GB1560172A

GB1560172A - -(ureido- or thioureido-)acetamido pencillins and cephalosporins processes for their preparation and compositions containing them

Info

Publication number: GB1560172A
Application number: GB46014/77A
Authority: GB
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1976-11-06
Filing date: 1977-11-04
Publication date: 1980-01-30
Also published as: PT67170A; JPS5359693A; NL7712188A; IT1090243B; SE7712506L; AU3040477A; FR2370052B1; IL53279A0; PT67170B; FR2370052A1

Description

(54) a-(UREIDO- OR THIOUREIDO-)ACETAMIDO PENICILLINS AND CEPHALOSPORINS, PROCESSES FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM (71) We, MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG, a German body corporate, of 61 Darmstadt, Frankfurter Strasse 250, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention is concerned with certain novel lactams, that is a-(ureido- or thioureido-)acetamido penicillins and cephalosporins, with processes for their preparation and which compositions containing them.

We have found that lactams of formula I:

in which Z is phenyl, RO-phenyl, cyclohexen-l-yl, cyclohexa-l, 4-dienyl or thienyl, R and R' are each H or alkyl-(O)nCO, n is 0 or 1, R2 and R3 are each H, halogen, NO2, NH2, alkylamino, dialkylamino or acylamino or together are -CH=CH-CH=CH-, in which a CH group may optionally be replaced by N and/or an H atom may optionally be replaced by R4 or two H atoms may optionally be replaced by R4 and R5, R4 and R5 are each alkyl, alkoxy, dialkylamino or halogen or together are -CH=CH-CH=CH-, in which a CH group may optionally be replaced by N, W is H, OH or alkyl, X is O or S, B is H or methoxy, A is -C9CH3)2-CHQ-, -CH2-CE=CQ- or -CH2-C(CH2Y)=CQ-, Q is -COOH, tetrazol-5-yl or, if Y is,

COOT, Is halogen or alkoxy, Y is H, OH, -OCOCH3, -O-CONH2,

or -5-Het, R6 is H or CONH2, and Het is 3-methyl- 1 ,2,4-thiadiazol-5-yl, 5-methyl-I ,3,4-oxadiazol-2-yl, 1,3,4- thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, tetrazol-5-yl, 1 -methyl-tetrazol-5-yl, 1,2,3-triazol-4-yl, 4-methyl-oxazol-2-yl or I -oxido-2-pyridyl, and wherein the alkyl, acyl and alkoxy groups each have 14 C atoms, provided that when A is -C(CH3)2-CH(COOH, Z is o-RO-phenyl or m- RO-phenyl, p-alkyl-(O)n-CO-phenyl, cyclohexen-l-yl or thienyl and/or W is hydroxyl and/or R2 or R3 is halogen, NO2, NH2, alkylamino, dialkylamino or acylamino, and/or B is methoxy, and the readily hydrolysable esters of compounds in which Q is COOH, and physiologically acceptable salts of said lactams and esters are well tolerated and have valuable pharmacological properties. These compounds have good in vitro and in vivo activity against pathogenic microorganisms, including Gram-positive and Gram-negative bacteria, and are distinguished by a broad spectrum of action.The compounds are active, in particular, against microorganisms of the genera Pseudomonas, for example Pseudomonas aeruginosa, and Proteus, for example Proteus mirabilis. They also have activity against, for example, Escherichia coli and Klebsiella pneumoniae. These activities can be demonstrated, for example, in conventional manner on cultures of bacteria in vitro. Activity against bacteria which are resistant towards other cephalosporin and penicillin antibiotics has also been found.

The chemotherapeutic activity of these compounds in vivo is preferably determined on mice. Pharmaco-kinetic investigations, for example determination of the concentration of the active compounds in the serum, from which the biological half-life periods can be calculated, are preferably carried out on dogs.

Tests can also be carried out on mice, rats rabbits or other mammals.

The foregoing compounds can, therefore, be used as medicaments in human and veterinary medicine, in particular for combating bacterial infections. They can also be used as intermediate products for the preparation of further medicaments.

The lactams of formula I, their readily hydrolysable esters and the physiologically acceptable salts of these compounds are novel and constitute one aspect of the present invention.

The term "readily hydrolysable esters" is used herein to refer to esters having an ester group which can be rapidly hydrolysed in vivo and which is pharmocologically acceptable. Esters of this type are conventional in the chemistry of peniciliins and cephalosporins and those skilled in the art known which ester groups are suitable.

Preferred readily hydrolysable esters correspond to formula I in which Q is a COOR7 group and R7 is tert.-alkyl, alkoxyalkyl, alkanoyloxyalkyl, alkanoylamidoalkyl, N-alkyl-alkanoylamidoalkyl, alkoxycarbonyloxyalkyl, phthalidyl (=2-oxo-3H-benzo [ci-furan-3-yl), 2-oxo-tetrahydro-5-furyl, 2-oxo-3 alkyl-tetrahvdro-5-furyl, trialkylsilyl, arylalkyl, alkoxyarylalkyl, benzhydryl, trichloroethyl or aroylalkyl, the alkyl, alkoxy and alkanoyl groups having in each case I--6 C atoms, the aryl groups having in each case 6-10 C atoms and the aroyl groups having in each case 7-11 C atoms.

Accordingly, R, is preferably alkanoyloxymethyl (for example, acetoxymethyl, propionyloxymethyl, isobutyryloxymethyl or pivaloyloxymethyl), 1alkanoyloxyethyl (for example, I-acetoxyethyl, l-propionyloxyethyl, 1isobutyryloxyethyl or l-pivaloyloxyethyl), alkanoylamidomethyl (for example, pivaloylamidomethyl), N-alkylalkanoylamidomethyl (for example, Nmethylpivaloylamidomethyl), alkoxycarbonyloxymethyl (for example, ethoxycarbonyloxymethyl) or l-alkoxycarbonyloxyethyl (for example, 1ethoxycarbonyloxyethyl or l-tert.-butoxycarbonyloxy) and is further preferably tert.-butyl, methoxymethyl, phthalidyl, 2-oxo-3-methyltetrahydro-5-furyl, trimethylsilyl, benzyl, methoxybenzyl, such as p-methoxybenzyl, benzhydryl, trichloroethyl or benzoylmethyl.

The alkyl, acyl and alkoxy groups in the compounds of formula I have 14 C atoms and preferably 1 or 2 C atoms. Alkyl is preferably methyl, secondarily ethyl and may also be n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl. Acyl may, for example, be alkanoyl or alkylsulphonyl; it is preferably acetyl or methylsulphonyl and may also, for example, be formyl, propionyl, butyryl, isobutyryl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl and isobutylsulphonyl, and also substituted alkanoyl or alkylsulphonyl. such as chloroacetyl or methoxyacetyl. Alkoxy is preferably methoxy, secondarily ethoxy and may also be n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.butoxy.Dialkylamino is preferably dimethylamino and may also, for example, be methylethylamino, diethylamiono, di-n-propylamino, diisopropylamino or di-nbutylamino. Acylamino may, for example, be alkanoylamino or alkylsulphonylamino; it is preferably acetylamino or methylsulphonylamino and may also, for example, be formylamino, propionylamino, butyrylamino, isobutyrylamino, ethylsulphonylamino, propylsulphonylamino or nbutylsulphonylamino. Halogen is preferably Cl, secondarily Br and may also be F or I.

The Z radical is preferably phenyl; the Rand R' radicals are preferably H. If Z is a RO-phenyl group, the RO substituent is preferably in the p-position of the phenyl ring; accordingly, Z is also preferably p-hydroxyphenyl, and may also be o- or m-hydroxyphenyl. Thienyl is preferably 3-thienyl and may also be 2-thienyl.

The parameter n is preferably 1.

The R2 radical is preferably H, Cl or Br; the R3 radical is preferably H; in addition, the R2 and R3 radicals may together be -CH=CH-CH=CH- in which one CH group may optionally be replaced by N. They therefore form, conjointly with the pyridine ring, a pyridine, quinoline or 1,5-, 1,6-, 1,7- or l,8-naphthyridine system which preferably has no further substituents apart from the substituted ureido group in the 3-position and the hydroxyl group in the 4-position. Among the napthyridines, the l,5-naphthyridines are preferred. The R4 radical is preferably CH3, OCH3, N(CH3)2 or Cl; the R5 radical is preferably CH3 or Cl. If R4 and R5 together are -CH=CH-CHCH-, a benzo[flquinoline, benzo[g]quinoline or benzo[h]quinoline system is present.If these radicals together are an aza-1,3butadienyl group, a phenanthroline system or a pyrido-naphthyridine system is present; among the phenanthrolines, the l,10-phenanthrolines are preferred.

The W radical is preferably H or OH; the X radical is preferably 0; the B radical is preferably H.

The Q radical is preferably a COOH group. Accordingly, the A radical is preferably -C(CH3)2-CH(COOH or -CH2-C(CH2Y)=C(COOH)-.

The Y radical is preferably H, -OCOCH3, 5-methyl-l,3,4-thiadiazol-2-yl-thio or l-methyl-tetrazol-5-yl-thio.

Preferred compounds according to the invention are those compounds of formula I in which at least one of the above-mentioned radicals has one of the preferred meanings indicated above. Some of the preferred groups of compounds can be expressed by means of the partial formulae Ia to If which follow and which correspond to formula I and wherein the radicals not designated in greater detail have the meanings indicated in formula I, but wherein: : in Ia, A is -CH2-CE=CQ- or -CH2-C(CH2Y)=CQ-; in Ib, Z is phenyl, p-hydroxyphenyl or cyclohexa-l,4-dienyl, R' is H, R2 and R3 are each H or together are -CH=CH-CH=CH-, in which one CH may optionally be replaced by N and/or one H atom may optionally be replaced by R4 or two H atoms may optionally be replaced by R4 and R5, W is H, X is 0, B is H, A is -CH2-C(CH2Y)=C(COOH) and Y is H, -OCOCH3 or -S-Het;; in Ic, Z is phenyl or p-RO-phenyl, R2 is H, Cl or Br, R3 is H, or R2 and R3 together are -CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=C(Cl)-CH=CH-, -CH=CH-C(CH3)=CH-, -CH=CH- C(OC2H5)=CH- or -CH=CH-CCl=CH-, W is H or OH, X is 0, B is H, A is -C(CH3)2-CH(COOH or -CH2-C(CH2Y)=C(COOH)- and Y is H, -OCOCH3, 5-methyl-1,3,4-thiadiazol-2-yl-thio or l-methyl-tetrazol-5ylthio, provided that when A is -C(CH3)2-CH(COOH)-, Z is o- or m-RO-phenyl or p-alkyl-(O)-CO-phenyl and/or W is hydroxyl and/or R2 is Cl or Br; in Id, R2 is halogen or acylamino and A is -C(CH3)2 -CH(COOH;; in le, Z is phenyl or p-hydroxyphenyl, R1 is H, R2 is Cl, Br or CH3SO2NH-, R3 is H, W is H or OH, X is 0, B is H and A is -C(CH3)2-CH(COOHH; and in If, Z is phenyl or p-hydroxyphenyl, R1 is H, R2 is H, Cl or Br, R3 is H, or R2 and R3 together are -CH=CH-CH=CH- or -N=CH-CH=CH-, W is H or OH, X is 0, B is H, A is -CH2-C(CH2Y)=C(COOH and Y is H, -OCOCH3, 5-methyl-1,3,4-thiadiazol-2-ylthio or 1-methyl-tetrazol-5ylthio; and the readily hydrolysable esters of compounds in which Q is COOH and the physiologically acceptable salts of these lactams and esters.

The compounds of formula I possess several centres of asymmetry, among them an asymmetric carbon atom, which is adjacent to the Z group. The symbols "D", "L" and "DL" relate to this centre of asymmetry. It is to be understood that formula I encompasses both the "racemates" and the optically active forms of these compounds. The D-forms of the compounds of formulae I and Ia to If, which are derived, for example, from ampicillin, pivampicillin, amoxycillin, cefaloglycin, cefalexin or cefatrizin, are preferred.

The present invention also comprises a process for the preparation of a compound according to the invention, which comprises: (i) reacting a lactam of formula II:

in which A, B and Z have the above-stated meanings, or, when Q is COOH, a readily hydrolysable ester thereof, or a physlogically acceptable salt of such a lactam or ester, or a reactive derivative of such a lactam, ester or salt, with a compound of formula III:

in which R1, R2, R3, W and X have the above-stated meanings, or a reactive derivative thereof, or (ii) reacting an amino-lactam of formula IV:

in which A and B have the above-stated meanings, or, when Q is COOH, a readily hydrolysable ester thereof, or a physiologically acceptable salt of such an aminolactam or ester, or a reactive derivative of such an amino-lactam, ester or salt, with a compound of formula V::

in which Z, R', R2, R3, W and X have the above-stated meanings or a reactive derivative thereof, or (iii) treating a readily hydrosable ester of a lactam of formula I with a solvolysing agent or treating a benzyl ester or a benzyl ether of such a lactam with a hydrogenolysing agent.

When a compound of formula I in which Y=-OCOCH3 is obtained by any of the foregoing processes, it may be reduced to form a compound I in which Y=H, or reacted with a thiol of the formula Het-SH, in which Het has the above-stated meaning, or corresponding mercaptide, to obtain a compound I in which Y= --SS-Het, or reacted with a compound of the formula R6-Py, in which Py is pyridyl and R6 has the above-stated meaning, to obtain a compound I in which

An ester obtained by any of the foregoing processes may be hydrolysed or a compound of formula I obtained by any of the foregoing processes may be converted into an ester thereof by treatment with an esterifying agent and/or a resulting compound of formula I may be converted into a physiologically acceptable salt thereof by treatment with an acid or base.

The compounds of formula I are prepared by methods are known in themselves and are described in the literature (for example in the standard work Houben-Weyl, Methoden der Organischen Chemie ("Methods of Organic Chemistry"), Georg-Thieme-Verlag, Stuttgart) and, in particular, in the literature of the synthesis of penicillin and cephalosporin derivatives, including German OLS 2,450,668, and, specifically, under the reaction conditions which are known to be suitable for such reactions.

All the starting materials for the preparation of the compounds of formula I can, if desired, be formed in situ, that is without isolation from the reaction mixture in which they are formed, and are immediately reacted further to give the compounds of formula I. This applies, in particular, to the unstable carbamic acids III and the derivatives thereof.

Suitable reactive derivatives of the carboxylic acids II, IV and V are, for example, their salts, for example their sodium, potassium or triethylamine salts, or their readily hydrolysable esters, for example their trialkylsilyl esters (in which the alkyl group preferably has up to 4 C atoms). The amino derivatives II and IV can be used in the form of their N-trialkylsilyl derivatives (in which the alkyl group preferably has up to 4 C atoms), and the carbamic acids III are preferably used in the form of their "lactones" (2,3-dihydro-oxazolo-[4,5-c]pyridin-2-ones).

Suitable reactive derivatives of the acids of formula V are, in particular, halides, preferably chlorides or bromides, anhydrides and mixed anhydrides, as well as azides and activated esters, for example p-nitrophenyl esters, p-nitrophenyl thioesters or cyanomethyl esters. Examples of suitable mixed anhydrides of the acids of formula V are those with alkanoic acids, in particular with acetic acid and substituted acetic acids, for example pivalic acid, and anhydrides with carbonic acid half-esters, such as can be obtained, for example, by reacting an acid of formula V with chloroformic acid benzyl ester, p-nitrobenzyl ester, isobutyl ester, ethyl ester or allyl ester.

The starting materials of formula II (for example, ampicillin, amoxycillin, epicillin, cefaloglycin, cefalexin) and the readily hydrolysable esters of compounds in which Q is COOH, are known or can be prepared analogously to known compounds by methods which are known in themselves, for examples by acylating the largely known amino-lactams of formula IV and, if desired, subsequently reacting cephalosporanic acid derivatives of formula II (Y=-OCOCH3) thus obtained with thiols of the formula Het-SH (or with reducing agents or with compounds of the formula R6-Py) to give compounds of formula II

in the course of this reaction, it is preferable to block reactive groups temporarily.

The starting materials of formula III and their derivatives, in particular their "lactones" referred to in greater detail above, are for the most part known from German OLS 2,450,668. The "lactones" are readily accessible by reacting the corresponding 3-amino-4-hydroxy-pyridines, 3-amino-4-hydroxy-quinolines or 3amino-4-hydroxy-naphthyridines or the correspondingly substituted benzoquinolines, phenanthrolines or pyridonaphthyridines, with phosgene in the presence of pyridine.

The compounds of formula V can be prepared by reacting the compounds of formula III or their "lactones" with acids of the formula ZKH(NH2ACOOH (for example, cr-amino-phenylacetic acid). The starting materials for the solvolysis or hydrogenolysis according to the invention can be obtained analogously, though in this case additional functional groups are present in the molecule.

The compounds of formula I are preferably obtained by reacting the compounds of formulae II and III or their reactive derivatives. This reaction is preferably carried out in the presence of at least one inert solvent at a temperature of from -20" to +35"C, preferably from 0 to 250C. Suitable inert solvents are, for example, chlorinated hydrocarbons, in particular methylene chloride, and also chloroform, 1,2-dichloroethane, trichloroethylene or carbon tetrachloride; and ethers, such as tetrahydrofuran or dioxan, ketones, such as acetone, amides, such as dimethylformamide (DMF), sulphoxides, such as dimethylsulphoxide, or nitriles, such as acetonitrile.If the starting compound of formula II is used in the form of a salt thereof, it is preferred to make the salt in situ using the appropriate base, for example triethylamine, pyridine or aqueous sodium hydroxide solution. In this case, an excess of the base can also serve as the solvent.

The compounds of formula I can also be prepared by reacting an aminolactam of formula IV (or a salt or, when Q=COOH, ester thereof) with an acid of formula V (or a reactive derivative thereof). This reaction is also preferably carried out in the presence of at least one of the above-mentioned inert solvents within the temperature range indicated. If a salt of the acid IV is used, an excess of the base serving to form this salt, such as triethylamine, pyridine or aqueous sodium hydroxide solution, can be used as the solvent in this case also.

A compound of formula IV, or (preferably) when Q=COOH a readily hydrolysable ester thereof, can also be reacted with an acid of formula V in the presence of an agent which splits off water, for example a carbodiimide, silch as dicyclohexylcarbodimide, and preferably in the presence of at least one of the above-mentioned inert solvents and within the temperature range indicated, to given a compound of formula I, or (preferably) when Q=COOH a readily hydroslysable ester thereof.

The lactams of formula I can also be obtained by treating a readily hydrolysable ester of such a lactam with a solvolysing agent or treating a benzyl ester or a benzyl ether of such a lactam with a hydrogenolysing agent.

Solvolysis of readily hydrolysable esters, for example the trimethylsilyl esters of the compounds of formula I, is preferably carried out under very mild conditions in order not to endanger the other groups present in the molecule which can be split solvolytically. In general, the reaction is carried out in an aqueous or partially aqueous medium at a pH of from 3 to 10 and at a temperature of from 0 to 300C, preferably from 150 to 300C. The trimethylsilyl esters referred to can be split, for example, even by means of water or an alcohol, such as methanol or ethanol, at room temperature.

Hydrogenolysis of benzyl esters and benzyl ethers of compounds of formula I can be carried out, for example, by treatment with hydrogen in the presence of a heavy metal catalyst, preferably a noble metal catalyst, such as platinum or palladium, at a temperature of from 0 to 300 C, preferably at room temperature, and under a pressure of from 1 to 100 atmospheres, preferably from 1 to 5 atmospheres, in the presence of an inert solvent, for example an alcohol, such as methanol or ethanol, an ether, such as tetrahydrofuran or dioxan, or a carboxylic acid, such as acetic acid. The reaction time is preferably from 10 minutes to 2 hours.

In a resulting product of formula I (Y=-OCOCH3), the acetoxymethyl group can be reduced to a methyl group, for example by hydrogenation in the presence of a noble metal catalyst under the above-mentioned conditions, preferably with a palladium catalyst at about 2030 C and 2-10 atmospheres.

A resulting cephalosporanic acid derivative of formula I (Y=-OCOCH3) can be converted into the corresponding thioether of formula I (R=SHet) by reaction with a mercaptan of the formula Het-SH. A salt of the cephalosporanic acid is preferably reacted with a salt of the thiol in water or aqueous acetone at a temperature of from 20 to 1000C and a pH of from 4 to 8. Suitable salts are, in particular, the alkali metal salts, above all the sodium salts.

A resulting cephalosporanic acid derivative of formula I (Y=-OCOCH3) can also be converted into the corresponding internal pyridinium salt I

Q=COOB) by treatment with a compound of the formula R6-Py (pyridine, picolinamide, nicotinamide or isonicotinamide), preferably in the presence of an excess of KSCN and water at a temperature of from 20 to 70 C. preferably at 50 C.

A resulting cephalosporanic acid derivative of formula I (Y=OCOCH3) can also be hydrolysed to give the corresponding deacetylcephalosporanic acid derivative of formula I (Y=OH), preferably in a weakly acid aqueous buffer solution by an enzymatic route.

If desired, a resulting carboxylic acid of formula I can be converted, by reaction with an esterifying agent, into a readily hydrolysable ester thereof. For example, a salt, for example a triethylamine salt, of a carboxylic acid of formula I can be converted into the corresponding ester by means of a halide of the formula R7-CI or R7-Br (in which R7 has the above-stated meaning) for example, pivaloyloxymethyl chloride. This esterification is preferably carried out in the presence of one or more inert solvents at a temperature of from 0 to 300 C, preferably at room temperature. The use of a mixture of a halogenated hydrocarbon, such as methylene chloride, and DMF as the solvent is particularly preferred.

A resulting hydroxy compound of formula I (Z=HO-phenyl and/or R'=H) can be converted into the corresponding alkanoyl derivatives (I, R and/or R'=alkyl-CO--) or alkoxycarbonyl derivatives (I, R and/or R1=alkyl-O-CO-) by esterification with a reactive derivative of an acid of the formula alkyl-(O),-- COOH. This esterification is preferably carried out under the above-described conditions. Suitable reactive derivatives are, for example, the chlorides (such as, acetyl chloride or chloroformic acid ethyl ester).

Esterification of deacetylcephalosporanic acid derivatives of formula I (Y=OH) to give the corresponding carbamates of formula I (Y=-OCONH2) can be carried out by known methods, for example by reaction with chlorosulphonyl isocyanate and subsequent hydrolysis in a strongly acid aqueous phosphate buffer solution.

A resulting compound of formula I can also be converted into an acid addition salt thereof by treatment with an acid. Strong acids which give physiologically acceptable salts are preferred for this purpose, for example mineral acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid, or strong organic carboxylic, sulphonic or sulphuric acids, such as formic acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, ptoluenesulphonic acid, dodecylbenzenesulphonic acid or 2hydroxyethanesulphonic acid or laurylsulphuric acid.

An acid of formula I can also be converted into a metal or ammonium salt thereof by treatment with a base. Sodium and potassium salts can be obtained, for example, by dissolving the acid of formula I in the calculated quantity of dilute sodium or potassium hydroxide solution and subsequently evaporating the solution.

Salts with organic bases, such as diethylamine, triethylamine, diethanolamine, triethanolamine, N-ethyldiethanolamine, pyrrolidine, piperidine, N-ethylpiperidine, 1 -(2-hydroxyethyl)-piperidine, morpholine, procaine, benzylamine, dibenzylamine and l-phenylpropyl-2-amine, can be obtained, for example, by reaction with the corresponding amines in an inert solvent, for example methylene chloride.

Alkali metal salts of the acids of formula I can also be obtained, for example, by adding an alkali metal salt (for example, K salt) of diethylacetic acid to an alcoholic, preferably methanolic, solution of an acid of formula I and precipitating the desired salt by adding an organic solvent, such as diethyl ether.

As indicated above, the compounds according to the invention can be used as medicaments in human and veterinary medicine. The present invention also comprises, therefore, a pharmaceutical composition comprising at least one compound according to the invention and an inert, physiologically acceptable carrier. Such compositions may, if desired, contain one or more further active compound(s).

Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral administration or topical application and which do not react with the new compounds, for example, water, vegetable oils, benzyl alcohol, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc, petroleum jelly or cholesterol.

Compositions in the form of tablets, dragees, capsules, syrups, elixirs or drops are suitable for oral administration, compositions in the form of suppositories are suitable for rectal administration, compositions in the form of solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants are suitable for parenteral administration, and compositions in the form of ointments, creams or powders are suitable for topical application. If the novel compounds are to be administered in the form of portions of powder, the packaging material, such as small paper envelopes or paper capsules, are also suitable carriers. The new compounds can also be lyophilised and the resulting lyophilisates can be used for the preparation of injection formulations.All the above compositions can be sterilised and/or can contain auxiliary substances, such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavourings and/or aroma substances. If desired, the compositions can also contain further active compounds, for example further antibiotics (such as aminoglycoside antibiotics, for example gentamycin, tobramycin or amikacin) for broadening the spectrum of action, anti-inflammatory agents, antimycotic agents and/or vitamins. Solutions which are administered intramuscularly may, if desired, be administered together with analgesics.

The compounds according to the invention are, in general, administered in the same way as known lactam antibiotics, such as ampicillin, carbenicillin, pivampicillin, cefalotin or cefazolin. The daily dosage is preferably from 0.2 to 100 mg/kg of body weight. The specific dose for each particular patient depends, however, on the most diverse factors, for example on the activity of the particular compound employed, on the age, body weight, general state of health, sex, and diet of the patient, on the point in time and the route of the administration, the excretion rate, the combination of medicaments and the severity of the particular disease to which the therapy applies. Parenteral administration is preferred.

When the composition according to the invention is in dosage unit form, each dosage unit preferably comprises from 20 to 10,000, more preferably 100 to 1000, mg of the active compound(s).

Each of the compounds of formula I mentioned in the examples which follow is particularly suitable for the preparation of pharmaceutical compositions.

In order that the invention may be more fully understood, the following examples are given by way of illustration only. In the examples, all temperatures are in "C. Infrared spectra (IR) were determined in KBr. Rf values were determined on silica gel with 85:15 dioxan-water; the spots become light in colour after spraying with H2PtC16/KI. ACS=7-aminocephalosporanic acid, DMF=dimethylformamide, DMSO=dimethylsulphoxide. Compounds with a free COOH group are generally obtained in a hydrated form, usually as dihydrates, more rarely as trihydrates.

Example 1 4.05 g of cefaloglycin (Rf 0.35) are dissolved in a mixture of 225 ml of methylene chloride, 25 ml of DMF and 10 ml of triethylamine and 1.36 g of 2,3dihydro-oxazolo [4,5-c]-pyridin-2-one are then added at 00. The mixture is stirred for I hour at 20 and is then extracted several times with water. Washing is carried out with ethyl acetate, first at pH 9 and then at pH 7, and dilute hydrochloric acid is added until the pH is 2.The crude, precipitated D-7-[α-(N'-4-hydroxy-3-pyridyl- ureido)-α-phenyl-acetamido]-cephalosporanic acid (D-3-acetoxymethyl-7-[α-N'- 4 - hydroxy - 3 - pyridyl - ureido) - α - phenyl - acetamid] - 8 - oxo - 5 - thia - 1 azabicyclo[4,2,0]oct - 2 - ene - (2) - carboxylic acid) is filtered off, washed with water and dried over P2O5; Na salt, IR 3,280, 1,760, and 1,666 cm-l; Rf 0.40.

Examples 2 to 73 By means of: 2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 9-methyl-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 9-ethyl-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 9-methoxy-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 9-ethoxy-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 9-chloro-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 9-bromo-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 8-methyl-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 8-ethyl-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 8-methoxy-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 8-ethoxy-2, 3-dihydro-oxazolo [4,5-c] quino!in-2-one, 8-chloro-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 8-bromo-2,3-dihydro-oxazolo[4,5-c]-quinolin-2-one, 8-dimethylamino-2,3-dihydro-oxazolo[4.5-c]quinolin-2-one, 8-diethylamino-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one - 7-methyl-2,3-dihydro-oxazolo[4,5-c]quinoline-2-one, 7-ethyl-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 7-isobutyl-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 7-methoxy-2,3-dihydro-oxazolo[4,5-clquinolin-2-one, 7-ethoxy-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 7-fluoro-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 7-chloro-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 7-bromo-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 7-iodo-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 6-methyl-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 6-ethyl-2,3-dihydro-oxazolo [4,5-c] quinolin-2-one, 6-methoxy-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 6-cethexy-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one; 6-chloro-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 6-bromo-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 7,8-dimethyl-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 7,8-dichloro-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one, 7-chloro-8-methyl-2,3-dihydro-oxazolo[4,5-c]quinolin-2-one 2,3-dihydro-oxazolo[4,5-c]-1,5-naphthyridin-2-one, 6-methyl-2,3-dihydro-oxazolo[4,5-c]- 1 ,5-naphthyridin-2-one, 6-ethyl-2,3-dihydro-oxazolo[4,5-c]-1,5-naphthyridin-2-one, 6-methoxy-2,3-dihydro-oxazolo[4,5-c]-1,5-naphthyridin-2-one, 6-ethoxy-2,3-dihydro-oxazolo[4,5-c]-1,5-naphthyridin-2-one, 2,3-dihydro-oxazolo[4,5-c]- 1 ,6-naphthyridin-2-one, 6-methyl-2,3-dihydro-oxazolo[4,5-c] - 1 ,6-naphthyridin-2-one, 6-methoxy-2,3-dihydro-oxazolo[4,5-c]-1,6-naphthyridin-2-one, 6-chloro-2,3-dihydro-oxazolo[4,5-c]-1,6-naphthyridin-2-one, 6-bromo-2,3-dihydro-oxazolo[4,5-c]-1,6-naphthyridin-2-one, 2,3-dihydro-oxazolo[4,5-c]- 1 ,7-naphthyridin-2-one, 6-chloro-2,3-dihydro-oxazolo[4,5-c]-1,7-naphthyridin-2-one, 6-bromo-2,3-dihydro-oxazolo[4,5-c]-1,7-naphthyridin-2-one, 2,3-dihydro-oxazolo[4,5-c]-1,8-naphthyridin-2-one, 7-methyl-2,3-dihydro-oxazolo[4,5-c]- 1 ,8-naphthyridin-2-one, 2,3-dihydro-oxazolo[4,5-c]-benzo [g]quinolin-2-one, 2,3-dihydro-oxazolo[4,5-c]-1,10-phenanthrolin-2-one, 4-hydroxy-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 4-methyl-2,3-dihydro-oxazolo[4,5-c]pyridn-2-one, 4-n-butyl-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 6-fluoro-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-fluoro-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 6-chloro-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-chloro-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 6-bromo-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-bromo-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-iodo-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-nitro-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-amino-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-methylamino-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-n-butylamino-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-dimethylamino-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-diethylamino-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-di-n-butylamino-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-formamido-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-acetamido-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-butyramido-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, 7-methylsulphonamido-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, [obtainable by reduction of 3,5-dinitro-4-hydroxy-pyridine to 3,5-diamino-4hydroxypyridine, reaction with 1 mol of methanesulphonyl chloride in pyridine to give 3-amino-4-hydroxy-5-methylsulphonamidopyridine (Rf 0.52) and reaction with phosgene in pyridinel.

4-hydroxy-7-chloro-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one and 4-hydroxy-7-bromo-2,3-dihydro-oxazolo[4,5-c]pyridin-2-one, the following compounds are obtained analogously to Example 1 by reaction with cefaloglycin trifluoroacetate: 2. D-7-[α(N'-4-Hydroxy-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid : Na salt, IR : 3,300, 1762 and 1,660 cm-1 ; Rf 0.54.

3. D-7-[α-(N'-4-Hydroxy-5-methyl-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

4. D-7-[α-(N'-4-Hydroxy-5-ethyl-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

5. D-7-[α-(N'-4-Hydroxy-5-methoxy-3-quinolyl-uredo)-α-phenyl-acetamido]- cephalosporanic acid.

6. D-7-[α-(N'-4-Hydroxy-5-ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

7. D-7-[α-N'-4-Hydroxy-5-chloro-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

8. D-7-[α-(N'-4-Hydroxy-5-bromo-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

9. D-7-[α-(N'-4-Hydroxy-6-methyl-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

10. D-7-[a-(N'-4-Hydroxy-6-ethyl-3-q uinolyl-ureido)-a-phenyl-acetamido]- cephalosporanic acid.

11. D-7-[-(N'-4-Hydroxy-6-methoxy-3-quinolyl-ureido)--phenyl- acetamido]-cephalosporanic acid.

12. D-7- [-(N'-4-Hydroxy-6-ethoxy-3-quinolyl-ureido)-Qephenyl-acetamido] cephalosporanic acid.

13. D-7-[α-(N'-4-Hydroxy-6-chloro-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid Na salt, IR : 3,380, 1760 and 1,668 cm-1 ; RF 0.60.

14. D-7-[α(N'-4-Hydroxy-6-bromo-3-quinolyl-uredo)-α-phenyl-acetamido]- cephalosporanic acid.

15. D-7-[α(N'-4-Hydroxy-6-dimethylamino-3-quinolyl-ureido)-α-phenyl- acetamido]-cephalosporanic acid.

16. D-7-[α-(N'-4-Hydroxy-6-diethylamino-3-quinolyl-ureido)-α-phenyl- acetamido]-cephalosporanic acid.

17. D-7-[α-(N'-4-Hydroxy-7-methyl-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid, Na Salt, IR : 3,400, 1,762 and 1,662 cm-1, ; Rf 0.67 (in 70:30 dioxan-water).

18. D-7-[α-(N'-4-Hydroxy-7-ethyl-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

19. D-7-[α(N'-4-Hydroxy-7-isobutyl-3-quinolyl-ureido)-α-phenyl-acet- amido]-cephalosporanic acid.

20. D-7-[a-(N'-4-Hydroxy-7-methoxy-3-quinolyl-ureido)-a-phenyl- acetamido]-cephalosporanic acid.

21. D-7-[α-(N'-4-Hydroxy-7-ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid, Na salt, IR: 3,400, 1,755 and 1,660 cm-'; Rf 0.57.

22. D-7-[α-(N'-4-Hydroxy-7-fluoro-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

23. D-7-[α-(N'-4-Hydroxy-chloro-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid, Na salt, IR : 3,400, 1,765 and 1,670 cm-1, Rf 0.62, 24. D-7-[α-(N'-4-Hydroxy-7-bromo-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

25. D-7-[α-(N'-4-Hydroxy-7-iodo-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

26. D-7-[a-(N'-4-Hydroxy-8-methyl-3-quinolyl-ureido-a-ph enyl-acetamido]- cephalosporanic acid.

27. D-7-[α-(N'-4-Hydroxy-8-ethyl-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

28. D-7-[a-(N'-4-Hydroxy-8-methoxy-3-quinolyl-ureido)-a-phenyl- acetamido]-cephalosporanic acid.

29. D-7-[α-(N'-4-Hydroxy-8-ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

30. D-7-[α-(N'-4-Hydroxy-8-chloro-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

31. D-7-[α-(N'-4-Hydroxy-8-bromo-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

32. D-7-[a-(N'-4-Hydroxy-6,7-dimethyl-3-q uinolyl-ureido)-a-phenyl- acetamido]-cephalosporanic acid.

33. D-7-[a-(N'-4-Hydroxy-6,7-dichloro-3-quinolyl-ureido)-a-phenyl- acetamido]-cephalosporanic acid, 34. D-7-[α-(N'-4-Hydroxy-6-methyl-7-chloro-3-quinolyl-ureido)-α-phenyl- acetamido]-cephalosporanic acid.

35. D-7-[α-(N'-4-Hydroxy-1,5-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]- cephalosporanic acid, Na salt, IR : 3,430, 1,760 and 1,678 cm-1 ; Rf 0.20.

36. D-7-[α-(N'-4-Hydroxy-8-methyl-1,5-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-cephalosporanie acid.

37. D-7-[α-(N'-4-Hydroxy-8-ethyl-1,5-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-cephalosporanic acid.

38. D-7-[α-(N'-4-Hydroxy-8-methoxy-1,5-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-cephalosporanic acid.

39. D-7-[α-(N'-4-Hydroxy-8-ethoxy-1,5-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-cephalosporanic acid.

40. D-7-[a-(N'-4-Hydroxy- 1 ,6-naphthyrid-3-yl-ureido)-a-phenyl-acetamido]- cephalosporanic acid.

41. D-7-[a-(N'-4-Hydroxy-8-methyl- 1,6-naphthyrid-3-yl-ureido)-cr-phenyl- acetamido]-cephalosporanic acid.

42. D-7-[α-(N'-4-Hydroxy-8-methoxy-1,6-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-cephalosporanic acid.

43. D-7-[a-(N'-4-Hydroxy-8-ehloro- 1 ,6-naphthyrid-3-yl-ureido)-a-phenyl- acetamido]-cephalosporanic acid.

44. D-7- [a-(N'-4-Hydroxy-8-bromo- 1,6-naphthyrid-3-yl-ureido)--phenyl- acetamido]-cephalosporanic acid.

45. D-7-[a-(N'-4-Hydroxy- 1 ,7-naphthyrid-3-yl-ureido)-a-phenyl-acetamido]- cephalosporanic acid.

46. D-7-[α-(N'4-Hydroxy-8-chloro-1,7,-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-cephalosporanic acid.

47. D-7-[α-(N'-4-Hydroxy-8-bromo-1,7-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-cephalosporanic acid.

48. D-7-[a-(N'-4-Hydroxy- 1 ,8-naphthyrid-3-yl-ureido)-a-phenyl-acetamido]cephalosporanic acid.

49. D-7-[cr-(N'-4-Hydroxy-7-methyl- 1 ,8-naphthyrid-3-yl-ureido)-a-phenyl- acetamido]-cephalosporanic acid.

50. D-7-[α-(N'-4-Hydroxy-3-benzo[g]quinolyl)-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

50a. D-7-[α-(N'-4-Hydroxy-1,10-pnenanthrol-3-yl-ureido)-α- phenylacetamido]-cephalosporanic acid.

51. D-7-[a-(N'-2 4-Dihydroxy-3-pyridyl-ureico)-a-phenylacetamido]- cephalosporanic acid.

52. D-7-[α-(N'-2-Methyl-4-hydroxy-3-pyridyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

53. D-7-[sr-(N'-2-n-B utyl-4-hydroxy-3-pyridyl-ureido)-a-phenyl-acetamidolcephalosporanic acid.

54. D-7-[α-(N'-4-Hydroxy-5-fluoro-3-pyridyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

55. D-7-[α-(N'-4-Hydroxy-6-fluoro-3-pyridyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

56. D-7-[α-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid, Na salt, IR 3,300, 1,765 and 1,670 cm-1; Rf 0.53.

57. D-7-[α-(N'-4-Hydroxy-6-chloro-3-pyridyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

58. D-7-[α-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid, Na salt, IR 3,300, 1,766 and 1,670 cm-t; Rf 0.54.

59. D-7-[α-(N'-4-Hydroxy-6-bromo-3-pyridyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

60. D-7-[α-(N'-4-Hydroxy-5-iodo-3-pyridyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

61. D-7-[a-(N'-4-Hydroxy-5-nitro-3-pyridyl-ureido)-a-phenyl-acetamidol cephalosporanic acid.

62. D-7-(a-(N'-4-Hydroxy-5-amino-3-pyndyl-ureido)-a-phenyl-acetamidol - cephalosporanic acid.

63. D-7-[a-(N'-4-Hydroxy-5-methylamino-3-pyridyl-ureido)-a-phenyl- acetamido]-cephalosporanic acid.

64. D-7-[a-(N'-4-Hydroxy-5-n-butylamino-3-pyridyl-ureido)-a-phenyl- acetamido]-cephalosporanic acid.

65. D-7-[a-(N'-4-Hydroxy-5-dimethylamino-3-pyridyl-ureido)-a-phenyl- acetamido]-cephalosporanic acid.

66. D-7- (a-(N'-4-Hydroxy-5-diethylamino-3-pyridyl-ureido)-a-ph enylacetamido]-cephalosporanic acid.

67. D-7-[α-(N'-4-Hydroxy-5-di-n-butylamino-3-pyridyl-ureido)-α-phenyl- acetamido]-cephalosporanic acid.

68. D-7-la-(N'-4-Hydroxy-5-formamido-3-pyridyl-ureido)-a-phenyl- acetamido]-cephalosporanic acid.

69. D-7-[(g-(N'-4-Hydroxy-5-acetamido-3-pyridyl-ureido)-a-phenyl- acetamido]-cephalosporanic acid.

70. D-7-[α-(N'-4-Hydroxy-5-butyramido-3-pyridyl-ureido)-α-phenyl- acetamido]cephalosporanic acid.

71. D-7-[α(N'-4-Hydroxy-5-methylsulphonamido-3-pyridyl-ureido)-α-phenyl- acetamido]-cephalosporanic acid.

72. D-7-[a-(N'-2,4-Dihydroxy-5-chloro-3-pyridyl-ureido)-a-phenyl- acetamido]-cephalosporanic acid; Na salt, IR 3,350, 1,755 and 1,610 cm-'.

73. D-7-[α-(N'-2,4-Dihydroxy-5-bromo-3-yridyl-ureido)-α-phenyl- acetamido]-cephalosporanic acid: Na salt, IR 3,350, 1,755 and 1,605 cm-'.

Example 74 4.04 g of ampicillin trihydrate (Rf 0.35) are dissolved in a mixture of 100 ml of methylene chloride, 5 ml of DMF and 7 ml of triethylamine, 1.7 g of 7-chloro-2,3 dihydro-oxazolo[4,5-c]pyridin-2-one (obtainable from 3-chloro-4-hydroxy-5aminopyridine and phosgene in pyridine) are then added and the mixture is stirred for 2 hours at 20 and extracted several times with water. The weakly alkaline aqueous phase is acidified slowly and extracted at various pH values with ethyl acetate. The extracts obtained at pH 34 are dried over MgSO4 and evaporated.

After triturating the residue with diethyl ether, D-zz-(N'-4-hydroxy-5-chloro-3- pyridyl-ureido)-benzylpenicillin is obtained. Na salt, IR 3,300, 1,768 and 1,665 cm-'; Rf 0.51.

Examples 75 to 178 The following are obtained analogously to Example 74 from the corresponding penicillin derivatives and the corresponding "lactones" of the carbamic acids of the formula III: 75. D-α-(N'-2,4-Dihydroxy-3-pyridyl-ureido)-benzylpenicillin; Na salt, IR 3,400, 1,765 and 1,605 cm-1.

76. D-α-(N'-4-Hydroxy-5-fluoro-3-pyridyl-ureido)-benzyl-pencillin.

77. D-α-(N'-4-Hydroxy-6-fluoro-3-pyridyl-ureido)-benzyl-pencillin.

78. D-α-(N'-4-Hydroxy-6-chloro-3-pyridyl-ureido)-benzyl-penicillin.

79. D-α-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-benzyl-penicillin: Na salt, IR 3,300, 1,770 and 1,664 cm-1 ; Rf 0.51.

80. D--(N'-4-Hydroxy-6-bromo-3-pyridyl-ureido)-benzyl-pencillin.

81. D-a-(N'-4-Hydroxy-5-iodo-3-pyridyl-ureido)-benzyl-penicillin.

82. D-a-(N'-4-Hydroxy-5-nitro-3-pyridyl-ureido)-benzyl-penicillin.

83. D-α-(N'-4-Hydroxy-5-amino-3-pyridyl-ureido)-benzyl-penicillin.

84. D-α-(N'-4-Hydroxy-5-methylamino-3-pyridyl-ureido)-benzylpenicillin.

85. D-α-(N'-4-Hydroxy-5-n-butylamino-3-pyridyl-ureido)-benzylpenicillin.

86. D-α-(N'-4-Hydroxy-5-dimethylamino-3-pyridyl-ureido)-benzylpencillin.

87. D-α-(N'-4-Hydroxy-5-diethylamino-3-pyridyl-ureido)-benzylpenicillin.

88. D-α-(N'-4-Hydroxy-5-di-n-butylamino-3-pyridyl-ureido)-benzylpencillin.

89. D-α-(N'-4-Hydroxy-5-formamido-3-pyridyl-ureido)-benzylpencillin.

90. D-α-(N'-4-Hydroxy-5-acetamido-3-pyridyl-ureido)-benzylpencillin.

91. D-α-(N'-4-Hydroxy-5-butyramido-3-pyridyl-ureido)-benzylpenicillin.

92. D-α-(N'-4-Hydroxy-5-methylsulphonamido-3-pyridyl-ureido)- benzylpencillin.

93. D-ct-(N'-4-Hydroxy-5-ethylsulphonamido-3-pyridyl-ureido)- benzylpenicillin.

94. D-a-(N'-4-Hydroxy-5-n-butylsulphonamido-3-pyridylureido) benzylpenicillin.

95. D-α-(N'-2,4-Dihydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin ; Na salt, IR 3,400, 1,770 and 1,590 cm-1.

96. D-α-(N'-2,4-Dihydroxy-5-bromo-3-pyridyl-ureido)-benzylpencillin ; Na salt, IR 3,400, 1,770 and 1,590 cm-1.

97. D-α-(N'-2,4-Dihydroxy-3-pyridyl-ureido)-p-hydroxy-benzylpenicillin.

98. D-α-(N'-4-Hydroxy-5-fluoro-3-pyridyl-ureido)-p-hydroxybenzylpenicillin.

99. D-α-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-p-hydroxybenzylpenicillin; Na salt, IR 3,300, 1,768 and 1,665 cm-1 ; Rf 0.43.

100. D-α-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-p- hydroxybenzylpenicillin; Na salt, IR 3,300, 1,768 and 1,663 cm-1 ; Rf 0.45.

101. D-α-(N'-4-Hydroxy-5-iodo-3-pyridyl-ureido)-p-hydroxybenzylpenicillin.

102. D-α-(N'-4-Hydroxy-5-nitro-3-pyridyl-ureido)-p-hydroxyenzylpenicillin.

103. D-α-(N'-4-Hydroxy-5-amino-3-pyridyl-ureido)-p- hydroxybenzylpenicillin.

104. D-α-(N'-4-Hydroxy-5-methylamino-3-pyridyl-ureido)-p- hydroxybenzylpenicillin.

105. D-Q-(N'-4-Hydroxy-5-dimethylamino-3-pyridyl-ureido)-p- hydroxybenzylpenicillin.

106. D--(N'-4-Hydroxy-5-diethylamino-3-pyridyl-ureido)-p- hydroxybenzylpenicillin.

107. D-α-(N'-4-Hydroxy-5-formamido-3-pyridyl-ureido)-p- hydroxybenzylpenicillin.

108. D-α-(N'-4-Hydroxy-5-acetamido-3-pyridyl-ureido)-p- hydroxybenzylpenicillin.

109. D--(N'-4-Hydroxy-5-methylsulphonamido-3-pyridyl-ureido)-p- hydroxybenzylpenicillin; Na salt, IR 3,400, 1,765 and 1,670 cm-'; Rf 0.47.

110. D-a-(N'-4-Hydroxy-5-ethylsulphonamido-3-pyridyl-ureido)p hydroxybenzylpenicillin.

111. D-α-(N'-2,4-Dihydroxy-5-chloro-3-pyridyl-ureido)-p hydroxybenzylpenicillin ; Na salt, IR 3,335, 1,760 and 1,600 cm-1.

112. D-(r-(N'-2,4-Dihydroxy-5-bromo-3-pyridyl-ureido)-p- hydroxybenzylpenicillin; Na salt, IR 3,400, 1,765, 1,650 and 1,610 cm-'.

113. D-a-(N'-4-Hydroxy-3-pyridyl-ureido)-o-hydroxybenzylpenicillin.

114. D-L-(N'-4-Hydroxy-5-chloro-3-pyridyl-u hydroxybenzylpenicillin.

115. D-α-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-o- hydroxybenzylpenicillin.

116. D-a-[N'-4-Hydroxy-1,5-naphthyrid-3-yl-ureido]-o- hydroxybenzylpenicillin.

117. D-α-(N'-4-Hydroxy-3-pyridyl-ureido)-m-hydroxybenzylpenicillin.

118. D-α-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-m hydroxybenzylpenicillin.

119. D-a-[N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-mhydroxybenzylpenicillin.

120. D-α-[N'-4-Hydroxy-1,5-napthyrid-3-yl-ureidol-m- hydroxybenzylpenicillin.

121. D-a-(N'-4-Hydroxy-3-pyridyl-ureido)-p-acetoxybenzylpenicillin.

122. D-a-(N'-4-Hydroxy-5-ch1oro-3-pyridy1-ureido)-pacetoxy benzylpenicillin.

123. D-a-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-p-acetoxybenzylpenicillin.

124. D-a-[N'-4-Hydroxy- 1 5-naphthyrid-3-yl-ureido] -p-acetoxybenzylpenicillin.

125. D-α-(N'-4-Hydroxy-3-pyridyl-ureido)-p-isobutyryloxy-benzylpenicillin ; Na salt, IR, 1,785, 1,760 and 1,680 cm-1 ; Rf 0.58.

126. D-a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-p-isobutyryloxy- benzylpenicillin.

127. D-a-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-p-isobutyryloxy- benzylpenicillin.

128. D-α-[N'-4-Hydroxy-1,5-naphthyrid-3-yl-ureido]-p-isobutyryloxy- benzylpenicillin.

129. D-a-(N'-4-Hydroxy-3-pyridyl-ureido)-p-methoxyzarbonyloxy- benzylpenicillin.

130. D-a-(N'-4-Hydroxy-3-pyridyl-ureido)-p-ethoxycarbonyloxy- benzylpenicillin.

131. D-α-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-p-ethoxycarbonyloxy- benzylpenicillin.

132. D-α-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-p-ethoxycarbonyloxy- benzylpenicillin.

133. D-α-[N'-4-Hydroxy-1,5-naphthyrid-3-yl-ureido]-p-ethoxycarbonyloxy- benzylpenicillin.

134. D-hz-(N'-4-Hydroxy-3-pyridyl-ureido)-p-n-propoxycarbonyloxy- benzylpenicillin.

135. D-a-(N'-4-Hydroxy-3-pyridyl-ureido).p-isopropoxycarbonyloxy- benzylpenicillin.

136. D-a-(N'-4-Hydroxy-3-pyridyl-ureido)-p-isobutoxycarbonyloxy- benzylpenicillin.

137. D-a-(N'-4-Hydroxy-3-pyridyl-ureido)-cyclohex- 1 -enylmethyl-penicillin.

138. D-a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-cyclohex- 1 -enylmethylpenicillin.

139. D-el!-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-cyclohex- 1 -enylmethylpenicillin.

140. D-a-[N'-4-Hydroxy- 1 ,5-naphthyrid-3-yl-ureido]-cyclohex- 1 -enylmethylpenicillin.

141. D-α-(N'-4-Hydroxy-3-pyridyl-ureido)-thien-2-yl-methyl-penicillin.

142. D-α-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-thien-2-yl-methyl- penicillin.

143. D-a-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-thien-2-yl-methyl- penicillin.

144. D-α-[N'-4-Hydroxy-1,5-naphthyrid-3-yl-ureido]-thien-2-yl-methyl Penicillin.

145. D-α-[N'-4-Hydroxy-3-pyridyl-ureido)-thien-3-yl-methyl-pencilcillin.

146. D-α-[N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-thien-3-yl-methyl- penicillin.

147. D-a-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-thien-3-yl-methyl- penicillin.

148. D-a- [N'-4-hydroxy- 1 ,5-naphthyrid-3-yl-ureido] -thien-3-yl-methylpenicillin.

149. D-α-(N'-4-Hydroxy-3-pyridyl-ureido)-6-methoxybenzylpencicillin.

150. D-α-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin pivaloyloxymethyl ester ; IR 3,260, 2,960, 1,785, 1,760 and 1,660 cm-1 ; Rf 0.80.

151. D-α-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-benzylpenicillin pivaloyloxymethyl ester.

152. D-α(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)p-hydroxybenzylpenicillin pivaloyloxymethyl ester.

153. D-α-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-p-hydroxybenzylpenicillin pivaloyloxymethyl ester.

154. D-a-(N'-4-Hydroxy-3-pyridyl-ureido)-p-acetoxy-benzylpenicillin pivaloyloxymethyl ester.

155. D-a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-p-acetoxy- benzylpenicillin pivaloyloxymethyl ester.

156. D-a-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-p-acetoxy- benzylpenicillin pivaloyloxymethyl ester.

157. D-cr-[N'-4-Hydroxy- 1,5-naphthyrid-3-yl-ureido]-p-acetoxy- benzylpenicillin pivaloyloxymethyl ester.

158. D-a-(N'-4-Hydroxy-3-pyridyl-ureido)-p-ethoxycarbonyloxy- benzylpenicillin pivaloyloxymethyl ester.

159. D-a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-p-ethoxycarbonyloxy- benzylpenicillin pivaloyloxymethyl ester.

160. D-a-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-p-ethoxy-carbonyloxybenzylpenicillin pivaloyloxymethyl ester.

161. D-a-[N'-4-Hydroxy- 1 ,5-naphthyrid-3-yl-ureido]-p-ethoxycarbonyloxy- benzylpenicillin pivaloyloxymethyl ester.

162. D-a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin 1 - pivaloyloxyethyl ester.

163. D-a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin isobutyryloxymethyl ester.

164. D-a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin l-isobutyryloxyethyl ester.

165. D-a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin acetoxymethyl ester.

166. Da(N'-4Hydroxy-5-chloro-3-pyn'dyl-ureido)-benzylpenicillin 1 - acetoxyethyl ester.

167. D--(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin propionyloxymethyl ester.

168. D--(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin 1propionyloxyethyl ester.

169. D-a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin 2,2dimethylpropionamidomethyl ester.

170. D--(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin Nmethyl-2,2-dimethylpropionamidomethyl ester.

171. D-a-(N'-4Hydroxy-5-chloro-3-pyn'dyl-ureido)-benzylpenicillin ethoxycarbonyloxymethyl ester.

172. D--(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin ethoxycarbonyloxyethyl ester.

173. D-a-(N'-4-Hydroxy5-ch1oro-3-pyridyl-ureido)-benzylpenicil1in 1-tert.- butyloxycarbonyloxyethyl ester.

174. D-ct-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin phthalidyl ester.

175. D-a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin 2-oxo-3methyltetrahydro-5-furyl ester.

Example 176 D - 7 - [a - (N' - 4 - Hydroxy - 3 - pyridyl - ureido) - a - phenylacetamido] desacetoxycephalosporanic acid is obtained analogously to Example 1 from cefalexin (Rf 0.30) and 2,3-dihydro-oxazolo[4,5-c]pyridin-2-one. Na salt, IR: 3,400, 1,768 and 1,662 cam~'; Rf 0.35.

Examples 177 to 223 The following are obtained analogously from cefalexin and the corresponding cyclic carbamates: 177. D-7-[α-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

178. D-7-[α-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

179. D-7-[a-(N'-4-Hydroxy-3-quinolyl-ureido)-a-phenyl-acetamido]- desacetoxycephalosporanic acid; Na salt, IR: 3,300, 1,760 and 1,660 cm~'; Rd 0.50.

180. D-7-[α-(N'-4-Hydroxy-5-methyl-3-quinolyl-ureido)-α-acetamido]- desacetoxycephalosporanic acid.

181. D-7-[α-(N'-4-Hydroxy-5-ethyl-3-quinoyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

182. D-7-[a-(N'-4-Hydroxy-5-methoxy-3-quinolyl-ureido)-a-phenyl- acetamido]-desacetoxycephalosporanic acid.

183. D-7-[α-(N'-4-Hydroxy-5-ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

184. D-7- [a-(N'-4-Hydroxy-5-chloro-3-quinolyl-ureido)-a-phenyl-acetamido]- desacetoxycephalosporanic acid.

185. D-7-[α-(N'-4-Hydroxy-5-bromo-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

186. D-7-[α-(N'-4-Hydroxy-6-methyl-3-quinolyl-ureido)-α-phenyl-acetmid]- desacetoxycephalosporanic acid.

186. D-7-[α-(N'-4-Hydroxy-6-ethyl-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

188. D-7-[a-(N'-4-Hydroxy-6-methoxy-3-quinolyl-ureido)-a-phenyl- acetamido]-desacetoxycephalosporanic acid.

189. D-7- [-(N'-4-Hydroxy-6-ethoxy-3-quinolyl-ureido)-ce-phenyl-acetamido]- desacetoxycephalosporanic acid.

190. D-7-[α-(N'-4-Hydroxy-6-chloro-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid; Na salt, IR: 3,400, 1758 and 1,670 cm-1; Rf 0.56.

191. D-7-[α-(N'-4-Hydroxy-6-bromo-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

192. D-7-[ct-(N'-4-Hydroxy-6-dimethylamino-3-quinolyl-ureido)-,z-phenyl- acetamido]-desacetoxycephalosporanic acid.

193. D-7-[α-(N'-4-Hydroxy-7-methyl-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid; Na salt, IR : 3,350, 1,765 and 1,670 cm-1; Rf 0.50.

194. D-7-[α-(N'-4-Hydroxy-7-ethyl-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

195. D-7-[a-(N'-4-Hydroxy-7-methoxy-3-quinolyl-ureido)-(z-phenyl- acetamido]-desacetoxycephalosporanic acid.

196. D-7-[α-(N'-4-Hydroxy-7-ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic aci; Na salt, IR: 3,400, 1,756 and 1,670 cm-1; Rf 0.55.

197. D-7-[a-(N'-4-Hydroxy-7-chloro-3-quinolyl-ureido)-a-phenyl-acetamido]- desacetoxycephalosporanic acid; Na salt, IR: 3,300, 1,759 and 1,660 cm-1; Rf 0.58.

198. D-7-[α-(N'-4-Hydroxy-7-bromo-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

199. D-7-[α-(N'-4-Hydroxy-8-methyl-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalsoporanic acid.

200. D-7-[α-(N'-4-Hydroxy-8-ethyl-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

201. D-7-[a-(N'-4-Hydroxy-8-methoxy-3-quinolyl-ureido)-cg-phenyl- acetamido]-desacetoxycephalosporanic acid.

202. D-7-[α-(N'-4-Hydroxy-8-ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

203. D-7-[α-(N'-4-Hydroxy-8-chloro-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

204 D-7-[α-(N'-4-Hydroxy-8-bromo-3-quinolyl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

205. D-7-[a-(N'-4-Hydroxy-6,7-dimethyl-3-quinolyl-ureido)-a-phenyl- acetamido]-desacetoxycephalosporanic acid.

206. D-7- [a-(N'-4-Hydroxy-6,7-dichloro-3-quinolyl-ureido)-a-phenyl- acetamido]-desacetoxycephalosporanic acid.

207. D-7-[α-(N'-4-Hydroxy-6-methyl-7-chloro-3-quinolyl-ureido)-α-phenyl- acetamido]-desacetoxycephalosporanic acid.

208. D-7-[α-(N-4-Hydroxy-1,5-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid; Na salt, IR: 3400, 1760, 1655 cm-'; RF 0.23 (dioxan:water 70:30).

209. D-7-[a-(N'-4-Hydroxy-8-methyl- 1 ,5-naphthyrid-3-yl-ureido-a-phenyl- acetamido]-desacetoxycephalosporanic acid.

210. D-7-[(r-(N'-4-Hydroxy-8-ethyl- 1 ,5-naphthyrid-3-yl-ureido)-a-phenyl- acetamidol-desacetoxycephalosporanic acid.

211. D-7-[cr-(N'-4-Hydroxy-8-methoxy- 1,5-naphthyrid-3-yl-ureido)--phenyl- acetamido]-desacetoxycephalosporanic acid.

212. D-7- [a-(N'-4-Hydroxy-8-ethoxy- 1 ,5-naphthyrid-3-yl-ureido)-a-phenvl- acetamido]-desacetoxycephalosporanic acid.

213. D-7-[α-(N'-4-Hydroxy-1,6-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

214. D-7-[α-(N'-4-Hydroxy-8-methyl-1.6-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-desacetoxycephalosporanic acid.

215. D-7-[α-(N'-4-Hydroxy-8-methoxy-1.6-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-desacetoxycephalosporanic acid.

216. D-7-[α-(N'-4-Hydroxy-8-chloro-1.6-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-desacetoxycephalosporanic acid.

217. D-7-[α-(N'-4-Hydroxy-8-bromo-1,6-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-desacetoxycephalosporanic acid.

218. D-7-[α-(N'-4-Hydroxy-1.7-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

219. D-7-[α-(N'-4-Hydroxy-8-chloro-1,7-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-desacetoxycephalosporanic acid.

220. D-7-[α-(N'-4-Hydroxy-8-bromo-1,7-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-desacetoxycephalosporanic acid.

221. D-7-[α-(N'-4-Hydroxy-1,8-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]- desacetoxycephalosporanic acid.

222. D-7-[α-(N'-4-Hydroxy-7-methyl-1,8-naphthyrid-3-yl-ureido)-α-phenyl- acetamido]-desacetoxycephalosporanic acid.

223. D-7-[α-(N'-4-Hydroxy-1,10-phenanthrol-3-yl-ureido)-α-phenyl- acetamido]-desacetoxycephalosporanic acid.

Examples 224 to 249 Analogously to Example 1 D-7-(α-Amino-α-hydroxyphenyl-acetamido)-cephalosporanic acid.

D-7-(α-amino-α-cyclohexa-1,4-dienyl-acetamido)-cephalosporanic acid, cefatrizin, D-3-fluoro-7-(a-aminophenylacetamido)-3-cephem-4-carboxylic acid, D-3-chloro-7-(α-aminophenylacetamido)-3-cephem-4-carboxylic acid.

D-3-bromo-7-(tr-aminophenylacetamido)-3-cephem-4-carboxylic acid, D-3-iodo-7-(a-aminophenylacetamido)-3-cephem-4-carboxylic acid, D-3-methoxy-7-(a-aminophenylacetamido)-3-cephem-4-carboxylic acid, D-3-ethoxy-7-(a-aminophenylacetamido)-3-cephem-4-carboxylic acid, D-3-n-butoxy-7-(a-aminophenylacetamido)-3-cephem-4-carboxylic acid, D-3-(1 -methyl4etrazol-5-yl-thiomethyl)-7-(a-amino-a-p-hydroxyphenyl- acetamido)-3-cephem-4-carboxylic acid, D-3-(5-methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-(α-amino-α-p hydroxyphenyl-acetamido)-3-cephem-4-carboxylic acid (cefaparol) and D-3-pyridiniummethyl-7-(α-amino-α;-p-hydroxyphenyl-acetamido)-3-cephem- 4-carboxylate, by means of the corresponding cyclic carbamates, give: 224. D-7-[α-(N'-4-Hydroxy-3-pyridyl-ureido)-α-p-hydroxyphenyl-acetamido]- cephalosporanic acid.

225. D-7-[a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-a-p-hydroxyphenyl- acetamido]-cephalosporanic acid.

226. D-7-[a-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-a-p-hydroxyph enyl- acetamido]-cephalosporanic acid.

227. D-7-[α-(N'-4-Hydroxy-1,5-naphthyrid-3-yl-ureido)-α-p-hydroxyphenyl- acetamido]-cephalosporanic acid.

228. D-7-[a-(N'-4-Hydroxy-3-pyridyl-ureido)-a-cyclohexa- 1 4-dienyl- acetamidol-cephalosporanic acid.

229. D-3-(1,2,3-Triazol-4-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3-pyridyl-ureido)- α-p-hydroxy-phenyl-acetamido]-3-cephem-4-carboxylic acid.

230. D-3-(1,2,3-Triazol-4-yl-thiomethyl)-7-[t pyridyl-ureido)-a-p-hydroxyphenylacetamidol-3-cephem-4-carboxylic acid.

231. D-3-Fluoro-7-[α-(N'-4-hydroxy-3-pyridyl-ureido)-α-phenylacetamido]-3- cephem-4-carboxylic acid.

232. D-3-Chloro-7-[α-(N'-4-hydroxy-3-pyridyl-ureido)-α-phenylacetamido]-3- cephem-4-carboxylic acid.

233. D-3-Bromo-7-[α-(N'-4-hydroxy-3-pyridyl-ureido)-α-phenylacetamido]-3- cephem-4-carboxylic acid.

234. D-3-Iodo-7-[α-(Nj'-4-hydroxy-3-pyridyl-ureido)-α-phenylacetamido]-3- cephem-4-carboxylic acid.

235. D-3-Methoxy-7-[α-(N'-4-hydroxy-3-pyrdyl-ureido)-α-phenylacetamido]- 3-cephem-4-carboxylic acid.

236. D-3-Ethoxy-7-[α-(N'-4-hydroxy-3-pyridyl-ureido)-α-phenylacetamido]-3- cephem-4-carboxylic acid.

237. D-3-n-Butoxy-7-[α-(N'-4-hydroxy-3-pyridyl-ureido)-α-phenylacetamido]- 3-cephem-4-carboxylic acid.

238. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3-pyridyl- ureido)-α-p-Hydroxyphenylacetamido]-3-cephem-4-carboxylic acid.

239. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl-7-[α-(N'-4-hydroxy-5-chloro-3- pyridyl-ureido)-α-p-hydroxyphenylacetamido]-3-cephem-4-carboxylic acid.

240. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-bromo-3- pyridyl-ureido)-α-p-hydroxyphenyl-acetamido]-3-cephem-4-carboxylic acid.

241. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α(N'-4-hydroxy-1,5- naphthyrid-3-yl-ureido)-a-p-hydroxyphenylacetamido]-3-cephem-4-carboxylic acid.

242. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3- pyridyl-ureido)-α-p-hydroxyphenyl-acetamido]-3-cephem-4-carboxylic acid.

243. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- chloro-3-pyridyl-ureido)-α-hydroxyphenylacetamido]-3-cephem-4-carboxylic acid.

244. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- bromo-3-pyridyl-ureido)-α-p-hydroxyphenylacetamid]-3-cephem-4-carboxylic acid.

245. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-1.5- naphthyrid-3-yl-ureido)-α-p-hydroxyphenylacetamido]-3-cephem-4-carboxylic acid.

246. D-3-Pyridiniummethyl-7-[a-(N'-4-hydroxy-3-pyridylureido)-a-p- hydroxyphenylacetamido]-3-cephem-4-carboxylate.

247. D-3-Pyridiniummethyl-7-[α-(N'-4-hydroxy-5-chloro-3-pyridyl-ureido)-α- p-hydroxyphenylacetamido]-3-cephem-4-carboxylate.

248. D-3-Pyridiniummethyl-7-[α-(N'-4-hydroxy-5-bromo-3-pyridyl-ureido)-α- p-hydroxyphenylacetamido]-3-cephem-4-carboxylate.

249. D-3-Pyridiniummethyl-7- [a-(N'-4-hydroxy- 1, 5-naphthyrid-3-yl-ureido)-a- p-hydroxyphenylacetamidoj-3-cephem-4-carboxylate.

Example 250 Analogously to Example 1, 6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3 (tetrazol-5-yl-)-penam and 2,3-dihydro-oxazolo[4,5-clpyridin-2-one gives D-7-[α- (N'-4-hydroxy-3-pyridyl-ureido)-α-phenylacetamid]-2,2-dimethyl-3-(tetrazol-5- yl)-penam.

Examples 251 to 257 Analogously to Example 250, the corresponding 3-(tetrazol-5-yl)-penams give : 251. D-7-[α-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-α-phenyl-acetamido]- 2,2-dimethyl-3-(tetrazol-5-yl)-penam.

252. D-7-[α-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-α-phenyl-acetamido]- acetamidol -2,2-dimethyl-3-(tetrazol-5-yl)-penam .

253. D-6-[a-(N'-4-Hydroxy- 1 ,5-naphthyridy-3-yl-ureido)-a-phenyl- acetamdio]-2,2-dimethyl-3-(tetrazol-5-yl)-penam.

254. D-6-[α-(N'-4-Hydroxy-3-pyridyl-ureido)-α-p-hydroxyl-acetamido]- 2,2-dimethyl-3-(tetrazol-5-yl)-penam.

255. D-7-[α-(N'-4-Hydroxy-3-pyridyl-ureido)-α-(2-thienyl)-acetamido]-2,2- dimethyl-3-(tetrazol-5-yl)-penam.

256. D-7-[α-(N'-4-Hydroxy-3-pyridyl-ureido)-α-(3-thienyl)-acetamido]-2,2 dimethyl-3-(tetrazol-5-yl)-penam.

257. D-6-[a-(N'-4-Hydroxy-3-pyridyl-ureido)-a-(cyclohexa- 1 ,4-dienyl)- acetamido]-2,2-dimethyl-3-(tetrazol-5-yl)-penam.

Examples 258 to 263 Analogously to Example 1, ampicillin or cefaloglycin and 4-hydroxy-3-pyridylisothiocyanate or substituted 4-hydroxy-3-pyridyl-isothiocyanates, give: 258. D-α-(N'-4-Hydroxy-5-chloro-3-pyridyl-thioureido)-benzylpenicillin.

259. D-α-(N'-4-Hydroxy-5-bromo-3-pyridyl-thioureido)-benzylpenicillin.

260. D-7-[a-(N'-4-Hydroxy-3-pyridyl-thioureido)-a-phenylacetamido]- cephalosporanic acid.

261. D-7-[a-(N'-4-Hydroxy-5-chloro-3-pyridyl-thioureido)-- phenylacetamido]-cephalosporanic acid.

262. D-7-[(z-(N'-4-Hydroxy-5-bromo-3-pyridyl-thioureido)-- phenylacetamido]cephalosporanic acid.

263. D-7-[a-(N'-4-Hydroxy-l ,5-napthyrid-3-yl-thioureido)-a- phenylacetamidol-cephalosporanic acid.

Example 264 a) 22.9 g of phosphorus pentachloride are added to a suspension of 28.7 g of DL-2-(N'-4-hydroxy-3-pyridylureido)-phenylacetic acid (obtainable by reacting the triethylamine salt of a-aminophenylacetic acid with 2,3-dihydro-oxazolo[4,5c]pyridin-2-one) in 500 ml of chloroform and the mixture is stirred at 200 overnight.

It is then evaporated and the residue is dissolved in benzene and once more evaporated. This procedure is repeated a total of 3 times and the crude acid chloride thus obtained is used for the following reaction.

27.2 g of 7-ACA and 70 ml oftriethylamine are stirred in 220 ml of methylene chloride for one hour at 20 . The acid chloride, dissolved in 70 ml of methylene chloride is added dropwise to this solution, while stirring and cooling, and the mixture is stirred for a further hour at 200. It is extracted several times with water and the combined aqueous extract are washed with ether and the pH is adjusted to 2 with hydrochloric acid, while stirring. The precipitated DL-7-[a-(N'-(4-hydroxy 3-pyridyl-ureido)-a-phenyl-acetamido]-cephaosporanic acid is dried at 20 .

b) In order to obtain the potassium salt, the cephalosporanic acid obtained in accordance with a) is dissolved at 0 in the calculated quantity of 0.5 N aqueous potassium hydroxide solution, the mixture is filtered and the filtrate is concentrated to dryness at 20--300.

By using 6-aminopenicillanic acid, DL-a-(N'-4-hydroxy-5-chloro-3-pyridyl- ureido)-benzylpencillin is obtained analogously to a) and the corresponding potassium salt is obtained from it analogously to b).

Example 265 25 ml of thionyl chloride are added dropwise, while cooling, to a solution of 28.7 g of D-2-(N'-4-hydroxy-3-pyridyl-ureido)-phenylacetic acid in 500 ml of DMF.

The mixture is stirred for two hours at 200 and is evaporated under reduced pressure. The crude acid chloride thus obtained is reacted with 7-ACA analogously to Example 267, D7-[(N'A-hydroxy-3-pyridyl-ureido)-a-phenyl-acetamidol- cephalosporanic acid being obtained.

Example 266 1 ml of chloroformic acid ethyl ester is added, at -8 to 100, to 3.25 g of the Na salt of DL-2-(N'-4-hydroxy-3-pyridyl-ureido)-2-p-hydroxyphenylacetic acid in 50 ml of dry acetone and the mixture is stirred for 1 hour at -8 to --100. The sodium chloride is then filtered off and the filtrate is added to a stirred solution of 3.1 g of the K salt of 7-ACA in 30 ml of water and 50 ml of acetone. After stirring at 200 for one hour, the solvents are evaporated off. The residue is taken up in 50 ml of methanol. Undissolved matter is filtered off and the potassium salt of DL-7-[a-(N'- 4-hydroxy-3-pyridyl-ureido)-a-p-hydroxy-phenyl-acetamidol -cephalosporanic acid is precipitated from the filtrate by adding diethyl ether.

Example 267 A suspension of 40.8 g of DL-a-(N'-4-hydroxy-3-pyridyl-ureido)-phenylacetic acid p-nitrophenyl ester (obtainable from the acid chloride and p-nitrophenol) in 300 ml of chloroform is added dropwise at 0 to a solution of 35.4 g of 7-ACA triethylammonium salt and 11.2 ml of triethylamine in 450 ml of chloroform and the mixture is then stirred for 2 hours at 20 . It is then evaporated at 300 and the residue is taken up in water/methyl isobutyl ketone and the pH is adjusted to 2.1 with sulphuric acid, the phases are separated and the aqueous layer is extracted once more with methyl isobutyl ketone.The organic extracts are combined, washed with water and extracted several times with sodium bicarbonate solution in such a way that the aqueous fraction reaches a pH of 6.8-7.0. The phases are separated, the organic phase is extracted once more with water and the combined aqueous phases are washed several times with diethyl ether and evaporated at 200 to give the sodium salt of DL-7-[a-N'-(4-hydroxy-3-pyridyl-ureido)-a-phenyl- acetamido]-cephalosporanic acid.

Example 268 A solution of 38.6 g of 7-ACA pivaloyloxy-methyl ester, 20.6 g of dicyclohexylcarbodiimide and 28.7 g of D-a-(N'-hydroxy-3-pyridyl-ureido)- phenylacetic acid in a mixture of 150 ml of DMF and 150 ml of methylene chloride is stirred for 2 hours at 200. The dicyclohexylurea formed is filtered off and the filtrate is filtered through silica gel. Evaporation gives D-7-[a-(N'-4-hydroxy-3- pyridylureido)-er-phenylacetamido]cephalosporanic acid pivaloyloxymethyl ester.

Example 269 a) 1 g of D-7-[a-(N'-4-hydroxy-3-pyridyl-ureido)-a-phenylacetamidol- cephalosporanic acid trimethylsilyl ester obtainable by reacting cefaloglycin successively with hexamethyldisilazane and with 2,3-dihydro-oxazolo-[4,5-c]pyridin-2-one) is shaken with 5 ml of water for 30 minutes at 20 and the resulting D-8-[α-4-hydroxy-3-pyridyl-ureido)-α-phenyl-acetamido]-cephalosporanic acid is filtered off.

b) 5.86 g of the triethylamine salt of D-7-[a(N'-4-hydroxy-3-pyridyl-ureido)-a phenyl-acetamido]-cephalosporanic acid are dissolved in 100 ml of methylene chloride and 20 ml of DMF, a solution of 1.51 g of pivaloyloxymethyl choride in 5 ml of methylene chloride is added dropwise at 200 and the mixture is stirred for a further 2 hours at 200 and is washed with water. After drying and evaporation, D-7 [α-(N'-4-hydroxy-3-pyridyl-ureido)-α-phenyl-acetamido]-cephalosporanic acid pivaloyloxymethyl ester is obtained.

Example 270 A suspension consisting of 1 g of D-7-[α-4-hydroxy-3-pyridyl-ureido)-α- phenyl-acetamido]-cephalosporanic acid benzyl ester (obtainable from cefaloglycin benzyl ester and 2,3-dihydro-oxazolo-[4,5-cl-pyridin-2-one), 0.2 g of 10% Pd-on charcoal and 100 ml of methanol is shaken for one hour at 200 and normal pressure and is filtered and evaporated to give D-7-[a-(N'-4-hydroxy-3- pyridyl-ureido)-a-phenyl-acetamido]-cephalosporanic acid.

Example 271 A solution of 1 g of D-7-[cr-(N'-4-hydroxy-3-pyridyl-ureido)-ct-phenyl- acetamido]-cephalosporanic acid and I g of ammonium bicarbonate in 15 ml of water is hydrogenated over 80 mg of palladium oxide hydrate at 0 and 3.5 atmospheres. The mixture is filtered, evaporated and purified by chromatography to give D-7-[a-(N'-4-hydroxy-3-pyridyl-ureido)-a-phenyl-acetamidol- desacetoxycephalosporanic acid.

Example 272 5.41 g of D-7-[α-(N'-4-hydroxy-3-pyridyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid and 1.16 g of 1-methyl-tetrazole-5-thiol are added, while stirring, to 100 ml of water heated to 750, the pH is adjusted to 4.8 with NaHCO3 and the mixture is warmed for 2 hours to 800. It is then cooled and poured onto ice and hydrochloric acid is added until pH 2 is reached. The resulting D-3-(1-methyltetrazol - 5 - yl - thiomethyl) - 7 - 1a - (N' - 4 - Hydroxy - 3 - pyridyl - ureido) - a phenyl - acetamido] - 3 - cephem - 4 - carboxylic acid is filtered off, washed with water and dried over P2Os. Na salt, IR: 3,270, 1,758 and 1,658 cm-'; Rf 0.38.

Examples 273 to 340 The following are obtained analogously to Example 272 from the corresponding cephalosporanic acids by means of l-methyl-tetrazole-5-thiol: 273. D-3-( 1 -Methyltetrazol-5-yl-thiomethyl)-7-la-(N'-4-hydroxy-3-quinolyl- ureido)-a-phenyl-acetamidol-3-cephem-4-carboxylic acid, Na saft; IR: 3,330, 1,765 and 1,668 cm-1; Rf 0.53.

274. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-methyl-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

275. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-ethyl-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

276. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-methoxy-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

277. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-ethoxy-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

278. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-chloro-3 quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

279. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-bromo-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

280. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6-methyl-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

281. D-3-( 1 -Methyl-tetrazol-5-yl-thiomethyl)-7- [(E-(N'-4-hyd roxv-6-ethyl-3 quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

282. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6-methoxy-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

283. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6-ethoxy-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

284. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6-chloro-3- quinolyl-yreido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid, Na salt, IR : 3,400, 1,763 and 1,668 cm-1 ; Rf 0.56.

285. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6-bromo-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

286. D-3-(1-Methyl-tetrrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6- dimethylamino-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

287. D-3-(1 -Methyl-tetrazol-5-yl-thiomethyl)-7-[a-(N'-4-hydroxy-7-methyl-3- quinolyl-ureido)-α-phenyl-acetamidol-3-cephem-4-carboxylic acid.

288. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-(α-(N'-4-hydroxy-7-ethyl-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

289. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α'-4-hydroxy-7-methoxy-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

290. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-ethoxy-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid ; Na salt, IR : 3,380, 1,768 and 1,668 cm-1 ; Rf 0.56.

291. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-chloro-3- quinolyl-ureido)-α-phenyl-acetamidol-3-cephem-4-carboxylic acid, Na salt. IR: 3,400, 1,765 and 1,670 cm-1 ; Rf 0.57.

292. D-3-(1 -Methyl-tetrazol-5-yl-thiomethyl)-7-[a-(N'-4-hydroxy-7-bromo-3 quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

293. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8-methyl-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

294. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8-ethyl-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

295. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α(N'-4-hydroxy-8-methoxy-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

296. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8-ethoxy-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

297. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8-chloro-3- q uinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

298. D-3-(1 -Methyl-tetrazol-5-yl-thiomethyl)-7-[a-(N'-4-hydroxy-8-bromo-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

299. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6,7-dimethyl- 3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

300. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6,7-dichloro- 3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

301. D-3-(1 -Methyl-tetrazol-5-yl-thiomethyl)-7-[a-(N'-4-hydroxy-6-methyl-7 chloro-3-quinolyl-ureido)-α-phenyl-actamido]-3-cephem-4-carboxylic acid.

302. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-1,5- naphthyrid-3-yl-ureido)-αphenyl-acetamido]-3-cephem-4-carboxylic acid.

303. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8-methyl-1,5 naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

304. D-3-(1-Methyl-tetrazol-5-yl-thomethyl)-7-[α-(N'-4-hydroxy-8-ethyl-1,5- naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

305. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α(N'-4-hydroxy-8-methoxy- 1,5-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

306. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8-ethoxy- 1,5-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic aicd.

307. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-1,6-anphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

308. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8-methyl- 1,6-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

309. D-3-(1~methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8-methoxy- 1,6-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

310. D-3-(1-Methyl-tetrzol-5-yl-thiomethyl)-7-[α-4-hydroxy-8-chloro- 1,6-naphthyrid-3-yl-ureido)-α-phenyl-acetamidol-3-cephem-4-carboxylic acid.

311. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8-bromo- 1,6-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

312. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-1,7- naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

313. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8-chloro- 1,7-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

314. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8-bromo- 1,7-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

315. D-3-(1-Methyl-tetrazol-5-yl-thomethyl)-7-[α-(N'-4-hydroxy-1,8- naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

316. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-methyl-1,8- naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

317. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-1,10- phenanthrol-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

318. D-3-(1-Methyl-tetrazol-5-yl-thomethyl)-7-[α-(N'-2,4-dihydroxy-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

319. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl-7-[α-(N'-2-methyl-4-hydroxy-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

320. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-2-n-butyl-4-hydroxy-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

321. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-fluoro-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

322. D-3-(1 -Methyl-tetrazol-5-yl-thiomethyl)-7- [a-(N1-4-hydroxy-6-fluoro-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

323. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-chloro-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

324. D-3-( 1 -Methyl-tetrazol-5-yl-thiomethyl)-7-[a-(N'-4-hydroxy-6-chloro-3 pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

325. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-bromo-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

326. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6-bromo-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

327. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-iodo-3- pyridyl-ureido)-α-phenyl-acetamdo]-3-cephem-4-carboxylic acid.

328. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-nitro-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

329. D-3-(1 -Methyl-tetrazol-5-yl-thiomethyl)-7-[a-(N'-4-hydroxy-5-am ino-3- pyridyl-ureido)--phenyl-acetamido]-3-cephem-4-carboxylic acid.

330. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- methylamino-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

331. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-n- butylamino-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

332. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-dimethyl- amino-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

333. D-3-(1-Methyl-tetrazol-5-ylthiomethyl)-7-[α-(N'-4-hydroxy-5- diethylamino-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

334. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-di-n- butylamino-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

335. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- formamido-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

336. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-acetamido- 3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

337. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- butyramido-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

338. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- methylsulphonamido - 3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

339. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-2,4-dihydroxy-5-chloro- 3-pyridyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid: Na salt. IR: 3,400, 1,765 and 1,610 cm-1.

340. D-3-( I -Methyl-tetrazol-5-yl-thiomethyl)-7-[a-(N'-2,4-dihydroxy-5-bromo- 3-pyridyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid: Na salt, IR: 3,400, 1,760 and 1,610 cm-1.

Examples 341 to 409 The following are obtained analogously to Example 272 from the corresponding cephalosporanic acids by means of 5-methyl-l,3,4-thiadiazole-2- thiol: 341. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid; Na salt, IR: 3,270, 1,765 and 1,670 cm-1, Rf 0.40.

342. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3- q uinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid: Na salt, IR: 3,350, 1,770 and 1,665 cm-': Rf 0.55.

343, D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- methyl-3-quinolyl-ureido)-α-phenyl-acetamidol-3-cephem-4-carboxylic acid.

344. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- ethyl-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cehem-4-carboxylic acid.

345. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- methoxy-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

346. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-4-hydroxy-5- ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

347. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-N'-4-hydroxy-5- chloro-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

348. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- bromo-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

349. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6- methyl-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

350. D-3-(5-Methyl- I ,3,4-thiadiazol-2-yl-thiomethyl)-7- [a-(N'-4-hydroxy-6- ethyl-3-quinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

351. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-)(N'-4-hydroxy-6- methoxy-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

352. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thomethyl)-7-[α-(N'-4-hydroxy-6- ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

353. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6- chloro-3-quinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid, Na salt, IR: 3,350 1,763 and 1,670 cm-i; Rf 0.57.

354. D-3-(5-Methyl-1,3,4-thiadaizol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6- bromo-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxyli acid.

355. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6- dimethylamino-3-q uinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

356. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7- methyl-3-quinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

357. D3-(5-Methyl-l ,3,4-th iadiazol-2-yl-thiomethyl)-7-[cg-(N'-4-hydroxy-7- ethyl-3-q uinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

358. D-3-(5-Methyl- I ,3,4-thiadiazol-2-yl-thiomethyl)-7- [a-(N'-4-hydroxy-7- methoxy-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

359. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7- ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid; Na salt, IR: 3,400, 1,763 and 1,672 cm-1; Rf 0.56.

360. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thlomethyl)-7-[α-(N'-4-hydroxy-7- chloro-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid, Na salt, IR: 3,400, 1,765 and 1,670 cm-'; Rf 0.57.

361. D-3-(5-Methyl-1,3,4-thladiazol-2-yl-thlomethyl)-7-[α-(N'-4-thdroxy-7- bromo-3-quinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

362. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8- methyl-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

363. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8- ethyl-3-q uinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

364. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8- methoxy-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

365. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8- ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

366. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8- chloro-3-quinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

367. D-3-(5-Methyl- 1,3,4-thiadiazol-2-yl-th iomethyl)-7-[a-(N '-4-hydroxy-8 bromo-3-q uinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

368. D-3-(5-M ethyl- 1 ,3,4-thiadiazol-2-yl-thiomethyl)-7- [a-(N'-4-hydroxy-6, 7- dimethyl-3-quinolyl-ureido)-a-phenyl-acetamido] -3-cephem-4-carboxylic acid.

369. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6,7-] dichloro-3-q uinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

370. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6- methyl-7-chloro-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

371. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-1,5- naphthyrid-3-yl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid, Na salt, IR: 3,320, 1,767 and 1,662 cm-1; Rf 0.18.

372. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7[α-(N'-4-hydroxy-8- methyl-1.5-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

373. D-3-(5-Methyl- 1 ,3,4-thiadiazol-2-yl-thiomethyl)-7-[a-(N'-4-hydroxy-8- ethyl-1,5-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

374. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[a-(N'-4-hydroxy-8- methoxy-1,5-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

375. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8- ethoxy- I ,5-naphthyrid-3-yl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

376. D-3-(5-Methyl- 1 ,3,4-thiadiazol-2-yl-thiomethyl)-7-[a-(N'-4-hydroxy- 1,6 naphthyrid-3-yl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

377. D-3-(5-Methyl- 1,3,4-thiadiazol-2-yl-thiomethyl)-7-[-(N'-4-hydroxy-8- methyl ,6-naphthyrid-3-yl-ureido)-cr-phenyl-acetamido] -3-cephem-4-carboxylic acid.

378. D-3-(5-Methyl- 1 ,3,4-thiadiazol-2-y1-thiomethyl)-7-[a-(N'-4-hydroxy-8- methoxy-1,6-naphthyriud-3-yl-yreido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

379. D-3-(5-Methyl-l ,3,4-thiadiazol-2-yl-thiomethyl)-7-[a-(N'-4-hydroxy-8- chloro-1,6-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

380, D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-8- bromo-1.6-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

381. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-1,7- naphthyrid-3-yI-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

382. D-3-(5-Methyl-t ,3,4-thiadiazol-2-yl-thiomethyl)-7-[a-(N'-4-hydroxy-8- chloro-l ,7-naphthyrid-3-yl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

383. D-3-(5-Methyl- 1,3,4-thiadiazol-2-yl-thiomethyl)-7-[(z-(N'-4-hydroxy-8- bromo- 1 ,7-naphthyrid-3-yl-ureido-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

384. D-3-(5-Methyl- I ,3,4-thiadiazol-2-yI-thiomethyl)-7-[a-(N'-4-hydroxy- 1,8 napthyrid-3-yl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

385. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7- methyl-1,8-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

386. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-1,10- phenantrol-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

387. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-N'-2,4-dihydroxy-3- pyridyl-ureido)--phenyl-acetamido]-3-cephem-4-carboxylic acid.

388. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-N'-2-methyl-4- hydroxy-3-pyridyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

389. D-3-(5-Methyl- I ,3,4-thiadiazol-2-yl-thiomethyl)-7-[a-(N'-2-n-butyl-4- hydroxy-3-pyridyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

390. D-3-(5-Methyl- 1 ,3,4-thiadiazol-2-yI-thiomethyl)-7-[a-(N'-4-hydroxy-5- fluoro-3-pyridyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

391. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6- fluoro-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

392. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- chloro-3-pyridyl-yreido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

393. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6- chloro-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

394. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(-N'-4-hydroxy-5- bromo-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic cid.

395. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6- bromo-3-pyridyl-ureido)-sg-phenyl-acetam ido]-3-cephem-4-carboxylic acid.

396. D-3-(5-Methyl-1.3.4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- iodo-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

397. D-3-(5-Methyl- 1 ,3,4-thiadiazol-2-yl-thiomethyl)-7- [a-(N'-4-hydroxy-5- nitro-3-pyridyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

398. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- amino-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

399. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- methylamino-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

400. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-n- butylamine-3-pyridyl-ureido)-α-henyl-acetamido]-3-cephem-4-carboxylic acid.

401. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- dimethylamino-3-pyridyl-ureido)-α-henyl-acetamido]-3-cephem-4-carboxylic acid.

402. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- diethylamino-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

403. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-di- n-butylamino-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

404. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- formamido-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

405. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- acetamido-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

406. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- butyramido-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

407. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-)N'-4-hydroxy-5- methylsulphonamido-3-pyridyl-ureido)-a-phenyl-acetamido]-3-cephem-4- carbolcylic acid.

408. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α(N'-2,4-dihydroxy-5- chloro-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid ; Na salt, IR: 3,400, 1,765 and 1,610 cm-t.

409. D-3-(5-Methyl-1,3,4-thiadiazlo-2-yl-thiomethyl)-7[α-(N'-2,4-dihydroxy-5- bromo-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid; Na salt, IR: 3,400, 1,760 and 1,610 cm-1.

Examples 410 to 465 The following are obtained analogously to Example 272 from the corresponding cephalosporanic acid and either 3-methyl-1,2,4-thiadiazole-5-thiol, 5-methyl-1,3,4-oxaidazole-2-thiol, 1,3,4-thiadiazole-2-thiol, tetrazole-5-thiol, 1,2,3triazole-4-thiol, 4-methyl-oxazole-2-thiol or 1-oxido-pyridine-thiol: 410. D-3-(3-Methyl- 1,2,4-thiadiazol-5-yl-thiomethyl)-7-[a-(N'-4-hydroxy-3 pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

411. D-3-(3-Methyl-1,2,4-thiadiazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- chloro-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cphem-4-carboxylic acid.

412. D-3-(3-Methyl- 1 ,2,4-thiadiazol-5-yl4hiomethyl)-?-[a-(N'A-hydroxy-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

413. D-3-(3-Methyl-1,2,4-thiadiazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6- chloro-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

414. D-3-(3-Methyl-1,2,4-thiadiazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7- methyl-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic aicd.

415. D-3-(3-Methyl-1,2,4-thiadiazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7- ethoxy-3-quino1yl-ureido)-a-phenylacetamidol-3-cephem-4-carboxylic acid.

416. D-3-(3-icikthyl-l ,2,44hiadiazol-5-yl-thiomethyl)-7-[a-(N'-4-hydroxy-7- chloro-3-q uinolyl-ureido)-cr-phenyl-acetamido]-3-cephem-4-carboxylic acid.

417. D-3-(3-Methyl- I ,2,4-thiadiazol-5-yl-thiomethyl)-7-[a-(N'-4-hydroxy- 1,5 naphthyrid-3-yl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

418. D-3-(5-Methyl-1,3,4-oxadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

419. D-3-(5-Methyl-1,3,4-oxadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- chloro-3-pyridyl-ureido)-α-phenyl-acetamido-3-cephem-4-carboxylic acid.

420. D-3-(5-Methyl-1,3,4-oxadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3- quinolyl-ureido)-α-phenyl-acetamido-3-cephem-4-carboxylic acid.

421. D-3-(5-Methyl-1,3,4-oxadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6- chloro-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

422. D-3-(5-Methyl-1,3,4-oxadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7- methyl-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

423. D-3-(5-Methyl-1,3,4-oxadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7- ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

424. D-3-(5-Methyl-1,3,4-oxadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7- chloro-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

425. D-3-(5-Methyl-1,3,4-oxadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-1,5- naphthyrid-3-yl-ureido)-α-phenyl-aacetamido]-3-cephem-4-carboxylic acid.

426. D-3-(1,3,4-Thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3-pyridyl- ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

427. D-3-(1,3,4-Thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-chloro-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

428. D-3-(1,3,4-Thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3-quinolyl- ureido-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

429 D-3-(1,3,4-Thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6-chloro-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

430. D-3-(1,3,4-Thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-methyl-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic aicd.

431. D-3-(1.3.4-Thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-methyl-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

432. D-3-(1,3,4-Thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-chloro-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

433. D-3-(113,4-Thiadiazol-2-yl-thiomethyl)-7-[-(N'-4-hydroxy-1 5- naphthyrid-3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

434. D-3-(Tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3-pyridyl-ureido)-α- phenyl-acetamido]-3-cephem-4-carboxylic acid.

435. D-3-(Tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-chloro-3-pyridyl- ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

436. D-3-(Tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3-quinolyl-ureido)-α- phenyl-acetamido]-3-cephem-4-carboxylic acid.

437. D-3-(Tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-chloro-3-quinolyl- ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

438. D-3-(Tetrazol-5-yl-thiomethyl)-7- [a-(N'-4-hydroxy-7-methyl-3-q uinolyl ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

439. D-3-(Tetrazol-5-yl-thiomethyl)-7-[a-(N'-4-hydroxy-7-ethoxy-3-quinolyl- ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

440. D-3-(Tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-chloro-3-quinolyl- ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

441. D-3-(Tetrazol-5-yl-thiomethyl)-7-[-(N'-4-hydroxy- 1 ,5-naphthyrid-3-yl- ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

442. D-3-(1,2,3-Triazol-4-yl-thiomethyl)-7-[α-(N'-hydroxy-3-pyridyl-ureido)- α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

443. D-3-(1,2,3-Triazol-4-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-chloro-3-pyridyl- ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

444. D-3-( 1 ,2,3-Triazol-4-yl-thiomethyl)-7-[ct-(N' ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

445. D-3-(1,2,3-Triazol-4-yl-thiomethyl)-7-(α-(N'-4-hydroxy-6-chloro-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

446. D-3-(1,2,3-Triazol-4-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-methyl-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

447. D-3-(1,2,3-Triazol-4-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-ethoxy-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

448. D-3-(1,2,3-Triazol-4-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-chloro-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

449. D-3-(1,2,3-Triazol-4-yl-thiomethyl)-7-[a-(N'-4-hydroxy- 1,5-naphthyrid-3yl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

450. D-3-(4-Methyl-oxazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3-pyridyl- rueido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

451. D-3-(4) Methyl-oxazol-2-yl-thiomethyl)-7-[α-(N'-4j-hydroxy-5-chloro-3 pyridyl-ureido)-α-phenyl-acetamidol-3-cephem-4-carboxylic acid.

452. D-3-(4-Methyl-oxazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3-quinolyl- ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

453. D-3-(4-Methyl-oxazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6-chloro-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

454. D-3-(4-Methyl-oxazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-methyl-3- quinolyl-ureido)-α-phenyl-acetamidol-3-cephem-4-carboxylic acid.

455. D-3-(4-Methyl-oxazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-ethoxy-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

456. D-3-(4-Methyl-oxazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-chloro-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

457. D-3-(4-Methyl-oxazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-1,5-napthyrid- 3-yl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

458. D-3-(1-Oxido-pyridin-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3-pyridyl- ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

459. D-3-(1-Oxido-pyridin-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5-chloro-3- pyridyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

460. D-3-(1-Oxido-pyridin-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3-quinolyl- ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

461. D-3-(1-Oxido-pyridin-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-6-chloro-3- quinolyl-ureido)-α-phenyl-acetamidol-3-cephem-4-carboxylic acid.

462. D-3(1-Oxido-pyridin-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-methyl-3- quinolyl-ureido)-α-phenyl-acetamidol-3-cephem-4-carboxylic acid.

463. D-3-(1-Oxido-pyridin-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-ethoxy-3- quinolyl-ureido)-α-phenyl-acetamidol-3-cephem-4-carboxylic acid.

464. D-3-(1-Oxido-pyridin-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-chloro-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

465. D-3-(1-Oxido-pyridin-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-1,5- naphthyrid-3-yl-ureido)-α-phenyl-acctamido]-3-cephem-4-carboxylic acid.

Example 466 A mixture of 563 mg of the Na salt of D-7-[α-(N'-4-hydroxy-3-pyridyl-ureido)- α-phenyl-acetamido]-cephalosporanic acid, 2.4 g of KSCN, 120 mg of pyridine and 0.6 ml of water is kept at 50 for 25 hours. The mixture is subjected to chromatography over a loosely crosslinked polystyrene exchanger (eluting agent: water) and evaporated to give D-7-[α-(N'-4-hydroxy-3-pyridyl-ureido)-α-phenyl- acetamido] -3-pyridiniummethyl-3-cephem-4-carboxylate.

Example 467 to 469 The following are obtained analogously to Example 466: 467. D-7-[α-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-α-phenyl-acetamido]-3- pyridiniummethyl-3-cephem-4-carboxylate.

468. D-7-[α-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-α-phenyl-acetamido]- 3-pyridiniummethyl-3-cephem-4-carboxylate.

469. D-7-[α-(N'-4-Hydroxy-1,5-naphthyrid-3-yl-ureido-α-phenyl-acetamido]- pyridiniummethyl-3-cephem-4-carboxylate.

Example 470 D-7-[α-(N'-4-Hydroxy-3-pyridyl-ureido)-α-phenyl-acetamido]-3-(3- carbamoylpyridiniummethyl)-3-cephem-4-carboxylate is obtained analogously to Example 466 using nicotinamide.

Example 471 to 475 The following are obtained analogously to Example 470 using nicotinamide, picolinamide or isonicotinamide: 471. D-7-[α-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-α-phenylacetamido]-3- (3-carbamoylpyridiniummethyl)-3-cephem-4-carboxylate.

472. D-7-[α-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-α-phenylacetamido]-3- (3-carbamoylpyridiniummethyl)-3-cephem-4-carboxylate.

473. D-7-[α-(N'-4-Hydroxy-1,5-naphthyrid-3-yl-ureido-α-phenylacetamido]-3- (3-carbamoylpyridiniummethyl)-3-cephem-4-carboxylate.

474. D-7-[α-(N'-4-Hydroxy-3-pyridyl-ureido)-α-phenyl-acetamido]-3-cephem- 3-(2-carbamoylpyridinlummethyl)-4-carboxylate.

475. D-7-[α-(N'-4-Hydroxy-3-pyridylureido)-α-phenyl-acetamido]-3-cephem- 3-(4-carbamoylpyridiniummethyl)-4-carboxylate.

Example 476 a) 5.41 g of the potassium salt of D-7-[a-(N'-4-hydroxy-3-pyridyl-ureido)-a- phenyl-acetamido]-cephalosporanic acid (obtainable from the free acid by adding the calculated quantity of aqueous KOH and lyophilising the resulting potassium salt solution) are brought into intimate contact with citrus acetyl esterase in an aqueous phosphate buffer at pH 6.5 for 15 hours, and the potassium salt of D-3-hydroxymethyl-7-[a-(N'-4-hydroxy-3-pyridyl-ureido)-a-phenyl- acetamido]-3-cephem-4-carboxylic acid is isolated (see Biochem. J., 81, 591 [1961]).

b) 523 mg of the K-salt of 3-hydroxymethyl-7-[a-(N'-4-hydroxy-3-pyridyl- ureido)-cr-phenyl-acetamido]-3-cephem-4-carboxylic acid are suspended in 10 ml of acetonitrile. 0.2 ml of chlorosulphonyl isocyanate are added at 00, under nitrogen and while stirring. The mixture is stirred for 1.5 hours. The solvent is distilled off and the resulting residue is taken up in 15 ml of 0.1 N phosphate buffer and covered with a layer of 15 ml of ethyl acetate. The pH value of the aqueous layer is adjusted to 1.6 and the mixture is stirred at room temperature for 2.5 hours.

The pH value is then adjusted to 8.0 with potassium phosphate. The organic phase is again extracted with phosphate buffer (pH=8). The combined aqueous extracts are acidified at 0 to pH 2 with aqueous HC1 and are extracted with ethyl acetate.

The extracts are dried over Na2SO4. After distilling off the solvent, D-3 carbamoyloxymethyl-7-[α-N'-4-hydroxy-3-pyridyl-ureido)-α-phenyl-acetamido]-3- cephem-4-carboxylic acid is obtained.

Examples 477 to 479 The following are obtained analogously to Example 476 from the corresponding cephalosporanic acids by enzymatic ester-splitting and subsequent reaction with chlorosulphonyl isocyanate: 477. D-3-Carbamoyloxymethyl-7-[a-(N'-4-hydroxy-5-chloro-3-pyridyl-ureido)- a-phenylacetamido]-3-cephem-4-carboxylic acid.

478. D-3-Carbamoyloxymethyl-7-[a-(N'-4-hydroxy-5-bromo-3-pyridyl- ureido)-cr-phenylacetamido]-3-cephem-4-carboxylic acid.

479. D-3-Carbamoyloxymethyl-7-[a-(N'-4-hydroxy- 1 ,5-naphthyrid-3-yl- ureido)-er-phenylacetamido]-3-cephem-4-carboxylic acid.

Example 480 535 mg of D-a-(N'-4-hydroxy-5-chloro-3-pyridyl-ureido)-p- hydroxybenzylpenicillin are dissolved in 10 ml of DMF, 1 ml of triethylamine is added and a solution of 327 mg of chloroformic acid ethyl ester in 3 ml of dioxan is added dropwise at 00, while stirring. The mixture is stirred for a further 20 minutes at 0 , poured into ice water, stirred for 10 minutes and acidified to pH 3 with hydrochloric acid and the resulting D-a-(N'-4-ethoxycarbonyloxy-5-chloro-3- pyridyl-ureido)-p-ethoxycarbonyloxy-benzylpenicillin is filtered off.

Example 481 to 495 The following are obtained analogously to Example 480 from the corresponding p-hydroxybenzylpenicillins by esterification: 481. D-α-(N'-4-Ethoxycarbonyloxy-3-pyridyl-ureido)-p-ethoxycarbonyloxy- benzylpenicillin.

482. D-a-(N'-4-Ethoxycarbonyloxy-5-bromo-3-pyridyl-ureido)-p- ethoxycarbonyloxy-benzylpencillin.

483. D-ct- [N'-4-Ethoxycarbonyloxy-3-( 1, 5-naphthyridyl)-ureido]-p- ethoxycarbonyloxy-benzylpenicillin 484. D-a-(N'-4-Acetoxy-3-pyridyl-ureido)-p-acetoxy-benzylpenicillin.

485. D-hz-(N'-4-Acetoxy-5-chloro-3-pyridyl-ureido)-p-acetoxy- benzylpenicillin.

486. D-a-(N'-4-Acetoxy-5-bromo-3-pyridyl-ureido)-p-acetoxy- benzylpenicillin.

487. D-α-[N'-4-Acetoxy-1,5-naphthyrid-3-yl-ureido]-p-acetoxy- benzylpenicillin.

488. D-a-(N'-4-Ethoxycarbonyloxy-3-pyridyl-ureido)-p-ethoxycarbonyloxy- benzylpenicillin pivaloyloxymethyl ester.

489. D-a-(N'-4-Ethoxycarbonyloxy-5-chloro-3-pyridyl-ureido)-pethoxycarbonyloxy-benzylpenicillin pivaloyloxymethyl ester.

490. D-a-(N'-4-Ethoxycarbonyloxy-5-bromo-3-pyridyl-ureido)-p- ethoxycarbonyloxy-benzylpenicillin pivaloyloxymethyl ester.

491. D-a-[N'-4-Ethoxycarbonyloxy-l ,5-naphthyrid-3-yl-ureido]-p- ethoxycarbonyloxy-benzylpenicillin pivaloyloxmethyl ester.

492. D-a-(N'-4-Acetoxy-3-pyridyl-ureido)-p-acetoxy-benzylpenicillin pivaloyloxymethyl ester.

493. D-aN'A-Acetoxy-5-chloro-3-pyridyl-ureido)-p-acetoxy-benzylpeniciIlin pivaloyloxymethyl ester.

494. D-a-(N'-4-Acetoxy-5-bromo-3-pyridyl-ureido)-p-acetoxy-benzylpenicillin pivaloyloxymethyl ester.

495. D-a-[N'-4-Acetoxy-3-(l,5-napthyridyl)-ureido]-p-acetoxy- benzylpenicillin pivaloyloxymethyl ester.

Example 496 1 g of D-7-[a-(N'-4-hydroxy-3-pyridyl-ureido)--phenyl-acetamidol- cephalosporanic acid is dissolved in 5 ml of methylene chloride and 5 ml of triethylamine and the mixture is evaporated at 2025 to give the corresponding triethylamine salt.

The following examples of pharmaceutical compositions are given by way of illustration only.

Example A: Tablets A mixture consisting of 2 kg of the Na salt of D-7-[a-(N'-hydroxy-3-pyridyl- ureido)-a-phenyl-acetamido]-cephalosporanic acid [or the Na salt of D-a(N'-4- hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin], 5 kg of lactose, 1.8 kg of potato starch, 0.1 kg of magnesium stearate and 0.1 kg of talc is pressed in conventional manner to give tablets, each containing 200 mg of active compound.

Example B: Dragees Tablets are pressed in the same way as in Example A and are then coated in conventional manner with a coating consisting of sugar, potato starch, talc, and tragacanth.

Example C: Capsules 5 kg of the Na salt of D-7-[a-(N'-4-hydroxy-3-quinolyl-ureido)-a-phenylacetamido]-cephalosporanic acid [or the Na salt of D-a-(N'-4-hydroxy-5-chloro-3pyridyl-ureido)-benzylpenicillin] are filled in conventional manner into hard gelatine capsules, each capsule containing 500 mg of the active compound.

Example D: Ampoules A solution of 500 g of the sodium salt of D-3-(5-methyl-1,3,4-thiadiazol-2-yl- thiomethyl) - 7 - [a - (N' - 4 - hydroxy - 3 - quinolyl - ureido) - a - phenyl - acetamido] - 3cephem-4-carboxylic acid [or the Na salt of D-cr-(N'-4-hydroxy-5-chloro-3-pyridyl- ureido)-benzylpenicillin]is dissolved in 3 1 of twice distilled water, which is sterile filtered, filled into ampoules, lyophilised under sterile conditions and the ampoules are then sealed under sterile conditions. Each ampoule contains 500 mg of active compound.

Example E: Ampoules Ampoules are prepared in the same way as in Example D, each of which contains 300 mg of D-7-[a-(N'-4-hydroxy-3-quinolyl-ureido)-a-phenyl-acetamido] - cephalosporanic acid in the form of sodium salt (or the Na salt of D-a-(N'-4-hydroxy- 5-chloro-3-pyridyl-ureido)-benzylpenicillin).

Tablets, dragees, capsules and ampoules which contain one or more of the other compounds according to the invention can be obtained similarly.

Claims

WHAT WE CLAIM IS:

1. Lactams of formula I:

in which Z is phenyl, RO-phenyl-cyclohexen-1-yl-, cyclohexa-l, 4-dienyl or thienyl, R and R' are each H or alkyl-(O)-n-CO-, n is 0 or 1, R2 and R3 are each H, halogen, NO2, NH2, alkylamino, dialkylamino or acylamino or together are -CH=CH-CH=CH-, in which a ClI group may optionally be replaced by N and/or an H atom may optionally be replaced by R4 or two H atoms may optionally be replaced by R4 and R5, R4 and R5 are each alkyl, alkoxy, dialkylamino or halogen or together are -CH=CH-CH=CH-, in which a CH group may optionally be replaced by N, W is H, OH or alkyl, X is O or S, B is H or methoxy, A is -C(CH3)2-CHQ-, -CH2-CE=CQ-or-CH2-C(CH2Y)=CQ-, Q is -COOH, tetrazol-5-yl or, if Y is

COO@, E is halogen or alkoxy, Y is H, OH, -OCOCH3, -O-CONH2,

or -5-Het, Rs is H or CONH2, and Het is 3-methyl-1,2,4-thiadiazol-5-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 1,3,4thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, tetrazol-5-yl, l-methyl-tetrazol-5-yl, 1,2,3-triazol-4-yl, 4-methyl-oxazol-2-yl or 1-oxido-2-pyridyl, and wherein the alkyl, acyl and alkoxy groups each have 1-4 C atoms, provided that when A is -C(CH3)2-CH(COOH)-, Z is 0-RO-phenyl or m RO-phenyl, p-alkyl-(O)n-CO-phenyl, cyclohexen-1-yl- or thienyl and or W is hydroxyl and/or R2 or R2 is halogen, NO2, NH2, alkylamino, dialkylamino or acylamino, and/or B is methoxy, and the readily hydrolysable esters of compounds in which Q is COOH, and the physiologically acceptable salts of 2 said lactams and esters.

2. D-7-[α-(N'-4-Hydroxy-3-pyridyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

3. D-7-[-(N'-4-Hydroxy-3-quinolyl-ureido)-a-phenyl-acetamidol- cephalosporanic acid.

4. D-7-[α-(N'-4-Hydroxy-6-chloro-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

5. D-7-[α-(N'-4-Hydroxy-7-methyl-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

6. D-7-[α-(N'-4-Hydroxy-7-ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

7. D-7-[α-(N'-4-Hydroxy-7-chloro-3-quinolyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

8. D-7-[α-(N'-4-Hydroxy-1,5-naphthyrid-3-yl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

9. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3-pyridyl- ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

10. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3-quinolyl- ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

I 1. D-3-(1 -M ethyl-tetrazol-5-yl-thiomethyl)-7-[a-(N'-4-hydroxy-6-chloro-3- quinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

12. D-3-(1 -Methyl-tetrazol-5-yl-thiomethyl)-7-[a-(N'-4-hydroxy-7-ethoxy-3- quinolyl-ureido)-a-phenyl-acetamidol-3-cephem-4-carboxylic acid.

13. D-3-(1-Methyl-tetrazol-5-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7-chloro-3- q uinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

14. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3- pyridyl-ureido)-a-phenyl-acetamidol -3-cephem-4-carboxyl ic acid.

15. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-3- quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

16. D-3-(5-Methyl- I ,3,4-thiadiazol-2-yl-thiomethyl)-7- [a-(N'-4-hydroxy-6- chloro-3-q uinolyl-ureido)-a-phenyl-acetamido] -3-cephem-4-carboxylic acid.

17. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-7- ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]-3-cephem-4-carboxylic acid.

18. D-3-(5-Methyl- 1 ,3,4-thiadiazol-2-yl-thiomethyl)-7-[a-(N'-4-hydroxy-7- chloro-3-quinolyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

19. D-3-(5-Methyl- 1,3,4-thiadiazol-2-yl-thiomethyl)-7-[-(N'-4-hydroxy- 1,5naphthyrid-3-yl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

20. D-7-[-(N'-4-Hydroxy-3-pyridyl-ureido)--phenyl-acetamidol- deacetoxycephalosporanic acid.

21. D-7-[a-(N'-4-Hydroxy-3-quinolyl-ureido)-a-phenyl-acetamido]- deacetoxycephalosporanic acid.

22. D-7-[α-(N'-4-Hydroxy-6-chloro-3-quinolyl-ureido)-α-phenyl-acetamido]- deacetoxycephalosporanic acid.

23. D-7-[α-(N'-4-Hydroxy-7-methyl-3-quinolyl-reido)-α-phenyl-acetamido]- deacetoxycephalosporanic acid.

24. D-7-[α-(N-4-Hydroxy-7-ethoxy-3-quinolyl-ureido)-α-phenyl-acetamido]- deactoxycephalosporånic acid.

25. D-7-[α-(N'-4-Hydroxy-7-chloro-3-quinolyl-ureido)-α-phenyl-acetamido]- deacetoxycephalosporanic acid.

26. D-7-[α-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-α-phenyl-acetamido]- cephalosporanic acid.

27. D-7-[-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)--phenyl- acetamido]ceEhalosporanic acid.

28. D-7-[α-(N'-2,4-Hydroxy-5-chloro-3-pyridyl-ureido)-α-phenyl- acetamido]-cephalosporanic acid.

29. D-7-[a-(N'-2,4-Dihydroxy-5-bromo-3-pyridyl-ureido)-a-phenyl- acetamido]-cephalosporanic acid.

30. D-a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin.

31. D-a-(N'-2,4-Dihydroxy-3-pyridyl-ureido)-benzylpenicillin.

32. D-a-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-benzylpenicillin.

33. D-α-(N'-2,4-Dihydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin.

34. D-α-(N'-2,4-Dihydroxy-5-chlomo-3-pyridyl-ureido)-benzylpenicillin.

35. D-α-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-p-hydroxybenzylpenicillin.

36. D-α-(N'-4-Hydroxy-5-bromo-3-pyridyl-ureido)-p-hydroxybenzylpenicillin.

37. D-hz-(N'-4-Hydroxy-5-methylsulphonamido-3-pyridyl-ureido)-p- hydroxybenzylpenicillin.

38. D-a-(N'-2,4-Dihydroxy-5-chloro-3-pyridyl-ureido)-p- hydroxybenzylpenicillin.

39. D-a-(N'-2,4-Dihydroxy-5-bromo-3-pyridyl-ureido)-phydroxybenzylpenicillin.

40. D-α-(N'-4-Hydroxy-3-pyridyl-ureido)-p-isobutyryloxy-benzylpenicillin.

41. D-a-(N'-4-Hydroxy-5-chloro-3-pyridyl-ureido)-benzylpenicillin pivaloyloxymethyl ester.

42. D-3-(1 -Methyl-tetrazol-5-yl-thiomethyl)-7-[cr-(N'-2,4-dihydroxy-5-chloro- 3-pyridyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

43. D-3-(1-Methyl-tetrazol-5-yl-thomethyl-7-[α-(N'-2,4-dihydroxy-5-bromo-3- pyridyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

44. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-4-hydroxy-5- chloro-3-pyridyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

45. D-3-(5-Methyl-1,3,4-thiadiazol-2-yl-thiomethyl)-7-[α-(N'-2,4-dihydroxy-5- chloro-3-pyridyl-ureido)-zz-phenyl-acetamido]-3-cephem-4-carboxylic acid.

46. D-3-(5-Methyl- I ,3,4-thiadiazol-2-yl-thiomethyl)-7-[a-(N'-2,4-dihydroxy-5- bromo-3-pyridyl-ureido)-a-phenyl-acetamido]-3-cephem-4-carboxylic acid.

47. A process for the preparation of a lactam of formula I specified in claim 1.

or a readily hydrolysable ester of a compound in which Q is COOH or a physiologically acceptable salt of such a lactam or ester, which comprises reacting a lactam of formula II:

in which A, B and Z have the meanings specified in claim 1, or, when Q is COOH, a readily hydrolysable ester thereof, or a physiologically acceptable salt of such a lactam or ester, or a reactive derivative of such a lactam, ester or salt, with a compound of formula III:

in which R1, R2, R3, W and X have the meanings specified in claim 1, or a reactive derivative thereof.

48. A process for the preparation of a lactam of formula I specified in claim 1.

or a readily hydrolysable ester of a compound in which Q is COOH or a physiologically acceptable salt of such a lactam or ester, which comprises reacting an amino-lactam of formula IV:

in which A and B have the meanings specified in claim 1, or when Q is COOH, a readily hydrolysable ester thereof, or a physiologically acceptable salt of such an amino-lactam or ester, or a reactive derivative of such an amino-lactam, ester or salt, with a compound of formula V:

in which Z, R', R2, R3, W and X have the meanings specified in claim 1, or a reactive derivative thereof.

49. A process for the preparation of a lactam of formula I specified in claim 1, which comprises treating a readily hydrolysable ester of such a lactam with a solvolysing agent or treating a benzyl ester or a benzyl ether of such a lactam with a hydrogenolysing agent.

50. A process according to any of claims 47 to 49, in which, when a compound of formula I in which Y=-OCOCH3 is obtained, it is reduced to form a compound I in which Y=H, or is reacted with a thiol of the formula Het--SH, in which Het has the meaning specified in claim 1, or a corresponding mercaptide, to obtain a compound I in which Y=-S-Het, or is reacted with a compound of the formula R-Py, in which Py is pyridyl and R6 has the meaning specified in claim 1. to obtain a compound I in which

51.A process according to any of claims 47 to 50, in which, when an ester of a compound I is obtained, it is hydrolysed or, when a compound I is obtained, it is converted into a readily hydrolysable ester thereof by treatment with an esterifying agent or a compound I is converted into a physiologically acceptable salt thereof by treatment with an acid or base.

52. A process for the preparation of a lactam of formula I specified in claim 1, or a readily hydrolysable ester of a compound in which Q is COOH or a physiologically acceptable salt of such a lactam or ester, substantially as herein described in any of Examples 1 to 496.

53. A pharmaceutical composition which comprises at least one compound as claimed in any of claims 1 to 46 and an inert, physiologically acceptable carrier.

54. A pharmaceutical composition according to claim 53 which is in dosage unit form, each dosage unit containing from 100 to 1000 mg of said compound(s).

55. A pharmaceutical composition substantially as herein described in any of Examples A to E.