JPS6253993A - Novel compound, its production and pharmaceutical composition containing said compound - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a group of novel β-lactam derivatives.
It has antibacterial activity and is also effective against a wide range of microorganisms, especially Gram 6.
Infection of animals, especially animals, including humans, caused by bacteria.
treatment is valuable. The present invention also provides such compounds,
Regarding the method for producing intermediates used in the production of the compound, and
The present invention relates to pharmaceutical compositions comprising antimicrobially active compounds. [Prior Art] European Patent Application No. 82303821.1 (Public
No. 0071395) is a β-lactam ring carbo
α-formamide (formamide) on the carbon atom adjacent to the nyl group
lumamidil) [fjl! A group of β-lactas with groups
The amount of anti-antibiotics disclosed. [Summary of the invention] Within this group of compounds are cephalosporins with excellent antibacterial properties.
It was found that phosphorus derivatives exist. Therefore, the present invention provides the formula (1) %Formula% In the formula C, R1 haphenyl, It4A phenyl, cyclohexyl
Cenyl, cyclohexagenyl or oxygen, sulfur
or containing up to 3 heteroatoms selected from nitrogen.
Also optionally hydroxy, amino, halogen, 1#, and
Substituted by mino or C+~6 alkoxy, even if
is a good 5- or 6-membered complex culture; R2 is hydrogen or optionally substituted C+'Ns;
is an alkyl group; and R3 is one or two nitrogen atoms.
optionally substituted with a 5- or 6-atom
-membered compound crucible group; or R2 and R3 are
One or two nine elements together with the bonded nitrogen atom
optionally substituted n, including heterozygous IQ, 5-
Or 6-Hano? R4 is of the formula (a), (b) or (C); R11R7 B (wherein R6 is halogen; trifluoromethyl; hydroxy
C, C1-6 alkoxy, halogen, carboxy, sia
No, carbamoyl, amino, C1-6 alkyloxy Z
carbonylamino, arylthio, -SOs and oxo
selected from n, optionally substituted with up to two groups, n, and
01-6 alkyl which may be present; Ct-6 alkenyl; C
2-6 alkynyl; C3-7 cycloalkyl; C3-7
Cycloalkenyl; C3-7 cycloalkyl 01-6 a
alkyl; cyano; CI~6 alkylthio; arylthio
;Sulfonamide;Arylamino;Arylamide;
CI~6 alkoxy; carbamoyl: N-hydroxyl
Rubamoyl; Formyl: Hydroxyiminomethyl; C1
~6; C1~6 alkylamide; di(C+ ~6 alkyl
) Amide; CI~6 alkylcarponyloxy; Ali
carbonyloxy; carboxy + C1-6 alkoxy
Cycarbonyl; Aryloxycarbonyl; C1-6 a
Rukoxycarbonyloxy; aryloxycarbonyl
oxy; aryloxy; aralkyloxy; ary
carbonyl; CI~6 alkylamino; or di(C1
~6) alkylamino: R7 and R8 are R6
It's exactly as specified! 7R', R' and Ra are the same -
or different; or one or two groups R' r R' or R8
represents hydrogen: X is a group -CHtX"CHz -C in the formula
x' ao , s straddle group NR" [wherein R22 is H or C
I-6 alkyl]; or X is a group
-(CHz)n - (where n has the value 2, 3 or 4)
or has the formula -(CH2)p -C
H=CH-(CHz)q-C In the formula, p and q are the same
are integers that may be different, and their values are 0.1 or 2.
and p+q has the value 1 to 3); or
Formula -〇(CHz)mO-C where m has the value 1 or 2
is an integer); or
are optionally substituted together with the bonds in the ring
6-membered aromatic carbocyclic ring or oxygen, nitrogen and sulfur
optionally substituted with 1 to 3 heteroatoms selected from
j, optionally 5- or 6-fi heteroaromatic ring
) is a substituted pyridinium group; and C02R' is a substituted pyridinium group of
is a boxy or carboxylate anion or a group R
1 is an easily removable carboxy protecting group] or a salt thereof.
provide The compound of the invention of the formula ([1) is a quaternary salt and a pyridine salt.
The positive charge on the nium moiety R4 always varies depending on the counter anion.
There must be a certain amount of time. Counteranions are molecules
Negatively charged groups within e.g. carboxylate anion C02R
' or the counteranion is an external inorganic or organic
It exists as an anion. In the compound of the formula (formamide group is -NH-CH
The hydrogen atom of the O moiety is cis or trans, and
Among them, the cis conformation is the most common conformation. As used herein, the term "aryl" refers to up to 5
fluorine, chlorine, CI~6 alkyl, C1~6 alkoxy
, halo(C+~6)alkyl, hydroxy, amino, carbon
ruboxy, CI~6 alkoxycarbonyl, aryl
xycarbonyl, CI~6 alkoxycarbonylCCr
~6) Alkyl, nitro, aryloxycarbonyl
xy, aryl01-6 alkyloxycarponyloxy
C, 01-6 alkyloxycarbonyloxy, C1-
6-alkylcarbonyloxy, arylcarbonyloxy
C, Ali/L/ C1-6 alkylcarponyloxy or
is due to the aryl01-6 alkyloxycarponyl group
optionally substituted phenyl and naphthyl;
I'm spoiled. The term "heterocyclyl" as used herein refers to mono- or fused aromatic
Represents an aromatic or non-aromatic heterocyclic ring, which contains oxygen, nitrogen and
containing up to 4 heteroatoms selected from n and sulfur;
Within 3 halogens, C1-6 alkyl, C1-6 a
Rukoxy, halo(C+~6)alkyl, hydroxy, a
Mino, carboxy, 01-6 alkoxycarbonyl, 0
1-6 alkoxycarbonyl (C1-6) alkyl, a
optionally substituted with lyl or oxo group, even if
good. Appropriately, a complex-type tomb contains 1 to 7 PII atoms.
Preferably, it consists of 5 or 6 atoms. heterocyclyl group
Depending on the nature of the compound in formula (1), two or more mutually
These may occur in variable forms and are within the scope of the present invention.
,ru. The term "halogen" refers to fluorine, chlorine, bromine and iodine
. In the formula skeleton of this specification, the carbon atoms shown in fl are asymmetrical.
Therefore, the compound of formula (1) contains two optically active dia
exist as stereoisomers. Generally made from D side chain
The D-9 isomer shows the highest antibacterial activity and is therefore the D-9 isomer.
compounds or DL mixtures are preferred, and D compounds are particularly preferred.
. Compounds of formula (1) having a preferred D side chain can be prepared by conventional methods.
separated from the mixture of both diastereoisomers by
or produced from intermediates with D 1i411 chains.
,sell. Suitably, the substituted phenyl group of R1 is C+~6 alkyl.
Kill, phenyl, halogen, amino, nitro, hydroxy
C, C1-6 alkylamide, carbamoyl, carboxy
C, C1-6 alkoxycarbonyl, aryloxycarbonyl
Rubonyl, halo(C+~6)alkyl, oxo(Cs~
6) Alkyl, C1-6 alkylcarbonyl, aryl
Carbonyl, C1-6 alkylamino, di(C+-6)
alkylamino, or sulfonamide (amine and hydride)
The roxy group is optionally protected, and is optionally protected.
, is a phenyl group substituted with up to three groups. To the hydroxy or amine group attached to the phenyl ring of R1
Any protecting groups associated with
Esters and conventional chemicals or acids that can be hydrolyzed in the body
Combines groups that can be cleaved by elementary methods. Hydroxy and amino-Hanawa are protected R6 and ρ.
Comprehensive method for cleaving r+, protected, and derivatives
For example, T-Fist Double Worker Gun 17-n (T,
W. Greene) [Proteikp Group]
S in Organic Synthesis (Pro-tec
tive Groups in Organic 5y
ntHesia) J
Wiley-Interscie-nce*
New York, 1981] is particularly suitable.
Protecting groups include 3- and/or 4-hydroxy in R1.
When protecting groups, esters or carbonates (both
Hydrolyzed in vivo, ketal and ketal
Sometimes it is written as r Tf (P ether).
(tetrahydropyranyloxy derivatives).
nothing. For example, when R1 is 3- or
is 4-aminophenyl, a suitable protecting group is, for example, amino
Including those that provide carbs and carbamates. 21 solid hydroxy group is attached to the phenyl ring of R1,
For example, when R1 is 3,4-dihydroxyphenyl
It is logical that one or both of the hydroxyl groups are protected.
Let's understand. Both hydroxy groups are protected1. different times
Protecting groups are used for the hydroxyl groups.
It is more convenient that the protecting groups used are the same.
I understand. For example, regarding the 3- and/or 4-hydroxy group of R1
Examples of suitable hydroxy protecting groups are formyl and optionally
C1-6 alkylcarbonyl which may be substituted and
R-carbonyl groups such as acetyl, chloroacetyl,
Dichloroacetyl and benzoyl; optionally substituted
optionally C] ~6 alkoxycarponyl and aryl
01-6 alkoxycarbonyl e.g. ethoxycarbonyl
trimethylsilylethoxycarbonyl, benzyl
oxycarbonyl and 4-nitrobenzyloxycarbonyl
le; and optionally? C2~6
alkenyloxycarponyl e.g. allyloxycarbo
Contains nil. For example, the appropriate 3- and/or 4-hydroxy group of R1
Other examples of hydroxy protecting groups are aryl, arylC1-
6 alkyl, optionally substituted, C1-6 alkyl
Rukiru, C! which may be optionally substituted fl! ~6Arke
nyl, optionally consisting of any substituent in
Examples are/% Rogen, Hydroxy, CI~6Alkoxy, C
I~6 alkylthio, cyano, nitro, carboxy, carbon
RuboneRCr~6 alkyl ester, carbamoyl, alkyl ester,
min, mono(C+~6) alkylamino, di(C+~6
) alkylamino, and up to 3 groups (identical)
may also be different). Preferences regarding the 3- and/or 4-hydroxy group of R1
Alkyl protecting groups include, for example, methyl or ethyl, [optionally
(C+~6)alkoxy or (C+~6)alkylthio
Substituted by e.g. methoxy, ethoxy or methylthio
(may be included). Other useful protecting groups are methoxy
Ethoxymethyl and (trimethylsilyl)ethoxymethy
It is le. Furthermore, R1 is 3,4-dihydroxyphenyl
When , the hydroxyl group is retained by the alkylene bridge.
R1 is, for example, 3,4-methylenedioxyphenyl, 3,
4-ethylenedioxyphenyl or i 3.4-[1,1
-dimethyl-(methylenedioxy)] Huffel. Preferences regarding the 3- and/or 4-hydroxy group of R1
The aryl C1-6 alkyl protecting groups include benzyl and 4-
Contains nitrobenzyl. Preferred silyl protecting groups are C]~6 alkyl and/or
may be substituted by a phenyl group and for example
trimethylsilyl, t-butyldimethylsilyl, t-butyldimethylsilyl
Tyldiphenylsilyl, triethylsilyl, isogoropi
triphenylmethyldimethylsilyl, triphenylmethyldimethylsilyl
Including. Got it. The silyl ether r/'i obtained by methods well known to those skilled in the art, e.g.
T, W, Greene
(supra) or Mφ Lalonde (M, La1ond)
e) and HlChan (T, HlChan)
)'s ``5ynthesis J 1
Written by September 985, pages 817-845.
n, may be cleaved by the following method. A particularly preferred hydroxy protecting group is acetyl. From the foregoing, one preferred group of adducts according to the present invention is
The group R1 is phenyl, 3-hydroxyphenyl, 3-(
C+~6alkylcarponyloxy)phenyl, 3-(
ArylC+-6alkyloxycarponyloxy)
phenyl, 4-hydroxyphenyl, 4-(C3-6 al
Kylcarponyloxy)phenyl, 4-(arylC1
~6alkyloxycarbonyloxy)phenyl, 3.
4-dihydroxyphenyl, 3r4-cy(C+~6a
alkylcarbonyloxy)-phenyl, 3,4-di(a
Ryl C+-6 alkyloxycarponyloxy)phene
Nyl, 2-/'O,4# 5-di(C1-6 alkyl
carbonyloxy)phenyl, 2-hero415-
Dihydroxyphenyl, 2-halo 4,5-di(ary)
C1-6 alkyloxycarponyloxy)phenyl
, 3.4-methylenedioxyphenyl, 2-chenyl
Or 2-It's obvious that it's a frill. Particularly preferred groups 1tL are phenyl, 3,4-dihydro
xyphenyl, 3,4-diacetoxyphenyl, 2-k
Rolo-4,5-diacetoxyphenyl, 2-chloro-4
, 5-dihydroxyphenyl, 3,4-methylene dioxy
Cyphenyl, 2-chenyl & [2-furyl. R'' alone or in a 5- or 6-membered combination of R2 and R3
Suitable groups include 01-6 alkyl, 02-6 alkyl
Nyl, C2-6 alkynyl, C3-cycloalkyl or
is a C4-8 cycloalkenyl group; aryl; oxo:C
I~6 alkyl, Ct~6 alkenyl, C3~7 cyclo
Alkyl, phenyl, pyridyl, pyrimidyl or benzyl
Hydroxy group optionally substituted by metal;
lucapto; C1-6 alkylthio; CI-6 alkylthio;
sulfonyl; or up to 2 01-6 alkyl, C2-6
alkenyl, C3-7 cycloalkyl, aryl or base
an amine group which may be optionally substituted with an amine group;
include. Also, the two substituents on the ring are 5- or 6-membered carbon atoms.
Field residues or n, 3 or more selected from oxygen, nitrogen and ψyellow
Residues of 5- or 6-membered heterocyclic fields containing heteroatoms in
Let's form. Suitable f substituents for R6 are hydrogen, 01-6 alkyl, C+~
6 alkoxy, carbamoyl, phenyl, pyridyl, (
2-N-t-butoxycarbonylamino-2-carboxy
c) Ethyl, 03-7 cycloalkyl, C1-18 alkyl
Contains kylthio or C1-6 alkyl sulfonates. Preferably R6 is hydrogen, methyl, ethyl, 1-butyl,
Methoxy, carbamoyl, phenyl, 2-pyridyl, (
2-N-t-butoxycarbonylamino-2-carboxy
c) Ethyl, cyclopropyl, n-propyl, isopropyl
Lopil or -CHzCHzSO3-. Suitable f logging for R7 is hydrogen, 01-6 alkyl, C3-
7 Cypo Ilekyl, Hydroxy C, ~6 Alkyl/l/
, C, ~6 alkylcarbonyl, C1-6 alkoxy,
(halogen or carbamoy) vf-containing tr. Preferably R7 is hydrogen, methyl, ethyl, hydroxymethane.
Chyl, hydroxypropyl, acetyl, chlorine, methoxy
Or carbamoyl. Suitable substituents for R8 are hydrogen, CI~6 alkyl and C
Contains s-7 cycloalkyl. Preferably R8 is hydrogen or ethyl. Suitably X has the formula -(CHz)n -, where n is 3 or 4
(preferably 3). Other suitable groups for X include the formula % Formula % Preferably R4 is 4-ethylpyridinium, 4-cyclo
Propylpyridinium or a 2,3-cyclobendenopyridinium group of formula. Examples within the easily removable carboxy-containing group of R5
For example, pharmaceutically acceptable in vivo hydrolyzable esters.
Contains ester groups that combine groups. Any lIt@ group present in the compound of formula (1)
Carboxy-protected derivatives of the desired carboxy group (in vivo
(including water-degradable esters) and salts are within the scope of the present invention.
It is understood that 1. Good morning. Also within the scope of the present invention
Any optional substituent present in the compound of formula (1)
Also included are acid addition salts of amino or it-substituted amino groups. The β-lactam antibiotic compounds of the present invention can be used in pharmaceutical compositions.
Since the purpose is to eliminate the need for
The new compound is pharmaceutically acceptable, i.e. the compound of formula (1a)
or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable living body
It is easily understood that it is an ester that can be hydrolyzed in
nyo. HCHO = H (in the formula, R1 * R" * R3 * R' and the appetizer are the formula (1
), and the group C02R is carboxy
The pharmaceutically acceptable salts of the compounds of formula (1) are primarily those of the formula
Compound (Ia) or a pharmaceutically acceptable salt or pharmaceutical thereof
Production of esters that are acceptable and capable of degrading water in vivo
It is used as an intermediate for. Salt in compound of formula (1)
is prepared by salt exchange in a conventional manner.1. Good morning. Similarly, the pharmaceutically unacceptable carboxy-protected inducer of formula (1)
The conductor, for example, R5 is an easily removable carboxy protecting group.
A compound of formula (1) is a pharmaceutically acceptable compound of formula (1a).
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof
Intermediates for the production of in vivo hydrolyzable esters
Use it as, yo. From the foregoing, among the quaternized salts of the present invention of formulas (1) and (la)
Subgroup (1b) and its pharmaceutically acceptable salts and biological substances
and (lc) and
The existence of esters that can be hydrolyzed in vivo
I understand. HCHO 3 H + CO2″″ Mi H (in the formula, R1* R” * R3* R’ and bone are the formula (1
) defined for n, Y balances the positive charge of R4
Suitable for pharmaceutically acceptable stoichiometric proportions
In a preferred embodiment of the present invention, the compound of formula (1) is an inorganic or organic anion.
This is indicated by In, Bunmu (1b). (Be
Tines are isolated non-adjacent cationic and anionic parts.
and has a hydrogen atom bonded to the cationic site.
It is defined as a compound with no tfr. ) The compound of the present invention of formula (1) or (Ia) is represented by formula (Ic)
j, where the counteranion Y is suitably an inorganic acidophile.
Preferably, it is derived from mineral acids. Therefore, in formula (Ic), the anion Y is suitably chloride.
, bromide, iodide, phosphate (i.e. 1/3POa”)
or a sulfate (i.e. 1/2SO4''-). Preferably Y is a chloride. Conversion of betaine of sub-formula (lb) to salt of sub-formula (1c)
The conversion and vice versa are easily accomplished by conventional methods. For example, salts of sub-formula (lc) can be prepared by treatment with dilute mineral acids such as hydrochloric acid.
According to the theory, it can be produced from betaine of the lower formula (lb).
. The quaternized salt in formula (1c) is also analogous to the conventional method of salt exchange.
It is manufactured by means of ion exchange resins. The β-lactam antibiotic compounds of the present invention can be used in pharmaceutical compositions.
As long as they are aiming to be able to stay
a qualitatively pure form, such as at least 50 yen, more appropriately
At least 75% pure and preferably at least 95% pure
It is easy to provide the best quality (chi is heavy t/heavy base thin).
It is understood that impure products of zero oxides cannot be used in pharmaceutical compositions.
It is not necessary to use it to produce a purer form.
. Although the purity of the intermediate compound of the present invention is not strictly required, it is substantially
The naturally pure form is preferred as a β-lactam antibiotic compound;
It's easy to understand what's important. preferably possible
Insofar as the compounds of the invention are obtained in crystalline form. Certain compounds of the invention may be crystallized from organic solvents.
When crystallizing or recrystallizing, the crystal solvent is
be present in the product. The invention thus includes within its scope
Contains solvents. Similarly, some of the compounds of the present invention may contain water.
may be crystallized or recrystallized from a containing solvent. like this
The water of the place water is formed n, so. The present invention falls within its scope.
to stoichiometric hydrate and produce by methods e.g. freeze-drying.
It includes various waxy water-containing compounds that can be formed. A suitable easily removable carboxylic acid for the group -CO2R'
Xyl protecting groups include esters that can be hydrolyzed in vivo
The groups meet to form an ester derivative of a carboxylic acid. induction
The body is preferably one that can be easily cleaved. Suitable ester-forming carboxyl groups can be extracted under conventional conditions.
It is removed by j, and it can be removed. Such a group of Ra
is benzyl, p-methoxybenzyl, benzoylmethyl
, p-nitrobenzyl, 4-pyridylmethyl, 2.2.
2-trichloroethyl, 2.2.2-tribromoethyl
t-butyl, t-amyl, allyl, diphenylmethylene
ru, triphenylmethyl, adamantyl, 2-benzyl
Oxyphenyl, 4-methylthiophenyl, tetrahydro
Roflu-2-yl, tetrahydropyran-2-yl, penyl
tachlorophenyl, acetonyl, p-1 luensulfur
onylethyl, methoxymethyl, silyl, stannyl
or phosphorus compound group, formula -N=CHR"' (wherein H1a is
an oxime group (which is aryl or heterocyflic),
or groups that can be hydrolyzed in vivo, such as those defined above.
including. The carboxyl group can be prepared using conventional methods appropriate to the particular Rs group.
e.g. by acid- and base-catalyzed hydrolysis or with oxygen.
By catalyzed hydrolysis or the remainder of the molecule is substantially
Any of the above by hydrogenolysis under unaffected conditions,
will be regenerated from the ester of J Appropriate pharmaceutically acceptable in-vivo hydrolyzable esthetics
The group flJ is easily decomposed in the human body, and the parent acid or
Including those that leave that fence. A suitable ester group of this type is
(1), (il), (li+) and (1 part)
Ceremony is held. Ra -C02CH-0,CO,Rb(1) -C0zCHz -0Rf(Ill)NH2 (In the formula, Ra° is hydrogen, C1-6 alkyl, 03-7
is loalkyl, methyl or phenyl, and Rb is C+~
6 alkyl, C1-6 alkoxy, phenyl, benzyl
,03~acycloalkyl,C]~6alkylC3~F
Cycloalkyl, 1-amino01-6alkyl or 1-
(C+~6 alkyl) amine 01~6 alkyl
; or Ra and Hb together contain 1 or 2 meth
1,2-phene optionally substituted with an xy group
form a nylene group; RC is a methyl or ethyl group.
represents optionally substituted n, C1-6 alkylene;
and Rd and He are independently 01-6 alkyl
represents; Rf represents C1-6 alkyl; Rg represents
hydrogen or halogen, C1-6 alkyl or C1
Optionally up to 3 groups selected from ~6 alkoxy
represents optionally substituted phenyl; and Q is an acid
Examples of suitable in vivo hydrolysable ester groups include
Acyloxyalkyl groups such as acetoxymethyl, piva
Loyloxymethyl, α-acetoxyethyl, α-piva
loyloxyethyl, 1-(cyclohexylcarbonyl
oxy)furotsu-1-yl and (1-aminoethyl)ka
Rubonyloxymethyl; alkoxycarbonyloxymethyl
Alkyl groups such as ethoxycarbonyloxymethyl and α
-Ethoxycarbonyloxyethyl; dialkylamino
Alkyl especially di-lower alkylaminoalkyl groups e.g.
Methylaminomethyl, dimethylaminoethyl, diethyl
Aminomethyl or diethylaminoethyl; lactone base example
For example 7 talidyl and dimethoxyphthalidyl; and the second
β-lactam antibiotics or β-lactamase inhibitors
Contains conjugated esters. Other suitable pharmaceutically acceptable biohydrolysable agents
The stell group has the formula (wherein R9 is hydrogen, C1-6 alkyl or phenyl).
) Noso n5. One particularly preferred subgroup within the invention is formula C11) (formula
The middle R"+" and R4 are the same as defined in relation to formula (1).
Yes, and HIO is hydrogen, CI"""8 alkyl, ant
C1-6 alkyl or aryl; Rlm and
and R12 are the same or different and hydrogen, C1-6 alkyl, ha
rogene, amino, hydroxy or C]~6 alkoxy
1l-IR" and R12 are 5- or 6-negative
residues of carbocyclic rings or selected from oxygen, nitrogen and sulfur
5- or 6-negative heterocyclic containing up to 3 heteroatoms
(forming all the residues of the ring) or its pharmaceutically acceptable
The present invention provides salts or esters that can be hydrolyzed in vivo. Regarding the groups RIG, R11 and R12 of formula (It)
Suitable CI~6 alkyl groups are methyl, ethyl, n- and
Iso-propyl, n-1 secondary-, iso- and tertiary-methy
Including files.゛Preferably RIG is ethyl or 3-chlorophenyl
be. Preferably R11 and R12 are hydrogen. Most preferably RIG is ethyl and di R11 and RI2
are both hydrogen. Particular compounds within the invention include the following and their pharmaceutical
Contains acceptable salts and in vivo lysable esters.
nothing. 7β-CD-2-((4-ethyl-2,3-dioxopi
perazin-1-yl) carbonylaminoco-2-phenylene
acetamido)-3-(4-ethylpyridinium)metal
Chil-7α-formamide-cef-3-M-4-cal
Boxylate 3- (2,3-cyclopentenopyridiny
um)methyl-7β-CD-2-(3,4-diacetate)
xyphenyl)-2-[(4-ethyl-2,3-dioxyl)
sopiperazin-1-yl)carbonylaminocoacetoa
Mido]-7α-formamide-ceph-3-M-4-ka
Ruboxylate 3-(2,3-cyclopentenopyridinium)methyl
-7β-CD -2-(3,4-dihydroxyphenyl
)-2-((4-ethyl-2,3-dioxopiperazine
-1-yl)carbonylaminocoacetamide]-7α
-Formamide-cef-3-M-4-carboxylate
7β-(D, L-2-((4-ethyl-2,3-diox
sopiperazin-1-yl)carbonylamino)-2-(
fluor-2-yl)acetamide]-7α-formamide
-3-(4-ethylpyridinium)methyl-cef-3-
Em-4-carboxylate 7β-CD, L-2-((4-ethyl-2,3-dioxylate)
Sopiperazin-1-yl)carbonylamino]-2-
(cheno-2-yl)acetamide]-3-(4-ethyl)
lupyridinium) methyl-7α-formamide-cef-
3-Em-4-carboxylate 7β-[D, L-2-((4-ethyl-213-dioxylate)
sopiperazin-1-yl)carbonylamino] -2-
(3,4-methylenedioxyphenyl)acetamide)
-3-(4-ethylpyridinium)methyl-7α-phor
Muamido-cef-3-em-4-carboxylate 7β-CD-2-[2-chloro-4,5-diacetoxy
phenyl)-2-((4-ethyl-2,3-dioxopi
perazin-1-yl) carbonylaminocoacetamide
]-3-(4-ethylpiperidinium)methyl-7α-
Formamide-cef-3-em-4-carboxylate 7β-(1)-2-((4-ethyl-2,3-dioxo
Piverazin-1-yl) carbonylaminoco-2-phene
nylacetamide]-7α-formamide-3-(3-
hydroxymethylpyridinium) methyl-ceph-3-e
Mu-4-carboxylate 7β-(D-2-((4-ethyl)
methyl-2,3-dioxopiperazin-1-yl)carbo
nylaminoco-2-phenylacetamide]-7α-pho
lumamido-3-(4-methylpiperidinium)methyl
-Cef-3-M-4-carboxylate 7β-CD-
2-[(4-ethyl-2,3-dioxopiperazine-1
-yl)carbonylaminoco-2-phenylacetamide
]-3-(3-ethyl-4-methylpyridinium)metal
Chil-7α-formamide-cef-3-M-4-cal
boxylate 7β-CDT2-[(4-ethyl-2,3-dioxopi
perazin-1-yl) carbonylaminoco-2-phenylene
[acetamide]-7α-formamide-3-(3-(
3-Hydroxypropyl)pyridinium comethyl-ceph
-3-em-4-carboxylate 7β-CD-2-((4-ethyl-2,3-dioxopi
perazin-1-yl) carbonylaminoco-2-phenylene
[acetamide]-7α-formamide-3-(4-formamide)
phenylpyridinium) methyl-cef-3-em-4-ka
ruboxylate 3- (2,3-cyclohexenopyridi
) Methyl-7β-CD-2-((4-ethyl-2
,3-dioxopiperazin-1-yl]carbonyl amine
-2-phenylacetamide]-7α-formua'
midocef-3-em-4-carboxylate aβ-(D-2-((4-ethyl-2,3-dioxopi
perazin-1-yl)carbonylaminoco-2-2enyl
[acetamide]-7α-formamide-3-(3-methane)
(toxypyridinium) methyl-cef-3-em-4-ka
Ruboxylate 7β-CD-2-(3,4-diacetate
xyphenyl)-2-((4-ethyl-2,3-dioxyl)
sopiperazin-1-yl)carbonylaminocoacetoa
]-7α-formamide-3-(quinolinium)
Tyl-cef-3-em-4-carboxylate 3-(4-(tertiary-methyl)pyridinium comethyl-7
β-CD-2-[(4-ethyl-2,3-dioxopipe
radin-1-yl)carbonylaminoco-2-phenyl
Acetamide]-7α-formamide-cef-3-M
-4-carboxylate 7β-CD-2-((4-(3-chloro7enyl) -
2,3-dioxopiperazin-1-yl)carbonyl
Amino]-2-phenylacetamide]-3-(4-ethyl
(Tylpyridinium) Methyl-7α-Formamide-Cef
-3-Em-4-carboxylate aβ-(D-2-((4-ethyl-2,3-dioxopi-
perazin-1-yl) carbonylaminoco-2-phenylene
[acetamide]-7α-formamide-3-(4-methane)
(toxypyridinium) methyl-cef-3-em-4-ka
ruboxylate 7β-CD-2-((4-ethyl-2,
3-Dioxopiperazin-1-yl)carbonylamino
]=2-phenylacetamide]-7α-formamide
-3-(4-(prop-1-yl)pyridinium comethi)
Roucef-3-em-4-carboxylate 7β-CD-2-((4-ethyl-2,3-dioxopi
perazin-1-yl) carbonylaminoco-2-phenylene
[acetamide]-3-(2-ethelpyridinium)metal
Chil-7α-formamide-cef-3-M-4-cal
Boxylate 7β-[D-2-((4-ethyl-2,3
-dioxopiperazin-1-yl)carbonylaminoco
-2-phenylacetamide]-3-(3-ethylpyri
Zinium) methyl-7α-formamide-ceph-3-e
Mu-4-carboxylate 3-(4-cyclopropylpi
lysinium)methyl-7β-CD-2-[(4-ethyl
-2,3-dioxopiperazin-1-yl)carbonyl
Aminoco-2-phenylacetamide]-7α-form
Amido-cef-3-em-4-carboxylate 3-(
4-cyclopropylpyridinium)methyl-7β-CD
-2-(3,4-diacetoxyphenyl)-2-((
4-ethyl-2,3-dioxopiperazin-1-yl)
carbonylaminocoacetamide]-7α-formamide
Docef-3-em-4-carboxylate 3-(4-cyclopropylpyridinium)methyl-7β
-CD-2-(3,4-dihydroxyphenyl)-2
-((4-ethyl-213'dioxopiperazine-1-
carbonylaminocoacetamide]-7α-phor
Muamido-cef-3-em-4-carboxylate 7β-CD-2-((4-ethyl-2,3-dioxopi
perazin-1-yl) carbonylaminoco-2-phenylene
[acetamide]-7α-formamide-3-(4-(
isopropyl)pyridinium comethyl-cef-3-em
-4-carboxylate 7β-CD-2-((4-ethyl
(2,3-dioxopiperazin-1-yl)carbonyl
[ruamino]-2-phenylacetamide]-7α-phor
Muamido-3-(4-(pyrid-2-yl)pyridinium)
Mucomethyl-cef-3-em-4-carboxylate 7β-CD-2-(3,4-diacetoxyphenyl)-
2-((4-ethyl-2,3-dioquine piperazine-1
-yl)carbonylaminocoacetamide]-3-(4
-ethylpyridinium)methyl-7α-formamide-
Cef-3-M-4-carboxylate 7β-CD-2-(3,4-dihydroxyphenyl)
-2-((4-ethyl-2,3-dioxopiperazine-
1-yl)carbonylaminocoacetamide)-3-(
4-ethylpyridinium)methyl-7α-formamide
- Cef-3-M-4-carboxylate The antibiotic compounds of the present invention can be used with respect to other antibiotics to those skilled in the art.
human or veterinary drugs according to techniques and methods well known per se.
It can be administered in any convenient way in any urban area.
and within the scope of the present invention are pharmaceutically acceptable
The antibiotic compound of the present invention may be combined with a suitable carrier or additive.
For example, a pharmaceutically acceptable compound of formula (la) or its
Pharmaceutically acceptable salts or pharmaceutically acceptable in vivo hydration
The composition containing the degradable ester may be administered by any suitable route, such as oral or parenteral route.
It may be prescribed for administration by topical or topical administration. set
Compositions include tablets, capsules, powders, granules, troches, and creams.
or solutions such as oral or sterile parenteral solutions or suspensions.
It would be in the form of Tablets and capsules for oral administration may be in unit dosage form.
With conventional additives such as syrup, arabic
gum, gelatin, sorbitol, tragacanth or poly
Vinylpyrrolidone; fillers such as lactose, sucrose,
Corn starch, calcium phosphate, sorbitol
Or glycine, tablet lubricant M, stearin modified Magne
silium, talc, polyethylene glycol or silica;
Disintegrants such as potato starch; or Wf capable of moistening
agents such as sodium lauryl sulfate.
. Tablets are prepared according to methods well known in normal pharmaceutical practice.
It will be coated. Oral solutions may be e.g. aqueous or
Oily suspension, solution, emulsion, syrup or liquid
in xyl form or in a suitable medium of water or pond before use.
It is provided as a dry product that is reconstituted. Such solutions may contain conventional additives such as suspending agents, e.g.
Vitol, methylcellulose, g) V course syrup,
gelatin, hydroxyethyl cellulose, carboxyme
Chillcellulose, aluminum stearate gel or water
Naturalized edible fats, emulsifiers such as lecithin, sorbitan mono
Oleate or gum arabic; non-aqueous medium (including edible oil)
(e.g. almond oil, oily esters e.g. glycerin)
storage, propylene glycol or ethyl alcohol;
agents such as methyl or haplovir p-hydroxybenzoate
or hasorbic acid and, if desired, conventional flavoring or
May contain colorants. The layering agent is a conventional sludge paste such as cocoa powder or other
Contains glycerides. Compound and sterile vehicle (water is preferred) for parenteral administration
Liquid unit dosage forms are manufactured using. Depending on the medium and concentration used, the compound may be suspended in the medium.
dissolved or dissolved. In manufacturing the solution, the compound is
Dissolve in water for injection, sterile filter, and place in a suitable vial or container.
Enter the sample with a t'16 seal. Advantageously auxiliary agents such as local anesthetics, preservatives and buffers
The agent may be dissolved in the medium. Combined to increase stability
The product is placed in a vial, then frozen, and water
is removed under reduced pressure. The lyophilized powder is then placed in a vial.
Seal the bottle, and attach the vial of water for injection.
Supply and liquefy before use. Parenteral 11 fluids are essentially
The compound is prepared in the same way, but the compound is dissolved in a bath.
suspended in a medium at 90°C, and sterilization is not achieved by filtration.
j-No. Compounds are oxidized before being suspended in sterile media.
Sterilize by exposure to tyrene. advantageously
A surfactant or wetting agent may be included in the composition to improve the level of the compound.
Helps uniform distribution. The composition preferably contains 0.1-99.5% by weight depending on the method of administration.
or 10 to 60% by weight of active substance. When the composition consists of dosage units, each unit preferably contains 50
It will contain ~500 μ of active ingredient. used to treat adults
The administration is preferably dependent on the route and frequency of administration.
average of 100η to 129 per adult patient (70ky)
For example, it will range from 1,500 to 1,500 days per day. This dose is 1
This corresponds to about 1.5 to 170 η/yu per day. Throw as appropriate.
The amount given is a daily allowance! l11~6g. Daily administration is suitably administered several times over a 24 hour period.
given by administering the compound. Typically, 250η is administered four times a day, but in reality
The optimal dosing regimen and frequency for each patient will depend on the patient's age,
Varies depending on body weight and response and may vary depending on your doctor's dosage.
There will be an opportunity to choose between different doses and frequency of administration. like this
The range of administration is within the scope of this invention. A pharmaceutically acceptable compound of the invention of formula (Ia) or its
Salts or in vivo hydrolyzable esters may be used within the above dosage range.
When administered in the surrounding area, there is no tm sexual effect. The antibiotic compound according to the invention may be used alone in the composition according to the invention.
or other antibiotics and/or β-lactams.
Combinations with tamase inhibitors may be used. Advantageously, the composition comprises an ill compound or a compound thereof.
It is made of salt or ester that can be tolerated. (fil) (In the formula, A is hydroxyl; i# substituted hydroxyl; thio
Formula 5O2R" [In the formula, R13 is 01-6 alkyl
] group; thiol; amino; mono- or thiol
Drocarbyl amino; mono- or di-acyl amino
*Optionally, triazolyl may be added;
or as described in European Patent No. 0053893, etc.
It is a tetrazolyl curtain that may be arbitrarily disposed of, such as
) Other advantageous compositions are β-lactamase inhibitors of formula (IV)
agent or its pharmaceutically acceptable salt or hydrolyzed in vivo.
A pharmaceutically acceptable drug compound of formula (la) with water ester
Biological compounds or their salts or substances that can be hydrolyzed in vivo
sterol and a pharmaceutically acceptable carrier or additive. (IV) (In the formula, B is hydrogen, halogen, or the formula [1 (14 and [(Is are the same or different and
, zoj, is hydrogen, C1-6 alkoxycarbonyl or haka
carboxy or its pharmaceutically acceptable salt]
Ru. ) Other suitable β-lactamase inhibitors are listed in the published Danish patent.
(permission) European specialization equivalent to JJI 324/85
Patent Application No. 85100521.5 (Publication No. 0154
132) and European Patent Application No. 81301683
．． No. 9 (Publication No. 0041768)
Contains 6-alkylidene penem. Other suitable β-lactamase inhibitors are 6β-bromopeni
Silanic acid and its salts and esthetics that can be hydrolyzed in vivo
and 6β-iodopenicillanic acid and its salts and living organisms
Contains esters that can be hydrolyzed in Such a set of the invention comprising β-lactamase inhibitors
The composition is formulated in a conventional manner. The present invention also provides therapeutically effective antibiotics of formula (la) of the present invention.
Substance compounds or their salts or Essences that can be hydrolyzed in vivo
Infections in humans and animals caused by administration of
The pharmaceutically acceptable method of the invention of formula (Ia), including the method of treating
Compatible with antibiotic additives or their salts or hydrolyzed in vivo
A wide range of Durham-positive and Durham-negative esters
active against bacteria in immunocompromised patients.
It is used to treat a wide range of bacterial infections, including
Good morning. Pharmaceutically acceptable compounds of the invention of formula (1a) among many other uses
Citrus compounds or their salts or substances that can be hydrolyzed in vivo
STER is used to treat infections of the respiratory tract and urethral tract in humans.
of value and also used to treat mastitis in livestock.
It will be done. The special advantage of the antimicrobially active compound of the present invention is that
Due to its stability against β-lactamase enzymes, β
- Effective against lactamase-producing Hososhiba. The present invention further provides formula (V) HCHO yo H (wherein R4 and R5 are the same as above and any reactive group is
The amino group may be protected or unprotected, and the amino group may be
A compound of the formula (Vl) R' -CH-C02) (optionally substituted with a group that causes the same reaction) or a salt thereof is a compound of the formula (Vl) R' -CH-C02) )Regarding 1.
and any reactive groups are protected, even if
treatment with an N-acylated derivative of the acid of
If necessary or desired, one or more of the following steps: (1) Optional.
(II) Group -C(hR'' t- to other O group -C0zR5
A method for producing a compound of formula (1), which comprises performing an IE conversion; (i+i) conversion to the product sonic salt.
provide. Compounds of formula (la) can be prepared in a similar manner, but their
The method further provides, if necessary, that the product is pharmaceutically acceptable.
Salts or pharmaceutically acceptable esthetics that can be hydrolyzed in vivo
The process consists of converting the In the compound of formula (V), the positive charge of R4 is external or molecular.
Balanced by the counteranions present in the groups within
I understand that, right? acylation and to the amine group of the starting material of formula (V).
Suitable optionally present groups include N-silyl, N-star
Nyl and N-phosphorus groups such as trialkylsilyl groups
For example, trimethylsilyl, trialkyltin group)'
)-n-butyltin, formula-p, R16R17 (in the formula
R111 is alkyl, )-roalkyl, aryl, alkyl
Alkyl, alkoxy, haloalkoxy, aryloxy
cy, aralkyloxy or dialkylamino group;
R1? is the same as R16 or is a halogen or R16
and R17 together form a base).
This phosphorus group is -P□0 A preferred group for the above purpose is trimethylsilyl.
is suitably a suitable silylating agent such as trimethylsilyl
By reacting the loride with a compound of formula (V)
introduced in situ before acylation. The silylation reaction is carried out suitably in an inert atmosphere, preferably under an algo
in an inert anhydrous solvent such as dichloromethane.
Wat+, yeah. Organic bases such as N,N-dimethylani
Add phosphorus to aid the reaction. Reactions are usually carried out at high temperatures.
It is carried out at 30-60°C, preferably 40-50°C. Reactive N-acylated derivatives of acid (Vl) can be prepared using the method described above.
used. Not only the selection of reactive derivatives but also the substitution of acid substituents
It may be influenced by academic characteristics. Suitable N-acylated derivatives are acid halides, preferably
Contains acid chloride or bromide. Reeds caused by acid halides
acid binders such as tertiary amines (e.g. pyridine or
dimethylaniline), molecular sieves, inorganic bases (e.g. charcoal), molecular sieves, inorganic bases (e.g. charcoal),
calcium acid or sodium bicarbonate) or oxirane (
(combines hydrogen halides released during the acylation reaction)
It is done in the presence of. The oxirane is preferably (C+
~6) -1,2-alkylene oxide such as ethylene oxide
or propylene oxide. Using acid halides
The acylation reaction is carried out in an aqueous or non-aqueous medium such as water, acetate, etc.
Tetrahydrofuran, Ethyl acetate, Dimethylacetate
amide, dimethylformamide, acetonitrile, dichloromethane
in lolomethane, 1,2-dichloroethane or mixtures thereof
-50°C to +50°C, preferably -20°C to +20°C
It should be done at a temperature within this range. Also, the reaction is carried out in water-immiscible solvents.
especially aliphatic esters or ketones such as methyl isobutyl
carried out in unstable emulsions of ketones or butyl acetate
n, like. Acid halide is acid (Vl) or its salt or reactive derivative
body and halogenating (e.g. chlorinated or brominated) agents e.g.
Phosphorus pentachloride, thionyl chloride, oxalyl chloride or phosge
It is produced by reacting with n. Also, N-acylated derivatives of acid (Vl) are symmetrical or mixed anhydrides.
It must be something. A suitable mixed anhydride is an alkoxyformic anhydride.
or e.g. carbonic acid monoester, trimethylacetic acid, thioacetic acid
acids, diphenylacetic acid, benzoic acid, phosphoric acids (e.g.
acid, phosphoric acid, phosphine) or aromatic or aliphatic
sulfonic acids (e.g. p-toluenesulfonic acid or meth)
sulfonic acid). Symmetric anhydrides are used
When n, the reaction is 2. as a catalyst. (Existence of 5J Ruijin
Please do it below. Another N-acylated derivative of acid (■) is acid azide or active
esters such as 2-mercaptopyridine, cyanmeth
nor, p-nitrophenol, 2,4-sinitrophe
/-ru, thiophenol, halophenol (pentachrome)
monomethoxyphenol, N-
Hydroxysuccinimide, N-hydroxybenzotri
Azole, or 8-hydroxythiline; or amide example
N-acylsaccharin, N-acylthiazolidine-2
-thione or N-acylphthalimide; or acid and oxy
alkylidene iminoes produced by reaction with
It's tell. Other reactive N-acylated derivatives of acid (Vl) are examples of condensation rules.
For example, carbodiimide, N,N'-diethyl-, dipropylene
- or diisopropylcarbodiimide, N,N'-
Chlorhexylcarbodiimide, or N-ethyl-N-[
3-(dimethylamino)propyl]carbodiimide; suitable
suitable carbonyl compounds such as N,N'-carbonyldiyl
midazole or N,N'-carbonylditriazole;
Inxacillinium salts such as N-ethyl-5-phenyl
Isoxazolinylam-3-sulfonate or N-t-
Butyl-5-methylisoxazolinium Berkley
Also, 1dN-alkoxycarbonyl 2-alkoxy-
1,2-dihydroquinoline e.g. N-ethoxycarbonyl
by 2-ethoxy-1,2-dihydroquinoline.
It contains reactive intermediates formed by reactions in situ. other contractions
The agent is a Lewis acid (e.g. BBr3-C6HFl): or
Contains phosphoric acid silking agents such as diethylphosphoryl cyanide.
nothing. The condensation reaction is preferably carried out in an organic reaction medium, e.g.
Tyrene, dimethylformamide, acetonitrile, alkaline
Coal, benzene, dioxane or tetrahydrofuran
It is done inside. Other methods of forming N-acylated derivatives of acids of formula (Vn)
is a lower acyltriamide, preferably N,N-dimethyl
(contains chloroformamide) and logenated hydrocarbon solvents are preferred.
Preferably heno-logenated carbonyl in dichloromethane.
or oxalyl chloride or phosphoryl chloride, e.g.
N6 bath previously formed by adding phosphorus oxychloride
In treating acids of formula (Vl) as liquids or suspensions,
0 The N-acyl of the acid of formula (Vl) so derived
The compound derivative may then be reacted with the compound of formula (V).
. The acylation reaction can be conveniently carried out with an acid binding agent, if desired.
For example, it can be carried out at -40°C to +30°C in the presence of pyridine.
. A catalyst such as 4-dimethylaminopyridine can also be optionally added.
Let's go. The preferred solvent for the above acylation reaction is dichloro
It's Lomethane. Preferred intermediates of formula (V) are of formula (VA) (wherein R4 is 1
) is the same as 1 construction record). Therefore, the preferred method for producing the compound of formula (1) is
(VA) HCHO3H (in the formula, R4 is the same as above and any reactive group is unprotected)
, and the amine group may optionally result in acylation.
A compound of the formula
(Vl) R1-CH-C0tH Old ■ O R21(3 (In the formula, 1tl l R” l R3 and tatami are in formula (1)
and any reactive groups are protected as defined for n,
treatment with an N-acylated derivative of the acid (optional) and then if necessary or
If desired, one or more of the following steps; (1) optional protection;
removing the group; (11) converting the group -CCh- to the group -CO2R'; (
li+) converting the product into a salt. Compounds of formula (Ia) can be prepared in a similar manner, except that
The method further provides, if necessary, that the product is pharmaceutically acceptable.
Salts or pharmaceutically acceptable esthetics that can be hydrolyzed in the body
It consists of the process of converting to Other preferred intermediates of the aforementioned formula (V) have the formula (■)
or its acid addition salt. HCHO 3 H CChR” (■) (In the formula, R4 is as defined for formula (1), and RX
is hydrogen or an easily removable carboxy protecting group.
and 2 is the appropriate stoichiometry to balance the positive charge of R4.
An inorganic or organic anion present in stoichiometric proportions. ) a suitable easily removable carboxy protecting group for RX;
is an easily removable carboxylic acid suitable for Rs.
The protective groups mentioned above may be used. The compound of formula (1) may also be represented by the formula (■) as described above.
or its acid addition salt (in the formula, any reactive group is protected)
) and the N-acyl of the acid of formula (Vl) mentioned above.
derivatives (in the formula, any reactive group may be protected)
) and then react with 1 ff if necessary or desired.
The following steps for k or more: (1) removing any purulent groups; (11) converting the group Rx into the group RII; (**+) conversion
V is manufactured by converting the product into a salt. Formula (■) reacts with the N-acylated derivative of the acid of formula (■)
Regarding the adduct of the amino group in the compound of formula (■),
It would first be necessary to introduce a group that causes the
. Such groups suitable for this purpose are
may optionally be present on the amine group in the compound of formula (V)
j, including none of the above. Preferred groups to be introduced into the amine group in the compound of formula (■)
is trimethylsilyl. The silylation reaction is advantageously carried out using salts.
Acylation with silylating agents without simultaneous addition of groups
It is done on the spot before the reaction. Suitable silylating agents include, for example, N-(trimethylsilyl)a
Cetamide, N,0-bis(trimethylsilyl)aceto
Amide, N,0-bis(trimethylsilyl)trifluoro
Roacetamide, N-methyl-N-trimethylsilylua
Cetamide, N-methyl-N-trimethylsilyl triph
fluoroacetamide, N,N'-bis(trimethylsilyl)
) urea, and N,O-bis(trimethylsilyl)carbonate.
Including Rubamatewo. A preferred silylating agent is N-(trimethane).
tylsilyl)acetamide. Silylation reaction is appropriate
For example, 30-60°C, preferably 40°C.
An inert anhydrous organic solvent such as dichloromethane at ~50°C
It will be held in the middle of the day. The method described above may optionally include a small amount of halogen, e.g.
For example, tri(C+~6)alkylsilyl halide
This is especially done in the presence of trimethylsilyl chloride.
. Two preferred groups in the compound of formula (νII) are chloride and
It is a bromide. As mentioned above, the reactive N-acylated derivative of acid (■) has the formula (
# of the compound of formula (1) from the compound of
The selection of n, 7 reactive derivatives is based on the substituents of the acid of formula (Vl).
Affected by chemical properties. Suitable N-acylated derivatives of acid C■) are compounds of formula (V)
Suitable for use in the method for producing the compound of formula (1) from a substance.
This includes the splash mentioned above. Such an appropriate N
The method for producing the -acylated derivative was described above. Preferred N-acylated derivatives of acids of formula ('V1) are acids
Halides are most preferably acid chlorides;
For use, newly manufactured from the corresponding tR(Vl) before use.
n, like. Production of acid nologenide from acid of formula (Vl)
Suitable halogenating agents have been described above. Preferred halogenating agents are oxalyl chloride and thionyl chloride.
and phosgene. In formula (■), the group C02RX is preferably carboxy
It is. Other preferred groups for RX are diphenylmethyl (ben
Zhydryl) and tri(C+~6 alkyl)silyl, especially
It is trimethylsilyl. Trimethylsilyl group is appropriately
is suitable for silylating the amino group in the compound of formula (■).
4-carboxylation using the silylating agent mentioned above.
Introduced into the C group, so. In particular, formula (V) is an intermediate in the chemical history of formula (+) mentioned above.
The adduct is of the formula (νIl co・Rx(W) (where RX is the same as above, and R11l is a leaving group and diy
is 0 or 1) or its acid addition salt and formula (IX), (X) or
is (XI) (IX) (X) (XI
) (wherein R', R7, R'' and X are the same as above
) (When R1' is an acyloxy group, the group CO2Rx is free.
The acid form or its salts must be reacted with tdt +S pyridine and then, if necessary,
(1) converting the group HX into the group R6; (11) converting the sulfoxide (where y is 1 and
) to sulfide (in the formula, y is 0)
; < m) produced by converting the product into a salt. Suitable leaving groups R19 are 10genides such as iodides or
Includes bromide or acyloxy groups such as acetoxy groups. Preferably R19 is an acetoxy group or a bromine atom. Particularly suitable acid addition of raw materials of formula (■) in the aforementioned method
The salt is trifluoroacetate. The adduct of formula (Vl) is European Patent Application No. 82303
821.1 (Publication No. 0071395) n
, Manufactured as such. When R19 is an acetoxy group, the formula (
■ Conversion of the compound of 8) is preferably present if necessary.
And uniform f? Examples of water-immiscible organic solvents that give 4 liquids
It is carried out in an aqueous medium with acetone. The reaction is suitably carried out using an alkali metal iodide such as sodium iodide.
or alkali metal thiocyanates such as potassium thiocyanate.
carried out in the presence of cyanates and generally high porosity e.g.
It is carried out at 40-80°C and preferably at about 60°C. When the reaction is complete (e.g. analytical method e.g. reverse phase HPLC)
(confirmed by
Ion I (P20SS J resin (obtained from Mitsubishi Kasei)
) and the product is
If necessary or desired, present in R4 with 11 decorations.
Compounds of formula (V) in which any reactive group may be protected
get something The acid addition salt of the above-mentioned compound of formula (■) is suitably represented by formula (■)
It is produced by reacting a compound with a mineral acid.
. In another embodiment, the acid addition salt of the above-mentioned compound of formula (■) is
suitably reacting a compound of formula (VA) with a mineral acid and
Also, if necessary or desired, the carboxy group can be replaced with a group Co 2
It would be produced by conversion to Rx. The above reaction is generally carried out using a water-immiscible organic solvent such as acetone.
, ethanol, propan-1-ol or propan-2
- in an aqueous medium at room temperature by addition of dilute mineral acids in the presence of
So, let's do it. The reaction mixture was heated to 0-10°C to aid product isolation.
Generally cooled to below 5℃. In a preferred embodiment, the compound of formula (■) is converted into an acid addition salt.
The mineral acid used in the conversion of the compound of formula (VA) is of formula H2C
In the formula, Z is as defined for the formula (■)) t-
do. Transferring the compound of formula (VA) to the acid addition salt of the compound of formula (■)
A particularly suitable mineral acid for the conversion is dilute hydrochloric acid. The compound of formula (V) and its salts and protected octaderivatives are new
are useful intermediates and therefore these compounds are
Forms another aspect of the invention. Specific compounds in formula (V) and salts thereof are listed under formula (VA).
Contains the following compounds. 7β-amino-3-(4-ethylpyridinium)methyl
-7α-formamide-ceph-3-M-4-carboxy
sylate 7β-amino-3-(2,3-cyclopentenoviridine)
um) Methyl-7α-formamide-cef-3-m-
4-carboxylate 7β-amino-7α-formamide-3-(3-hydro
(oxymethylpyridinium) methyl-cef-3-em-4
-carboxylate 7β-amino-7α-formamide-3-(4-methyl
Pyridinilla p) Methyl-cef-3-em-4-carboxy
Sylate 7β-amino-3-(4-(2-N-t-butoxylic)
Bonylamino-2-carboxy)ethylpyridinium co
Methyl-7α-formamide-ceph-3-M-4-ka
ruboxylate 7β-amino-3-(3-ethyl-4-methylpyridiny)
um)-methyl-7α-formamide-cef-3-m
-4-carboxylate 7β-amino-7α-forma
Mido-3-[3-(3-hydroxypropyl)pyridiny]
Umcomethyl-cef-3〒M-4-carboxylate
3-(3-acetylpyridinium)methyl-7β-ami
No-7α-formamide-cef-3-M-4-carbo
xylate 7β-amino-7α-formamide-3-(4-phenylacetate)
Lupyridinium) May Rousseff-3-M-4-Cal
Boxylate 7β-amino-3-(3-carbamoylpyridinium)
Methyl-7α-formamide-ceph-3-M-4-ka
ruboxylate 7β-amino-3-(2,3-cyclohexenopyridine
um) Methyl-7α-formamide-cef-3-m-
4-carboxylate 7β-amino-7α-formamide-3-(3-methoxy
cypyridinium) methyl-cef-3-em-4-carbo
Xylate 7β-amino-3-(3-chloropyridinium)methyl
-7α-formamide-ceph-3-M-4-carboxy
Sylate 7β-amino-7α-formamide-3-(quinolinium)
Methyl-cef-3-em-4-carboxylate 7β-amino-3-(4-(tert-butyl)pyridinium)
Methyl-7α-formamide-cef-3-M-4
-carboxylate 7β-amino-7α-formamide-3-(4-methoxy
cypyridinium) methyl-cef-3-em-4-carbo
Xylate 7β-amino-3-(4-carbamoylpyridinium)
Methyl-7α-formamide-ceph-3-M-4-ka
ruboxylate 7β-amino-7α-formamide-3-[4-(pro-
(p-1-yl)pyridiniumcomethyl-cef-3-em
-4-carboxylate 7β-amino-7α-forma
Mido-3-(ivoxylate 7β-amino-3-(2-ethylpyridinium)methyl
-7α-formamide-ceph-3-M-4-carboxy
Sylate 7β-amino-3-(3-ethylpyridinium)methyl
-7α-formamide-ceph-3-M-4-carboxy
Sodium sylate 7β-amino-7α-formamide-3-(
4-(2-sulfoethyl)pyridiniumcomethyl-ceph
-3-em-4-carboxylate 7β-amino-3-
(4-cyclopropylpyridinium)methyl-7α-pho
lumamide-cef-3-em-4-carboxylate 7β-amino-7α-formamide-3-[4-(iso
propyl)pyridinium comethyl-cef-3-m-4
-carboxylate 7β-amino-7α-formamide-3-[4-(pyri
(d-2-yl)pyridiniumcomethyl-cef-3-em
-4-carboxylate Certain compounds within formula (V) and
The salts include the following acid addition salts of the compound of formula (■). 7β-ammonio-3-(2,3-cyclopentenobiliary)
Zinium) methyl-7α-formamide-ceph-3-e
Mu-4-carboxylic acid dichloride salt ((dichlorid
e5alt). The compound of formula (1) can also be suitably prepared using the formula (yiHCHO3H (, l1l) (wherein R1, R4, Rs and tatami are as above α-a).
The mino group is optionally substituted with a group that causes acylation.
A compound of the formula (Xl[l) O2H (wherein any reactive group may be protected)
and the N-acylated derivative of
If desired, 1 aL or more of the following steps: (1) Optional protection
remove group; (if) group -C0tR't" 94 tft-J6
- Conversion to C02R'; (iii) converting the product to
It is purified by converting it into salt. “Among others, the above formula (X
The second compound is the compound of formula (V) and formula (XIV) described above.
R” CH-CChH N)(Ft2o(x■)
rj group) with the N-acylated derivative of the acid of Rz
o t-produced by removing n, so. Suitable amine protecting groups R20 are well known to those skilled in the art.
They do not destroy the rest of the molecule (under conventional conditions)
It will be removed. Examples of amine protecting groups for Hzo are 01-41 alkyl, Ct
~4 alkoxy, trifluoromethyl, halogen or nitrogen
phenyl ring with one or two substituents selected from
optionally substituted with n, optionally benzyl: up to 3
C optionally substituted with a halogen atom
+~4 alkoxycarbonyl e.g. tertiary-butoxycarboxylic
carbonyl and 2.2.2-trichloroethoxycarbonyl
optionally substituted as in benzyl above;
Penzyloxycarbonyl that may be present: allyloxycarbonyl
Luponyl; also includes triethyl. Compounds of formula (Xll) are also compounds of formula (V) and formula
(XV) R" CHC (hH NatsuNs (XV) (in the formula, R1 and Tatami are the same as above) is reacted with an N-acylated derivative of α-azidic acid, and then
Conventional methods (e.g. catalytic hydrogenation or triphenyl
Reaction with ruphosphine then yields the phosphinimine
The azide group is reduced to an amino group by hydrolysis of
The compound of formula (Xll) can also be prepared by combining the compound of formula (V) with the compound of formula
(XVI) R1 part-C02H? (In the formula, R1 and Tatami are the same as above)
phthalate derivatives and then phthalimide by conventional methods.
It is produced by converting the do group into an amine group.
. The present invention relates to Bunmu (XVI) l CozRx C formula R11R"lR3#RX lR191yl: Bone
[same as in tl] A compound of the above formula (IX), (X) or (XI)
is treated with substituted pyridine, provided that R111 is acyl.
When an oxy group, the group C (hR” is in the form of a free acid or a salt thereof)
(n, must) then, if necessary, (1) convert the group RX into the group Hs; (11) convert the sulfoxide (where y is 1 and
) to sulfide (in the formula, y is 0)
(iii) providing a method for producing a compound of formula (1) comprising converting the product into a salt;
Ru. Suitable leaving groups R19 are halides such as iodides or odorants.
or acyloxy groups such as acetoxy groups. The present invention is based on the following formula:
Any reactive groups may be protected (HX is hydrogen or
is an easily removable carboxy protecting group and R21
is C+~6 alkyl, aryl or benzyl) with heavy metal ions such as mercury, silver, thallium, lead
or treated with copper and then nucleophilic formamide in situ
treated with derivatives and then, if necessary, under more than 1 m.
The following steps: (1) Remove any protecting groups; C11) Group RX = t- to group R5 4i[1s; (+;
+) proposes a method for producing a compound of formula (1) by converting the product into a salt.
provide The above method is described in European Patent Application No. 84300338.5 (Publication No. 0115405).
It is similar to the one described. At the end of the above method and the following compound of formula (1) is prepared:
Removal of protecting groups may be necessary in other methods of
Probably. Deprotecting groups can be removed by any convenient method known to those skilled in the art.
It has been done to such an extent that it is not permissible to do so.
It does not cause any harmful side reactions. R1 acetate
A particularly suitable method for converting xy groups to hydroxy groups is
Sodium nitrite aqueous solution or sodium bicarbonate aqueous solution
treatment with esterases, especially citrus acetyl esters
Treatment with tellase t”fm.The hydroxy group of R1 is
Lyle ether, stored as trimethylsilyl ether
When protected, silyl groups are usually removed by acid hydrolysis.
Action 1. Ru. In another aspect, the present invention provides the formula (XX) = H co2RX , where R'+R"l"+R'+bone, R"and R"
Any reactive group as defined for (X14)
is treated with a nucleophilic derivative of formamide and then
If necessary, the following steps above IJ4: (1) Group HX
(II) removing any protecting groups; (fil) converting the product into a salt.
provide. The present invention is based on Bunmu (XX)' C0zRX C in the formula R"+R2+R"+R'lx and rJ +uMfl
1'o1m tear any reactive groups are protected,
) and then if necessary 1
More than one of the following steps: (1) Remove any protecting groups; (il) Group Rx'l! ; R' to E exchange; (fil
') converting the product into a salt;
provide. A suitable formylating agent is the reagent 4-formyl-2-methyl-
1,3,4-Thiadiazoline-5-thione
H-yazawa and S-Go
to) [Tetrahedron Letters (TAah-edr
on Letters) J 1985 #26
s 370:3-3706] or mixed anhydride analogy
Contains formic acid acetic anhydride. The reaction is due to the presence of a tertiary base in the 4th part.
In the presence of an aprotic solvent such as dichloromethane, chloroform
lum, dimethylformamide, tetrahydrofuran,
xamethylene phosphoramide or dimethyl sulfoxide
Temperatures ranging from -50°C to 30°C may be used. reaction
Preferred tertiary bases used in are of the pyridine type, e.g.
It is a base of lysine, lutidine or picoline. One method for producing the compound in formula (XX) has been patented in Europe.
M No. 823^21.1 (Publication No. 0071395)
Those who have been described or are similar to the method described.
It is the law. Another method for producing the compound of formula (XX) is to prepare the compound of formula 0 [)
It consists of treating the chemical compound with ammonia. A method for producing a compound of formula (1) is a compound of formula (XXI) H (wherein is SR"l, SOR" or NH2).
and RL section, R” #R41RX I R21 and
+ formamidyl
It is clear from the above that it consists of In this specification, "formamidylation" refers to
It means conversion to NHCHO. The antibiotic additive of the present invention has a wide range of gram-negative and gram-negative
These bacteria are active against E. coli and other bacteria.
li (E, colt) For example, ESS, JT4゜JT4
25 and NCTC10418; Pseudomonas (Ps
eu-domonas) Spp e.g. P31 Ergi
aeruginosa such as 10662 and da
Dalgleish; Serratia 0
marcescens (5erratia marcescens)
s ) US32; Klebsiella erogenes (Kleb
siellaaerQquenes) A; Enzoro
IDnterobacter
cloacae ) Nl; P * Mirabilis (m1r
abilis) e.g. C977 and 889; P, mol
Crab (moraganii); P *Rettgeri
(rettgeri) B, subtilis (5ubtil)
is ); Stachylococcus aureus (5 tap
h, aureus) for example Oxford (0xf
ord) and Russell (Ru5sell): N
e catarrhalis 15
02; Streptococcus faecalis (5trep
, faecalis) I; β-haemolyticus
Treb (5 trep,) Contains CNI Ot. [Example] The following example describes the production and biological activity of the compound of the present invention.
Show your gender. Reference Example 1 7β-amino-7α-formamide cephalosporanate t-butyl 7β; amino-7α-formamide cephalosporanate
Sporanate (109,27 mmol) 1-Triff at room temperature
Ruoro vinegar r! 1I (100, y) was commonly understood. 1 hour
The solution was then evaporated and the residue triturated with ether.
The title product was obtained as a yellowish solid.
It was dried under vacuum (7.959.94%). this substance
is 7β-amino-7α-formamide cephalosporan
European Patent Application No. 00 as acid trifluoroacetate
For example, as already described in Example 34 (e) of No. 71395,
n, there is. Example 1 7β-(D-2-((4-ethyl-2,3-dioxopi)
perazin-1-yl) carbonylaminoco-2-phenylene
[acetamide]-3-(4-ethylpyridinium)metal
Chil-7α-formamide-cef-3-M-4-cal
Boxylate (a) 7β-amino-3-(4-ethylpyridinium)
Methyl-7α-formamide-ceph-3-M-4-ka
7β-amino-7α-formamide cef in ruboxylate water (8d)
Allosporanic acid (200~, 0.64m%)'f: iodine
Sodium (6707N?, 4.47 mJl)
z) and 4-ethylpyridine (428η+ 4.0 m
mol). Add acetone while stirring and mix evenly.
A bath liquid was obtained. Heating the mixture to 60℃ results in loss of raw materials
The reaction time was monitored by reverse phase HPLC (reaction time approx.
．． 5 hours). After cooling to room temperature, the mixture was compressed under reduced pressure.
Setone was removed. Dilute the concentrate with water and dilute
Extract with lolomethane (x2). Concentrate the aqueous phase under reduced pressure.
Shrunk. ＃Condensed product ``Dianion HP20SS J 4
] 74 fat (Mitsubishi Kasei) chromatography initial water
It was then eluted with an acetone/water mixture F). Contains eluent
The product was concentrated under reduced pressure and then lyophilized to give the title metal product (1
00η) obtained νmax(KBr) 3368, 1767
, 1675, 1635(ah). and 16111M-”; δH(D20) (main row
Tamer) 1.30 (3H, t, J7.5Hz), 2.9
6 (2H1 (1, J7.5Hz). 2H, ABq with 3.16 and 3.58C or less,
Jl 7.6Hz). 5.24 and 5.35 (with the following 2H, ABq,
Jl 4.7Hz). 5.25 (IH,s), 7.92 (2H,d, J6.
4Hz), 8.17(IH,s), and 8.73(2
H, d, J6.4Hz); (F, A. B, (thioglycerol) (+ve ion) MI (+
363]. (b) D-2-((4-ethyl-2,3-dioxopipe
radin-1-yl)carbonylaminoco-2-phenyl
Acetyl chloride catalytic amount f % N,N-dimethylformamide
D-2-[(4-E) in dry dichloromethane (5y/)
methyl-2,3-dioxopiperazin-1-yl)carbo
nylamino]-2-phenylacetic acid (115~+0.3
6 mmol) to oxalyl chloride (91#9.0.72m
mol) was added. The mixture was stirred at room temperature for 1.25 hours and then
evaporated under reduced pressure. Dissolve the residue in dry dichloromethane.
Re-evaporated (x2). Vacuum dry the residue and further
o'1aX (CHzC/2) used without purification
3280.1800°1720 and 1695cW1-”
. (c) 7β-(D-2-((4-4thyl-2,3-dio
xopiperazin-1-yl)carbonylamino]-2-
phenylacetamide)-3-(4ethylpyridinium)
) Methyl-7α-formamide-cef-3-M-4-
Carboxylate N, N-dimethylanisoy (2331
19,1,92 mmol) and hydrimethylchlorosilane (
104W. dry dichloromethane (5-) containing 0.96 mmol)
7β-amino-3-(4-ethylpyridinium)
Chil-7α-formamide-cef-3-M-4-cal
Hoxyley) (87+W, 0.24 mmol) for 45 minutes.
Refluxed under argon. Cool the bath liquid and
D-2-((4-ethyl) in dry dichloromethane (5-)
(2,3-dioxopiben-1-yl)carbonylate
Ruami/)-2-phenylacetyl chloride (Example 1
(b) product) was added with stirring at room temperature. reaction
Monitored by reverse phase HPLC. After about 40 minutes, the reaction mixture
Dilute with dichloromethane and extract with water (x3).
I put it out. The separated aqueous extract was added to dichloromethane (
was first subjected to chromatography on HP20SS resin.
The raw material containing the 0-bath stripping solution was stripped with an acetone/water mixture.
The product was compressed under reduced pressure and then lyophilized to obtain the title metal product (72n).
i, containing about 20% L-isomer) was obtained. umax (KBr) 3422.3300 (sh), 17
78°1710(ah), 1676.1636. and 1
616α-1; δH(DtO) (D isomer, main locus
tamer), especially 1.18 (3H, t, J7.2Hz),
1.32 (3H, t, J7.6Hz), 2.81 and 3
．． 40 (with 2H, ABq.,, 417.5 Hz), 2.97 (21 (, q, J7.
6Hz), 3.51 (2H, q, J7.2Hz), 3.
66 (2H, m), 3.97 (2H. m), 5.14 and 5.31 (2H, ABq, Jl4.
4Hz). 5.33 (IH, s), 5.49 (IH, s), 7.3
0-7.55 (5H, m), 7.89 (2H, d, J6
．． IHz), 8.15 (IH.s), 8.67 (2H,d, J6.IHz); (F
, A, B, (thioglycerol) (+ve ion) M
E(”664]. Example 2 3-(2,3-cyclopentenoviridinium)methyt
v-'7R-r ding)-')-11-A-Xn ding
Jy k j J/ j 〒Nil)-2-(
(4-ethyl-2,3-dioxobipe-y')7-1-
carbonylaminocoacetamide]-7α-phor
Muamido-cef-3-em-4-carboxylate Method A (a) 7β-amino-3-(2,3-cyclopentenopylene)
Lysinium) methyl-7α-formamide-cef-3-
7β-A in em-4-carboxylate water (10d)
Mino-7α-formamide cephalosporanic acid (0,6
& , 1.9 mmol) to sodium iodide (2,09,
13,3 mmol) and 2,3-cyclopentinoviridine
(1,439°12.0 mmol) was added. acetone
In addition, the mixture was heated to 60 °C to form a homogeneous bath liquid, and the reverse phase H
Monitored by PLC. After about 6 hours, bring the mixture to room temperature.
It was cooled and concentrated under reduced pressure. #I The sinter is made of HP20SS resin.
romatographed first in water and then in an acetone/water mixture.
more eluted. The product containing the eluent was concentrated under reduced pressure and then frozen.
After drying, the title compound (0.35!9) was obtained. umax (KBr) 3402.3275 (sh), 1
768. 1675, and 1616 cm-”; δH(DzO)
(main rotamer) 2.20-2.40 (2H, m),
3.05-3.25 (3H, m). 3.25-3.45 (2H, m), 3.50 (IH, A
Bq low field arm, J17.6Hz), 5.
2H, ABq, J15 with 22 and below 5.36C
．． 2Hz), 5.23 (IH, s), 7.76 (IH,
m), 8.16 (IH, s), 8.28 (IH, d, J
7.7Hz), 8.49 (IH, d, J6.2Hz)
; (F, A, B. (+ve ion) (thioglycerol) ME (+a
75). (b) D-2-(3,4-diacetoxyphenyl)
-2-((4-ethyl-2,3-dioxopiperazine-
1-yl) carbonylaminocoacetyl chloride in a catalytic amount of E-dried N,N-dimethylformamide at 0°C.
D-2-(3,
4-diacetoxyphenyl)-2-[(4-ethyl-2
,3-dioxopiperazin-1-yl) carbonyl amine
] Oxalyl chloride (448 Wq. 3, 53 mmol) was added to acetic acid (78611Ii. 1.77 mmol). Stir the mixture and
Set (×2). Vacuum dry the residue and do not further purify it.
It was used directly. umax(CHzCg2)3275+1950(sh)
e1775e1715 and 1690 cm-'. (c) 3-(2,3-cyclopentenopyridinium)
) Methyl-7β-CD-2-(3,4-diacetoxy
phenyl)-2-((4-ethyl-2,3-dino)acetate
toamide]-7α-formamide-cef-3-M-4
-carboxylate N,N-dimethylaniline (853 capes * 7.04 mmol
) and hydrimethylchlorosilane (573+v. 5,28 mmol) in dry dichloromethane (15 r
7β-amino-3-((2,3-cyclopene
tenopyridinium)methyl]-7α-formamidose
Fu-3-M-4-carboxylate (3301Ni,
0.88 nmol) was added under argon for 30 minutes under a stream of N. Cool the solution with 1- and dry dichloromethane;
D-2-(3,4-diacetoxyphene) in (6d)
Nyl)-2-((4-ethyl-2,3-dioxopipera
din-1-yl) carbonylaminocoacetyl chloride
(3/5 of the product of Example 2(b)) was stirred in chamber 1.
I added. The reaction was monitored by reverse phase HPLC. reaction is complete
At that time, the mixture was diluted with dichloromethane and extracted with water.
Out nine (x3). Combined aqueous extracts in dichloromethane
The aqueous phase, washed (x2), was concentrated in vacuo and concentrated.
First, apply chromatography to tHP20ss resin.
Eluted with water and then with an acetone/water mixture. Contains eluent
The product was compressed under reduced pressure and then frozen W1# to give the title compound (
3954° (containing about 30% L isomer) was obtained. umax (KBr) 3390 (sh), 3289.17
72°1710 (sh), 1682. &bi1617tan-
1; δH(DzO)CD isomer, mainly 1o-pmer), special
1.17 (31(,t, J7.2Hz), 2.1
0-2.40 (8H, m), 2.69 (IH, ABq. high field arm, J17.3Hz), 3.05-
3.40 (5H. m), 3.49 (2H, q, J7.2Hz), 3.55
-3.75 (2H=m), 3.80-4.10 (2H,
m), 5.15-5.40 (2H. m), 5.32 (IH, s), 5.50 (IH, a),
7.20-7.55 (3H, m), 7.65-7.80
(IH, m), 8.15 (IH. s), 8.20-8.50 (2H, m) s (F, A, B
(+ve ion) (CHCl s /cyamyl 7x) -
) MH+7923. Method B (d) 7β-ammonio-3-(2,3-cyclopente
nopyridinium) methyl-7α-formamide-cef-
7β-Amino- in 3-M-4-carboxylic dichloride salt 2.5N salt #l (0,ss!>
3-(2,3-cyclopentenopyridinium)methyl-
7α-Formamide-Cef-3-M-4-carboxy
(130 cape 0.35 mmol) was vigorously stirred.
Add to propan-2-ol (50 mg) all remaining
The resulting material was further diluted with 2.5N hydrochloric acid (2XO, 25m2).
I washed it out. The obtained n,9 suspension was kept at about θ°C for 1 hour.
Ta. The solid was removed from the oven and washed with Prono (No2-ol).
and dried in vacuo over pentoxide to give the title compound (7
9IIIP, 51ch) It was obtained. λmax (HzO) 270nm (1m9860)
; νmax (KBr) 3362.2560 (sh)
, 1980 (wk), 1789°168? , and 161
8α-1; δHLD20 ) (main rotamer) 2.3
0 (2H, apparent finch, J 7.7Hz
), 3.17 (2H, teJ7.7Hz), 3.3
1 and 3.55 (2H, Ab (1°J17.8Hz)
, 3.33 (2H,t, J7.6Hz), 5.31
(I He s L, +5.35 and 5.45 (2, H
,ABq,J15.3Hz)7.65-7.85(I
H, m), 8.26 (IH, s, unclear IH. d, J8.3Hz), 8.40-8.60 (IH, m)
; (FAB (+ve ion) (thioglycerol) Iv
[+ (free base) 375) (e) 3- (2,3-
cyclopentenopyridinium)methyl-7β-CD −
2-(3,4-diacetoxyphenyl)-2-((4-
ethyl-2,3-dioxopiperazin-1-yl)cal
Bonylaminocoacetamide]-7α-formamide-
Cef-3-M-4-carboxylate N-()limethylsilyl)acetamide (224*1
-54 mmol) in dry dichloromethane (5d) containing
7β-ammonio-3-(2,3-cyclopentenopyryl)
Zinium) methyl-7α-formamide-ceph-3-e
Mu-4-carboxylic acid dihydrochloride (69111!, 0.15
When a WA suspension of 4 mmol) was stirred at room temperature for 3.75 hours,
Complete dissolution occurred. in dry dichloromethane (3-)
D -2-(3,4-diacetoxyphenyl)-2-
((4-ethyl-2,3-dioxopiperazine-1-y
carbonylamino] Acetyl chloride [Example 2 (
The corresponding acid (101”W) was prepared using the method described in b).
, 0.231 mmol) to add the newly backtracked]
(monitored by reverse phase HPGC). 0.33 hours later
Furthermore, D-2-(3,4-diacetoxyphenyl)-2-
[(4-ethyl-2,3-dioxopiperazine-1-y
carbonylaminocoacetyl chloride (0,077
mmol) [in dry dichloromethane (1IRt)] was added.
and purified as in Example 2(C) for an additional 1 h.
The title compound (37q, 28%) was then obtained. Example 3 '4-19-Q-syJ lopentine nobildinium
-7β-CD-2-(3,4-dihydroxyphenylene
)-2-((4-ethyl-2,3-dioxopiperazi)
carbonylaminocoacetamide]-7
α-Formamide-cef-3-M-4-carboxylene
3-(2,3-cyclopene) in water (20,d) at room temperature
tenopyridinium) methyl-7β-CD-2-(3,4
-diacetoxyphenyl)-2-((4-ethyl-2,
3-Dioxopiperazin-1-yl)carbonylamino
coacetamide]-7α-formamide-ceph-3-e
Mu-4-carboxylene) (3547 Da + 0.45
2.5 t (w/v) sodium carbonate into a stirred solution of
Add thorium water bath solution to bring it to 8.0, then add sulfur dioxide all at once.
Sodium (142 μm. 1.13 mmol) was added. The pH of the mixture was further adjusted to 2.
Add 5% (w/v) sodium carbonate water bath solution.
The value was maintained at 8.579.0. The reaction was reversed phase HPL
Monitored by C. After about 40 minutes, the crude mixture was heated to HP 2.
0 SS Before chromatography, first add acetate to water and fire.
Reduce the product containing 0 eluent eluted with V/water mixture.
The title compound (Cape 213,
About 25% of the L isomer was obtained. Jmax (HzO) 271nm ('ml 7034)
r L'max(KBr)3400.3299,17
79.1710 (sh), 1676° and 1616cr
n-7δH (D20) CD isomer, main rotamer)
Especially 1.17 (3H,t, J7.2Hz), 2.0
-2.4 (2H, m). 2.80 (IH, ABqO high field arm 7
．． 5Hz). 3.10-3.75 (9H, complex m), 3.
80-4.10 (2H, m), 5.1-5.4 (4H,
m), 6.70-7.00 (3H, m), 7.65-7.80 (IH, m), 8.14 (I
H,s). 8.15-8.50 (2H, m); (F, A, B, (
+ve ion) (thioglycerol) ■r'7os]. Example 4 7β-CD, L-2-((4-ethyl-2,3-dio
xopiperazin-1-yl)carbonylamino]-2-
(Flu-2-yl)acetamide]-7α-formamide
Do-3-(4-ethylpyridinium)methyl-cef-3
-M-4-carboxylate N,N-dimethylanili
(2021112, 1,66 mmol) and trimethyl
Dry dichloromethane (7-) containing chlorosilane (135 my. 1,25 mmol)
7β-amino-3-(4-ethylpyridinium)
Chil-7α-formamide-cef-3-M-4-cal
Boxylate (75■, 0.208 mmol) about 0.5
Refluxed under argon for an hour. Got it. Cool the bath solution (7) in dry dichloromethane (5-),
L -2-((4-ethyl-2,3-dioxopiperazi
carbonylamino]-2-(fluor-2-
yl) acetyl chloride [n as described in Example 1(b),
freshly prepared from the corresponding acid (80 kg. 0.26 mmol) by the method described in Muroyama.
Add while stirring. The reaction was monitored by reverse phase HPLC.
did. After 2 hours the purification described in Example 1(c) was carried out.
The title compound (43N 1.32%) was obtained. γmax (KBr) 3417, 3300 (sh)
, 1775. 1710(sh), 1675.1640. and 1615
cm-”; δH(DzO) (D/L ratio, approx. 3
:2) (main rotamer) 1.20 (3H,t, J7.
2Hz), 1.33 (3H,t, J7.5Hz). 2.98 (2H, q, J7.5Hz, unclear IH, A
BqO high field arm, 40-3.63 (3
H, m), 3.65-3.80 (2H, m), 3.90
-4.15 (2H, m), 5.15-5.55 (3H=
m), 5.70 (0,6H,s ), 5.72 (0,4
H,s). 6.35-6.70 (2H, m), 7.45-7.65
(, IH, rn). 7.80-8.00 (2H, m), 8.17 (0.4H
, s), 8.18 (0,6H+ s ), and 8.6
0-8.80 (2H, m); (F', A, B. (+veioy) (f;i glycerol/H20) M
H+6=,54). Example 5 7β-CD, L-2-[(4-ethyl-2,3-dio
xopiperazin-1-yl)carbonylamino]-2-
(cheno-2-yl)acetamide]-3-(4-ethyl)
lupiperidinium) methyl-7α-formamide-ceph
-3-M-4-carboxylate N,N-dimethylanily(485yy, 4.0m
mole) and trimethylchlorosilane (362N9°3.
7β in dry dichloromethane (7d) containing 0 mmol)
-amino-3-(4-ethylpyridinium)methyl-7
α-Formamide-cef-3-M-4-carboxylene
-) (181'IIIg, 0.50 mmol) about 0.5
Refluxed under argon for an hour. The resulting solution was cooled and dried.
Glue, L-2-((4-ethyl) in chloromethane (5d)
(2,3-dioxopiperazin-1-yl)carbonyl
Ruamino]-2-(cheno-2-yl)acetyl chloride
[Corresponding by the method described in Example 1(b)]
A solution of freshly prepared fl.
It was added with stirring at room temperature. The reaction was monitored by reverse phase HPLC.
I watched it. After about 0.25 hours as described in Example 1(c)
The title compound (160q, 48-)t-
Obtained. λmax(HzO) 227nrn(am24218)
:vmax (KBr)3380.3280.17
81.1710 (sh), 1684°1635, and
16153-; δH(DzO)CD/L ratio, approximately 3
:2) (main rotamer) 1.18 (3H,t, J7.
2Hz). 1.30 (3H, t, J7.5Hz), 2.96 (2H
,q, J7.5H2, ambiguous IH, high fee of ABq
arm), 3.50 (2H,q, J7.2Hz
, indistinct IH, ABq low field arm), 3.
60-3.80 (2H, m), 3.90-4.10 (2
H. m), 1.2H, A with 5.18 and 5.33C or less
Bq, J14.5Hz), 5.21 and 5.41C or less
with 0.8H, ABq, J14.5Hz),
5.29(0,4-H,s), 5.35(0,6
H,s), 5.80(0,6H,s), 5
．． 82(0,4H,/,s), 6.95-7.
10 (IH, m), 7.15-7.30elH, m),
7.32-7.50 (IH, m), 7.80-8.00
(2H, m), 8.13 (0,4H.s), 8.16 (0,6H,s), and 8.55-8.
80 (2H-m) CF, A, B, (+ve ion) (chi
oglycerol/MeOH) ynt 670 ]. Example 6 7β-CD, L-2-((4-ethyl-2,3-dio
xopiperazin-1-yl)carbonylamino]-2-
(3,4-methylenedioxyphenyl)acetamide]
-3-(4-ethylpyridinium)methyl-7α-phor
Muamido-cef-3-em-4carboxylate N,N-dimethylanily(243jlP, 2.0mmol
dry dichloromethane (10,d) containing trimethylchlorosilane (163q. 1.5 mmol)
7β-amino-3-(4-ethylpyridinium)
Chil-7α-formamide-cef-3-M-4-cal
Boxylate (91+IP, 0.25 mmol) was added to approx.
Refluxed under argon for 5 hours. When obtained, take a bath and cool the shiso.
and dried dichloromethane (5-), L-2-(
(4-ethyl-2,3-dioxopiperazin-1-yl
) carbonylamino]-2-(3,4-methylene dioxy
Cyphenyl) acetyl chloride [described in Example 1(b)
The corresponding acid (113q, 0.31m mole)
(freshly prepared from 1999) was added with stirring at room temperature. reaction
was monitored by reverse phase HPLC. Approximately 0.75 hours later
Purification as described in Example 1(c) yielded the title compound (
74 Cape, 42 Chi) were obtained. λmax(HtO) 249nm (1m18991);
umax (KBr) 3410.3300 (sh), 17
79.1710(sh), 1676,]640. and 1
616 cm-1; δH<D20) CD/L ratio,
approximately 4:1) (main rotamer) 1.19 (,3H.t, J7.2Hz), 1.32 (3H,t, J7.5H
z), 2.80-3.10 (3H, m), 3.35-3
．． 60 (3H, m), 3. tiO-3,80(2H, m
), 3.85-4.10 (2H, m), 5.10-5.
50 (4H, m), 5.75-6.05 (2H, m),
6.75-7.10 (3H, m), 7.80-8.00
(2H, m), 8.13 (0,2H, s), 8.
16 (0,8H,ts) and 8.65-8.80 (2
H, m); (F, A, B, (+ve ion) (chi)
Example 7 7β-(D-2-(2-chloro-4,5-diacetoxy)
phenyl)-2-((4-ethyl-2,3-dioxopi
perazin-1-yl)carbonylamino]acetamide
)-3-(4-ethylpyridinium)methyl-7α-pho
lumamide-cef-3-em-4-carboxylate N,N-dimethylanili 7 (24311?, 2.0 mmol
) and trimethylchlorosilane (1634°1.5m
7β- in dry dichloromethane (7ad) containing
Amino-3-(4-ethylpyridinium)methyl-7α
-Formamide-cef-3-M-4-carboxylate
) (91 mF, 0.25 mmol) for about 0.5 hours.
The mixture was refluxed under a vacuum. The resulting solution was cooled and washed with dry dichloromethane.
D-2-((4-ethyl-2,3-di) in tan(5-)
oxopiperazin-1-yl)carbonyl 7mi/]-2
-(2-chloro-4,5-diacetoxyphenyl)acetate
tyl chloride [corresponding acid by the method of Example 2(b)]
(147q, 0.313 mmol)] was stirred at room temperature.
Added while stirring. The reaction was monitored by reverse phase HPLC.
Ta. After about 0.75 hours purification as described in Example 1(c)
The title compound (6011F, 28%) was obtained. 1°21 (3H, t, J7°OHz) per 1 tamer)%
, 1.35 (3H. t, J7.5Hz), 2.20-2.45 (6H, m)
, 2.80-3.10 (3H, m), 3.40-3.6
3 (3H, m), 3.64-3.85 (2H, m), 3
．． 85-4.15 (2H, m), 5.10-5.70 (
3H, m), 5.97 (IH, s), 7.30-7.6
0 (2H, m) 7.80-8.05 (2H, m), 8.
20 (IH, s), and 8.55-8.85 (2H,
m); (F, A, B, (+ve ion) (thioglyceride)
o −/L/ ) MFr' 814 ). Example 8 7β-CD-2-((4-ethyl-2,3-dioxopi
perazin-1-yl)carbonylamino]-2-pheny
ruacetamide]-7α-formamide-3-(3-hyperacetamide)
(Droxymethylpyridinium) Methyl-cef-3-em
-4-carboxylate (a) 7β-amino-7α-pho
lumamide-3-(3-hydroxymethylpyridinium)
) Methyl-cef-3-em-4-carboxylate 7β
-amino-7α-formamide cephalosporanic acid (0
, 2go 0.64 mmol) [in water (6-)] in Example 2
Sodium iodide (0,846
&, 5.64 mmol) and 3-pyridinemethanol (0
, 271tst, 2.82 mmol)
The title compound (0,098#, 43%) was obtained at Oumax (KBr) 3372.1764.1670. Reach
and 16113-”δH (D 0) (main rotamer) 3
．． 19 and 3.63 (2H, AB (1°J17.6Hz
), 4.91 (2H, s), 5.28 (IH, a). 5.35 and 5.48 (2H, ABq, J14.7Hz
), 8.11 (IH, dd, J7.7 and 5.9Hz
), 8.19 (IH, s). 8.56 (IH, d, J7.7Hz), 8.87 (IH
, d, J5.9Hz) and 8.95 (IH,s). (b) 7β-CD-2-((4-"4J'-2e3
-dioxopiperazin-1-yl)carbonylaminoco
-2-phenylacetamide]-7α-formamide-
3-(3-hydroxymethylpyridinium)methyl-se
3-M-4-carboxylate 7β-amino-7α-formamide-3-(3-hydro
(oxymethylpyridinium) methyl-cef-3-em-4
-carboxylene) (75 wq. 0.21 mmol) was suspended in anhydrous dichloromethane (5-).
Cloudy chlorotrimethylsilane (0.14m, 1.26
mmol) and N,N-dimethylaniline (0.27mmol. 2.13mmol) were added under argon and the mixture was refluxed for 1 hour.
A passing thought. The resulting fi nine bath solution was cooled to room temperature and diluted with anhydrous dichloromethane.
1)-2-((4-ethyl-2,
3-dioquine piperazin-1-yl)carbonylamino
]-2-Phenylacetyl chloride [Example 1 (b)
Please note that the corresponding acid (88”F, 0.2
Manufactured from 8mmol) and add tiger. After a further 0.5 h the purification described in Example 1(C)
The title compound (50 kg, 36%) was obtained. λmax(H*O) 256nm (am14152)
; νmax (KBr)3291.1782.1
715. ]675. and 1615 Tan″″1:δH(Dz
O) CD isomer; main rotamer) especially 1.17 (3H
. t, J7.2Hz), 2.86 (IH, d, J17.6
Hz; High 2 yield door of ABq-A)-3,47(2
H-qeJ7.2Hz; ABq low field arm;
Overlap IH, d), 3.65 (2H, 'm), 3
．． 95(2)Lrn), 4.84(2H,s), 5.
1-5.6 (4H, complex m) = 7-3-7
．． 6 (5H-m)s 8.0-8.2 (2, m), 8
．． 51 (IH, m), and 8.7-8.95 (2H,
m); (F, A, B, (thioglycerol/Hh
O)■r666). Example 9 7β-CD-2-((4-ethyl-2,3-dioxopi
perazin-1-yl)carbonylamino]-2-pheny
[acetamide]-7α-formamide-3-(4-methane)
methylpyridinium) methyl-cef-3-em-4-cal
Boxylate (a) 7β-amino-7α-formamide-3-(4-
Methylpyridinium) Methyl-cef-3-m-4-ka
Ruboxylate 7β-amino-7α-formamide cephalosborane #
(0,29,0,64 mmol) is described in Example 2 (transformation)
Sodium iodide (0,846
9,5,64 mmol) and 4-methyl, pyridine (0,
274d, 2.82 mmol) to form the title
A compound (0,0919,41'4) was obtained. ymax(KBr)3371.1762.1675,1
640. and 1511m-'; δH(DsO) (main a
-117) 2.64 (3H-s), 3.15 and 3.5
8 (2H, A11q, J17.6Hz). 5.23 and 5.34 (2H, ABq, J14.7Hz
), 5.26 (IH, s), 7.88 (2H, d, J6
．． 3Hz), 8.16 (IH. m)s and 8.69 (2H, d, J6.5Hz). (bl 7β-CD-2-((4-ethyl-2,3-di
oxopiperazin-1-yl) carbonylated ζ-2
-phenylacetamide]-7α-formamide-3-
(4-methylpyridinium)methyl-cef-3-m-
4-carboxylate 7β-amino-7α-formamide)”-3-(4-methyl
(lupyridinium) methyl-cef-3-em-4-calpho
xylene) (86W, 0.247 mmol) in Example 8.
Acylated as described to contain about 20 SL-isomers
The title compound (62 Misaki, 39 Chi) was obtained. λmax(HxO) 253nm(aml 5783
); νmax(KBr)3400.1780.1
710,1680.1636. and 16103-”;
δ[D鵞0)(j;)-isomer; major rotamer) especially
1.18 (3H, t, J7.2Hz), 2.66 (3H
,s). 2.83 and 3.42 (2H, ABq, J17.6Hz
), 3.50 (2H, m), 3.70 (2H, m), 4
．． 0 (2H, m), 5.1-5.5 (41 (, comple
m)e7.3-7.6(5Hzm)*7.86(
2H, broad d, J5.9Hz), 8.
15 (IH. sL and 8.63 (2H, de, Ifi, 6Hz
) ; (F, A, B. (HI3)MH+650]. Example 10 7β-amino-3-(4-(2-Nt-butoxycarboxylic acid)
Bonylamino-2-carboxy)ethylpyridinium co
Methyl-7α-formamide-ceph-3-M-4-ka
ruboxylate 7β-amino-7α-formamide cephalosporanic acid
(100η, 0.317 mmol) and sodium iodide (4
18ηm 2.78 mmol) and 4-[2-Nt-
Butoxycarbonylamino-2-carboxy]ethylpi
Water (1
2m) and acetone (1d). mix at 6 o'clock
The mixture was heated to 60° C. for a while, cooled, and then heated, and the F solution was concentrated. The concentrate was purified as described in Example 2(&) to give ca.
0% 4-(2-Nt-butoxycarbonylamino-
The title compound containing 2-carbo-xy)ethylpyridine (
143W) was obtained. uma:c(KBr)3403.1764.1683.
and 160 Bcrtt-'δHtDxO) (main row
Tamer) especially 1.34 (9H,a), 3.0-
3.3 (2H, m), 3.4-3.7 (2H, m), 4
．． 42 (IH. m), 5.25 (IH, s), 5.28 and 5.40
(2HeABq. J14.6Hz), 7.96 (2H, d, J6.5Hz
), 8.16 ((1u * a ) m and 8.81
(2H, d, J6.5Hz); (F, A. B, (thioglycerol) MH+522]. Example 11 7β-CD-2-((4-ethyl-2,3-dioxopi
perazin-1-yl)carbonylaminoco-2-queni
[acetamide]-3-(3-ethyl-4-methylpyry
Zinium) methyl-7α-formamide-ceph-3-e
Mu-4-carboxylate (a) 7β-amino-3-(3-ethyl-4-methylpi
Lysinium) methyl-7α-formamide-cef-3-
Em-4-carboxylate 7β-amino-7α-phor
Muamidocephalosporan [(0,29,0,64mMo
) t-Sodium iodide (0,846#, 5.64mmol)
) and 3-ethyl-4-methylpyridine (0,341
9,2,82 mmol) in water (6d) and
The mixture was heated at 60c for 7 hours. Cool the solution in vacuum
Concentrate to about 2d and title ``lt composition 0.0
98 &, 41 S) as described in Example 2(a)
It was isolated like this. umax(KBr)3367.3300.1767.1
676, and 1616 Tan°1; δH1tO) (main lo
Tamer) 1.25 (3H. t, J7.5Hz), 2.57 (3H, s), 2.81
(2H=(1-J 7.5Hz), 3.11 and
3.53 (2H, ABq, J17.5Hz), 5.18
and 5.29 (2H, ABq, J] 4.7Hz). 5.22 (IH, s), 7.79 (IH, d, J6) 1
z), 8.14 (IH, s ), 8.53 (IH, d,
J6Hz), and 8.58(IH,s); (F,
A, B, (glycerol/H20)■t377). (b) 7β-CD-2-((4-ethyl-2,3-dio
xopiperazin-1-yl) carbonylaminoco-2-
phenylacetamide]-3-(3-ethyl-4-methy
lupyridinium) methyl-7α-formamide-cef-
3-Em-4-carboxylate 7β-amino-3-(3-ethyl-4-methylbi;
Eum) Methyl-7α-formamide-cef-3-M
-4-carboxylate (98++v. 0,26 mmol) chlorotrimethylsilane (0,2
de1.56 mmol) and N,N-dimethylaniline (
0.25d, 2.08mmol). Suspended in methane (5d) and refluxed the mixture for 1 hour.
. The resulting solution was cooled to room temperature and inorganic dichloromethane was added.
D-2-1'' (4-ethyl-2
, 3-dioquine piperazin-1-yl) carbonyl amine
]-2-phenylacetyl chloride [Example 1~)]
The corresponding acid (125 s 0.39 m model)
(manufactured from )) was added. After an additional hour the title product (35 mF, 19%) (ca.
5, including the L isomer) as described in Example 1(c).
It was isolated as follows. λmax(H*O)257nm(1m16714);L
'max(KBr)3400.3300,1780,1
710,1682. and 1617 cm-”; δH(D
20) CD isomer; main rotamer) especially 1.15 (3
H, t, J7.1Hz), 1.21 (3H, t, J7.
5Hz), 2.56(3H,s), -2,7-2,9(
3H, m), 3.3-3.55 (3H, m), 3.64
(2H, Broad 5) e3.94 (2H9m) e5.0
7 and 5.25 (2H, ABq, J14.6Hz)5.
31 (IH, s), 5.46 (IH, s), 7.2-7
．． 5 (5H. m), 7.76 (IH, d, J6Hz), 8.13 (I
H,s). 8.46 (IH, d, J6Hz), and 8.53 (
IH, s ); (F@A, B, (glycerol/H snow
0) MI (+6783° Example 12 7β-CD-2-((4-ethyl-2,3-dioquimpi)
perazin-1-yl) carbonylaminoco-2-phenylene
[acetamide]-7α-formamide-3-(3-(
3-Hydroxypropyl)pyridinium comethyl-ceph
-3-Em-4-carboxylate (ω 7β-amino-7α-formamide-3-(3-
43-Hydroxypropyl)pyridinium comethyl
F-3-M-4-carboxylate 7β-amino-7α-formamide cephalosporanic acid
(0.39, 0.95 mmol) as described in Example 2(a)
iodide in water as shown) IJum (1,26g18
．． 4 mmol) and 3-(3-pyridyl)propane-1
- Reacted with ol (0.55d, 4.2mmol).
The title compound (0.1679.45%) was obtained. νmax(KBr)3360.3260.1767.1
675. and l 5 ] 5cs−”; δH(DsO
) (main rotamer) 1.91 (2H. complex m), 2.91 (2H, complex
m) s3.12 and 3.56 (2H=ABq, J1
7.5Hz), 3°61 (2H, t, J5.22 (IH
,s), 5.25 and 5.37 (2f(. ABq, J14.6Hz), 7.9-8.0(lH, m
), 8.14 (IIl, s ), 8.42 (IH, m)
, 8.72 (IH, m), and 8.79 (IH, s
); (F, A, B, (Glycero”/H*O)
(b) 7β-CD-2-((4-ethyl-2,3-dio
−゛〜・o“kin bimarazin-1-yl)carbonyl
Aminoco-2-phenylacetamide]-7α-form
Amido-3-(3-(3-hydroxypropyl)pyridi)
Niumcomethyl-cef-3-em-4-carboxylate
7β-amino-7α-formamide-3-(3-(3-
Hydroxypropyl)pyridinium comethyl-cef-3
-M-4-carboxylate (100q, 0.26m
mol) t″ suspended in anhydrous dichloromethane (5d)
Lolotrimethylsilane (0.2fILt, 1.56mmol)
) and N,N-dimethylaniline (0,26d, 2
．． 08rnmol) was added and the mixture was heated with argon for 1 hour.
Reflux occurred at the bottom. Add anhydrous diluted solution to the resulting cooled solution at room temperature.
D-2-((4-ethyl-
2,3-dioxopiperazin-1-yl)carbonyla
Minoko-2-phenylacetyl〉loride [Example 1 (b)
) Please note that the corresponding acid (1041!II, 0.
33 mmol] was added. 1.5 hours later
product (63q, 36ti) (contains approximately 15% L isomer)
was isolated as described in Example 1(c). λmaxcH*o) 259mm (1m16078
): umax(KBr)3400.3300.1
783.1710.1676, and 1616y++-”
; δH (DtO) CD isomer; main rotamer)
1.16 (3H, t, J7Hz), 1.90 (2H,
m), 2.80 and 3°39 (2H, ABq, j17.
6Hz), 2.85 (2H, m). 3.47 (2H, q, J7Hz), 3.5-3.7 (4
H, m), 3.9-4.1 (2H, m), 5.1-5.
4 (2H, m, overlap δ5.31.IH, s)
, 5.46 (IH, s), 7.3-7.6 (5H. m), 7.9 (IH, m), 8.13 (IH, s), 8
．． 4 (IH. m) * 8.7 (IH, m) e and 8.75 (IH,
s): CF, A, B. (Glycerol/H!0)MH+694). Example 13 3-(3-acetylpyridinium)methyl-7β-ami
No7α-Formamide Cef-3-M-4-Carbo
Xylate 7β-amino-7α-formamide cephalospora/acid
(0.3 g, 0.94 mmol) as described in Example 2(a)
Sodium iodide in water (10d) at 60°C for 6 hours as described above.
(1,269#, 8.46 mmol) and 3-acetyl
Lupyridine (0.48 ml, 4.34 mmol) and
By reacting, the surface-treated material (0,122g, 3496) was obtained.
Tokuko Oumax (KBr) 3422, 1761, 1700
(sh), 1673 and 161551-”; δH
(D20) (main rotamer) 2.81 (3H,s)
, 3.22 and 3.68 (2H, ABq, !J17.6
Hz) 5.29 (IH,s), 5.41 and 5.47
(2H, ABq, !J14.7Hz), 8.20 (IH
, s), 8.29 (IH, m). 9.08 (IH, m), 9.18 (IH, m), and 9
．． 59 (IH. 3), Example 14 7β-CD-2-((4-ethyl-2,3-dioxopi
perazin-1-yl) carbonylaminoco-2-phenylene
[ruacetamide]-7α-formamide)”-3-(4-
phenylpyridinium) methyl-cef-3-em-4-
Carboxylate (a) 7β-amino-7α-forma
Mido-3-(4-phenylpyridinium)methyl-cef
-3-M-4-carboxylate 7β-amino-7α-formamide cef in water (6 m)
Example of allosporanic acid (0.2 g, 0.64 mmol)
(described in 2(a)) IJum(0,
846! ? , 5.64 mmol) and 4-phenylpyridi
(0,437 Lj, 2.81 mmol)
The title product (0,066g, 26%) was obtained. νmax(I(Br)3373, 1770, 167
6, 1637, and 1620α-1; δH(DsO
) (main rotamers) 3.19 and 3.61 (2H, A
Bq, J17.6Hz), 5.26 (IH,s). 5.28 and 5°40 (2H, ABq, J14.6Hz
), 7.55-7.7 (3H, m), 7.85-8.0
(2H, m), 8.16 (IH. s), 8.30 (2H, d, J6Hz), and 8.85
(2H, d. J 6Hz) ; (F, A, B, (glycerol
/dimethyl sulfoxide) MH"411]. (b) 7β-CD-2-((4-ethyl-2,3-dio
xopiperazin-1-yl) carbonylaminoco-2-
phenylacetamide]-7α-form7mi)'-3-
(4-722rupyridium)methyl-cef-3-em
-4-carboxylate 7β-amino-7α-formamide-3-(4 phenyl
hyricinium) methyl-cef-3-em-4-carboxy
Sylate (60 Cape e0.146 mmol) t-chlorotri
Methylsilane (0.11m, 0.99mmol) and
Anhydrous dicumethane (5-) containing N,N-dimethylaniline (0,15d. 1.18rnmol)
and the mixture was refluxed under argon for 1 hour. The resulting solution was cooled to room temperature and diluted with anhydrous dichloromethane (0
, 5m) in D-2-((4-ethyl-2,3-diox
Sopiperazin-1-yl)carbonylamino)-2-7
22-acetyl chloride [described in Example 1(b),
Prepared from the corresponding acid (58-51-82 mmol)
] was added. After about 40 minutes the title product (23~, 22ch)
(contains about 20-L isomer) as described in Example 1(C)
It was isolated as described. λmax (H snow 0) 294nm (Am20045.
); umax(KBr)340te3300.1
781.1710(ah), 1679° and 1634m
-1; δH(DzO) (D isomer; main rotamer)
Especially 1.11 (3H, t, J7Hz), 2.85 (IH
. ABq high field arm, J18Hz), 3.3-
3.7. (5H, complex m), 3.8-3.9 (2Hz
m), 5.11 (IH, ABqO high field
arm 15.2Hz; low field arm unclear),
5.34 (IH,s ), 5.44 (IH,s )7.
1-7.5 (5H, m), 7.5-7.7 (3k (, m
), 7.8-7.9 (2H, m), 8.05-8.3 (
3H, m), and 8.75-8.85 (2H, m); (
F, A, B, (glycerol/H20) ME (+7
123 Example 15 7β-amino-3-(3-carbamoylpyridinium)
Methyl-7α-formamide-ceph-3-M-4-ka
ruboxylate 7β-amino-7α-formamide cephalosporanic acid
(0.43 g, 1.36 mmol), nicotinamide (0
, 244,9,2 mmol] and sodium iodide (2,4
9, 15, 9 mmol) was dissolved in water (10 m) and the pH was adjusted to 2.
Adjusted to 6.3 with M sodium hydroxide solution. mixed
Heat the material to 60°C under argon for 5 hours, cool and adjust the pH.
Adjusted to 6.5 again with 2M sodium hydroxide solution. H
Chromatography and fractionation of P20SS resin
The title product (0,138 g, 26%
) met. λmax261nm (1m12120) ;umax
(KBr) 3340 *1765.1675. as well as
1610 saw-1; δH (DzO) (main rotamer) 3
．． 18 and 3゜63(2)(, Abq,, Jl7.6z
). 5.26 (IH,s ), 5.38 and 5.51 (2f
(, ABq, Jl4.6Hz), 8.15 (IH, a)
, 8.22 (IH, m), 8.93 (IH, m), 9.
11 (11(,m), and 9.38(IH,s). Example 16 3-(2,3-cyclohexenopyridinium)methyl
-7β-CD-2-[(4-ethyl-2,3-dioxo
Piperazin-1-yl]carbonylaminoney-2-phe
nylacetamide]-7α-formamide-cef-3-
Em-4-carboxylate (a) 7β-amino-3-
(2,3-cyclohexenopyridinium)methyl-7α
-Formamide-cef-3-emu-4-carboxylate
7β-amino-7α-formamide cephalosporan
Acid (0,2'!, 0.64 mmol)'f: Water (5d
) and sodium iodide (0,8469°5
, 64 mmol) and 2,3-cyclohexenopyridine
(0,375 g, 2.81 rnmol) was added. Ace
A homogeneous solution was obtained by adding t
The mixture was heated at 60°C for a while. As described in Example 2(e)
The reaction mixture was purified to give the title product (0,751ii1
．． 32%) t-obtained. νmax(KBr)3369.1771.1675. Reach
and 1615α-1; δH(DzO) (main rotamer
) 1.8-2.1 (4H, complex m), 2.9
-3.15 (4H, 2 (hard complex m) 3.1
6 and 3.48 (2H, ABq, Jlo, 5Hz; m
High field arm partially obscured by δ
2.9-3.15). 5.23? j+5.43 (2H, ABq, Jl 5
．． 5Hz ), 5.25 (IH,s ), 7.76 (I
H, m), 8.18 (IH, s), 8.23 (IH+m
) * and 8.57 (IH, m); (F, A, B, (gri
Serol/H2O)■Hi389]. (b) 3-(2,3-cyclohexenopyridinium)
) Methyl-7β-(D-2-((4-ethyl-2,3
-dioquinpiperazin-1-yl]carbonylamino]
-2-phenylacetamide]-7α-formamide-
Cef-3-M-4-carboxylate 7β-amino-3-(2,3-cyclohexenopyridine
um) Methyl-7α-formamide-cef-3-m-
4-carboxylene) (120■.0,32m)v)'k Chlorotrimethylsilane
Ran (0,24d, 1.92mmol) and N,N-dimethyl
Free containing thylaniline (0.32m, 2.56mmol)
The mixture was suspended in water dichloromethane (54) and
The mixture was refluxed under a vacuum for 15 minutes. The obtained solution was cooled to room temperature.
D-2-((4
-ethyl-2,3-dioxopiperazin-1-yl)ka
rubonylaminoco-2-phenylacetyl chloride
The corresponding acid (86η*
0.27 mmol] was added. Approximately 40 minutes later
The title product (47■, 22%) (contains about 25% L isomer)
) was isolated as described in Example 1(c). umax(KBr)3421,1777.1710.1
676, and 1612α-1; δH(DzO) (D isomerism
body; main rotamer) especially 1.16 (3H,t, J7H
z), 1.7-2.0 (4H, 2 complex r
n) s2.79 and 3.23 (2H, ABq, 718
Hz), 2.85-3.1 (4H, m), 3.47 (2
H, q, J7Hz), 3.66 (2H, broad 8)
* 3.97 (2H, m) 15.20 and 5.40 (2
H, ABq, Jl 6Hz), 5.32 (IH. m), 5.49 (IH, s), 7.3-7.5 (5H,
m), 7.6-7.8 (IH, m), 8.13 (IH,
s), 8.19 (IH, m), and 8.43 (IH, m
); (F, A, B, thioglycerol/H20)MH”
690]. Example 17 7β-(D-2-((4-ethyl-2,3-dioxopi
perazin-1-yl) carbonylaminoco-2-phenylene
-7α-formamide-3-(3-acetamide)
(toxypyridinium) methyl-cef-3-em-4-ka
Ruboxylate (a) 7β-amino-7α-formamide
Do-3-(3-methoxypyridinium)methyl-cef-
3-M-4-carboxylate 7β-amino-7α-formamide cephalosporic acid
(0,29,0,64 mmol) for 6 hours under argon.
Sodium iodide (0,846 &, 5,64
mmol) and 3-methoxypyridine (0,367J7
, 3.37 mmol). Example 2(a)
The reaction mixture was purified to give the title product (0
, 1099, 47%). pmax(KBr)3369.1766.1676, and
and 1610α-1:δH(D!O) (main rotamer)
3.16 and 3.61 (2H. ABq, J17.6Hz), 4.03 (3H, s), 5
．． 26 (IH. fi), 5.26 and 5.41 (2H, ABq, J14
Hz), 7.98 (IH, m), 8.13 (IH, m)
, 8.17 (IH, s). 8.53(]H,m), and 8.68(IHes)-c
b) 7ti-cD-2-r, <4-ethyl-2,3-di
Oxopiperazin-1-yl)carbonylamino)-2
-phenylacetamide]-7α-formamide-3-
(3-methoxypyridinium)methyl-cef-3-em
-4-carboxylate 7β-amino-7α-formamide-3-(3-methoxy
cypyridinium) methyl-cef-3-M-4-carpo
Kijire) (91W9.0゜25mmol) in chlorotri
Methylsilane (0.19m, 1.5mmol) and N,N
-dimethylanili7 (0,33 qt. 2.6 mmol) in anhydrous dichloromethane (5-)
The suspended mixture was refluxed under argon for 75 hours. The resulting solution was cooled to room temperature and diluted with anhydrous dichloromethane (1
D-2-((4-ethyl-2,3-dioxo
piperazin-1-yl) carbonylaminoco-2-phene
Nyl acetyl chloride (Example 1 can) as described in
The corresponding acid (12°'9 e 0.37 m%)
[manufactured by] was added. After stirring at room temperature for about 0.75 hours, the title product
product (106Tn9.64%) (approximately 20% L isomer)
) are described in Example 1(c), and are simply explained in the following. λmax (H*O) 250nm (1m12469)
;pmax(KBr)3431.1780,1710
．． 1675. and 1611m-1; δH(D20)C
D isomer; main rotamer) especially 1.18 (3H. t, J7Hz) 2.83 (IH, ABqO high field
Arm ÷ J17Hz), 3.48 (2H, q, J7Hz
) (unclear approximately δ3.43 (IH, ABq low field
arm), 3.67 (2H, broad s), 3°97 (
3H,! I), overlap 3°9-4.1 (2H. m), 5.35 (IH, s), 5.52 (IH, a),
7.3-7.5 (5H, rn), 7.95 (IH, m)
, 841 (lH, m). 8.15 (IH, s ), 8.47 (IH, m) = and
8.66 (IH. s); (F, A, B, (Glycer I11-le/H
20) MH+6663. Example 18 7β-amino-3-(3-chloropyridinium)methyl
-7α-formamide-ceph-3-M-4-carboxy
7β-amino-7α-formamide cef in sylate water (6d)
Sodium iodide to allosporanic acid (100+0.31 mmol)
Thorium (670-m4.47 mmol) and 3-chloro
Pyridine (778~, 4.21 mmol) was added. Ace
Add a ton of saturated sodium bicarbonate to form a uniform solution.
The temperature was adjusted to 6.5 by adding a water solution. 60% of the mixture
℃ and the reaction was monitored by reverse phase HPLC.
Ta. After about 7 hours, purification similar to Example 2(a) yielded the title
A fossilized fish (25 Cape, 21 Chi) was obtained. pmax (KBr) 3365.3280 (sh), 17
63.1671° and 1609cIn″l; δH(D2
0') (main rotamer) 3.17 and 3.64C
2H, ABq, J17.4Hz), 5.27 with the following
(lr(.5) e5.31 and 2J(,AB
Q, J15.5Hz), 8.09 (IH, dd, J8.
1 and 7.0Hz), 8.17(IH,s), 8
．． 63 (IH, d, J8.IHz), 8.93 (IH=
d, J7. OHz), and 9.16 (IH,s)
. Example 19 7β-CD-2-(3,4-diacetoxyphenyl)
-2-((4-ethyl-2,3-dioxopiperazine-
1-yl)carbonylaminocoacetamide]-7α-
Formamide-3-(quinolinium)methyl-cef-3
-Em-4-carboxylate (a) 7β-amino-7
α-Formamide-3-(quinolinium)methyl-cef
-3-M-4-carboxylate 7β-amino-7α-formamidose in water (15 m)
Iodination to phalosporanic acid (0.69, 1.90 mmol)
Sodium (2,529,16,8 mmol) and quinoli
(1,089.8.4 mmol) of acetone was added.
Add while stirring to create a homogeneous solution for about 6.5 hours.
Heated at 60°C (reaction monitored by reverse phase HPLC).
SifC). Purified as in Example 2(a) to obtain the title
A compound (0,113!9.15) was obtained. umax (KBr) 3373, 3240 (sh),
1772, 1668 and 1616an-"; δH(
DzO) 2H, A with below 3.14 and 3.42C
Bq, Jl7.6Hz), 5.19 (IH, s), 5.
2H, ABq, Jl with 74 and below 5.93C
5.4Hz), 7.90-8.13 (2H, rn)
, 8.15(IH,s) , 8.18-8.55
(3Hzm), and 9.05-9.30 (2H-m). (b) 7β-CD-2-(3,4-diacetoxy7enyl
)-2-((4-ethyl-2,3-dioxopiperazi)
carbonylaminocoacetamide]-7
α-Formamide-3-(quinolinium)methyl-cef
-3-M-4-carboxylate 7β-amino-7α-formamide-3-(quinolinium)
) Methyl-cef-3-em-4-carboxylate (
126y9, 0.33 mmol) in Example 2(c)
D -2-(3,4-diacetoxyphenyl)
-2-((4-ethyl-2,3-dioxopiperazine-
1-yl) carbonylaminocoacetyl chloride (implemented)
The corresponding acid (21411q, 0
．． 49 mmol)]
The title compound (1104°42%, containing about 30% L isomer)
) was obtained. umax (KBr) 3400, 3290, 1773
, 1710 (sh). 1675 and 1625αM-”; δH(DzO)CD
isomer; main rotamer) especially 1.19 (3H,t,
J7.4Hz), 2.10-2.40(6H,
m), 1.4H, A with 2.56 and 3.13C or less
Bq. J17Hz) 3.35-3.60 (2H, m), 3.6
0-3.80 (2H, m), 3.85-4.10 (2H
, m), 5.32 (0,7H.s), 5.50 (0,7H,s), 5.65-6.00
(2H, m). 6.95-7.55 (3H, m), 7.90-8.60
(6H, m). and 9.00-9.30 (2H, m): (F, A, B,
(+ve ion) (HzO/dimethyl sulfoxide/G
lycerol) ME ("802]. Example 20 3-(4-(tertiary-butyl)pyridinium comethyl-7
β-CD-2-((4-ethyl-2,3-dioxopipe
radin-1-yl)carbonylaminoco-2-phenyl
Acetamide]-7α-formamide-cef-3-M
-4-carboxylate (a) 7β-amino-3-(4
-(tertiary butyl)pyridinium]methyl-7α-form
Amido-cef-3-em-4-carboxylate 7β-amino-7α-formamide cephalosporanic acid
(0.39, 0.95 mmol) as described in Example 2(a)
4-(tertiary butyl)pyridine (0,567
9,4,2 mmol) and sodium iodide (1,26 g+
8.4 mmol) to give the title compound (0,1459
, 39 yen). λmax(HtO)228(ff1m11951) and
255nm (13240) umax (KBr) 3377
, 3280(ah), 1764, 1674. 1640(ah), and 1615α-1;δH(IhO
) 1.39 (9J(. s), 3.13 and 3.56 (with 2H, ABq
, Jl7.6, with 5.24 and 5.36C or less
2H, ABq, Jl4.6Hz), 5.24(IH,s
), 8.08 (2H, d, J6.7Hz). 8.16 (IH, s), and 8.75 (2H, d, J6
．． 7Hz); (F, A, B, (+ve ion) (thio
glycerol) MH+3913°(b) 3-(4-(three)
butyl]pyridinium]methyl-7β-(D-2-(
(4-ethyl-2,3-thioxopiverazin-1-yl
) carbonylaminoco-2-phenylacetamide]-
7α-Formamide-Cef-3-M-4-carboxy
Rate 7β-amino-3-(4-(tert-butyl)pyridinium)
] Methyl-7α-formamide-cef-3-M-4-
Carboxylate (11'71F. 0.31%) was prepared as described in Example 2(C) (D-
2-((4-ethyl-2,3-dioxopiperazine-1
-yl) carbonylaminoco-2-phenylacetyl
Correspond by the method described in Cerid [Example 1 can]
Newly manufactured from acid (144■ + 0.45 mmol)]
The title compound (137 Misaki, 66 Chi) was acylated by
Obtained. λmax(HtO)226Cgm21282) and 25
5 nm (13240); l'max (KBr) 341
0.3290, 1780° 1710 (sh), 1683
．． 1635. and 1616an″″1; δH(D20)
CD-isomer; main rotamer) 1.15 (3H,t,
J7. IHz), 1.37 (9H-a) $2.
75 and below 3.36C as well as 2H, ABq, Jl7.
7Hz), 3.47 (2H, q, J7.IHz) 3.5
5-3.75(2)(,m), 3.80-4.10(2
H, m). 2H, ABq, J with 5.12 and below 5.30C
l4.4Hz). 5.31 (IH, s), 5.47 (IH, s), 7.2
0-7.55 (5Hm), 8.04 (2H, d, J6.
2Hz), 8.21 (IH, a). and 8.68 (2H, d, J6.2Hz);
(F, A, B, (+ve ion) (thioglycerol)
)MFl+692]. Example 21 7β-(D-2-((4-(3-chlorophenyl)-2
,3-dioxopiperazin-1-yl) carbonyl amine
Noco-2-phenylacetamide]-3-(4-ethyl
pyridinium) methyl-7α-formamide-cef-3
-Em-4-carboxylate 7β-amino-3-(4-ethylpyridinium)methyl
-7α-formamide-ceph-3-M-4-carboxy
Sylate (87■, Q, 24 mmol) in Example 2(c)
D-2-((4-(3-chlorophenyl) as in
) -2,3-dioxopiperazin-1-yl)carbo
nylamino]-2-phenylacetyl chloride (Example
1 (b) with the corresponding acid (120 μ, 0.
30mmol) to new

[Produced in this way] The title compound (24■, 1
3%). umax (KBr) 34001310 (sh), 177
7.1710 (sh), 1683.1640, and 1
620crR-”; δH(1:1(CDs)zco/
DtO] CD isomer; main rotor f −) 1.37
(3Ht, J7.3Hz), 2.89 and 3.5
2H, ABq with 1C or less. Jl7.5Hz)2.95-3.10(2H,m),
4.00-4.35 (4H, m), 5.15-5.70
(4H, m), 7.30-7.70 (9H, m), 7.
90-8.10 (2H, m), 8.21 (IH. 8), and 8.75-9.00 (2H, m); (F,
A, B, (+va ion (thioglycerol) MH
+7463. Example 22 7β-CD-2-((4-ethyl-2,3-dioquinpiperazin-1-yl)carbonylaminoco-2-phenylacetamide]-7α-formamido-3-(4-methoxypyridinium)methyl -Cef-3-emu 4-carboxylate (a) 7β-amino-7α-formamido-3-(4-methoxypyridinium)methyl-Cef-
3-Em-4-carboxylate 7β-amino-7α-formamide cephalosporanic acid (0,331ge1.05 mmol) was prepared as described in Example 2(a), as 4-methoxypyridine (0,504F
, 4.62 mmol) and sodium iodide (1,399,
9.3 mmol) to give the title compound (0.154 g
, 40%) was obtained〇λmax (HzO) 245 nm (1m15427)
; νmax (KBr) 3370.3280 (sh),
1766.1674.1637. and 1615 crs-
”; δH(DtO) (main rotamer) 3.16 and 3.58 (with 2H, ABq, j 17.6
Hz), 4.11 (3H,s), 5.11 and 5
．． 2H, ABq, Jl4.5Hz),
5.23(IH,s), 7.35-7.55(2H.m)-8,16(IHss)s and 8.50-8.70
(2H, m). CF, A, B, (+ve ion) (glycerol/&O
)MEr'365). (b) 7β-(D-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-7T
-nylacetamide)-7α-formamide-3-(4
-methoxypyridinium)methyl-cef-3-em-4
-carboxylate 7β-amino-7α-formamido-3-(4-methoxypyridinium)methyl-cef-3
-M-4-carboxylene) (91m9.0.25m
mol) as in Example 2(c) <D-2-((4-
Ethyl-2,3-dioxopiperazin-1-yl)carbonylamino)-2-phenylacetyl chloride [Run f! 1 (b) prepared fresh from the corresponding acid (100 m, 0.313 mmol)] to give the title compound (70 IIv, 42 mmol). λmax(H2O) 244 nm (1m21071
); l'max(KBr)3411.1779,
1710 (sh), 1675, 1640 and 1620
, hs&) pieces −1; δH(DtO) (main rotamer)
1.18 (3H, ts, J7.IHz) 2.85 (I
H, ABqO High Fiery Field Arm 7.3Hz
), 3.35-3.75 (5H, m), 3.80-4.
04 (2H, m), 4.12 (3H, s), 5.02
and 5.17 (with the following 2H, ABq, Jl4.7H
z), 5.33 (IH, s) 5.52 (IH, a ),
7.25-7.60 (7Hym), 8.15 (IHss
), and 8.45-8.70 (2H, m); (F, A,
B. (+ve ion) (glycerol/H!O)■(”66
6). Example 23 7β-amino-3-(4-carbamoylpyridinium)
Methyl-7α-formamide-cef-3-em-4-carboxylate 7β-amino-7α-formamidecephalosporanic acid (215~to, 68 mmol) in water (7-) with 4-carbamoylpyridine (122'lF 1, Onl-E-nil) and sodium iodide A (800v
. 5,33 mmol) t-added. The ... of the mixture was adjusted to 6.5 by the addition VC of M sodium hydroxide solution. The mixture was heated to 60° C. and the reaction was monitored by reverse phase HPLC. The rewarmed mixture was cooled to room temperature for about 3.5 hours and the pH was readjusted to 6.5 with M sodium hydroxide solution. HP
Chromatography on a 20SSm fat, eluting first with water and then with an acetone/water mixture, followed by lyophilization afforded the title compound (90++v, 35t). νmax (KBr) 3300, 1760.1670. and Z 600cya-” ; δT((DzO) 3.2
2H, ABq, J18H with 0 and below 3.70C
z ), 5.30 (IH,s), 5.50 (2H. system in A), 8.20 (IH,s), 8.42 (2
H, d, J7Hz), and 9.13 (2H, d, J
7Hz) ; [F, A, B. (+ve ion) (thioglycerol/HsO)
MH+3783. Example 24 7β-amino-7α-formamide-3-(isonorinium)methyl-cef-3-em-4-carboxylate 7β-amino-7α-formamide cephalosporan [
1 (0,509, 1,59 mmol) as described in Example 2(a), so the isoquinoline <1.2039°9.
3 mmol) and sodium iodide (2.80? 18.7 mmol) to give the title compound (0.082 mmol).
9.13chi) was obtained. νmax (KBr) 3350, 2380 (ah), 17
66.1670 and 1611cIn-7δH (DzO)
(main rotor f-) 2H, ABq, 'J17.7Hy,), 5.26 with below 3.20 and 3.61C
(IH,s), 5.45 and 5.56 (with the following 2
H, ABq, J14.5Hz), 7.95-8.10
(IH, m), 8.17 (IH.s), 8.20-8.30 (2H, m), 8.35
-8.53 (2H. m, ), 8.50 - 8.65 (IH, m) = and 9.7
5(IH,s); CF, A, B, (+ve ion)
(thioglycerol/MeOH) MH+3853. Example 25 7β-CD-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonylaminoco-2-phenylacetamide]-7α-formamide-3-(4-(
Glob-1-yl]pyridinium]methylcef-3-
Em-4-carboxylate (a) 7β-amino-7α-formamide-3-[4-
(Prop-1-yl)pyridinium comethyl-cef-3
-Em-4-carboxylate 7β-amino-7α-formamide cephalosporanic acid (0,284!i', 0
．． 95 mmol)'t-4-(prop-1-yl)pyridine (0,7219,5
, 95 mmol) and sodium iodide (1.05 g, 7.
00 mmol) to give the title compound (0,1359,
37 h) t-obtained. λmax(HsO) 227 (1m12187) and 25
5nm (13475); Max3360, 3280
．． 1770. 1676.1645(sh) = and 1615m-1; δ
H(D!O)(main rotor?-)0.92(3H,t
, J7.4Hz), 1.72 (2H, tq, J7.5
and 7.4Hz), 2.89 (2H,t, J7.5
Hz), 2H with below 3.3 and 3.56C,
ABq, J+17.6Hz), 5.22 and 5.33(
2H, ABq with the following. J14.7Hz), 5.23 (IH,s), 7.89
(2H, d, J6.4Hz), 8.14 (IH, s),
and 8.70 (2H, d, J6.4Hz); (F,
A, B, (+ve ion) (thioglycerol) yn
-r' 377]. (b) 7β-CD-2-((4-ethyl-2,3-
dioxopiperazin-1-yl)carbonylaminoco-
2-phenylacetamide]-7α-formamide-3
-(4-(prop-1-yl)pyridinium comethyl-
Cef-3-em-4-carboxylate 7β-amino-7α-formamido-3-[4-(prop-1-yl)pyridinium]methyl-cef-3-em-4-carboxylate (117 cape O-31 mmol ) as described in Example 2(c)K (D-2-((4-
Ethyl-2,3-dioxopiperazin-1-yl)carbonylaminoco-2-phenylacetyl chloride [corresponding acid (124
freshly prepared from ηe O, 39 mmol) to give the title compound (111W153%) (containing about 5% L isomer). umax (KBr) 3400, 3290, 1779
, 1710 (sh) 1676.1640. and 161
5 (71!-1; δH(DtO)CD isomer; main rotamer) 0.92 (3f(,t, J7.OHz)
, 1.16 (3H, t, J7.0Hz), 1.60
-1.90 (2H, m), 2H, ABq, Jl7.5Hz), 2.83-3 with below 2.78 and 3.38C
．． 05 (2H2m), 3.40-3.58 (2H, m)
, 3.60-3.80 (2H, m), 3.82-4
．． 15 (2H, m), 2H, ABq, J 14.8Hz), 5.11 and 5.29C or less.
31 (IH, s), 5.47 (IH, s), 7.25-
7.60 (5H, m) 7.75-8.00 (2H, m)
', 8.13 (IH,s ), and 8.60-8.80
(2H, m); (F, A, B, (+ve ion) (thioglycerol) MH+678). Example 26 7β-CD-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonylaminoco-2-phenylacetamide]-3-(2-ethylpyridinium)methyl-7α-formamide -Cef-3-M-4; Carboxylate (a) 7β-amino-3-(2-ethylpyridium)methyl-7α-formamide-Cef-3-M4
-7β-amino-7α-formamidocephalosporanic acid (200q, 0.64 mmol) in carboxylate water (8ml) t
- Sodium iodide (6
70”f, 4.47 mmol) and 2-ethylpyridine (
4281Mi, 4.0 mmol) to give the title compound (54 Wq, 23%). 1'max(KBr)3366.32B0.1772.
1675. and 1617 area-1; δH(IhO) (main rotamer) 1.40 (3H. t, J7.4Hz), 3.10-3.25 (3H, m)
, 3.52 (IH. ABq low field arm, Jl 7.6Hz),
5.25(]H. sl, 2H, ABq with below 5.32 and 5.49C
, Jl5.3Hz), 7.85-8.05(2H, m
), 8.18 (IH,s ). 8.40-8.52 (IH, m), and 8.70-8.
80 (IH, m). (b) 7β-CD-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonylaminoco-2-
phenylacetamido]-3-(2-ethylpyridinium)methyl-7α-formamide-cef-3-em-4
-carboxylate 7β-amine-3-(
2-ethylpyridinium) methyl-7α-formamide-cef-3-em-4-carboxylene 1- (91n
N,N-dimethylaniline (242q+2.0 mmol) in the presence of argon under reflux
and chlorotrimethylsilane ((109tIIi, 1
．． After 0.33 hours of reaction with 0.33 hours of reaction with 55" IF. 0.5 mmol), additional chlorotrimethylsilane (55" IF. 0.5 mmol) was added and reflux was continued for an additional 0.4 hours. ) in -2-[(4-ethyl-2,3dioxopiperazin-1-yl)carbonylaminoco-2-phenylacetyl chloride [the corresponding acid by the method described in Example 1(b)] (120 μm, freshly prepared from 0.375 mmol)] was added. After about 0.5 hours, Example 1 (c)
The title compound (61W,
37 thi) (containing about 20 thi L isomer) was obtained. umax (KBr) 3420, 3290 (sh),
1781, 1710(sh), 1677 and 162
4th stroke-1; δH (DtO) (D-isomer weight rotor?-
) 1.18 (3H,t, J7.IHz), 1.35
(3H, t, J 7.2Hz), 2.81 and 3.
31 (2HABq, Jl7.5Hz with the following), 3.
11 (2H, q, J7.2Hz). 3.50 (2H, q, J7.IHz), 3.60-3.
80 (2H, m) 3.90-4.10 (2H, m), 5
．． 20-5.50 (2H, m). 5.34 (IH, a), 5.50 (IH, s), 7.3
0-7.60 (5H, m), 7.80-8.05 (2H
, m), 8.15 (IH. s ), 8.40-8.55 (IH, m), and 8.5
5-8.70 (IH. m); (F, A, B, (+ve ion) (thioglycerol) ■ Tsuji 664). Example 27 7β-CD-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonylaminoco-2-phenylacetamide)-3-(3-ethylpyridinium)methyl-7α-formamide -Cef-3-em-4-carboxylate (a) 7β-amino-3-(3-ethylpyridinium)methyl-7α-formamide-cef-3-em-4
-Carboxylate 7β-amino-7α-formamidocephalosporanic acid (200 μ to, 64 mmol) in water (8 m) was prepared as described in Example 1(a) using sodium iodide (670 μl).
v, 4.47 mmol) and 3-ethylpyridine (428
"P, 4.0 mmol) to give the title compound (110
~, 47chi) were obtained. νmax(KBr)3370.3270.1770.1
675 and 1611m-1; δH(DtO) (main o-
pmer) 1.30 (3H-t, J7.6Hz)
, 2.89 (2H, q, J7.6Hz), 2H, ABq, J17.6Hz with below 3.16 and 3.59C)
, 5.25 (IH, s ), 5.28 and 2H, AB (1, 15, OHz ), 7.9 with below 5.40C
8 (IH, dd, J8.1 and 6.1Hz). 8.17 (IH, s), 8.44 (1'H, d, J8.
IHz), 8.74 (IH, d, J6.IHz')
, and 8.79(IH,s ): (F, A, B, (+
ve ion) (cyamylpheno-”/CHC11s
) MFr+363]. (b) 7β-CD-2-CC4-ethyl-2,3-
diotopabiberazin-1-yl)carbonylamino]-
2-phenylacetamido)-3-(3ethylpyridinium)methyl-7α-formamide-cef-3-em-
4-Carboxylate 7β-amino-3·-(3-ethylpyridinium)methyl-7α-formamide-cef-3-em-4-carboxylate (91 μ to, 25 mmol) in dry dichloromethane (7-) N,N-dimethylaniline (242
1F1! , 2.0 mmol) and chlorotrimethylsilane (1097v, 1.0 mmol). D-2-((4-ethyl-2,3-dioquinpiperazin-1-yl)carbonylaminoco-2-phenylacetyl chloride [Example 1 (freshly prepared from the corresponding acid (120 μm. 0.375 mmol) by the method described in (b)).
．． After 5 hours, purification as described in Example 1(c) afforded the title compound (86~, 52%) (containing about 25% L isomer). νmax (KBr) 3423.3300 (sh), 17
80.1710 (sh), 1680, and 161
5m-'; δH(D20) (p-isomer; main rotor?-) 1.18 (3H,t, J7.IHz). 1.24-1.35 (3H, m), 2.75-3.00
(3H, m). 3.35-3.58 (3H, m), 3.60-3.80
(2I(,m). 3.85-4.10(2H,m), 5.10-5.55
(4H, m). 7.25-7.55 (5H, m), 7.90-8.05
(IH, m). 8.15 (IH, s), 8.43 (IH, d, J8.4
Hz), 8.68 (IH, d, J5.4 Hz), and 8.73 (IH, s); CF, A, B, (+ve ion) (thioglycerol) MH+664] Example 28 Sodium 7β-amino- 7α-formamide-3-(
7 in water (10 m)
β-amino-7α-formamide cephalosporanic acid (
4-(2-sulfoethyl)pyridine (0,', 87 g, 1.0 mmol) and sodium iodide (1,65 g, 11.0 mmol) t
pH 6 by addition of 2.5 M sodium hydroxide solution
, 5. The resulting solution was heated to 60° C. for about 6 hours, then cooled and concentrated to about 6 Int. The concentrate was added dropwise to vigorously stirred acetone (100ml). Sinden t-
It was removed, washed with acetone, and dried under vacuum. The solid was dissolved in water and chromatographed on HP20SS resin eluting with water to give the title compound (74119, 23%). νmax (KBr) 3425, 3280 (sh),
1760, 1670. 1610.1190. and 1046βm-"; δH(
D20) (main rotamer) 3.15 and 3.60
2H, ABq, J18Hz), 3.38(
4H, s), 5.25 (IH, s), 5.35 (2°H
, AA' system), 8.02 (2H, d, J7Hz)
, 8.19(IH+s)- and 8.80(IH,d,J
7Hz). Example 29 3-(4-cyclopropylpyridinium)methyl-7β
-CD-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonylaminoco-2-phenylacetamide]-7α-formamide-cef-3-em-
4-carboxylate (a) 7β-amino-3-(
4-cyclopropylpyridinium) methyl-7α-formamide cephalosporanic acid (0.30 g, 0.95
mmol) with sodium iodide (1,269,8,4 mmol) and 4-cyclopropylpyridine (0,509,4,2 mmol) as described in Example 1(a) to give the title compound. (160 cm, 45 cm) t-obtained. λmax(HxO) 257 nm (1m19926)
;l'max(KBr) 3410. 3280(ah), 1766.1675.1635,
and 1610 cm-"; δH(DzO) (main rotamer) 1.08-1.24 (2H, m). /J'1.40-1.51 (2H1m), 2.20-2
．． 30 (IH, m). 3.13 and 3.56 (2H, ABq, J17.6Hz
), 5.17 and 5.28 (2H1ABq, J15.4
Hz), 5.24 (IH, a). 7.66 (2H, d, J6.9Hz), 8.16 (IH
, a), and 8.63 (2H, d, J6.9Hz);
(F, A, B, (thioglycerol) (+ve ion) MFr+375]. (b) 3-(4-cyclopropylpyridinium)methyl-7β-(D-2-((4-ethyl-2,3-di oxopiperazin-1-yl) carbonylaminoco-2-phenylacetamide]-7α-formagubicef-3-
7β-amino-3-em-4-carboxylate in dry dichloromethane (10d)
(4-cyclopropylpyridinium)methy71z-7α
- Formamide midcef-3-em-4-carboxylate (75 g, 0.2 mmol) was refluxed for 0.25 h under argon with N,N-dimethylaniline (194
1.6 mmol) and chlorotrimethylsilane (130
■m 1.2 m%le),! Let it react. D-2-(
(4-ethyl-2,3-thioxobiverazin-1-yl)carbonylaminoco-2-phenylacetyl chloride [corresponding acid (96111?. 0.3 m Newly produced from mole) was added. After 0.66 hours, purification as described in Example 1(c) afforded the title compound (60WI?, 44%) containing about 5% (7)L isomer. λmax (HzO) 258nm (1m24858)
; umax (KBr) 3400.3290.17
80.1710 (sh back 635 and 1620 return-l;
δH(IhO) (D isomer; main rotamer) 1.05
-1.15 (5H, m), 1.37-1.55 (2H,
m) = 2.15-2.33 (IH, m), 2.78 and 3.37 (2H, AE (1°J17.6Hz), 3.
49 (2H, qeJ7.3Hz), 3.58-3.77
(2H, m), 3.86-4.08 (2H, m), 5.
05 and 5.24 (2H, ABq, J14.6Hz),
5.32 (IH, a). 5.48 (IH, s), 7.27-7.57 (5H, m
), 7.62 (2H, d, J6.7Hz), 8.14 (
IH, s), and 8.53 (2H, d, J7.6H
z ) ; (F, A, B, (thioglycerol) (
+ve ion] MFr+676]. Example 30 3-(4-cyclopropylpyridinium)methyl-7β
-CD-2-(3,4-diacetoxy7enyl)-2-
((4-ethyl-2,3-dioxopiperazin-1-yl)carbonylaminocoacetamide)']-7α-formaξdocefu 3-M-4-carboxylate 7β-amino-3-(4-cyclo Propylpyridinium) methyl-7α-formamide-cef-3-em-4-
Carboxylate (73 kg. 0.195 mmol) was prepared as in Example 2(c) <D-2-(
The corresponding acid (125■, 0.293 mmol)] to give the title compound (5531F, 3
6%) (approximately 20%+7) containing the L isomer) was obtained. λmax (HhO) 259 nm (1m25091
) Niji max (KBr) 3434.328017
72.1710.1676.1635. and 1615c
m-'; δH(DzO)CD isomer; main rotamer) 1.17 (3H, t. J7.2Hz, unclear 2H, m), 1.40-1.5
5 (2H, m). 2.15-2.40 (7H, m), 2.68 and 3.3
3 (2H, ABq. 3.80 (2H, m), 3.85-4.10 (2H, m
), 5.00-5.30 (2H, m), 5.33 (IH
, s), 5.50 (IH, s) 7.20-7.55 (
3H, m), 7.64 (2H, d, J6.9Hz)
. 8.15 (IHls) e and 8.53 (2H, d, J6
．． 8Hz); (FAB (+ve ion) (thioglycerol) MFr+792]. Example 31 3-(4-cyclopropylpyridinium) methyl-7β
-(D-2-(3,4-dihydroxyphenyl)-2
-((4-ethyl-2,3-dioxopiperazine-1-
carbonylaminocoacetamide]-7α-formamide-cef-3-em-4-carboxylate
13-(4-cyclopropylpyridinium)methyl-7β-[D-22[3,4-
diacetoxyphenyl)-2-((4-ethyl-2-1dioxopiperazin-1-yl)carbonylaminocoacetamide]-7α-formamide-cef-3-em-
4-carboxylate (42, 0.053 mmol)
Sodium sulfite (17 capes, 0
．． 133 mmol) to give the title fraction (21-, 5
6%) (containing about 20% L isomer) was obtained. λmax (H2O) 259nm (1m25182); l
'max (KBr) 3380 (sh), 3285.17
79.1710 (ah). 1676.1637. and 1615(sh)cnl-1
;δH(DzO) (D isomer; main rotor?-) 1.
17 (3H,t, J7.IHz. Unclear 2H,m), 1.35-1.55 (2H,m)
, 2.10-2.30 (IH, m), 2.82 (IH,
ABq low field arm, J16.3Hz), 3.
30-3.57 (3H, m), 3.57-3.80 (2
H, m), 3.85-4.10 (2H, m), 5.05
-5.45 (4H, m), 6.70-7.05 (3H,
m), 7.50-7.70 (2H, m), 8.30 (I
H, s), and 8.40-8.70 (2H9m);
(F A B (+ve ion) (thioglycerol) ■ ("708). Example 32 7β-CD-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonylaminoco-2 -phenylacetamide]-7α-formua is do3-[4-(
Isopropyl)pyridiem-comethyl-cef-3-dimu-4-carboxylate (a) 7β-amino-7α-formamido-3-[4-(isopropyl)pyridiniumcomethyl-cef-3-em-4-carboxylate 7β
-Amino-7α-formamide cephalosporanic acid (0
, 39, 0,95 mmol] as described in Example 2(a).
, 4.2 mmol) and sodium iodide (1,269,
8.4 mmol) to give the title fraction (127η, 3
5 yen). λmax (H*0) 226 (Aml 1267 L and 254 nm (am12141); νmax (KBr)
3374, 3080 (sh). 1761.1675.1635. and 1610 cM-'
; δH (D20) (main rotamer) 1.33 (
6H,d, J6.8Hz), 3.15 and 3.
58 (2H, ABq, J17.6Hz), 3.24 (I
H, septet! 6.8Hz), 5.25
and 5.36 (2H, ABq, J14.6Hz), 5.
25 (IH, s), 7.96 (2H, d, J6.7Hz
), 8.17 (IH, s) = and 8.74 (2H, d
, J6.7Hz); (FAB (+ve ion)
(Thioglycerol) Tsuji 377.2M+H” 75
3]. (b) 7β-CD-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl7mino]-2
-phenylacetamide]-7α-formamide-3-
(4-(isopropyl)pyridiniumcomethyl-ceph-
3-Em-4-carboxylate N,N-dimethylanili 7 (328W, 2.7 mmol)
and trimethylchlorosilane 7 (2207·η. 2.03 mmol) in dry dichloromethane (10d)
7β-amino-7α-formamide-3-(4-(
Isopropyl)pyridinium comethyl-cef-3-em-4-carboxylate (127 eO, 338 mmol) was stirred for 1 hour at room temperature. Dry dichloromethane (0,
D-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonylaminoco-2-
A solution of phenylacetyl chloride (prepared fresh from the corresponding acid (162 μm, 0.507 mmol) by the method described in Example 1(b)) was stirred at room temperature,
and added to the solution. After 1 hour, the composition (91cm, 40%) (approximately 10-L
isomers) were isolated as described in Example 1(c). λmax (HzO) 253 (1 ml 7210), and 225 nm (1 m 21230); νmax (KBr
), 3412, 3290 (ah). 1779.1710(ah), 1678. and 1615
cW1-1; δH(DzO) (main rotamer, D isomer) 1.16 (3H, t. J7.2Hz), 1.31 (6H, d, J6.9Hz)
, 2.77 and 3.38 (2H1ABq, Jl 7.
6Hz), 3.22 (IH, Septet, J, 6.9
Hz), 3.48 (2H,q, J7.2Hz). 3.56-3.75 (ZH, m), 3.80-4.10
(2H, m). 5.12 and 5.30 (2H, ABq, Jl4.2Hz
), 5°32 (IH, s), 5.48 (IH, s), 7
．． 25-7.55 (5H. m), 7.92 (2H1d, J6.6Hz), 8.13
(IH*s). and 8.67 (2H, d, J6.6Hz); (FA
B (+ve ion) (thioglycerol)■(”678
). Leprosy Example 33 7β-CD-2-((4-ethyl-2,3-dioxopiperazin-1-yl)carbonylaminoco-2-2enylacetamide]-7α-formamide-3-(4-(
pyridiniumcomethyl-cef-3-
Em-4-carboxylate (a) 7β-amino-7α-formamide-3-[4-
(Pyrid-2-yl)pyridinium comethyl-cef-3
-M-4-carboxylate 7β in water (12,d)
-Amino-7α-formamide cephalosporanic acid (0
, 44f, 1.39 mmol)) as described in Example 2(a)) IJum (1,849, 12,
27 mmol) and 4-(pyrid-2-yl)pyridine (
0,9569,6,156 mmol) to give the title adduct (0,229,38%). λmax(FF;O)263tgmx538z), and 289 nm(1m16785);l'max(KBr
) 3419, 17171 and 1635 (bx) Tan-1;
δH (DzO) C mainly rotamer) 3.13 and 3.
61 (2H, ABq, Jl 7.6Hz), 5.3
1 and 5.39 (2H, AB (1, Jl4.9Hz)
, 5.37 (IH, s ), 7.64 (IH, ddd
, Jl, 1.5.0 and 7.4Hz), 8.0-
8.2 (3H, m), , 8.54 (2H, d, J6.8
Hz, 8.75 (IH. d, J4.3Hz), and 9.01 (2H,
d, J6.9Hz): (FAB (+ve ion) (thioglycerol) MI (+412). (b) 7β-CD-2-((4-ethyl-2,3-dioquinpiperazin-1-yl)carbonyl amino)-2-
phenylacetamide]-7α-formamide-3-(
4-(pyrid-2-yl)pyridinium comethyl-cef-3-em-4-carboxylate N,N-dimethylanili 7 (236!, 1.94 mmol) and hydrimethyl, chlorosilane (158-11,56
7β in dry dichloromethane (7-) containing mmol)
-amino-7α-formamide-23-[4-(pyrid-2-yl)pyridiniumcomethyl-cef-3-em-
4-carboxylate (100η+0.243mmol)
was refluxed under argon for 50 minutes. Furthermore, N,N-dimethylaniline (59 to 0.49 mmol) and hydrimethylchlorosilane (40
ml, 0.39rnmol) and the mixture was further diluted with
0 minutes of hustle and bustle. The mixture was cooled to about 0° C. (ice/water) and D-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetyl in dry dichloromethane (3d). Chloride [Example 1 (
The corresponding acid (116'9, 0.36
5 mmol) was added. After 2 hours the title compound (1061F9,61cs) (containing about 15% L isomer) was isolated as described in Example 1(c). λmax(HtO)262(4m145005)e and 284nm(grnl4000): urnax
(KBr) 3400 + 3290 e1781.1
710(sh), 1683.1634. and 1620 (
sh)z-'; δH(DzO)CD isomer; main rotor V-) 1.13 (311,t, J7.2Hz), 2
．． 89 and 3.48C2H, ABq. Jl7.8Hz), 3.45(2H,q, J7.2Hz
), 3.55-3.75 (2H, m), 3.80-4.
05 (2H, m), 5.21 and 5.44 (2H, AB
q, Jl5.0Hz), 5.35(IH,s). 5.45 (IH, s), 7.15-7.60 (5H, m
), 7.60-7.70 (lH, m), 7.80-8.
20 (2H, m), 8.14 (IH. a), 8.50 (2H, d, J6.7Hz), 8.76
(IH, d, J4, IHz), and 8.94 (2H,
d, J6.711z): CFAE (+ve ion) (thioglycerol) MI (+713). Example 34 7β-CD-2-(3,4-diacetoxyphenyl)-
2-((4-ethyl-2,3-dioquine piperazine-1
-yl)carbonylaminocoacetamide]-3-(4
-ethylpyridinium)methyl-7α-formamide-
Cef-3-M-4-carboxylate N,N-dimethylaniline (836W, 6.90 mmol) and trimethylchlorosilane (562sv. 5, 17 mmol) in dry dichloromethane (12d
) in 7β-amino-3-(4-ethylpyridinium)
Methyl-7α-formamide-cef-3-nimu-4-carboxylate (312 μ, 0.86 mmol) was added to approximately 0
．． Refluxed under argon for 5 hours. The resulting solution was cooled and dried in dichloromethane (approximately 10).
2-(3,4-diacetoxyphenyl)-2-((4-
Ethyl-2,3-dioxopiperazin-1-yl)carbonylaminocoacetyl chloride [prepared fresh from the corresponding acid (562 μ, 1.29 mmol) by the method of Example 2(b)] was stirred at room temperature. I added while doing so. After 1.25 hours, purification as in Example 1(c) gave the title compound (3
10■. 46%) (containing about 25 L isomers). λmax (HzO) 252nm (1m17443);
νmax (KBr) 3411.3285 (sh), 47
72.1710 (sh). 1682.1636. and 16156n-'; δH(
D20) (D isomer; main rotor?-) 1.17
(3H,t, J7.2Hz), 1.32(3
H, t, J7.5Hz), 2.26 (3H, s), 2.
28 (3H. s), 2.75 and 3.36 (2H, ABq, Jl
7.4Hz), 2.90-3.10 (2H, m),
3.49 (2H, q, J7.2Hz), 3.60-3.
80 (2H, m), 3.80-4.10 (2H, m),
5.15 and 5.33 (2H, ABq, Jl4.9Hz
), 5.34 (IH, s). 5.51 (IH, s), 7.15-7.60 (3H, m
), 7.90 (2H. MF("7sO). Example 35 7β-(D-2-(3,4-dihydroxyphenyl)
-2-((4-ethyl-2,3-dioxopiperazine-
1-yl)carbonylaminocoacetamide]-3-(
7β-CD-2-(3,4-diacetoxyphenyl)-2-((4- Ethyl-2,3-dioxopiperazin-1-yl)carbonylaminocoacetamido-3-(4-ethylpyridinium)methyl-7α-
Formamide-cef-3-em-4-carboxylate (701 da, 0.09 mmol) was dissolved in sulfite (28 m?, 0.225 mmol) as in Example 3.
mol) to give the title compound (42η, 67%) (containing about 25% of the L isomer). λmax(H2O) 248 nm (1m19118)
;νmax(KBr) 3390(sh), 3290
．． 1779.1710(ah), 1677°1638
, and 1618α-1; δHCD 0) (D isomer; main rotor?-) 1.15 (3H, t, J7.0Hz),
1.28 (3H, t. J7.3Hz), 2.81 (IH, ABqO high field arm 7.5Hz), 2.85-3.00
(2H, m), 3.30-3.55 (3H, m), 3.
55-3.75 (2H, m), 3.80-4.10 (2
H,m), 5.12 (high field arm of IH, ABq. Jl 4Hz), 5.28 (IH,s, vague low field arm of ABq, 5.32 (IH,s),
6.70-7.05 (3H, m). 7.75-7.95 (2H, m), 8.12 (IH, s
), and 8.55-8.65 (2H, rh); [FA
B (+ve ion) (thioglycerol/methanol)
MKF696]. The minimum inhibitory concentration (MIC) of the monster of the present invention against u36 E. coli DCO, K. pneumoniae T767, and B. aeruginosa NCTC10 was determined using Honor Agar [Oxoid Ltd.] *Basingstoke ) r UK] by serial dilution. The plates were seeded with 104 colony forming units and incubated overnight at 37°C. The MIC value shown in Table 1 was the lowest concentration of antibiotic that inhibited growth. Comparative data for European patent application 7β-(cheno-2-yl-acetamido)-cefu 3-emu 4-carboxylate (Compound A) are also shown.
Ru. MIC Data Table 1 E. coli DCOO, 120,525 K. pneumoniae 0.12 1
25 P. aeruginosa 1
8 5ONCTC10662 Agent Patent attorney Masaaki Akizawa Mitsunobu 1 person

Claims (66)

[Claims] (1) Formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is phenyl, substituted phenyl, cyclohexenyl, cyclohexadienyl, or is selected from oxygen, sulfur, or nitrogen. 5 containing up to 3 heteroatoms and optionally substituted with hydroxy, amino, halogen, substituted amino or C_1-_6 alkoxy
- or a 6-membered heterocyclic ring; R^2 is hydrogen or an optionally substituted C_1-_6 alkyl group; and R^3 is an optional ring containing 1 or 2 nitrogen heteroatoms; or R^2 and R^3 together with the nitrogen atom to which they are attached are 5- or 6-membered heterocyclic groups optionally substituted with Forms an optionally substituted 5- or 6-membered heterocyclic group containing atoms; R^4 is formula (a), (b) or (c): ▲ Numerical formula, chemical formula, table, etc. There are ▼ (a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (c) {In the formula, R^6 is halogen; trifluoromethyl; hydroxy, C_1-_6 Alkoxy, halogen, carboxy, cyano, carbamoyl, amino, C_1-_6 alkyloxycarbonylamino, arylthio, -SO^-
C_1-_6 alkyl optionally substituted with up to two groups selected from _3 and oxo; C_2-
_6 alkenyl; C_2-_6 alkynyl; C_3-_
7 cycloalkyl; C_3-_7 cycloalkenyl; C
_3-_7 cycloalkyl C_1-_6 alkyl; cyano; C_1-_6 alkylthio; arylthio; sulfonamide; arylamino; arylamide; C_1-
_6 alkoxy; carbamoyl; N-hydroxycarbamoyl; formyl; hydroxyiminomethyl; C_1~
_6 alkylcarbonyl; aryl; optionally substituted heterocyclyl; amino; nitro; hydroxy; C_1-_6 alkylamide; di(C_1-_6 alkyl)amide; C_1-_6 alkylcarbonyloxy; arylcarbonyloxy; carboxy; C_1～
_6 alkoxycarbonyl; aryloxycarbonyl; C_1-_6 alkoxycarbonyloxy; aryloxycarbonyloxy; aryloxy; aralkyloxy; arylcarbonyl; C_1-_6 alkylamino; or di(C_1-_6) alkylamino: R ^7 and R^8 are as defined for R^6, and R^6, R^7 and R^8 are the same or different; or one or one of the groups R^6, R^7 or R^8 2 represent hydrogen; X is a group -CH_2X^1CH_2- (in the formula, X^1 is O
, S or group NR^2^2 [wherein R^2^2 is H or C_
or X is a group -(CH_2)n-, where n is an integer having the value 2, 3 or 4; or ) P-C
H=CH-(CH_2)q- (where p and q are integers that may be the same or different, each having a value of 0, 1 or 2)
and p+q has the value 1 to 3); or is a group of the formula -O(CH_2)mO-, where m is an integer having the value 1 or 2; or together with the bond in the ring to which it is attached is an optionally substituted 6-membered aromatic carbocyclic ring or 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur forming an optionally substituted 5- or 6-membered heteroaromatic ring comprising a substituted pyridinium group of is an easily removable carboxy protecting group] or a salt thereof. (2) Formula ( I a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I a) (In the formula, R^1, R^2, R^3 and R^4 are the formula (I)
and the group CO_2R is a carboxy or carboxylate anion) or a pharmaceutically acceptable salt or pharmaceutically acceptable in vivo hydrolysable ester thereof. (3) R^1 is phenyl, 3-hydroxyphenyl, 3
-(C_1-_6 alkylcarbonyloxy)phenyl, 3-(arylC_1-_6 alkyloxycarbonyloxy)phenyl, 4-hydroxyphenyl, 4-(
C_1-_6 alkylcarbonyloxy) phenyl, 4
-(ArylC_1-_6 alkyloxycarbonyloxy)phenyl, 3,4-dihydroxyphenyl, 3,
4-di(C_1-_6 alkylcarbonyloxy)phenyl, 3,4-di(arylC_1-_6 alkyloxycarbonyloxy)phenyl, 2-halo-4,5-di(C_1-_6 alkylcarbonyloxy)phenyl,
2-halo-4,5-dihydroxyphenyl, 2-halo-
4,5-di(arylC_1-_6alkyloxycarbonyloxy)phenyl, 3,4-methylenedioxyphenyl; 2-thienyl or 2-furyl according to claim (1) or (2) Compound. (4) Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 and R^4 are as defined for formula (I), and R^1^0 is hydrogen, C_1-_8 alkyl, aryl or arylC_1-_6 alkyl; R^1^1 and R^1^2 are the same or different hydrogen,
C_1-_6 represents alkyl, halogen, amino, hydroxy or C_1-_6 alkoxy; or R^1^1
and R^1^2 is the residue of a 5- or 6-membered carbocyclic ring or the residue of a 5- or 6-membered heterocyclic ring containing up to 3 heteroatoms selected from oxygen, nitrogen and sulfur. A compound or a salt thereof according to any one of claims (1) to (3) (forming a group). (5) The compound according to claim (4), wherein R^1^0 is C_1-_4 alkyl. (6) Claim No. 4 in which R^1^0 is ethyl
) or the compound described in (5). (7) The compound is 7β-[D-2[(4-ethyl 2,3-
dioxopiperazin-1-yl)carbonylamino]-
2-phenylacetamido]-3-(4-ethylpyridinium)methyl-7α-formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo hydrolyzable The compound according to claim (1), which is a water ester. (8) The compound is pepyrazin-1-yl)carbonylamino]acetamido]-7α-formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolyzable ester thereof. A compound according to claim (1). (9) The compound is 3-(2,3-cyclopentenopyridinium)methyl-7β-[D-2-(3,4-dihydroxyphenyl)-2-[(4-ethyl-2,3-dioxopiperazine) -1-yl)carbonylamino]acetamido]-7α-formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt or pharmaceutically acceptable ester thereof that can be hydrolyzed in vivo A compound according to claim (1). (10) The compound is 7β-[D,L-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(fur-2-yl)acetamide]-7
A patent claim which is α-formamide-3-(4-ethylpyridinium)methyl-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo hydrolyzable ester Compounds according to scope (1). (11) The compound is 7β-[D,L-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(thien-2-yl)acetamide]-
A patent claim that is 3-(4-ethylpyridinium)methyl-7α-formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolyzable ester thereof A compound according to the scope item (1). (12) The compound is 7β-[D,L-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]-2-(3,4-methylenedioxyphenyl)
acetamido]-3-(4-ethylpyridinium)methyl-7α-formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolyzable ester thereof. A compound according to claim (1). (13) The compound is 7β-[D-2[2-chloro-4,5
-diacetoxyphenyl)-2-[(4-ethyl-2,
3-dioxopiperazin-1-yl)carbonylamino]acetamido]-3-(4-ethylpyridinium)methyl-7α-formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt or pharmaceutical thereof The compound according to claim (1), which is an acceptable in vivo hydrolyzable ester. (14) The compound is 7β-[D-2-[(4-ethyl-2
, 3-dioxopiperazin-1-yl)-carbonylamino]-2-phenylacetamide]-7α-formamide-3-(3-hydroxymethylpyridinium)methyl-cef-3-em-4-carboxylate or pharmaceuticals thereof The compound according to claim (1), which is an acceptable salt or a pharmaceutically acceptable in vivo hydrolyzable ester. (15) The compound is 7β-[D-2[(4-ethyl-2,
3-Dioxopiperazin-1-yl)-carbonylamino]-2-phenylacetamide]-7α-formamide-3-(4-methylpyridinium)methyl-cef-3
-Em-4-carboxylate or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo hydrolyzable ester, the compound according to claim (1). (16) The compound is 7β-[D-2-[(4-ethyl-2
,3-dioxopiperazin-1-yl)-carbonylamino]-2-phenylacetamido]-3-(3-ethyl-4-methylpyridinium)methyl-7α-formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolyzable ester thereof. (17) The compound is 7β-[D-2-[(4-ethyl-2
,3-dioxopiperazin-1-yl)-carbonylamino]-2-phenylacetamide]-7α-formamide-3-[3-(3-hydroxypropyl)pyridinium]methyl-cef-3-em-4-carboxy or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo hydrolyzable ester thereof.
Compound described in section 1). (18) The compound is 7β-[D-2-[(4-ethyl-2
,3-dioxopiperazin-1-yl)-carbonylamino]-2-phenylacetamide]-7α-formamide-3-(4-phenylpyridinium)methyl-cef-3-em-4-carboxylate or its pharmaceutical The compound according to claim 1, which is an acceptable salt or a pharmaceutically acceptable in vivo hydrolyzable ester. (19) The compound is 3-(2,3-cyclohexenopyridinium)methyl-7β-[D-2-([4-ethyl-2
, 3-dioxopiperazin-1-yl]carbonylamino)-2-phenylacetamide]-7α-formamide-cef-3-em-4-carboxylate or its pharmaceutically acceptable salt or pharmaceutically acceptable raw material. The compound according to claim (1), which is an ester that can be hydrolyzed in the body. (20) The compound is 7β-[D-2-[(4-ethyl-2
,3-dioxopiperazin-1-yl)-carbonylamino]-2-phenylacetamide]-7α-formamide-3-(3-methoxypyridinium)methyl-cef-3-em-4-carboxylate or its pharmaceutical The compound according to claim 1, which is an acceptable salt or a pharmaceutically acceptable in vivo hydrolyzable ester. (21) The compound is 7β-[D-2-(3,4-diacetoxyphenyl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]acetamide]-7α- Claim No. 1 which is formamide-3-(quinolinium)methyl-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo hydrolyzable ester. ) Compounds described in section 2. (22) The compound is 3-[4-(tributyl)pyridinium]methyl-7β-[D-2-[(4-ethyl-2,3-
dioxopiperazin-1-yl)carbonylamino]-
2-phenylacetamide]-7α-formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo hydrolyzable ester The compound described in section (1). (23) The compound is 7β-[D-2-[(4-(3-chlorophenyl)-2,3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamide]-
A patent claim that is 3-(4-ethylpyridinium)methyl-7α-formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolyzable ester thereof A compound according to the scope item (1). (24) The compound is 7β-[D-2[(4-ethyl-2,
3-Dioxopiperazin-1-yl)-carbonylamino]-2-phenylacetamide]-7α-formamide-3-(4-methoxypyridinium)methyl-cef-
The compound according to claim (1), which is 3-m-4-carboxylate or a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolyzable ester thereof. (25) The compound is 7β-[D-2[(4-ethyl-2,
3-Dioxopiperazin-1-yl)-carbonylamino]-2-phenylacetamide]-7α-formamide-3-[4-(prop-1-yl)pyridinium]methyl-cef-3-em-4-carboxy The compound according to claim (1), which is a ester or a pharmaceutically acceptable salt or a pharmaceutically acceptable biodegradable ester thereof. (26) The compound is 7β-[D-2[(4-ethyl-2,
3-Dioxopiperazin-1-yl)-carbonylamino]-2-phenylacetamide]-3-(2-ethylpyridinium)methyl-7α-formamide-cef-3
-Em-4-carboxylate or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo hydrolyzable ester, the compound according to claim (1). (27) The compound is 7β-[D-2[(4-ethyl-2,
3-dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamido]-3-(3-ethylpyridinium)methyl-7α-formamide-cef-3-
The compound according to claim (1), which is em-4-carboxylate or a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolyzable ester thereof. (28) The compound is 3-(4-cyclopropylpyridinium)methyl-7β-[D-2[(4-ethyl-2,3-
dioxopiperazin-1-yl)carbonylamino]-
2-phenylacetamide]-7α-formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo hydrolyzable ester Compound described in section 1). (29) The compound is 3-(4-cyclopropylpyridinium)methyl-7β-[D-2-(3,4-diacetoxyphenyl)-2-[(4-ethyl-2,3-dioxopiperazine-1 -yl)carbonylamino]acetamido]-7α-formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolyzable ester thereof. A compound according to scope item (1). (30) The compound is 3-(4-cyclopropylpyridinium)methyl-7β-[D-2-(3,4-dihydroxyphenyl)-2-[(4-ethyl-2,3-dioxopiperazine-1- yl)carbonylamino]acetamido]-7α-formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo hydrolyzable ester. A compound according to item (1). (31) The compound is 7β-[D-2[(4-ethyl-2,
3-Dioxopiperazin-1-yl)carbonylamino]-2-phenylacetamide]-7α-formamide-3-[4-(isopropyl)pyridinium]methyl-
The compound according to claim (1), which is cef-3-em-4-carboxylate or a pharmaceutically acceptable salt or ester thereof. (32) The compound is 7β-[D-2[(4-ethyl-2,
3-Dioxopiperazin-1-yl)-carbonylamino]-2-phenylacetamide]-7α-formamido-3-[4-pyrid-2-yl)pyridinium]methyl-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolyzable ester thereof. (33) The compound is 7β-[D-2-(3,4-diacetoxyphenyl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]acetamide]-3- (4-ethylpyridinium)methyl-7α
-Formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo hydrolyzable ester, the compound according to claim (1). (34) The compound 7β-[D-2-(3,4-dihydroxyphenyl)-2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonylamino]acetamide]-3-( 4-ethylpyridinium)methyl-7α
-Formamide-cef-3-em-4-carboxylate or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable in vivo hydrolyzable ester, the compound according to claim (1). (35) A pharmaceutically acceptable carrier or additive and an antibacterially effective amount of the pharmaceutically acceptable compound according to any one of claims (2) to (34). A pharmaceutical composition. (36) The pharmaceutical composition according to claim (35), further comprising a β-lactamase inhibitor. (37) Formula (V) ▲Mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R^4 and R^5 are as defined for formula (I); the amino group causes acylation is an amino group which may be optionally substituted with a group; and any reactive group may be protected) or its salt and formula (VI) ▲There are mathematical formulas, chemical formulas, tables, etc.▼( VI) N-acylated derivatives of the acids in which R^1, R^2 and R^3 are as defined for formula (I) and any reactive groups may be protected. then, if necessary, one or more of the following steps: (i) removing any protecting groups; (ii) converting the group -CO_2R^5 to another group -CO_2R^5
(iii) converting the product into a salt; Claims (1) to (34) consist of
A method for producing a compound described in any one of the paragraphs. (38) A compound of formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (in the formula, R^4 and R^5 are as defined for formula (I)) or a salt thereof. (39) The compound according to claim (38), wherein the group CO_2R^5 is a carboxylate anion. (40) Claim No. 3, wherein the compound is 7β-amino-3-(4-ethylpyridinium)methyl-7α-formamide-cef-3-em-4-carboxylate.
8) Compound described in section 8). (41) The compound is 7β-amino-3-(2,3-cyclopentenopyridinium)methyl-7α-formamide-
The compound according to claim (38), which is cef-3-em-4-carboxylate. (42) The compound is 7β-amino-7α-formamide-
The compound according to claim (38), which is 3-(3-hydroxymethylpyridinium)methyl-cef-3-em-4-carboxylate. (43) The compound is 7β-amino-7α-formamide-
Claim No. 3 which is 3-(4-methylpyridinium)methyl-cef-3-em-4-carboxylate
8) Compound described in section 8). (44) The compound is 7β-amino-3-[4-(2-N-
t-Butoxycarbonylamino-2-carboxy)ethylpyridinium]methyl-7α-formamide-ceph-
The compound according to claim (38), which is 3-em-4-carboxylate. (45) The compound is 7β-amino-3-(3-ethyl-4
-Methylpyridinium)methyl-7α-formamide-
The compound according to claim (38), which is cef-3-em-4-carboxylate. (46) The compound is 7β-amino-7α-formamide-
3-[3-(3-hydroxypropyl)pyridinium]
The compound according to claim (38), which is methyl-cef-3-em-4-carboxylate. (47) The compound is 3-(3-acetylpyridinium)methyl-7β-amino-7α-formamide-cef-3-
Claim No. 4 which is Em-4-carboxylate (
The compound described in item 38). (48) The compound is 7β-amino-7α-formamide-
3-(4-phenylpyridinium)-methyl-cef-3
-Em-4-carboxylate The compound according to claim (38). (49) The compound is 7β-amino-3-(3-carbamoylpyridinium)methyl-7α-formamide-ceph-
The compound according to claim (38), which is 3-em-4-carboxylate. (50) The compound is 7β-amino-3-(2,3-cyclohexenopyridinium)methyl-7α-formamide-
The compound according to claim (38), which is cef-3-em-4-carboxylate. (51) The compound is 7β-amino-7α-formamide-
3-(3-methoxypyridinium)methyl-cef-3-
Claim No. 4 which is Em-4-carboxylate (
The compound described in item 38). (52) Claim No. 3, wherein the compound is 7β-amino-3-(3-chloropyridinium)methyl-7α-formamide-cef-3-em-4-carboxylate.
8) Compounds described in section 8). (53) The compound is 7β-amino-7α-formamide-
The compound according to claim (38), which is 3-(quinolinium)methyl-cef-3-em-4-carboxylate. (54) Claim 38, wherein the compound is 7β-amino-3-[4-(tertiary-butyl)pyridinium]methyl-7α-formamide-cef-3-em-4-carboxylate. Compound. (55) The compound is 7β-amino-7α-formamide-
3-(4-methoxypyridinium)methyl-cef-3-
Claim No. 4 which is Em-4-carboxylate (
The compound described in item 38). (56) The compound is 7β-amino-3-(4-carbamoylpyridinium)methyl-7α-formamide-ceph-
The compound according to claim (38), which is 3-em-4-carboxylate. (57) The compound is 7β-amino-7α-formamide-
The compound according to claim (38), which is 3-[4-(prop-1-yl)pyridinium]methyl-cef-3-em-4-carboxylate. (58) The compound is 7β-amino-7α-formamide-
3-(isoquinolinium)methyl-cef-3-m-4
- The compound according to claim (38), which is a carboxylate. (59) Claim No. 3, wherein the compound is 7β-amino-3-(2-ethylpyridinium)methyl-7α-formamide-cef-3-em-4-carboxylate.
8) Compound described in section 8). (60) Claim No. 3, wherein the compound is 7β-amino-3-(3-ethylpyridinium)methyl-7α-formamide-cef-3-em-4-carboxylate.
8) Compound described in section 8). (61) Claim 38, wherein the compound is sodium 7β-amino-7α-formamide-3-[4-(2-sulfoethyl)pyridinium]methyl-cef-3-em-4-carboxylate compound. (62) The compound according to claim (38), wherein the compound is 7β-amino-3-(4-cyclopropylpyridinium)methyl-7α-formamide-cef-3-em-4-carboxylate. (63) The compound is 7β-amino-7α-formamide-
The compound according to claim (38), which is 3-[4-(isopropyl)pyridinium]methyl-cef-3-em-4-carboxylate. (64) The compound is 7β-amino-7α-formamide-
The compound according to claim (38), which is 3-(4-(pyrid-2-yl)pyridinium]methyl-cef-3-em-4-carboxylate. (65) Formula (VII) ▲Mathematical formulas, chemical formulas, tables, etc.▼(VII) (In the formula, R^4 is defined with respect to formula (I) and R^X is hydrogen or an easily removable carboxy protecting group. and Z is an inorganic or organic anion present in a suitable stoichiometric proportion to balance the positive charge of R^4) or an acid addition salt thereof. (66) Claim No. 65, wherein the compound is 7β-ammonio-3-(2,3-cyclopentenopyridinium)methyl-7α-formamide-cef-3-em-4-carboxylic acid dichloride salt. ) Compounds described in section 2.