R.sup.7, which may be the same or different, is a hydrogen atom, a halogen atom or a C.sub.1-6 alkyl, phenyl, naphthyl, benzyl, phenethyl, naphthylmethyl group which may be substituted; (iii) R.sup.8 --(Z.sup.1).sub.n --CH(--R.sup.9)--CONH-- group, wherein R.sup.8 is a C.sub.1-6 alkyl, C.sub.2-6 alkenyl, phenyl, naphthyl, furanyl, thienyl, benzothienyl, pyridyl, tetrazolyl, oxazolyl group which may be substituted and R.sup.9 is a hydrogen atom, carboxyl group, an amino group, a sulfo group, a sulfamoyl group, a carbamoyl group, a hydroxyl group, a formyloxy group, a carbamoyloxy group, Z.sup.1 is an oxygen atom or a sulfur atom and n is 0 or 1; (iv) R.sup.10 --CONH-- group, wherein R.sup.10 is pyridyl, imidazolyl, piperazinyl, thiazolyl or oxazolyl group which may be substituted; (v) ##STR9## wherein Z.sup.2 is a carbon atom or a nitrogen atom and R.sup.11 is a hydrogen atom, a C.sub.1-6 alkyl, C.sub.3-16 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, phenyl, naphthyl, benzyl, phenethyl, naphthylmethyl, pyridyl, furanyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, isoquinolyl, quinolyl, oxazolyl, isoxazolyl, tetrazolyl group which may be substituted; and (vi) ##STR10## wherein R.sup.12 represents one or two substituents selected from the group consisting of a hydrogen atom, a hydroxyl group, an acetoxy group and a halogen atom; X is an alkylene group, R.sup.2 is imidazolyl or pyrrolidinyl which may be substituted by one or more substituents selected from the group consisting of a halogen atom, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, an aminomethyl group, a sulfomethyl group, a carboxymethyl group, a cyanomethyl group, a fluoromethyl group, a chloromethyl group a difluoromethyl group, a trifluoromethyl group, a carbamoylmethyl group, an N-methylcarbamoylmethyl group, a sulfamoylmethyl group, an oxo group an N-methylaminomethyl group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a methoxy group, an ethoxy group, a fluoromethyl group, a difluoroethoxy group, a trifluoroethyl group, a sulfamoyl group, a carboxyl group, a methoxycarbonyl group, a cyano group, a nitro group, a vinyl group, an allyl group, a propargyl group, an ethynyl group, an acetoxy group, a formyloxy group, a carbamoyloxy group, an N-methylcarbamoyloxy group, an acetamide group, a formamide group, an acetyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroaetyl group, a hydroxyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group and R.sup.3 is a hydrogen atom, a negative charge or a residue of an ester which can form a pharmaceutically acceptable ester hydrolyzable in a living body; or a pharmaceutically acceptable salt thereof.
2. The derivative according to claim 1 wherein the substituent attached to R.sup.2 is a halogen atom, a methyl group, an ethyl group, a propyl group, a sulfomethyl group, a carboxymethyl group, a carbamoylmethyl group, a sulfamoylmethyl group, an oxo group, an amino group, a sulfamoyl group, a carboxyl group, an allyl group, a carbamoyloxy group or a hydroxyl group.
Patent Citations (3)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US4405778 | 1983-09-01 | Scaitazzini et al. | |
| FRX2190419 | 1974-02-01 | ||
| CHX605989 | 1978-10-01 |
Non-Patent Literature (1)
- Chemicl Abstracts, vol. 106, No. 11, 16th Mar. 1987, p. 575, Abstract No. 84238b, D. O. Spry et al.; "C(3)-Alkoxycephems".