IL141442A - Guanidine derivatives of cephalosporins - Google Patents

Abstract

A compound of the formula in free form, in the form of a salt and/or in the form of a solvate, wherein R1 denotes hydrogen or an ester moiety, Rxx denotes a group wherein Rx is a group of formula 1135 י" ב בסיון התשס" ד - June 1, 2004 Ry is NH and Rz is CH3; or Rx is -SCH3, Ry is a group of formula and Rz is hydrogen; or Rx is the group Ry is oxygen and Rz is hydrogen.

Description

Guanidine derivatives of cephalosporins Biochemie Gesellschaft m. b. H.

C. 131314 Ry Π — N-C-R i x . R2 ' wherein Rx is a group of formula N N- CHO or N NH or \__/ Ry is NH and R, is CH ; or 141442/2 la Rx is - SCH3 R is a group of formula = N or = N - C4H, and Rz is hydrogen; or Rx is the group Ry is oxygen and Rz is hydrogen. 970-9827 2 wherein R7 denotes alkyl or aryl Rg denotes hydrogen, cycloalkyl R, denotes hydrogen or alkyl R,o denotes hydrogen, alkyl, hydroxy, amino, phenyl, alkenyl, cycloalkyl,aryI, heterocyclyl of a group of formula -N=CH-Phe wherein Phe denotes aryl R, and R10 together with the nitrogen atom denote heterocyclyl, Z denotes oxygen, sulphur or N-R,3, wherein R13 denotes hydrogen, alkyl or cycloalkyl Ra denotes hydrogen, alkyl, aryl, cycloalkyl or heterocyclyl, or R4 and Rs together with the nitrogen atom denote heterocyclyl, Re denotes heterocyclyl, and Ac denotes (i) a group (ii) a group of formula - - Z 970-9827 3 wherein B denotes N or CH Z] denotes aryl, cycloalkyl, 1,4-cyclohexadienyl or heterocyclyl ¾ denotes hydrogen, alkyl or -CH2COOZ5, wherein Z denotes nydrogen, alkyl or cycloalkyl Z3 denotes hydrogen or alkyl Z4 denotes hydrogen or an organic radical D denotes oxygen or CH2.

A subgroup of the invention comprises each of the invidual groups of significances.

R, may be hydrogen or an ester moiety. An ester moiety includes alkyl, preferably Cwalkyl; arylalkyl, for example benzyl, alkoxybenzyl, such as 4-methoxybenzyl; indanyl, phthalidyl, alkoxymethyl, e.g. methoxymethyl; carbonyl-oxy(C1^)alkyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl and ester moieties which form with the COO- group a physiologically hydrolysable and acceptable ester, e.g. such- known to be hydrolysable ester groups in the field of cephalosporins. A compound of formula I may thus be in the form of an physiologically-hydrolysable and -acceptable ester. By physiologically-hydrolysable and -acceptable esters as used herein is meant an ester in which the COO-group is esterified and which is hydrolysable under physiological conditions to yield an acid which is itself physilogically tolerable at dosages to be administered. The term is thus to be understood as defining regular pro-drug forms. An ester moiety may be preferably a group which is easily hydrolysable under physiological conditions. Such esters may be administered preferably orally. Parenteral administration may be indicated if the ester per se is an active compound or, if hydrolysis occurs in the blood.

Y may be preferably hydrogen, unsubstituted alkyl or alkyl substituted by e.g. hydroxy or, preferably the residue of a carboxylic acid. The residue of a carboxylic acid includes the residue of a carboxylic acid in free form or in salt form, of a carboxylic acid ester and of a carboxylic acid amide. The carboxylic acid is, for example, "a C^ carboxylic acid, preferably a Q.j aliphatic carboxylic acid, an alkyl part thereof including lower alkyl. The alkoxy group of a carboxylic acid ester includes Cw, preferably CMalkoxy. Alkyl is preferably lower alkyl. The alkyl group is preferably unsubstituted or substituted by 970-9827 4 carboxylic acid residues.

R4 may be preferably hydrogen or alkyl, for example lower alkyl.

R5 may be preferably hydrogen; unsubstituted alkyl; alkyl substituted for example by oxo, alkyl or halogenated alkyl; amino; one or several fold substituted heterocyclyl; or a group of formulae Ed, He, Jflf. Heterocyclyl includes unsaturated or saturated heterocyclyl having, e.g. 5 or 6 ring members and, for example, 1 to 3 hetero atoms, such as N, O, S, preferably N, or condensed heterocyclyl, such as benzothiazolyl.

R4 and R5 together with the nitrogen atom may be heterocyclyl, having preferably 5 or 6 ring members and having preferably 1 to 3 heteroatoms, for example N atoms; which may be unsubstituted heterocyclyl; or one or several fold substituted heterocyclyl, for example by oxo, amino, alkyl.

Re may be saturated or unsaturated heterocyclyl; having preferably 5 or 6 ring members and having for example 1 or 2 nitrogen hetero atoms; for example unsubstituted heterocylclyl; or one or several fold substituted heterocyclyl, for example by amino, alkyl or thiono.

R7 may be preferably alkyl.

R8 may be preferably alkyl or cycloalkyl.

R, may be preferably hydrogen or lower alkyl.

RI3 may be preferably alkyl.

RI0 may be preferably hydrogen; aryl; alkenyl; cycloalkyl; unsubstituted alkyl; substituted alkyl, for example by hydroxy, halogen, heterocyclyl, such as pyridyl, amino, for example N(alkyl)2 or N*(alkyl)3; or a group - N = CH -AT wherein Ar denotes heterocyclyl; unsubstituted aryl; or substituted aryl, for example by hydroxy or alkoxy; preferably aryl which may be preferably phenyl.

R, and Rj0 together with the nitrogen atom may be heterocyclyl having preferably 5 or 6 ring members and 1 to 3 hetero atoms such as N, S, O, for example N, O; preferably saturated heterocyclyl. Heterocyclyl includes unsubstituted heterocyclyl, or substituted heterocyclyl, for example by acyl, formyl, alkyl, for example lower alkyl. Examples include pyrrolidine, morpholine, piperazine, preferably piperazine. 970-9827 5 Rn may be preferably hydrogen; unsubstituted alkyl; substituted alkyl, for example by aminoalkyl, diaminoalkyl, triaminoalkyl; aryl, such as dihydroxyphenyl; cycloalkyl; or unsubstituted heterocyclyl; or substituted heterocyclyl, for example by alkyl, thiono heterocyclyl; heterocyclyl having preferably 5 or 6 ring members and 1 to 3 hetero, preferably N atoms.1 If not otherwise stated there r any carbon- containing -group-jnay contain up to 20 carbon atoms, e.g. alkyl includes C1-20, e.g. C,.8 alkyl. Lower alkyl includes e.g.

C^alkyl, preferably C^alkyl. Alkenyl includes C2.2o, e.g. C2.s alkenyl. Lower alkenyl includes e.g. C^alkenyl, preferably C3alkyl. Cycloalkyl includes, for example, C^cycloalkyl, particularly C3, C5 or Cgcycloalkyl. Alkyl, alkenyl and cycloalkyl include unsubstituted alkyl, alkenyl and cycloalkyl; and, substituted alkyl, alkenyl and cycloalkyl, for example, by halogen, a sulphonic acid derivative, such as S03H, CF3, hydroxy, alkoxy, acyl, alkylamino, pyridyl. Cycloalkyl is preferably unsubstituted. Acyl includes CM2, e.g. C1-6acyl, particularly CMacyl. Acyl includes unsubstituted acyl and substituted acyl, for example, by hydroxy, alkoxy, amino. Aryl includes phenyl. Aryl may be unsubstituted aryl or substituted aryl, for example by alkyl, alkoxy, acyl, halogen, hydroxy, unprotected or protected amino. Alkoxy includes alkoxy wherein the alkyl part is as defined above.

Heterocyclyl includes heterocyclyl having 5 or 6 ring members and 1 to 3 nitrogen, sulphur and or oxygen hetero atoms including, for example, condensed heterocyclyl, such as for example benzthiazolyl. Heterocyclyl includes further unsubstituted hetercyclyl and substituted heterocyclyl, for example by oxo, alkoxy, hydroxy, thiono, mercapto, alkylthio, imino, alkylamino, alkylimino, amino, halogen, acyl, CF3, CHO, alkyl, cycloalkyl.

Carbamoyl includes the carbamoyl group or carbamoyl having alkyl and aryl residues. Z, denotes unsubstituted cycloalkyl, 1 ,4-cyclohexadienyI, heterocyclyl or aryl; and one or several fold substituted cycloalkyl, 1 ,4-cyclohexadiene, heterocyclyl or aryl; for example by carboxyl, amino, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, -CO-N(Z5Z6), -NCZ^-COOZj, Z6CO-, Z6OCO-, Z6COO-. ∑2 denotes hydrogen; CH2COOZ5; unsubstituted lower alkyl; one or several fold substituted lower alkyl, for example by carboxyl, amino, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen, -COZ5Z6, -NCZ^-COOZ^ Z6CO-, Z6OCO- or Z6COO-.

Z3 denotes hydrogen or lower alkyl.

Z4 denotes hydrogen or an organic radical; preferably hydrogen; lower alkyl; cycloalkyl; 970-9827 6 aralkyl; acyl; carboxyalkyi; Z6CO-, -QZ^COOZ,; or, preferably in the case that Z, in group B II co c denotes a group 2-amino-thiazol-4yl or 2-amino-thia-3,5diazol-4yl, Z4 denotes a group of formula 970-9827 7 wherein Z, and ZI0 independently of one another denote hydrogen or protected or unprotected carboxyl Zu denotes hydrogen or acetyl, Zu denotes unprotected or protected carboxyl, Z13 denotes hydrogen or methyl, Z14 denotes hydrogen; chloro; unprotected or protected carboxyl; methyl; isopropyl; hydroxy; methoxy; acetoxy, Z1S and Z16 denote independently from one another hydrogen, hydroxy, methoxy, ethoxy, 2-methoxyethox methoxy, acetoxy, chloroacetoxy, butan yloxy, methansulfonyloxy, p-toluenesulfonyloxy, amino, acetylamino, benzyloxycarbonylamino or methansulfonyl; or, Z,5 and Z16 denote together ethylendioxy or carbonyldioxy, ZJ7 denotes hydrogen, hydroxy, acetoxy, methyl, methoxy, chloroacetoxy, with the proviso, that not all of Z , ZL5, ZL6 and Z17 denote hydrogen, Z 6 and Z19 denote independently of one another hydrogen or methyl, ZJO, Zjt, Z^, Z23 and Zj4 denote independently of one another hydrogen, halogen or hydroxy, Z^ and ∑26 denote independently from one another hydrogen; C^aUcyl; unsubstituted phenyl; or substituted phenyl, Z27 denotes unsubstituted lower alkyl; or substituted lower alkyl, and ¾ denote independently of one another hydrogen or hydroxy, and n denotes 0 or 1, Z5 denotes hydrogen, alkyl, preferably lower alkyl, Z6 and 2q independently of one another denote hydrogen or alkyl, preferably lower alkyl, Zs and Ζη together with the carbon atom denote cycloalkyl, and Z5 and Z6 together denote cycloalkyl.

Z4 may be selected from the following groups: 970-9827 For example, Ac may denote a group of formula Preferably Ac denotes a compound of formula wherein W denotes CH or N V denotes CH or N-0 and R3 denotes hydrogen, acyl, carboxyl, alkyl.

The configuration of R3 in group of - C = V - R3 may be syn [(Z)] and anti [(E)] and is preferably syn [(Z)].

If R3 denotes 'alkyl, R3 includes unsubstituted alkyl or substituted alkyl, for example by halogen, carboxyl. Preferably denotes CH.

A compound of formulae I and V/ a may exist in equilibrium with tautomeric forms. The present invention includes a compound of formula V/a in any tautomeric form in which it may exist.

In another aspect the parent application provides a process for the production of a compound of formula I by reaction of a compound of formula wherein Ac is as defined in formula I and a) either a) Rj, denotes hydroxy and R,, and together form a bond, or β) denotes hydrogen, a cation, an ester forming group or a silyl group, and Rt, and R,. together denote oxo, 970-9827 17 in free form or in form of an acid addition salt with a group of formula H,N - R, IV -wherein R¾ is as defined in formula. I or b) reacting a compound of formula COOR, wherein Rt and R2 are as defined in formula I, with a compound of formula Ac-X' vn wherein Ac is as defined in formula I and X' denotes a leaving group.

If desired reactive groups may be protected with protecting groups, which may be, or, which are split off under the reaction conditions, or after termination of the reaction described above. A compound of formula I wherein R, denotes hydrogen may be converted into a compound of formula I, wherein Ri denotes an carboxylic acid ester group. A compound of formula I may be isolated from the reaction mixture in conventional manner.

Process a) may be carried out as follows: A compound of formula ΙΠ in a solvent which is inert under the reaction conditions, such as water, a mixture of water and a lower alcohol and/or dioxane-, or a dipolar aprotic solvent, for example dimethylformamide or dimethylsulfoxide, optionally mixed with an alcohol or water is reacted with a compound of formula IV at a temperature of about -20 to 50° C. An optimal pH may be adjusted by addition of an inorganic or organic acid or 970-9827 18 base. A compound of formula I thus obtained may be isolated in conventional manner, for example by addition of an anti-solvent or by chromatographic techniques.

Process b) may be carried out as follows: The reaction may be carried out as conventional, e.g. a compound of formula VI may be reacted with a compound of formula VH in sf solvent, for example- dissolved or suspended in a mixture of acetone water, for example at room temperature.

A reactive group may be protected, preferably by silyl protecting group technology.

Suitable solvents include solvents which are inert under the reaction conditions, such as chlorinated hydrocarbons, nitriles, such as acetonitrile, ethers, such as tetrahydrofuran or a mixture of such solvents. Further suitable solvents include dipolar aprotic solvents, e.g. N,N-dime&ylformamide. Protecting groups may be split off in conventional manner.

A starting compound of formula Π may, for example, be obtained by a) reaction of a compound of formula wherein either a) R. denotes a salt of -NH2 with an inorganic or organic acid, R'b denotes hydroxy, and R'c and R'd denote together a bond, or β) R. denotes NH2, R'd denotes hydrogen and R'b and R'c together denote oxo, with a silylation agent and, a compound obtained in step a) of formula 970-9827 19 wherein Sil denotes a silyl group and either a) R"b denotes -OSil and R"c and R"d together denote a bond β) R"d denotes Sil and R"b and R"e together denote oxo is acylated either directly in the reaction mixture or after isolation from the reaction mixture.

Acylation may be carried out as conventional.

A compound of formula Hie may be obtained a) for the production of a compound of formula which is an the form of a salt of an inorganic or organic acid and wherein R"'b denotes hydroxy and R"'c and R"'d together denote a bond, reacting a salt of an inorganic or organic acid of a compound of formula wherein R14 and R13 are the same or different and each denote hydrogen or an organic residue in an organic solvent optionally in the presence of water with ozone b) for the production of a compound of formula - treating a compound of formula Hie wherein Rm,_, R™e and R"*d ar as defined above, with a base.

Compounds of formulae IV are partially new and may be obtained analogously to ccnyentional methods, or, as described in the examples.

In this specification unless otherwise indicated the term "compound of formula Via" embraces the compound in any form, for example in salt form and free base form. The present invention thus includes a compound in free form or, where such forms exist, in salt form, for example in form of an acid addition salt, inner salt, quaternary salt and or in solvate, for example hydrate form thereof. Amine salts include for example trialkylamine, procaine, dibenzylamine and ben2ylamine salts. A free form of a compound of formula \l\ a may be converted into a salt form and vice versa.

In a further aspect the present invention provides a compound of formula V/a in free form; or in salt form, for example in acid addition salt form or in metal salt form; and a compound of formula N// a in solvate form.

In the following Examples the temperatures indicated are in degree Celsius.

Passages of the description which are not within the scope of the claims do not form part of the invention. 970-9827 31 Example 1 Dihydrochloride of 7-[(2-Amino-4-thiazoIyl)-(Z)-(methoxyimino)acetyI]amino- -3-[[(aminoiinino-methyl)hydrazono]methyl]-3-cephem-4-carboxyIic acid (Process a) 1.24 g of the hydrogen carbonate of aminoguanidine are dissolved in 9.15 ml of 2 N HCl and added under stirring to a solution of 3.2 g of the trifluoroacetate of N-(l ,4,5a,6-tetrahydro-3-hydroxy-l ,7-dioxo-3H,7H-azeto[2,l-b]furo[3,4-d][l ,3]- miazin-6-yl)-2-(2-aminothiazol-4yl)-(Z)-2-methoxyimino acetic acid amide in 125 ml of 4% aqueous acetonitrile. After ca. 90 minutes the precipitated dihydrochloride of 7-[(2-Arnino^-miazolyl)(memoxyimino)acetyl]arnino-3-[[(anunoiim hydrazono]methyl]-3-cephem-4-carboxylic acid is filtered off, washed with acetonitrile and dried.

Example 2 Dihydrochloride of 7-[[(2-Amino-4-thiazolyl)-(Z)-(hydroxyimino)acetyl]amino]- 3-[[(amino-iminomethyl)hydrazono]methyl]-3-cephem-4-carboxyIic acid (Process a) a) 10 g of the hydrochloride of N-( l,4,5a,6-tetrahydro-3-hydroxy- 1,7 -dioxo-3H,7H- azeto[2, 1 -b]furo[3,4-d][l ,3]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2- (acetoxyimino)-acetic acid amide are suspended in 160 ml of acetonitrile and treated with 53 ml of water and 11 ml of 8 N HCl. The reaction mixture is stirred for ca. 14 hours at room temperature. A clear solution is obtained in which the acetoxyimino group being hydrolyzed to give the hydroxyimino group, b) 3 g of the hydrogen carbonate of aminoguanidine are dissolved in 11 ml of 1 N HCl and added drop wise to the solution obtained in step a) which is cooled to 0°. After ca. 30 minutes the reaction mixture is warmed to room temperature and stirred for ca. another 2.5 hours. The dihydrochloride of 7-[[(2-Amino-4-thiazolyl)-(Z)- (hydroxyimino)acetyl]amino]-3-[[(amino-iminomethyl)hydrazono]methyl]- -3-cephem-4-carboxylic acid precipitate, is filtered off, washed with a mixture of acetonitrile and water, acetonitrile and with ether and dried. 970-9827 32 Example 3 Sodium salt of 7-[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino-3-[(methoxy- imino)methyl]-3-cephem-4-carboxylic acid (Process b) 0.5 g of 7-amino-3-[(methoxyimino)methyl]-3-cephem-4-carboxylic acid and 0.75 g of (2-amino-4-thiazolyl)(methoxyimino)acetic acid mercaptobenzthiazolyl ester are suspended iri'a mixture Of 2.4 ml · of- water- and 4.8 ml --of acetone. - Ga.; 1.8 ml of 2N sodium hydroxide solution are added dropwise in such a way that a pH of 8.0 is kept. The reaction mixture is stirred at 20° for ca. 1 hour. 2.4 ml of acetone are added dropwise. A clear solution is obtained within 3 hours. 120 ml of acetone are slowly added. A suspension is obtained which is cooled to 0°. After ca. 5 hours the precipitate formed is filtered off and redissolved in 4 ml of water. The clear solution is treated with 0.2 g of active charcoal and stirred for ca. 15 minutes. Active charcoal is filtered off and 100 ml of acetone are added within ca. 1 hour at 0°. The sodium salt of 7-[(2- amino^-thiazolyl)(memoxyirmno)acetyl]amino-3-[(methoxy-imino)methyl]-3-cephem-4- carboxylic acid is obtained in form of colourless crystals, which are filtered off, washed with ca. 5 ml of acetone and dried.

The compounds of the following TABLE 1 of formula IA (V is =N-0- in all of the Examples; and W is CH in Examples 4 to 68 and 70 to 138; and W is N in Examples 69 and 139 of TABLE 1) may be obtained in analogous manner to that described in Examples 1 to 3. Salt forms are exemplified. The configuration of R3 in group - C = N - R3 is syn [(Z)].

Case 970-9827 33 Table 1 Case 970-9827 Case 970-9827 Case 970-9827 36 Case 970-9827 Case 970-9827 38 Case 970-9827 Case 970-9827 Case 970-9827 41 Case 970-9827 42 Case 970-9827 43 Case 970-9827 44 Case 970-9827 45 Case 970-9827 46 Case 970-9827 47 Case 970-9827 48 Case 970-9827 49 Example 140 Dihydrochloride of 7-[2-(2-aminothiazol-4-yI)-(Z)-2-pentenoyIamino]- 3-[[(aminoimino-methyl)hydrazono]methyl]-3-cephem-4-carboxyIic acid 1 g of N-(l ,4,5a,6-tetrahydro-3-hydroxy-l ,7-dioxo-3H,7H-azeto[2,l-b]furo[3,4- d][l ,3]-thiazin-6-yl)-2-[2-(tert.-butoxycarbonylamino)thiazol-4-yl]-(Z)-2-pentenoic acid amide is dissolved in a mixture of 30 ml of methanol and 30 ml Of acetonitrile and 0.3 g of the hydrogencarbonate of aminoguanidine are added. A pH of 2.0 is adjusted by addition of methanolic HCI. Stirring is continued at room temperature. Within ca. 30 minutes a light coloured precipitate forms, which is filtered off after ca. 3 hours, washed with acetonitrile and ether and dried. The dihydrochloride of 7-[2-(2-arninothiazol-4-yl)-(Z)-2-pentenoylamino]-3-{ [(aminoimino- methyl)hydrazono]-methyl}-3-cephem-4-carboxylic acid is obtained in the form of a light yellow powder.

Example 141 Trifluoroacetate of 7-[(2-Amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl]amino- -3-(hydrazonomethyl)-3-cephem-4-carboxylic acid A suspension of 3 g of 7-[(2-arnino-4-thiazolyl)-(Z)-(methoxyimino)acetyl]amino-3- [[2-( 1 , 1 -dimethylethoxy)-2-oxoethoxy ]hydrazonomethyl]-3-cephem-4-carboxy lie acid in 75 ml of methylenchloride is treated at ca. 0° with 0,6 ml of anisol. 10 ml of trifluoro acetic acid are added dropwise under stirring. The solution obtained is stirred for ca. further 3 hours at 0°. The reaction mixture is poured into 600 ml of ether. The trifluoroacetate of 7-[(2-Amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl]- amino-3-(hydrazono)-3-cephem-4-carboxylic acid precipitates, is filtered off and dried.

Example 142 Hydrobromide of 7-[(2-amino-4-thiazolyl)-(Z)-(methoxyimino)acetyI]amino-3-[(4- methylthiazoI-2-yl)hydrazonomethyi]-3-cephem-4-carboxylic acid 1 g of 7-[(2-amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl]anuno-3-[(aininothioxome- thyl)-hydrazonomethyl]-3-cephem-4-carboxylic acid is suspended in 30 ml of acetonitrile and stirred after addition of 2.5 ml of N.O-bistrimethylsilylacetamide for Case 970-9827 50 ca. 20 minutes. The clear solution obtained is treated with 0.6 g of bromoacetone and stirred overnight. 1 ml of water are added. The precipitate is filtered off and dried. The hydrobromide of 7-[(2-arm^o-4-thia2olyl)-(Z)-(memoxyirruno)acetyl]arnino-3-[(4- methylthiazol-2-yl)hydrazonomethyl]-3-cephem-4-carboxylic acid is obtained as a yellow solid.

Example 143 Hydrobromide of 7-[(2-amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl]amino-3-[(4- methylthiazol-2-yl)methylhydrazonomethyI]-3-cephem-4-carboxylic acid 1 g of 7-[(2-amino-4-thiazolyl)-(Z)-(methoxyimino)acetyl]amino-3-[(aminothioxome- thyl)- methylhydrazonomethyl]-3-cephem-4-carboxylic acid is reacted in analogous manner as described in Example 142 with N.O-bistrimethylsilylacetamide and with bromoacetone. The hydrobromide of 7-[(2-arnino-4-thiazoiyl)-(Z)-(methoxyirnino)- acetyl]amino-3-[(4-methylthiazol-2-yl)methylhydrazonomethyl]-3-cephem-4- carboxylic acid is obtained as a yellow solid.

Example 144 Dihydrate of 6R-trans (Z)-7-[(2-Amino-4-thiazolyl)(methoxyimino)-acetyl]ami- no-3[t(imino(methyIamino)methyI)hydrazono]methyI]-3-cephem-4-carboxyiic acid 1.1 g of the dihydrochloride obtained according to Example 8 are dissolved in 25 ml of water, treated with 0.5 g of active charcoal and stirred for ca. 5 minutes. The almost colourless filtrate is poured into 5 ml of water under stirring. A pH of about 7 is kept by addition of 2.5% aqueous ammonia. The precipitate obtained is filtered off and dried. The dihydrate of 6R-trans (Z)-7-[(2-Amino-4-thiazolyl)- (methoxyimino)-acetyl]amino-3[[(imino(methylamino)methyl)hydrazono]- methyl]-3-cephem-4-carboxylic acid is obtained as a yellowish powder.

Example 145 6R-trans ( Z)-7-[(2-amino-4-thiazolyl)(methoxyimiho)acetyI]amino-3-[[(imi- no(methylamino)methyl)hydrazono]methyl]-3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy)ethyl ester .5 g of the dihydrate obtained according to Example 144 are dissolved in 55 ml of Case 970-9827 51 dimethylacetamide under addition of 1.43 ml tetramethylguanidine. This solution is cooled to 0°, treated with a solution of 4.4 g of 1-iodoethyl-isopropylcarbonate in 30 ml of toluene and stirred for ca. 90 minutes at 0°. The reaction mixture is poured into 1 liter of diethylether. The precipitate obtained is filtered off and stirred twice each with 500 ml of acetonitrile. The acetonitrile phases are combined, filtered and evaporated to a volume-of ca. 10 ml. The oily^esidue is treated with-400 ml of ..· .. water. A precipitate forms which is filtered off and dried. The precipitate is stirred with 700 ml of ethyl acetate. After evaporation of the ethyl acetate yellow coloured 6R-trans (Z)-7-[(2-amino-4-thiazolyl)-(memoxyiiruno)acetyl]amino-3-[[(imi- no(methylamino)methyl)hydrazono]methyl]— 3-cephem-4-carboxylic acid 1- (isopropoxycarbonyloxy)ethyl ester is obtained in the form of a diastereomeric mixture in the ratio of ca. 1 : 1.

Example 146 6 R- trans (Z)-7-[((Acetoxyimino)-2-amino-4-thiazolyl)acetyl]amino-3-[[(aminoimi- nomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid l-(isopropoxycarbo- nyloxy) ethyl ester 0,72 g of the hydrogen carbonate of aminoguanidine are dissolved in 5.2 ml of 2 N HC1. This solution is added to a solution of 2 g of 6R-trans (Z)-7-[((acetoxyimino)- 2-amino-4-thiazolyl)acetyl]amino-3-formyl-3-cephem-4-carbox lic acid l-(isoprop- oxycarbonyloxy)ethyl ester in 14 ml of acetonitrile containing 1.3 ml of water. The reaction mixture is stirred for ca. 45 minutes at room temperature and poured into 100 ml of acetonitrile. The precipitate formed is filtered off and dissolved in 100 ml of water. The pH of the solution obtained is adjusted to 7 by addition of 0.5 N aqueous sodium hydrogen carbonate. A yellow suspension is obtained which is extracted twice with a mixture of 200 ml of ethyl acetate and 40 ml of acetonitrile. The organic phases are combined, dried over NajSO,, and evaporated. 6R-trans (Z)- 7-[((acet-oxyimino)-2-amino-4-thiazolyl)acetyl]amino-3-[[(aminoiminome- thyl)hydrazono]-methyl]-3-cephem-4-carboxylic acid l-(isopropoxycarbonyloxy) ethyl ester is obtained in the form of a yellow diastereomeric mixture in the ratio of ca. 1 : 1.

Case 970-9827 52 Example 147 Ditosylate of 6R-trans (Z)-7-[(2-amino-4-thiazolyl)(hydroxyimino)acetyl]amino-3- [[(aminoiminomeihyl)hydrazono]methyJ]-3-cepheni-4-carboxylic acid (isoprop- oxycarbonyloxy)ethyl ester A solution of 0.6 g of a compound obtained according to Example 146 in a mixture of 50 ml of · acetonitrile and 20 ml of isopropanol is treated -with- 0.66 g of .the ... . monohydrate of toluene-4-sulfonic acid and stirred overnight at 25°. The reaction mixture is poured into 150 ml of tert.butyl-methylether. The precipitate obtained is filtered off, washed with tert.butyl-methylether and dried. The ditosylate of 6R-trans (Z)-7-[(2-amino-4-thiazolyl)(hydroxyimino)ac^tyl]arnino-3[[(aminoiminomethyl)- hydrazono]methyl]-3-cephem-4-carboxylic acid (isopropoxycarbonyloxy)ethyl ester is obtained in the form of a light coloured diastereomeric mixture in the ratio of ca. 1: 1.

Example 148 Dihydrochloride of 7-[[(2-amino-4 thiazoIyI)-(Z)-[(carboxymethoxy)imino]actyl]- amino]-3-[[(aminoiminomethyl)hydrazono]methyI]-3-cephem-4-carboxylic acid (Compound of Example 5) a} Dihydrochloride of 7-Amino-3-f f ( aminoiminomethyDhydrazonolmethyH-3- cephem-4-carboxylic acid To 1.0 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid in a mixture of 50 ml of acetonitrile and 5 ml of 2N HCl are added dropwise 0.6 g of the hydrogen carbonate of aminoguanidine, dissolved in 2.2 ml of 2N HCl. The dihydrochloride of 7-amino- 3-[[(aminoirr-inomethyl)hydrazono]methyl]-3-cephem-4-carboxylic acid precipitates, is filtered off, washed with acetonitrile and dried. b} Hydrochloride of 7-rrf2-amino-4-thiazolylVfZVrr2-(l .l -dimethylethoxy')-2- oxoetoxyliminolacetvnaminol-S-rrCaminoiminomethvnhvdrazonolmethyll-S- cephern-4-carboxylic acid 4 g of the dihydrochloride of 7-amino-3-[[(aminoiminomethyl)hydrazono]methyl]-3- cephem-4-carboxylic acid are dissolved in 80 ml of methanol. The solution is cooled Case 970-9827 53 to 0° and treated with a solution of 7 g of (2-amino-4-thiazolyl)-(Z)-[2-(l ,l - dimethylethoxy)-2-oxoethoxy]imino]thioacetic acid S-benzothiazol ester in 50 ml of methylene chloride. The reaction mixture is stirred for about 2.5 hours at 20°. About a third of the solvent is evaporated off and 120 ml of ether are added to the residue. The hydrochloride of 7-[[(2-amino-4-thiazolyl)-(Z)-[[2-(l ,l-dimethylethoxy)-2- oxoetoxyliminoJ^acetyllaminol^^ftiaimnoiminomethylJhydrazonoimethylj-S-cephem- 4-carboxylic acid precipitates, is filtered off, washed with ether and dried. c} Dihvdrochloride of 7-ilY2-amino-4 thiazolyn-CZVffcarboxymethoxy minolactvn- aminol-3-rrfaminoiminomethvnhvdrazono1methyll-3-cephem-4-carboxylic acid 3.5 g of the hydrochloride of 7-[[(2-amino-4-thiazolyl)-(Z)-[[2-(l ,l -dimethylethoxy)- 2-oxoetoxy]imino]acetyl]amino]-3-[[(aminoiminomethyl)hydrazono]methyl]-3- cephem-4-carboxylic acid are dissolved in 20 ml of trifluoroacetic acid at 0°. The solution is stirred for ca. 15 minutes at 0° and for ca. 1 hour at 20°. The reaction mixture is treated with 40 ml of ether. A precipitate forms, is filtered off, washed with ether, dried, dissolved in 15 ml of 2N HC1 and stirred for ca. 1 hour at 20°. A light brownish precipitate of the dihydrochloride of 7-[[(2-amino-4 thiazolyl)-(Z)- [(carboxy-methoxy)imino]actyl]-amino]-3-[[(aminoiminomethyl)hydrazono]methyl]-3- cephem-4-carboxylic acid is obtained, filtered off and dried.

The compounds of Examples 1 to 146 may be obtained as described in Example 147 using the appropriate starting material.

Compounds used as starting material may be prepared as follows: Example A) Trifluoroacetate of N-(l,4,5a,6-tetrahydro-3-hydroxy-l,7-dioxo-3H,7H-azeto[2,l- b]furo[3,4-d][l,3]-thiazin-6-yI)-2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetic acid amide a} Hydrochloride of 6-amino- .4.5a.6-tetrahvdro-3-hvdroxy-l ,7-dioxo-3H.7H-ace- toi2.1 -b1furof3.4-d1f l .31thiazin (hvdroxylactone of the hydrochloride of 7-amino- 3-formyl-3-cephem-4-carboxylic acid-) Case 970-9827 54 13.8 g of the hydrochloride of 7-amino-3-[(Z/E)-prop-l -en-l -yl]-3-cephem-4- carboxylic acid are dissolved in 200 ml of methanol. The solution is cooled to -50° and 8 1 of 02 containing ca. 2 percent v/v ozone are introduced per minute under stirring at this temperature. After ca. 20 minutes the hydrochloride of 6-amino- · l,4,5a,6-tetrahydro-3-hydroxy-l,7-dioxo-3H,7H-aceto[2,l-b]furo[3,4-d][l ,3]thiazin being practically -quantitatively formed and ozonolysis 4s terminated as determined by HPLC. 8 1 of N2 are bubbled through the reaction mixture within ca. 2 minutes. The slight cloudy solution is poured into 1400 ml of tert.butyl-methyl ether. The precipitate is filtered off under N2, washed with a little of tert.butyl-methyl ether and acetonitrile and dried. The hydrochloride of 6-amino- 1 , 4,5 a,6-tetrahydro-3-hydroxy- l ,7-dioxo-3H,7H-aceto[2,l-b]furo[3,4-d][l ,3]thiazin is obtained in the form of a white powder (HPLC content of more than 95%). bj (6R-trans')-7-Amino-3-formyl-8-oxo-5-thia-l-azabicvclor4.2.01oct-2-en-2- carboxylic acid (7-amino-3-formyl-3-cephem-4-carboxylic acid) 2.64 g of the hydrochloride of 6-amino-l ,4,5a,6-tetrahydro-3-hydroxy-l ,7-dioxo- 3H,7H-aceto[2,l-b]furo[3,4-d][l ,3]thiazin are dissolved in 50 ml of methanol. To this solution a solution of 0.78 g of pyridin in 10 ml of methanol is added dropwise under ice cooling and stirring. The precipitate obtained is filtered off moisture free under nitrogen, washed with a little methanol and dried. (6R-trans)-7-Amino-3- formyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid is obtained in the form of a light brownish powder.

IR (KBr): 1799 cm'1 (β-lactam), 1672 cm'1 (CHO), 1606 and 1542 cm"1 (carboxylate) UV-Spectrum: in H20 = 302 nm. c) Ν-Π .4.5a.6-Tetrahvdro-3-hvdroxy-l ,7-dioxo-3H.7H-azetof2.1 -blfuror3.4- diri .31thiazin-6-vn-2-(2-tritylaminothiazol-4-vn-(Z -2-methoxyiminoacetic acid amide g of 7-amino-3-formyl-3-cephem-4-carboxylic acid in 200 ml of acetonitrile : methylenchloride (1 : 1) are treated with 37.4 ml of N,0-bis(trimethylsilyl)acetamide at room temperature within ca. 5 minutes. After ca. 30 minutes the reaction mixture is cooled to -10° and 21 g of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetic Case 970-9827 55 acid chloride are added in 3 portions. The temperature raises to -5°. After ca. 45 minutes the reaction mixture is treated with 4 ml of water. The temperature raises to 20°. The reaction mixture is stirred for ca. 10 minutes and filtered. 15 g of active charcoal are added to this filtrate and stirring is continued for ca. 10 minutes. After filtration the solvent of the filtrate obtained is evaporated. The evaporation residue is treated with tert:butyl-methyl- ether. A crystalline,: almost. colourless precipitate is obtained, filtered off and dried. Crystalline N-(l,4,5a,6-Tetrahydro-3-hydroxy-l ,7- dioxo-3H,7H-azeto[2,l-b]furo[3,4-d][l ,3]thiazin-6-yl)-2-(2-tritylaminothiazol-4-yl)-2- methoxyiminoacetic acid amide is obtained in form of a diastereomeric mixture in the ratio of ca. 1 : 1. d) Trifluoroacetate of N-n .4.5a.6-tetrahvdro-3-hvdroxy-1.7-dioxo-3H.7H-azetor2.1 - acid amide g of N-(l ,4,5a,6-tetrahydro-3-hydroxy-l ,7-dioxo-3H,7H-azeto[2,l-b]furo[3,4- d][l ,3]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid amide are introduced into 20 ml of trifluoro acetic acid at 0°. The temperature raises to 10°. The reaction mixture is stirred for ca. 30 minutes at 0° and added dropwise into 200 ml of diethylether. The mixture obtained is stirred for ca. 5 minutes and filtered. A crystalline, diastereomeric mixture of the trifluoroacetate of N-( 1 ,4,5 a,6-tetrahydro-3- hydroxy-l ,7-dioxo-3H,7H-azeto[2,l-b]furo[3,4-d][l ,3]thiazin-6-yl)-2-(2-aminothiazol- 4-yl)-2-methoxyiminoacetic acid amide in the ratio of ca. 1 : 1 is obtained.

Example B) Trifluoroacetate of N-(l,4,5a,6-tetrahydro-3-hydroxy-l,7-dioxo-3H,7H-azeto[2,l- b] furo[3,4-d][l,3]-thiazin-6 yl)-(Z)-2-(2-aminothiazoI-4-yI)-2-(hydroxyimino)acetic acid amide is obtained in form of a light yellow powder analogously as described in Example A) c) to d) but using in step c) 2-(2-tritylaminothiazol-4-yl)-(Z)-2-hydroxyimino acetic acid chloride instead of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyimino-acetic acid chloride.

Case 970-9827 56 Example C) Hydrochloride of N-(l,4,5a,6-tetrahydro-3-hydroxy-l,7-dioxo-3H,7H-azeto[2,l- b]furo[3,4-d][l,3]-thiazin-6-yl)-2-(5-amino-l,2,4-thiadiazol-3-yl)-(Z)-2-(fluoro- methoxyimino)acetic acid amide A suspension of 3.73 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid in a mixture of 80 ml of methylenchloride and 30 ml of acetonitrile is. stirred at 0° with 16 ml of N,0-bis(trimethylsilylacetamide). Within ca.15 minutes a clear solution is obtained to which 3.9 g of (5-amino-l ,2,4-thiadiazol-3-yl)-(Z)-2-fluormethoxyiminoacetic acid chloride, obtainable for example as described in Example 1 of EP-0 590 681, are added. The reaction mixture is stirred for ca. 1 hour at 0°. 500 ml of acetonitrile containing 10 g of water are added and the mixture is filtered to remove insolubles. The filtrate is evaporated. The residue is treated with 500 ml of acetonitrile, the mixture is filtered and the filtrate is evaporated. The solid obtained is treated with tert.butyl-methyl ether and dried. The hydrochloride of N-(l ,4,5a,6-Tetrahydro-3- hydroxy-l ,7-dioxo-3H,7H-azeto[2,l-b]furo[3,4-d][l,3]-thiazin-6-yl)-2-(5-amino-l ,2,4- thi'adiazol-3-yl)-(Z)-2-(fluoro-methoxyimino)acetic acid amide is obtained in the form of a light brownish powder.

Example D) Hydrochloride of N-(l,4,5a,6-tetrahydro-3-hydroxy-l,7-dioxo-3H,7H-azeto[2,l- b]furo[3,4-d][l,3]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-(acetoxyimino)acetic acid amide 40 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid are suspended in 1500 ml of acetonitrile and cooled to 0°. Within ca. 20 minutes 170 ml of N,0-bis(trimethylsi- lyl)acetamide are added under stirring. Within ca.15 minutes at 0° a clear solution is obtained, which is cooled to -10° and to which 48 g of (2-aminothiazol-4-yl)-(Z)- (acetoxyimino)acetic acid chloride are added in portions in such a way that the temperature of the reaction mixture does not exceed - 8°. Stirring is continued for ca. 60 minutes at -10° and 168 ml of water are added. Stirring is continued for ca. further 20 minutes at 0° and for ca. 2 hours at room temperature. A crystalline precipitate forms, is filtered off, washed with ca. 350 ml of acetonitrile and ca. 100 ml of ether and dried. The hydrochloride of N-(l ,4,5a,6-tetra-hydro-3-hydroxy-l ,7- Case 970-9827 57 -dioxo-3H,7H-azeto[2,l-b]furo-[3,4-d][l ,3]-M -2-(acetoxyimino)acetic acid is obtained in form of a diastereomeric mixture in the ratio of ca. 1 :1.

Example E) Hydrochloride of N-(l,4,5a»6-tetrahydro-3-hydroxy-l,7-dioxo-3H,7H-azeto[2,l- b]furo[3,4-d][l,3]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-(hydroxyimino)acetic acid amide g of the hydrochloride of N-(l,4,5a,6-tetrahydro-3-hydroxy-l,7-dioxo-3H,7H- a2eto[2,l -b]furo[3,4-d][l ,3]mia2in-6-yl)-2-(2-arninothiazol-4-yl)-(Z)-2-(acetoxyimino)- acetic acid amide are suspended in 160 ml of acetonitrile and treated with 53 ml of water and 1 1 ml of 8 N HCl. The reaction mixture is stirred for ca. 14 hours at room temperature. A clear solution is obtained which is diluted with water-free acetonitrile to obtain the 3-fold volume. The solvent is evaporated off to obtain a volume of ca. 10 ml, which is treated with ca. 200 ml of acetonitrile. A precipitate forms which is treated with ether, filtered off and dried. The hydrochloride of N-( 1 ,4,5 a,6-tetrahy dro- 3-hydroxy-l,7-dioxo-3H,7H-azeto[2,l-b]furo[3,4-d][l,3]-thiazin-6-yl)-2-(2- aminothiazol-4-yl)-(Z)-2-(hydroxyimino)acetic acid amide is obtained in yellowish coloured form.

Example F) Trifluoracetate of N-(l,4,5a,6-tetrahydro-3-hydroxy-l,7-dioxO-3H,7H-azeto[2,l- b]furo[3,4-d][l,3-]-thiazin-6-yl)-2-(2-aminothiazol-4-yl)-(Z)-2-[(l-carboxy-l- methylethoxy)imino]acetic acid amide is obtained in form of a light brownish powder analogously as described in Example A) a) to c) but using 2-(2-tritylaminothiazol-4-yl)-(Z)-2-[(l-carboxy-l -methylethoxy)- iminoacetic acid chloride instead of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxy iminoacetic acid chloride.

Example G) N-(l,4,5a,6-Tetrahydro-3-hydroxy-l,7-dioxo-3H,7H-azeto[2,l.b]furo[3,4-d][l,3]- thiazin-6-yl)-2-[2-(tert.-butoxycarbonyIamino)thiazol-4-yl]-(Z)-2-pentenoic acid Case 970-9827 58 amide is obtained in form of a light brownish powder analogously as described in Example A) c) to d) but using 2-(2-(tert.butoxycarbonylamino)thiazol-4-yl)-(Z)-2-pentenoic acid chloride instead of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyimino-acetic acid " chloride.

Example H) Dihydrochloride of l-(hydrazinoiminomethyl)piperazine a} Hvdroiodide of 4-formyl-l -fiminofmethylthio methyl1piperazine .5 g of 4-formyl-l-piperazinecarbothioamide are suspended in 80 ml of methanol, treated with 22 g of methyliodide and refluxed. Within ca. lO minutes a clear solution is obtained. The mixture is cooled to room temperature. The solvent is evaporated.

Crystalline hydroiodide of 4-formyl-l-[imino(methylthio)methyl]piperazine is obtained.

) Hydrochloride of 4-formyl-l -fhydrazinoiminomethyl')piperazine 48.1 g of the hydroiodide of 4-fonnyl-l-[imino(methylthio)methyl]piperazine are dissolved in 100 ml of water, run through a column filled with 800 ml of a strong basic ion exchanger in chloride form and eluated with 850 ml of water. The solvent is evaporated to obtain a volume of ca. 100 ml which is treated with 7.35 g of hydrazinehydrate. The reaction mixture is stirred for ca. 1 hour at room temperature and the solvent is evaporated off. The oily hydrochloride of 4-formyl-l- (hydrazinoiminomethyl)piperazine crystallizes on drying. c} Dihydrochloride of l-fhydrazinoiminomethyDpiperazine 1 1 g of the hydrochloride of 4-formyl-l-(hydrazinoiminomethyl)piperazine are dissolved in 400 ml of methanol and treated with 50 of HCl_onc . The reaction mixture is stirred for ca. 14 hours at room temperature. A white precipitate forms, is filtered off, washed with methanol and ether, dried and recrystallized with water/ethanol. The dihydrochloride of l-(hydrazinoiminomethyl)-piperazine is obtained in crystalline, colourless form.

Case 970-9827 59 Analogous in the manner as described in Example H) compounds of formula IV of TABLE 2 may be obtained: TABLE 2 Case 970-9827 60 Example P) l-Amino-3-(2-hydroxyethyl)-4-methylguanidine 12.7 g of 2-methylamino-2-oxazoline ar dissolved in 50 ml of water, treated with 3 g of hydrazinehydrate and stirred for ca. 17 hours at room temperature. The solvent is evaporated and l-amino-3-(2-hydroxyethyl)-4-methylguanidine is obtained as oily residue crystallizing upon cooling. " Example Q) Hydrochloride of l,l-dimethyl-4-(hydra2inoiminomethyl)piperaziniumchlonde a) Hydroiodide of l.l-dimethyl-4-fimino('methylthio methyl1piperaziniumiodide 3.2 g of 4-methyl-l-piperazinecarbothioamide are suspended in 100 ml of methanol. 6.2 g of methyliodide are added and the mixture is refluxed for ca. 2 hours and cooled to 20° ab. The hydroiodide of l,l-dimethyl-4-[imino- (methylthio)methyl]piperaziniumiodide precipitates, is filtered off and dried. b) Hydrochloride of 1.1 -dimethv -Chydrazinoiminomethy piperaziniumchloride 6.57 g of the hydroiodide of l,l-dimethyl-4-[imino(methylthio)methyl]pipe- raziniumiodide are dissolved in 70 ml of water, run through a column filled with 150 ml of a strong basic ion exchanger in chloride form and eluated with 250 ml of water. Water is evaporated off the eluate to obtain to a volume of ca. 50 ml, which is treated with 0.9 ml of hydrazinehydrate and stirred overnight. The solvent is evaporated off and the residue obtained is treated with n-hexane. The hydrochloride of l ,l-dimethyl-4-(hydrazinoiminomethyl)piperaziniumchloride is obtained.

Example R) Trihydrochloride of l-[hydrazino(methylimino)methyl]piperazine a) Hydrochloride of S-methyl-2-methylisothiosemicarbazide A solution of 239.8 g of the hydroiodide of S-Methyl-2-methylisothiosemi- carbazide in 100 ml of water is run through a column filled with 1500 ml of a Case 970-9827 61 strong basic ion exchanger in chloride form and eluated with water. The eluate is lyophilized and the lyophilization residue is treated with ether. The precipitate is filtered off and dried. The hydrochloride of S-methyl-2-methylisothiosemi- carbazide is obtained as a white solid.

Melting point: 116 ° b} Hydrochloride of 4-formyl-l -rhydrazino methylimino^methyllpiperazine A mixture of 20 g of freshly distilled formylpiperazine and 27.3 g of the hydrochloride of S-methyl-2-methylisothiosemicarbazide in 250 ml of ethanol is refluxed overnight and the solvent is evaporated. The oily "residue is dissolved in 70 ml of hot isopropanol and the solution is slowly cooled to 20°. A precipitate forms and the mixture is allowed to stand for ca. 2 hours at 4°. The hydrochloride of 4-formyl-l-[hydrazino(methylimino)methyl]piperazine is filtered off and recrystallized from isopropanol. c) Trihvdrochloride of l-rhydrazino(methylimino)rnethyl1piperazine g of the hydrochloride of l-formyl-4-[hydrazino(methylimino)methyl]piperazine are dissolved in 250 ml of methanol. 50 ml of HCl∞nc are added, the mixture obtained is stirred overnight and the solvent is evaporated. A solid residue is obtained which is dried over solid KOH. The trihydrochloride of l-[hydrazino- (methylimino)methyl]piperazine is obtained in form of a white product.

In analogous manner as described in Example R) but reacting the hydrochloride of S-methyl-isothiosemicarbazide or the hydrochloride of S-methyl-2-methylisothiosemi- carbazide or the hydrochloride of S-methyl-4-methylisothiosemicarbazide with a corresponding amine compounds of formula IV of TABLE 3 may be obtained.

TABLE 3 Ex. R, Salt Case 970-9827 62 Example ) Hydrochloride of l-Amino-3-(3,4-dihydroxybenzyIidenamino)guanidine 1 g of the hydrochloride of diaminoguanidine are dissolved in 10 ml of 4 N HCl and diluted with 20 ml of methanol. This solution is treated quickly with a solution of 1 g of 3,4-dihydroxybenzaldehyde in 40 ml of methanol. The reaction mixture is stirred for some minutes at room temperature and the solvent is evaporated off. The residue is suspended in 50 ml of acetonitrile. The precipitate formed is filtered off and dried. The hydrochloride of l-amino-3-(3,4-dihydroxybenzylidenamino)- guanidine is obtained.

Example X) Hydroiodide of S-Methyl-4-cyclopropylthiosemicarbazide v.\ 295 mg of 4-cyclopropylthiosemicarbazide are dissolved in 5 ml of dry methanol and treated with 154 ml of methyliodide. The mixture is stirred at 40° under nitrogen for ca. 5 hours, cooled and treated with diethylether. A colourless precipitate of the Case 970-9827 63 hydroiodide of S-Methyl-4-cyclopropylthiosemicarbazide is formed, filtered off, washed with diethylether and dried.

Example Y) Hydroiodide of S-methyl-4-n-butylthiosemicarbazide 147 mg of 4-h-butylthiosemicarbazide-in 2j5~ml of dry -methanol are^treated .with 149 mg of methyliodide. The mixture is stirred under nitrogen for ca. 5 hours, cooled and treated with diethylether. A colourless precipitate of the hydroiodide of S-methyl-4-n- butylthiosemicarbazide is formed, filtered off, washed with diethylether and dried.

Example Z) l-Methyl-5-mercapto-l,2,4-triazol-3-carboxyIic acid hydrazide 0.48 g of l-methyl-5-mercapto-l,2,4-triazol-3-carboxylic acid methyl ester are dissolved in 10 ml of methanol, treated with 450 μΐ of hydrazinehydrate and stirred for ca. 2 hours at 20°. A precipitate of l-methyl-5-mercapto-l,2,4-triazol-3- carboxylic acid hydrazide is formed, filtered off, washed with methanol and dried. IR (KBr): 1669 crn 1, 1608 cm"1, 1517 cm"1 13C-NMR (300 MHz, DMSO-d6): 35.4 (NCH3); 143.3, 154.3 and 166.7 Example AA) Hydroiodide of l,5-dimethyl-2-(hydrazinoiminomethyl)pyrrol a} 1.5-Dimethylpyrrol-2-carbothioamide g of 2-cyano-l ,5-dimethylpyrrol are dissolved in 40 ml of ethanol and treated with 10 ml of triethylamine. 50 ml of an ethanolic H2S solution (3.8 g/100 ml) are added and the mixture is heated for ca. 15 hours in an autoclave at 70°. The reaction mixture is cooled and the solvent is evaporated off to obtain ca. a quarter of its volume. l,5-dimethylpyrrol-2-carbothioamide crystallizes upon cooling at 0° in the form of a light yellow precipitate. b) Hydroiodide of 1.5-dimethyl-2-rimino(methylthio methyl1pyrrol 1 g of l ,5-dimethylpyrrol-2-carbothioamide are dissolved in 20 ml of methanol Case 970-9827 64 and treated with 1.7 g of methyliodide. The reaction mixture is stirred for about 5 hours at room temperature. The solvent is evaporated until crystallization starts. The residue is cooled to ca. 0°. The crystalline hydroiodide of 1 ,5-dimethyl-2- [imino(methylthio)methyl]pyrrol is filtered off, washed with methanol and dried. c Hvdroiodide of 1.5-dimethyl-2-(Tivdrazinoirro^omethyl pyrrol 1.3 g of the hydroiodide of l,5-dimethyl-2-[imino(methylthio)methyl]pyrrol are dissolved in 20 ml of methanol. 0.28 g of hydrazinehydrate are added. The reaction mixture is stirred for ca. 3 hours, the solvent is evaporated off and the residue is recrystallized from acetonitrile/ether. The hydroiodide of l,5-dimethyl-2- (hydrazinoiminomethyl)pyrrol is obtained.

Example AB) Hydroiodide of 3,4-dihydroxy-2-(hydrazinoiminomethyl)benzene is obtained in analogous manner as described in Example AA), but using 3,4- dihydroxy-thiobenzamide instead of l,5-dimethylpyrroI-2-carbothioamide.

Example AC) 7-Amino-3-[[(carboxymethoxy)imino]methyI]-3-cephein-4-carboxylic acid A solution of 1.86 g of the hydrochloride of aminooxy acetic acid in 20 ml of water is treated under stirring at 0° with 3.16 g of the hydrochloride of 6-amino-l,4,5a,6- tetrahydro-3-hydroxy-l ,7-dioxo-3H,7H-azeto[2,l-b]furo[3,4-d][l,3]thiazin. The mixture is stirred for ca. 8 hours at 0°. 7-Amino-3-[[(carboxymethoxy)imino]methyl]- 3-cephem-4-carboxylic acid precipitates in form of colourless crystals, which are filtered off, washed with 5 ml of cold water and 5 ml of acetone and dried.

Example AD) 7-Amino-3-[(methoxyimino)methyl]-3-cephem-4-carboxylic acid A solution of 0.5 g of the hydrochloride of O-methylhydroxyTamine in 10 ml of water is treated under stirring at 0° with 1.38 g of 7-amino-3-forrnyl-3-cephem-4- carboxylic acid and stirred for ca. 8 hours at 0°. 7-Amino-3-[(methoxyimino)methyl]- 3-cephem-4-carboxylic acid precipitates in form of almost white crystals, which are Case 970-9827 65 filtered off, washed with 5 ml of cold water and 5 ml of acetone and dried.

Example AE) 7-Amino-3-[(hydroxyimino)methyl]-3-cephem-4-carboxylic acid a) A solution of 1.26 g of the hydrochloride of hydroxylamine in :7.5.ml of water is treated under stirring at 0° with 4.74 g of the hydrochloride of 6-amino-l ,4,5a,6- tetrahydro-3-hydroxy-l ,7-dioxo-3H,7H-azeto[2,l -b]furo[3,4-d][l ,3]thiazin and stirred for ca. 8 hours at 0° under nitrogen. The pH of the reaction mixture is adjusted to 3.5 using solid sodium hydrogen carbonate. 7-Amino-3-[(hydroxy- imino)methyl]-3-cephem-4-carboxylic acid precipitates in form of colourless crystals, which are filtered off, washed with ca. 5 ml of cold water and 5 ml of acetone and dried. b) A suspension of 0.79 g of the hydrochloride of 6-amino-l ,4,5a,6-tetrahydro-3- hydroxy-l,7-dioxo-3H,7H-azeto[2,l-b]furo(3,4-d][l,3]thiazin in 10 ml of dichloromethane is treated under stirring at 4° with 2.67 g of N.O-bis- (trimethylsilyl)acetamide. A clear solution is obtained within 10 minutes. 0.21 g of the hydrochloride of hydroxylamine are added. The reaction mixture is stirred for ca. 2 hours under nitrogen at 4° and the solvent is evaporated off. The residue is treated with 10 ml of isopropylalkohol, precooled to 1 °. 7-Amino-3-[(hydroxy- imino)methyl]-3-cephem-4-carboxylic acid precipitates in form of almost colourless crystals which are filtered off, washed with 5 ml of acetone and dried.

Analoguously as described in Examples AC) to AE) the compounds of Table 4 of formula VI may be obtained.

Table 4 Bsp: Ri R2 Salz Case 970-9827 66 Case 970-9827 67 ^-NMR-Spectra of the compounds obtained according to the Examples (Ex.) Ex. Spectrum 1 (300 MHz, CDjOD): 8.43 (s, IH, CH=N); 6.96 (s, IH, CH); 5.99 (d, J=4.9 Hz, IH, CH); 5.22 (d, J=4.9 Hz,: 1 H,.CH);-4.04 (s, 3H, OCH3); 3.99 and 3.56 (AB quartet, J=17.8 Hz, 2H, SCH2). 2 (90 MHz, DMSO-d6 + D20): 3.6 and 4.3 (AB quartet, J=18 Hz, 2H, SCH2); 5.3 (d, J=5.1 Hz, IH, β-lactam-H); 5.95 (d, J=5.1 Hz, IH, β-lactam-H); 6,95 (s, IH, thiazolyl-H); 8.35 (s, IH, CH=N). 3 (300 MHz, CD3OD): 7.97 (s, IH, CH=N); 6.84 (s, IH, CH); 5.69 (d, J=4.9 Hz, IH, CH); 5.13 (d, J=4.9 Hz, IH, CH); 4.13 and 3.93 (AB quartet, J=16.8 Hz, 2H, SCH2), 3.81 (s, 3H, OCH3); 3.67 (s, 3H, OCH3). 4 (300 MHz, CD3OD): 8.36 (s, IH, CH=N); 6.87 (s, IH, CH); 5.88 (d, J=4.9 Hz, IH, CH); 5.29 (d, J=4.9 Hz, 1 H, CH); 4.00 (s, 3H, OCH3); 3.95 and 3.60 (AB quartet, J=17.8 Hz, 2H, SCH2). (300 MHz, DMSO-d6): 3.57 and 4.43 (AB quartet, J=18.2 Hz, 2H, S-CH2); 4.71 (s, 2H, 0-CH2); 5.30 (d, J=5.0 Hz, IH, β-lactam-H); 5.91 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H);. 7.02 (s, IH, CH thiazol); 7.9 (broad 4H, NH); 8.29 (s, IH, CH=N); 9.88 (d, J=7.9 Hz, IH, NH); 12.25 (s, IH, OH). 6 (300 MHz, CD3OD): 8.10 (s, IH, CH=N); 7.01 (s, IH, CH); 5.84 (d, J=4.9 Hz, I H, CH); 5.29 (d, J=4.9 Hz, 1 H, CH); 3.98 (s, 3H, OCH3); 3.96 and 3.59 (AB quartet, J=16.8 Hz, 2H, SCH2): 7 (300 MHz, CD3OD): 8.26 (s, IH, CH=N); 7.04 (s, IH, CH); 5.90 (d, J=5.1 Hz, IH, CH); 5.24 (d, J=5.1 Hz, 1 H, CH); 4.05 (s, 3H, OCH3); Case 970-9827 68 4.32 and 3.65 (AB quartet, J=17.8 Hz, 2H, SCH2). (300 MHz, CD3OD): 8.46 (s, IH, CH=N); 6.99 (s, IH, CH); 5.95 (d, J=5.2 Hz, IH, CH); 5.27 (d, J=5.2 Hz, 1 H, CH); 4.01 (s, 3H, OCH3); 4.37 and 3.63 (AB quartet, J=18.1 Hz, 2H, SCH2); 2.95 (s, 3H, N-CH3). (90 MHz, DMSO-d6): 9.78 (d, J=8.0 Hz, IH, CONH); 8.26 (s, IH, CH=N); 6.91 (s, IH, CH); 7.32 (dd, J=7.3 Hz, 2H, HJ; 7.05 (d, J=7.3 Hz, 2H, H0); 6.78 (t, J=7.3 Hz, IH, H„); 5.76 (dd, J,=4.8 Hz, J2=8.0 Hz, IH, CH); 5.25 (d, J=4.8 Hz, 1 H, CH); 3.91 (s, 3H, OCH3); 4.16 and 3.76 (AB quartet, J=17.4 Hz, 2H, SCH2). (90 MHz, DMSO-d6): 2.25 (s, 3H, CH3CO); 3.65 and 4.55 (AB quartet, J=18 Hz, 2H, SCH2); 5.4 (d, J=5 Hz, 1 H, B-lactam-H); 5.95 (dd, J=5Hz and 8 Hz, IH, β-lactam-H); 7,32 (s, IH, thiazolyl-H); 8.4 (s, IH, CH=N); ,2 (d, J=8.0 Hz, IH, NH). (90 MHz, DMSO-d6): 1.12 (t, J=7.1 Hz, 3H, CH3); 3.29 (q, 2H, CHJ; 3.56 and 4.50 (AB quartet, J=18.1 Hz, 2H, SCH2); 3.93 (s, 3H, N-O- CH3); 5.30 (d, J=5Hz, IH, CH); 5.9 (q, J=6Hz, and 8Hz, IH, CH); 6.90 (s, IH, thiazolyl-H); 8.32 (s, IH, CH=N); 9.86 (d, J=8.0Hz, NH). (90 MHz, DMSO-d6): 1.85-2.15 (m, 4H); 3.25-3.7 (m, 5H, -CH2-N-CH2- and IH of SCH2); 4.0 (s, 3H, N-0-CH3); 4.5 (part of the AB quartet, J=18Hz, IH of SCH2); 5.3 (d, J=5Hz, IH, CH); 5.9 (q, J=5Hz and 8Hz, I H, CH); 7.0 (s, IH, thiazolyl-H); 8.8 (s, IH, CH=N); 10.1 (d, J=7.9Hz, NH). (90 MHz, DMSO-d6): 2.9 (broad s, 6H, N-CH3), 3); 3.6 and 4.5 (AB quartet, J=18Hz, 2H, SCH2); 3.9 (s, 3H, N-0-CH3); 5.3 (d, J=5Hz, IH, CH)); (q, J=5Hz and 8Hz, IH, CH); 6.95 (s, IH, thiazolyl-H); 8.75 (s, IH, CH=N); 9.95 (d, J=8Hz, NH).

Case 970-9827 69 14 (90 MHz, DMSO-d6): 3.65 (broad s, 4H, N-CH2-CH2-N); 3.5 and 4.4 (AB quartet, J=l 8Hz, 2H, SCH2); 3.9 (s, 3H, N-0-CH3); 5.3 (d, J=5.0Hz, IH, CH); 5.85 (q, J=5Hz and 8Hz, IH, CH); 6.9 (s, IH, thiazolyl-H); 8.35 (s, IH, CH=N); 9.9 (d, J=8Hz, NH). (90 MHz, DMSO-d6): .1.16 (t, J=7.1Hz 3H,-CH3); 1 :8-2 (m, 4H); 3.32 (q, 2H, CH2); 3.45-3.65 (m, 5H, -CH2-N-CH2- and IH of SCH2); 3.91 (s, 3H, N-O-CHj); 4.1 (part of the AB quartet, J=18Hz, IH of SCH2); 5.27 (d, J=5Hz, IH, CH); 5.9 (q, J=5Hz and 8Hz, IH, CH); 6.86 (s, IH, thiazolyl- H); 8.56 (s, IH, CH=N); 9.82 (d, J=8Hz, NH). 16 (90 MHz, DMSO-d6): 2.86 (broad s, 3H, N-CH3); 3.5 and 4.5 (AB quartet, J=18Hz, 2H, SCH2); 5.3 (d, J=6Hz, IH, CH); 5.9 (q, J=5Hz and 8Hz, IH, CH); 6.85 (s, IH, thiazolyl-H); 8.4 (s, IH, CH=N); 9.8 (d, J=8Hz, NH). 17 (90 MHz, DMSO-d6): 1.85-2.15 (m, 4H); 3.25-3.8 (m, 5H, -CH2-N-CH2- and IH of SCH2); 4.5 (part of the AB quartet, J=18Hz, IH of SCH2); 5.3 (d, J=5Hz, IH, CH); 5.85 (q, J=5Hz and 8Hz, IH, CH); 6.85 (s, IH, thiazolyl- H); 8.7 (s, IH, CH=N); 9.8 (d, J=7.9Hz, NH). 18 (90 MHz, DMSO-d6): 2.86 (broad s, 6H, N-CH3), 3); 3.55 and 4.47 (AB quartet, J=18.9Hz, 2H, SCH2); 5.31 (d, J=5.1Hz, IH, CH); 5.91 (q , J=5.1Hz and 7-9Hz, IH, CH); 6.8 (s, IH, thiazolyl-H); 8.58 (s, IH, CH=N); 9.72 (d, J=7.9Hz, NH). 19 (90 MHz, DMSO-d6): 3.7 (broad s, 4H, N-CH2-CH2-N); 3.55 and 4.35 (AB quartet, J=18.1Hz, 2H, SCH2); 5.31 (d, J=5.0Hz, IH, CH); 5.9 (q, J=5.1 Hz and 8Hz, IH, CH); 6.8 (s, IH, thiazolyl-H); 8.38 (s, IH, CH=N); 9.73 (d, J=8.0Hz, NH). (300 MHz, CD3OD): 8.34 (s, IH, CH=N); 7.06 (s, IH, CH); 5.93 (d, Case 970-9827 70 J=4.9 Hz, 1H, CH); 5.32 (d, J=4.9 Hz, 1 H, CH); 4.09 (s, 3H, OCH3); 4.33 and 3.64 (AB quartet, J=18.2 Hz, 2H, SCH2). 21 (90 MHz, DMSO-d6): 3.65 and 4.7 (AB quartet, J = 18 Hz, 2H, SCH2); 3.95 (s, 3 H, 0-CH3); 4.2 (part of the AB quartet, J = 18 Hz, 1H of SCHj); 5.3 (d, J = 5 Hz, 1 H, B-lactam-H);- 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 7.0 (s, 1 H, thiazolyl-H); 7 to 7.7 (m, 5 H, aromatic H); 8.45 (s, 1 H, CH=N);.9 (d, J = 8 Hz, NH). (90 MHz, DMSO-d6):3.55 and 4.6 (AB quartet, J = 18 Hz, 2H, SCH2); 3.93 (s, 3 H, O-CH3); 4.2 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 7.0 (s, 1 H, thiazolyl-H); 7 to 7.7 (m, 5 H, aromatic-H); 8.3 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). (90 MHz, DMSO-d6): 3.05 (d, J = 4 Hz, 3 H, NHCH3); 3.55 and 4.5 (AB quartet, J = 18 Hz, 2H, SCH2); 3.93 (s, 3 H, 0-CH3); 4.2 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.25 (d, J = 5 Hz, 1 H, B-lactam- H); 5.8 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.25 (s, 1 H, CH=N);8.4 (d, J = 4 Hz, NHCH3);9.85 (d, J = 8 Hz, NH). (90 MHz, DMSO-d6): 2.85 (s, 3H, NCH3); 3.1 to 3.7 (m, 9 H, 8 piperazi- nyl-H's and 1H of SCH2); 3.95(s, 3 H, OCH3); 4.1 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 3.95 (s, 3 H,0-CH3); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B-lactam-H);6.95 (s, 1 H, thiazolyl-H); 7.95 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). (90 MHz, DMSO-d6): 3.6 and 4.55 (AB quartet, J = 18 Hz, 2H, SCH2); 3.9 to 4.1 (m, 5 H, -OCH3 and -N-CH2-CH=CH2); 5.1 to 5.5 (m, 3 H, β- lactam-H and -N-CH2-CH=CH2); 5.7 to 6.1 (m,2H, β-lactam-H and N- CH2-CH=CH2);6.95 (s, 1 H, thiazolyl-H);8.3 (s, 1 H, CH=N); 9.95 (d, J = 8 Hz, NH).

Case 970-9827 71 26 (90 MHz, DMSO-d6): 1.7 to 2 (m, 2 H, -CH2-CH2-CH3); 3.1 to 3.5 (m, 4 H); 3.55 and 4.5(AB quartet, J = 18 Hz, 2H, SCH2); 3.95 (s, 3 H, O- CH3); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B- lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.3 (s, 1 H, CH=N); 9.9 (d, J = 8 - Hz, NH). 27 (90 MHz, DMSO-d6): 0.8 to 1.1 and 1.1 to 1.7 (m, 7 H, -CH2-CH2-CH3); 3.15 to 3.45 (m, 2 H, -NHCH2-); 3.6 and 4.55 (AB quartet, J = 18 Hz, 2H, SCH2); 3.95 (s, 3 H, 0-CH3); 5.3 (d, J = 5 Hz, 1 H, B-lactam-H); .85 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.4 (s, 1 H, CH=N); 9.95 (d, J = 8 Hz, NH). 28 (90 MHz, DMSO-d6): 3.05 (d, J = 4 Hz, 3 H, NHCH3); 3.65 (s, 3 H, NCH3); 3.55 and 4.6 (AB quartet, J = 18 Hz, 2H, SCH2); 3.93 (s, 3 H, 0-CH3); 4.2 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.3 (d, J = Hz, 1 H, B-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 7.0 (s, 1 H, thiazolyl-H); 8.6 (s, 1 H, CH=N); 9.4 (d, J = 8 Hz, NH). 29 300 MHz, DMSO-d6): 2.93 (d, J = 4.6 Hz, 3 H, NCH3); 3.4 to 3.6 (m, 5H); 3.6 to 3.8 (m, 4H); 3.93 (s, 3 H, 0-CH3); 4.2 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.3 (d, J = 5 Hz, 1 H, B-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 6.93 (s, 1 H, thiazolyl-H); 8.6 (s, 1 H, CH=N); 9.92 (d, J = 8 Hz, NH). (90 MHz, DMSO-d6): 1.3 (s, 9 H, -C(CH3)3); 3.55 and 4.55 (AB quartet, J = 18 Hz, 2H, SCH2); 5.3 (d, J = 5 Hz, 1 H, B-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.25 (s, 1 H, CH=N); 9.95 (d, J = 8 Hz, NH). 31 (90 MHz, DMSO-d6): 2.9 (s, 3 H, NCH3); 3.0 (s, 6 H, NCCH^; 3.6 and 4.2 (AB quartet, J = 18 Hz, 2H, SCH2); 3.95 (s, 3 H, 0-CH3); 5.3 (d, J = 5 Hz, 1 H, B-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 7.0 (s, Case 970-9827 72 1 H, thiazolyl-H); 8.55 (s, 1 H, CH=N); 9.95 (d, J = 8 Hz, NH). 32 (90 MHz, DMSO-d6) : 2.85 (s, 2 H); 3.55 and 4.6 (AB quartet, J = 18 Hz, 2H, SCHj); 3.95 (s, 3 H, 0-CH3); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H);. .85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.65 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). 33 (90 MHz, DMSO-d6): 3.4 to 3.8 (m, 9 H, morpholino H's and 1H of SCH2); 3.95 (s, 3 H, 0-CH3); 4.6 (part of the AB quartet, J = 18 Hz, IH of SCH2); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.7 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). 34 (300 MHz, DMSO-d6): 3.32 (s, 9H,-N+(CH3)3); 0.4 to 1 (m, 4 H, -CH2- CH ); 2.5 to 2.8 (m, 1 H); 3.65 and 4.17 (AB quartet, J = 18.1 Hz, 2H, SCH2); 3.94 (s, 3 H, 0-CH3); 4.8 (q, J = 17 Hz, 2H); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.94 (s, 1 H, thiazolyl-H); 8.26 (s, 1 H, CH=N); 9.93 (d, J = 8 Hz, NH). (90 MHz, DMSO-d6): 0.4 to 1 (m, 4 H, -CH2-CH2-); 2.5 to 2.8 (m, 1 H), 3.55 and 4.6 (AB quartet, J = 18 Hz, 2H, SCH2); 3.95 (s, 3 H, 0-CH3); .3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β- lactam-H); 6.9 (s, 1 H, thiazolyl-H); 8.35 (s, 1 H, CH=N); 9.85 (d, J = 8 Hz, NH). 36 (90 MHz, DMSO-d6): 3.6 and 4.55 (AB quartet, J = 18 Hz, 2H, SCH2); 3.95 s, 3 H, 0-CH3); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.9 (s, 1 H, thiazolyl-H); 8.5 (s, 1 H, CH=N); 9.85 (d, J = 8 Hz, NH); 10.4 (broad singulet, 1 H -NH-OH). 37 (90 MHz, DMSO-d6): 3.1 (s, 3 H, N-CH3); 3.55 and 4.6 (AB quartet, J = 18 Hz, 2H, SCH2); 3.9 (s, 3 H, 0-CH3); 5.3 (d, J = 5 Hz, 1 H, B-lactam- Case 970-9827 73 H); 5.85 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 6.9 (s, 1 H, thiazolyl-H); 8.7 (s, 1 H, CH=N); 9.85 (d, J = 8 Hz, NH). (300 MHz, DMSO-d6): 3.56 and 4.54 (AB quartet, J = 18.1 Hz, 2H, SCH2); 3.91 (s, 3 H, 0-CH3); 4.87 (d, J = 6.5 Hz, 2 H); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.89 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 6.88 (s, 1 H, thiazolyl-H); 7.6 (m, 2 H, pyridinyl-H); 8.15 (m, 1 H, pyridinyl-H); 8.39 (s, 1 H, CH=N); 8.86 (m, 1 H, pyridinyl-H); 9.83 (d, J = 8 Hz, NH). (300 MHz, DMSO-d6): 3.57 and 4.52 (AB quartet, J = 18.1 Hz, 2H, SCH2); 3.91 (s, 3 H, 0-CH3); 4.87 (d, J = 6 Hz, 2 H); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.89 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.88 (s, 1 H, thiazolyl-H); 8.15 (m, 1 H, pyridinyl-H); 8.38 (s, 1 H, CH=N); 8.45 (m, 1 H, pyridinyl-H); 8.8 (m, 1 H, pyridinyl-H); 8.85 (s, 1 H, pyridinyl-H); 9.91 (d, J = 8 Hz, NH). (300 MHz, DMSO-d6): 3.58 and 4.57 (AB quartet, J = 18.3 Hz, 2H, SCH2); 3.9 (s, 3 H, 0-CH3); 5.06 (broad singulet, 2 H); 5.3 (d, J = 5 Hz, 1 H, B-lactam-H); 5.88 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.94 (s, 1 H, thiazolyl-H); 8.02 (d, J = 6.6 Hz, 2 H, pyridinyl-H); 8.4 (s, 1 H, CH=N); 8.92 (d, J = 6.6 Hz, 2 H, pyridinyl-H); 9.91 (d, J = 8 Hz, NH). 41 (90 MHz, DMSO-d6): 3.65 and 4.35 (AB quartet, J = 18 Hz, 2H, SCH2); 3.9 (s, 3 H, 0-CH3); 4.2 (d, J = 7 Hz, 2H); 5.2 (d, J = 5 Hz, 1 H, B- lactam-H); 5.75 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 7.85 (s, 1 H, CH=N); 9.8 (d, J = 8 Hz, NH). 42 (90 MHz, DMSO-d6): 2.95 (broad duplet, 3 H, N-CH3); 3.0 to 3.3 (m, 4 H, -CH2-N-CH2); 3.4 to 3.8 (m, 5 H, -CH2-NH+-CH2- and 1H of SCH2); 3.85 (s, 3 H, 0-CH3); 4.1 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.25 (d, J = 5 Hz, 1 H, B-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.8 (s, 1 H, thiazolyl-H); 8.65 (s, 1 H, CH=N); 9.75 (d, J = Case 970-9827 74 8 Hz, NH). (90 MHz, DMSO-d6): 3.7 and 4.85 (AB quartet, J = 18 Hz, 2H, SCH2); 3.95 (s, 3 H, 0-CH3); 5.35 (d, J = 5 Hz, 1 H, β-lactam-H); 5.95 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 7.0 (s, 1 H, thiazolyl-H); 7.2 (t, J = 6 Hz, 1 H, pyridinyl-H); 7.4 (d, J = -8 Hz, 1 .H, -pyridinyl-H); 8.15 (t, J = 6 Hz, 2 H, pyridinyl-H); 8.55 (s, 1 H, CH=N); 9.95 (d, J = 8 Hz, NH). (90 MHz, DMSO-d6): 3.6 and 4.05 (AB quartet, J = 18 Hz, 2H, SCH2); 3.95 (s, 3 H, O-CH3); 5.25 (d, J = 5 Hz, 1 H, β-lactam-H); 5.75 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.9 (s, 1 H, thiazolyl-H); 8.5 (s, 1 H, CH=N); 9.85 (d, J = 8 Hz, NH). (300 MHz, DMSO-d6): 1.4 to 1.7 (n 6 H); 3.4 to 3.7 (m, 5 H, -CH2-N- CH2- and 1H of SCH2); 3.92 (s, 3 H, 0-CH3); 4.55 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.29 (d, J = 5 Hz, 1 H, β-lactam-H); .89 (dd, J = 5 Hz and 7.8 Hz, β-lactam-H); 6.89 (s, 1 H, thiazolyl-H); 8.6 (s, 1 H, CH=N); 9.84 (d, J = 7.8 Hz, NH). (90 MHz, DMSO-d6): 3.1 to 3.4 (m, 4 H, -CH2-NH+-CH2-); 3.65 and 4.65 (AB quartet, J = 18 Hz, 2H, SCH2); 3.85 (s, 3 H, 0-CH3); 4 to 4.3 (m, 4 H, -CH2-N-CH2-); 4.65 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.2 (d, J = 5 Hz, 1 H, B-lactam-H); 5.8 (dd, J = 5 Hz and 8 Hz, S-lactam-H); 6.75 (s, 1 H, thiazolyl-H); 8.5 (s, 1 H, CH=N); 9.7 (d, J = 8 Hz, NH). (300 MHz, DMSO-d6): 2.85 (broad singulet, 3 H, N-CH3); 3.54 and 4.52 (AB quartet, J = 18.1 Hz, 2H, SCH2); 3.93 (s, 3 H, 0-CH3); 5.3 (d, J = 5 Hz, 1 H, B-lactam-H); 5.89 (dd, J = 5 Hz and 7.9 Hz, β-lactam-H); 6.91 (s, 1 H, thiazolyl-H); 8.62 (s, 1 H, CH=N); 9.88 (d, J = 7.9 Hz, NH); 12.0 (s, 1 H, OH). 75 (90 MHz, DMSO-d6): 3.2 (s, 6 H, NCH3); 3.7 (s, 4 H, -N^CH^-N-); 3.65 and 4.0 (AB quartet, J = 17.8 Hz, 2H, SCH2); 3.95 (s, 3 H, 0-CH3); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.8 (s, 1 H, CH=N); 9.9 (d, J = 8 \ Hz, NH). (300 MHz, DMSO-d6): 3.7 and 4.13 (AB quartet, J = 17.8 Hz, 2H, SCH2); 3.9 (s, 3 H, 0-CH3); 5.31 (d, J = 5 Hz, 1 H, β-lactam-H); 5.89 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.92 (s, 1 H, thiazolyl-H); 8.13 (d, J = 6 Hz, 2 H, pyridinyl-H); 8.7 (s, 1 H, CH=N); 8.93 (m, 3 H, pyridinyl-H); 9.88 (d, J = 8 Hz, NH). (300 MHz, DMSO-d6): 2.94 (d, J = 4.7 Hz, 3 H, N-CH3); 3.29 (broad s, 6 H, N+(CH3)2); 3.3 to 3.7 (m, 9H, piperazinyl-H's and 1H of SCH2); 3.93 (s, 3 H, 0-CH3); 4.2 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.28 (d, J = 5 Hz, 1 H, β-lactam-H); 5.89 (dd, J = 5 Hz and 7.6 Hz, β-lactam-H); 6.9 (s, 1 H, thiazolyl-H); 8.1 (s, 1 H, formyl-H); 8.6 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). (300 MHz, DMSO-d6): 3.7 and 4.2 (AB quartet, J = 18 Hz, 2H, SCH2); 3.93 (s, 3 H, 0-CH3); 5.35 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.0 (AB quartet, J = 9 Hz, 2H); 6.93 (s, 1 H, thiazolyl-H); 8.2 (t, J = 7 Hz, 2 H), 8.7 (t, J = 7 Hz, 1 H) and 9.1 (d, J = 6 Hz, 2H), pyridinium-H; 8.32 (s, 1 H, CH=N); 9.95 (d, J = 8 Hz, NH). (90 MHz, DMSO-d6): 3.7 (s, 3 H, N-CH3); 3.65 and 4.1 (AB quartet, J = 18 Hz, 2H, SCH2); 3.95 (s, 3 H, 0-CH3); 5.35 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 7.0 (s, 1 H, thiazolyl-H); 8.75 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). (90 MHz, DMSO-de): 2.25 (s, 3 H, triazinyl-CH3); 3.5 and 4.65 (AB quartet, J = 18 Hz, 2H, SCH2); 4.0 (s, 3 H, 0-CH3); 5.35 (d, J = 5 Hz, 1 Case 970-9827 76 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.85 (s, 1 H, CH=N); 9.95 (d, J = 8 Hz, NH). 54 (90 MHz, DMSO-d6): 2.3 (s, 3 H, CH3); 1.8 to 2.1 (m, 1 H); 3.6 and 4.55.

(AB quartet, J = 18 Hz, 2H, SCH2); 3.95 (s, 3 H, 0-CH3); 5.35 (d, J = 5 •Hzv-1 H, β-lactam-H); 5;9 (dd, J = 5,Hz. and 8 Hz, B-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.65 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). 55 (90 MHz, DMSO-d6): 2.8 (broad duplet, 3H, N-CH3); 3.2 to 3.7 (m, 5 H, N-CH2-CH2-0 and 1H of SCH2); 3.95 (s, 3 H, 0-CH3); 4.5 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.3 (d, J = 5 Hz, 1 H, B-lactam-H); .85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.65 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). 56 (90 MHz, DMSO-dg): 3.7 and 4.15 (AB quartet, J = 18 Hz, 2H, SCH2); 4.0 (s, 3 H, 0-CH3); 5.35 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 7.0 (s, 1 H, thiazolyl-H); 7 to 7.8 (m, 4 H, aromatic-H); 8.45 (s, 1 H, CH=N); 9.95 (d, J = 8 Hz, NH). 57 (90 MHz, DMSO-d6): 3.35 broad singulet, 3 H, NCH3); 3.55 and 4.55 (AB quartet, J = 18 Hz, 2H, SCH2); 3.95 (s, 3 H, 0-CH3); 5.3 (d, J = 5 Hz, 1 H, B-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.15 (s, 1 H, CH=N); 9.85 (d, J = 8 Hz, NH). 58 (90 MHz, DMSO-d6): 2.95 (broad duplet, 3 H, NCH3); 3.35 (broad singulet, 3 H, NCH3); 3.65 and 4.65 (AB quartet, J = 18 Hz, 2H, SCH2); 3.95 (s, 3 H, 0-CH3); 5.3 (d, J = 5 Hz, 1 H, B-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 8.1 (s, 1 H, CH=N); 9.85 (d, J = 8 Hz, NH). 59 (90 MHz, DMSO-d6): 1 to 1.5 (m, 4 H, -CH2-CH2-); 1.8 to 2.1 (m, 1 H); 3.55 and 4.55 (AB quartet, J = 18 Hz, 2H, SCHj); 3.95 (s, 3 H, 0-CH3); Case 970-9827 77 .3 (d, J = 5 Hz, 1 H, B-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B- lactam-H); 6.9 (s, 1 H, thiazolyl-H); 8.65 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). 60 (90 MHz, DMSO-d6): 3.7 and 4.8 (AB quartet, J = 18 Hz, 2H, SCH2); 4.0 (s, 3 H, O-CHj); 5.35 (d, J -= 5 Hz, 1 ¾ B-lactam-H); 5.95 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 7.0 (s, 1 H, thiazolyl-H); 7.85 (dd, J = 4 Hz and 6 Hz, pyridinyl-H); 8.2 (dt, J = 2 and 8 Hz, pyridinyl-H); 8.5 (d, J = 6 Hz, pyridinyl-H); 8.9 (d, J = 4 Hz, pyridinyl-H); 8.95 (s, 1 H, CH=N); 9.95 (d, J = 8 Hz, NH). 61 (90 MHz, DMSO-d : 3.6 and 4.15 (AB quartet, J = 18 Hz, 2H, SCH2); 3.85 (s, 3 H, O-CH3); 5.25 (d, J = 5 Hz, 1 H, B-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 6.75 (s, 1 H, thiazolyl-H); 7.5 (dd, J = 5 Hz and 8 Hz, pyridinyl-H); 8.25 (broad duplet, J = 8 Hz, pyridinyl-H); 8.65 (broad triplet, J = 6 Hz, pyridinyl-H); 9.05 (s, 1 H, CH=N); 9.7 (d, J = 8 Hz, NH). 62 (300 MHz, DMSO-d6): 3.13 (broad duplet, 3 H, N-CH3); 3.29 (broad s, 6 H, N+(CH3)2); 3.4 to 3.75 (m, 5 H, -CH2-N+-CH2- and 1H of SCH2); 3.85 (s, 3 H, O-CHj); 4 to 4.3 (m, 4 H, -CH2-N-CH2-); 4.65 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.27 (d, J = 5 Hz, 1 H, B-lactam-H); .85 (dd, J = 5 Hz and 7.6 Hz, B-lactam-H); 6.78 (s, 1 H, thiazolyl-H); 8.75 (s, 1 H, CH=N); 9.75 (d, J = 7.6 Hz, NH). 63 (90 MHz, DMSO-d6 +TFA): 3.0 (broad duplet, 3 H, N-CH3); 3.2 (s, 9 H, N+(CH3)3); 3.5 to 3.8 (m, 5 H, N-CH2-CH2-N+ and 1H of SCH2); 3.90 (s, 3 H, O-CH3); 4.65 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.3 (d, J = 5 Hz, 1 H, B-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, B-lactam- H); 6.8 (s, 1 H, thiazolyl-H); 8.75 (s, 1 H, CH=N); 9.75 (d, J = 8 Hz, NH). 78 (90 MHz, DMSO-d6): 3.65 and 4.15 (AB quartet, J = 18 Hz, 2H, SCH2); 4.0 (s, 3 H, O-CHj); 5.25 (d, J = 5 Hz, 1 H, β-lactam-H); 5.8 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 7.0 (s, 1 H, thiazolyl-H); 7.2 (d, J = 5 Hz, 1 H, pyrimidinyl-H); 8.45 (s, 1 H, CH=N) 8.8 (d, J = 5 Hz, 1 H, pyrimidinyl-H); 9.9 (d, J = 8 Hz, NH). (90 MHz, DMSO-d6 +TFA): 4.0 (s, 3 H, 0-CH3); 3.6 and 4.65 (AB quartet, J = 18 Hz, 2H, SCH2); 5.25 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 7.0 (s, 1 H, thiazolyl-H); 8.3 (s, 1 H, CH=N); 9.85 (d, J = 8 Hz, NH). (90 MHz, DMSO-de): 3.2 (broad singulet, 3 H, N-CH3); 3.0 to 3.4 (m, 4 H, -CHJ-N-CHJ); 3.4 to 3.8 (m, 5 H, -CH2-NH+-CH2- and 1H of SCH2); 3.95 (s, 3 H, 0-CH3); 4.3 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.35 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 7.0 (s, 1 H, thiazolyl-H); 8.15 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). (90 MHz, DMSO-ds): 3.3 (s, 3 H, N-CH3); 3.3 (broad s, 6 H, N+(CH3)2); 3.3 to 3.7 (m, 9H, piperazinyl-H's and 1H of SCH2); 3.85 (s, 3 H, O-CH3); 4.25 (part of the AB quartet, J = 18 Hz, 1H of SCH2); 5.25 (d, J = 5 Hz, 1 H, B-lactam-H); 5.8 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.8 (s, 1 H, thiazolyl-H); 8.1 (s, 1 H, formyl-H); 8.15 (s, 1 H, CH=N); 9.75 (d, J = 8 Hz, NH). (90 MHz, DMSO-d6): 2.25 (s, 3 H); 3.65 (s, 3 H, N-CH3); 3.7 and 4.6 (AB quartet, J = 18 Hz, 2H, SCH2); 3.9 (s, 3 H, 0-CH3); 5.3 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.05 (d, J = 4 Hz, pyrrol-H); 6.85 (d, J = 4 Hz, pyrrol-H);~6.9 (s, 1 H, thiazolyl-H); 8.75 (s, 1 H, CH=N); 9.9 (d, J = 8 Hz, NH). (90 MHz, DMSO-d6): 3.5 and 4.45 (AB quartet, J = 20 Hz, 2H, SCH2); -9827 79 .25 (d, J = 5 Hz, 1 H, B-lactam-H); 5.75 (d, J = 55 Hz, 2H, -CH2F); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 8.25 (s, 1 H, CH=N);9.85 (d, J = 8 Hz, NH). (300 MHz, DMSO-d6): 1.13 (t, J=7.1 Hz, 3H, CH3); 3.31 (qd, J=7.1 and ca; 6 Hz, 2H, CH2); 3.55 and 4.47· (AB -quartet,, J= 18.1 Hz, 2H, S.CH2); 5.29 (d, J=5.0 Hz, IH, β-lactam-H); 5.89 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.78 (s, IH, CH thiazol); 8.01 (broad, 2H, NH); 8.19 (broad t IH, NH) ; 8.32 (s, IH, CH=N); 9.70 (d, J=7.9 Hz, IH, NH); 12.03 (s, IH, OH). (300 MHz, DMSO-d6): 2.98 (d, J=4.6 Hz, 3H, N-CH3); 3.56 and 4.46 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.28 (d, J=4.9 Hz, IH, β-lactam-H); 5.87 (dd, J=4.9 and 7.9 Hz, IH, β-lactam-H); 6.83 (s, IH, CH thiazol); 8.22 (s, IH, CH=N); 8.48 (q broad J=4.6 Hz, IH, NH); 9.75 (d, J=7.9 Hz, IH, NH); 11.63 (s, IH, OH); 12.28 (s, IH, OH). (300 MHz, DMSO-d6): 3.53 and 4.47 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.26 (d, J=5.0 Hz, IH, β-lactam-H); 5.88 (dd, J= .9 and 7.9 Hz, IH, β-lactam-H); 6.84 (s, IH, CH thiazol); 8.00 (s, IH, NH); 8.23 (s, IH, CH=N); 8.28 (s, IH, NH); 9.76 (d, J=7.9 Hz, IH, NH); 11.56 (s, IH, OH); 12.31 (s, IH, OH). (300 MHz, DMSO-d6): 1.16 (t, J=7.1 Hz, 3H, CH3); 1.90 (m broad, 4H, CH2); 3.39 (qd, J=7.1 and ca. 6 Hz, 2H, CH2); 3.56 (m broad, 4H, CH2); 3.63 and 4.07 (AB quartet, J=18.0 Hz, 2H, S-CH2); 5.28 (d, J=5.0 Hz, IH, β-lactam-H); 5.88 (dd, J=5.0 and 7.8 Hz, IH, β-lactam-H); 6.81 (s, IH, CH thiazol); 7.97 (t broad, J= ca. 6 Hz IH, NH); 8.60 (s, IH, -CH=N); 9.76 (d, J=7.8 Hz, IH, NH); 1 1.70 (s, I K OH); 12.26 (s, IH, OH). (300 MHz, DMSO-d6): 3.57 and 4.48 (AB quartet, J=18.1 Hz, 2H, Case 970-9827 80 S-CH2); 3.97 (broad, 2H, N-CH2-C=C); 5.1-5.3 (m, 2H, C=CH2); 5.30 (d, J=5.1 Hz, IH, β-lactam-H); 5.8-5.9 (m, IH, C-CH=C); 5.89 (dd, J=4.9 and 8.2 Hz, IH, β-lactam-H); 6.83 (s, IH, CH thiazol); 8.10 (s, 2H, NH); 8.34 (s, IH, CH=N); 8.41 (s, IH, NH); 9.77 (d, J=8.0 Hz, IH, NH); 12.26 (s, IH, OH); 12.38 (s, IH, OH). 75 (300 MHz, DMSO-d6): 1.89 (m broad 2H, CH2); 3.33 (s broad, 4H, N-CHj); 3.54 and 4.42 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.29 (d, J=5.0 Hz, IH, β-lactam-H); 5.89 (dd, J=5.0 and 8.0 Hz, IH, β-lactam-H); 6.76 (s, IH, CH thiazol); 8.29 (s, IH, CH=N); 8.38 (s, 2H, NH); 9.66 (d, J=8.0 Hz, IH, NH); 11.90 (s, IH, OH); 12.03 (s, IH, OH). 76 (300 MHz, DMSO-d6): 0.89 (t, 3H, C-CH3); 1.2-1.4 (m, 2H, C-CH2-C); 1.4-1.6 (m, 2H, C-CH2-C); 3.2-3.4 (m, 2H, N-CH2-C); 3.56 and 4.47 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.30 (d, J=5.0 Hz, IH, β-lactam-H); 5.89 (dd, J=5.0. and 7.9 Hz, IH, β-lactam-H); 6.83 (s, IH, CH thiazol); 8.04 (s, 2H, NH); 8.24 (s, IH, CH=N); 8.32 (s, IH, NH); 9.76 (d, J=7.9 Hz, IH, NH); 12.13 (s, IH, OH); 12.36 (s, IH, OH). 77 (300 MHz, DMSO-d6): 3.66 and 3.92 (AB quartet, J=17.9 Hz, 2H, S-CH2); 3.86 (s, 3H, 0-CH3); 5.27 (d, J=5.0 Hz, IH, β-lactam-H); 5.88 (dd, J=5.0 and 7.8 Hz, IH, β-lactam-H); 6.84 (s, IH, CH thiazol); 8.22 (s, IH, CH=N); 9.78 (d, J=7.8 Hz, IH, NH); 12.34 (s, IH, OH). 78 (300 MHz, DMSO-d6): 1.39 (s, 9H, C-CH3); 3.56 and 4.47 (AB quartet, J=18.0 Hz, 2H, S-CH2); 5.29 (d, J=5.0 Hz, IH, β-lactam-H); 5.89 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.81 (s, IH, CH thiazol); 7.90 (s broad 2H, NH); 7.99 (s broad IH, NH); 8.25 (s, IH, CH=N); 9.68 (d, J=7.9 Hz, IH, NH); 12.03 (s, IH, OH); 12.16 (s, l-H, OH). 79 (300 MHz, DMSO-d6): 2.92 (d, J=4.8 Hz, 3H, N-CH3); 3.03 (s, 6H, N-CH3); 3.61 and 4.17 (AB quartet, J=18.0 Hz, 2H, S-CH2); 5.29 (d, -9827 81 J=5.0 Hz, IH, β-lactam-H); 5.88 (dd, J=5.0 and 7.8 Hz, IH, β-lactam-H); 6.81 (s, IH, CH thiazol); 8.20 (q broad J=4.8 Hz, IH, NH); 8.55 (s, IH, CH=N); 9.76 (d, J=7.5 Hz, IH, NH); 1 1.83 (s, IH, OH); 12.28 (s, IH, OH). (300 MHz, DMSO-d6): 2,75 (s, 2H,:N-CH2); 3.55 and .4.54 (AB, quartet, J=18.1 Hz, 2H, S-CH2); 5.32 (d, J=5.1 Hz, IH, β-lactam-H); 5.93 (dd, J=5.1 and 7.9 Hz, IH, β-lactam-H); 6.79 (s, IH, CH thiazol); 8.59 (s, IH, CH=N); 9.73 (d, J=8.0 Hz, IH, NH); 12.13 (s, IH, OH). (300 MHz, DMSO-d6): 3.55 and 4.54 (AB quartet, J=18.1 Hz, 2H, S-CHj); 3.5-3.6 (m, 4H, CH2); 3.6-3.7 (m, 4H, CH2); 5.30 (d, J=5.1 Hz, IH, β-lactam-H); 5.89 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.84 (s, IH, CH thiazol); 8.35 (broad, 2H, NH); 8.65 (s, IH, CH=N); 9.80 (d, J=7.9 Hz, IH, NH); 12.27 (s, IH, OH); 12.51 (s, IH, OH). (300 MHz, DMSO-d6): 0.64 (m, 2H, cyclopr. CH2); 0.83 (m, 2H, cyclopr. CH2); 2.62 (m, IH, cyclopr. CH); 3.53 and 4.49 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.29 (d, J=5.0 Hz, IH, β-lactam-H); 5.89 (dd, J=5.0 and 8.0 Hz, IH, β-lactam-H); 6.79 (s, IH, CH thiazol); 8.09 (s, 2H, NH); 8.35 (s, IH, CH=N); 8.59 (s, IH, NH); 9.70 (d, J=8.0 Hz, IH, NH); 12.08 (s, IH, OH); 12.13 (s, IH, OH). (300 MHz, DMSO-d6): 3.54 and 4.48 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.29 (d, J=5.0 Hz, IH, β-lactam-H); 5.89 (dd, J=4.9 and 7.8 Hz, IH, β-lactam-H); 6.83 (s, IH, CH thiazol); 8.15 (s, 2H, NH); 8.39 (s, IH, CH=N); 9.79 (d, J=7.9 Hz, IH, NH); 1 1.21 (s, IH, OH); 12.15 (s, IH, OH); 12.44 (s, IH, OH). (300 MHz, DMSO-d6): 3.09 (s, 6H, N-CH3); 3.55 and 4.55 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.30 (d, J=5.0 Hz, IH, β-lactam-H); 5.89 (dd, J=5.0 and 7.8 Hz, IH, β-lactam-H); 6.84 (s, IH, CH thiazol); 8.07 (s, 2H, Case 970-9827 82 NH); 8.65 (s, IH, CH=N); 9.81 (d, J=7.9 Hz, IH, NH); 1 1.86 (s, IH, OH); 12.53 (s, IH, OH). 85 (300 MHz, DMSO-d6): 3.58 and 4.50 (AB quartet, J=18.0 Hz, 2H, S-CH2); 4.90 (d, J=6.4 Hz, 2H, N-CHj); 5.31 (d, J=5.1 Hz, IH, β-lactam-H); 5.90 (dd, J=5.2 and 7.8 Hz, IH, β-lactam-H); 6.84 (s, IH, CH thiazol); 7.6-7.8 (m, 2H, CH aromatic); 8.1-8.3 (m, IH, CH aromatic); 8.35 (s broad, IH, NH); 8.39 (s, IH, CH=N); 8.7-8.8 (m, 2H, CH aromatic); 9.3 (broad, IH, NH); 9.78 (d, J=7.8 Hz, IH, NH); 12.42 (s, IH, OH); 12.49 (s, IH, OH). 86 (300 MHz, DMSO-dg): 3.57 and 4.52 (AB quartet, J=18.0 Hz, 2H, S-CH2); 4.85 (d, J=6.6 Hz, 2H, N-CH2); 5.30 (d, J=5.0 Hz, IH, β-lactam-H); 5.90 (dd, J=5.0 and 7.8 Hz, IH, β-lactam-H); 6.82 (s, IH, CH thiazol); 7.9-8.1 (m, IH, CH aromatic); 8.38 (s, IH, CH=N); 8.4-8.6 (m, IH, CH aromatic); 8.8-8.9 (m, IH, CH aromatic); 8.9-9.0 (m, IH, CH aromatic); 8.7-8.8 (m, 2H, CH aromatic); 9.77 (d, J=7.9 Hz, IH, NH); 12.32 (s, IH, OH); 12.45 (s, IH, OH). 87 (300 MHz, DMSO-d6): 3.57 and 4.52 (AB quartet, J=18.1 Hz, 2H, S-CH2); 4.98 (d, J=6.2 Hz, 2H, N-CH2); 5.30 (d, J=5.0 Hz, IH, β-lactam-H); 5.90 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.81 (s, IH, CH thiazol); 7.9-8.0 (m, 2H, CH aromatic); 8.40 (s, IH, CH=N); 8.8-9.0 (m, IH, CH aromatic); 9.00 (s broad IH, NH); 9.76 (d, J=7.9 Hz, IH, NH); 12.30 (s, IH, OH); 12.56 (s, IH, OH). 88 (300 MHz, DMSO-de): 3.68 and 4.05 (AB quartet, J=17.9 Hz, 2H, S-CH2); 4.19 and 4.38 (AB quartet, J=16.4 Hz, 2H, N-CH2-C=0); 5.30 (d, J=5.0 Hz, IH, β-lactam-H); 5.87 (dd, J=5.0 and 7.7 Hz, IH, β-lactam-H); 6.87 (s, IH, CH thiazol); 7.86 (s, IH, CH=N); 9.82 (d, J=7.7 Hz, IH, NH); 1 1.35 (s, IH, OH); 12.45 (s, IH, OH). 83 (300 MHz, DMSO-d6): 3.58 and 4.64 (AB quartet, J=18.1 Hz, 2H, S-CHj); 5.29 (d, J=4.9 Hz, IH, β-lactam-H); 5.89 (dd, J=4.9 and 7.9 Hz, IH, β-lactam-H); 6.84 (s, IH, CH thiazol); 7.1-7.6 (m, CH aromatic); 8.33 (s, IH, CH=N); 9.78 (d, J=7.9 Hz, IH, NH); 10.03 (s, IH, NH); I I .86 (s, IH, OH); 12.35 (s, IH, OH). (300 MHz, DMSO-d6): 3.66 and 4.70 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.34 (d, J=5.0 Hz, IH, β-lactam-H); 5.92 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.84 (s, IH, CH thiazol); 7.0-7.2 (m, IH, CH aromatic); 7.2-7.3 (m, IH, CH aromatic); 8.0-8.2 (m, 2H, CH aromatic); 8.49 (s, IH, CH=N); 9.79 (d, J=8.0 Hz, IH, NH); 12.32 (s, IH, OH); 13.41 (s, I H, OH). (300 MHz, DMSO-d6): 3.65 and 4.03 (AB quartet, J=17.8 Hz, 2H, S-CH2); 5.27 (d, J=4.9 Hz, IH, β-lactam-H); 5.83 (dd, J=4.9 and 7.7 Hz, IH, β-lactam-H); 6.88 (s, IH, CH thiazol); 8.52 (s, IH, CH=N); 9.77 (d, J=7.7 Hz, IH, NH); 11.08 (s, IH, OH); 12.35 (s, IH, OH). (300 MHz, DMSO-d6): 1.51 (s, 3H, C-CH3); 1.54 (s, 3H, C-CH3); 2.86 (d, J=4.9 Hz, 3H, N-CH3); 3.55 and 4.50 (AB quartet, J=18.2 Hz, 2H, S-CH2); 5.32 (d, J=5.1 Hz, IH, β-lactam-H); 5.96 (dd, J=5.0 and 8.2 Hz, IH, β-lactam-H); 6.95 (s, IH, CH thiazol); 8.03 (s broad 2H, NH); 8.18 (s broad IH, NH); 8.32 (s, IH, CH=N); 9.74 (d, J=7.9 Hz, IH, NH); 12.19 (s, IH, OH). (300 MHz, DMSO-ds): 2.9 (broad, 3H, N-CH3); 3.54 and 4.50 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.30 (d, J=5.1 Hz, IH, β-lactam-H); 5.89 (dd, J=5.0 and 7.8 Hz, IH, β-lactam-H); 6.83 (s, IH, CH thiazol); 8.62 (s, IH, CH=N); 9.79 (d, J=7.9 Hz, IH, NH); 1 1 :98 (s,- IH, OH); 12.42 (s, IH, OH). (300 MHz, DMSO-d6): 3.39 (m broad 2H, CH2); 3.54 (m broad 2H, CH2); Case 970-9827 84 2.89 (d, J=4.6 Hz, 3H, N-CH3); 3.55 and 4.49 (AB quartet, J=18.0 Hz, 2H, S-CHj); 5.30 (d, J=5.0 Hz, IH, β-lactam-H); 5.90 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.79 (s, IH, CH thiazol); 8.61 (s, IH, CH=N); 9.71 (d, J=7.9 Hz, IH, NH); 1 1.73 (s, IH, OH); 12.10 (s, IH, OH). 95 (300 MHz, DMSO-d6): -2.26 (s,.-3H, .CH3); 3.57 and 4.70 ^AB , quartet, J=18.0 Hz, 2H, S-CH2); 5.33 (d, J=5.0 Hz, IH, β-lactam-H); 5.93 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.83 (s, IH, CH thiazol); 8.77 (s, IH, CH=N); 9.80 (d, J=7.9 Hz, IH, NH); 12.40 (s, IH, OH). 96 (300 MHz, DMSO-d6): 3.22 (m broad 4H, N-CH2); 3.55 and 4.52 (AB quartet, J=18.1 Hz, 2H, S-CH2); 3.85 (m broad 4H, N-CH2); 5.30 (d, J=5.0 Hz, IH, β-lactam-H); 5.90 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.82 (s, IH, CH thiazol); 8.5 (broad, 2H, NH); 8.65 (s, IH, CH=N); 9.76 (d, J=7.9 Hz, IH, NH); 9.82 (s, 2H, NH); 12.31 (s, IH, OH); 12.47 (s, IH, OH). 97 (300 MHz, DMSO-d6): 3.14 (s, 6H, N-CH3); 3.64 and 3.94 (AB quartet, J=17.9 Hz, 2H, S-CH2); 3.68 (s 4H, N-CH2); 5.28 (d, J=5.0 Hz, IH, β-lactam-H); 5.89 (dd, J=5.0 and 7.7 Hz, IH, β-lactam-H); 6.81 (s, IH, CH thiazol); 8.64 (s, IH, CH=N); 9.77 (d, J=7.7 Hz, IH, NH); 12.29 (s, IH, OH); 12.36 (s, IH, OH). 98 (300 MHz, DMSO-d6): 3.33 (s, 3H, N-CH3); 3.54 and 4.55 (AB quartet, J=18.3 Hz, 2H, S-CH2); 5.29 (d, J=5.0 Hz, IH, β-lactam-H); 5.91 (dd, J=5.1 and 7.9 Hz, IH, β-lactam-H); 6.76 (s, IH, CH thiazol); 8.10 (s, IH, CH=N); 8.2 (s, NH); 9.67 (d, J=7.8 Hz, IH, NH); 1 1.92 (s, IH, OH). 99 (300 MHz, DMSO-d6): 2.80 (s, 3H, CH3); 3.57 and 4.48 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.34 (d, J=5.1 Hz, IH, β-lactam-H); 5.94 (dd, J=5.1 and 7.9 Hz, IH, β-lactam-H); 6.82 (s, IH, CH thiazol); 8.55 (s, IH, CH=N); 9.28 (s, IH, NH); 9.80 (d, J=7.9 Hz, IH, NH); 9.90 (s, IH, NH); Case 970-9827 85 12.39 (s, IH, OH); 13.52 (s, IH, OH). 100 (300 MHz, DMSO-de): 3.58 and 4.46 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.34 (d, J=5.1 Hz, IH, β-lactam-H); 5.94 (dd, J=5.1 and 7.9 Hz, .

IH, β-lactam-H); 6.82 (s, IH, CH thiazol); 8.28 (dd, J=6.7 and 14.8 Hz, 1Η,·· N-CH=N); 8.58 (s,, lH, CH=N);,9.-58 (d, J=14.8 Hz ΙΗ,,ΝΗ); 9.77 (d, J=8.0 Hz, IH, NH); 9.9 (d, J=6.7 Hz IH, NH); 12.29 (s, IH, OH). 101 (300 MHz, DMSO-d6): 3.57 and 4.48 (AB quartet, J=18.0 Hz, 2H, S-CH2); 3.9 (s, 3H, 0-CH3); 5.33 (d, J=5.1 Hz, IH, β-lactam-H); 5.92 (dd, J=5.1 and 8.0 Hz, IH, β-lactam-H); 6.87 (s, IH, CH thiazol); 8.27 (dd, J=6. 9 and 14.6 Hz, IH, N-CH=N); 8.60 (s, IH, CH=N); 9.55 (d, J=14.4 Hz lHy NH); 9.79 (d, J=8.0 Hz, IH, NH); 9.91 (d, J=6.5 Hz IH, NH). 102 (300 MHz, DMSO-d6): 1.49 (s, 3H, C-CH3); 1.50 (s, 3H, C-CH3); 3.54 and 4.48 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.31 (d, J=4.9 Hz, IH, β-lactam-H); 5.97 (dd, J=4.9 and 8 Hz, IH, β-lactam-H); 6.84 (s, IH, CH thiazol); 8.29 (s, IH, CH=N); 9.^5 (d, J=8 Hz, IH, NH); 12.06 (s, IH, OH). 103 (300 MHz, DMSO-d6): 1.51 (s, 3H, C-CH3); 1.53 (s, 3H, C-CH3); 3.52 and 4.52 (AB quartet, J=18.3 Hz, 2H, S-CHJ; 5.30 (d, J=5.0 Hz, IH, β-lactam-H); 5.95 (dd, J=5.0 and 8.1 Hz, IH, β-lactam-H); 6.94 (s, IH, CH thiazol); 7.61 (s broad 2H, NH); 8.15 (s broad 2H, NH); 8.38 (s, IH, CH=N); 9.74 (d, J=8.1 Hz, IH, NH); 11.20 (s, IH, OH); 12.16 (s, IH, OH). 104 (300 MHz, DMSO-d6): 1.49 (s, 3H, C-CH3); 1.51 "(s, 3H, C-CH3); 3.56 and 4.52 (AB quartet, J=18.3 Hz, 2H, S-CH2); 4.90 (d, J=6.3 Hz, 2H, CH2); 5.32 (d, J=5.0 Hz, IH, β-lactam-H); 5.97 (dd, J=5.0 and 8.1 Hz, IH, β-lactam-H); 6.91 (s, IH, CH thiazol); 7.6-7.8 (m 2H, CH aromatic); Case 970-9827 86 8.2-8.3 (m 1H, CH aromatic); 8.38 (s, 1H, CH=N); 8.6-8.8 (m 1H, CH aromatic); 9.71 (d, J=8.2 Hz, 1H, NH); 12.48 (s, 1H, OH). 105 (300 MHz, DMSO-d6): 0.64 (m broad 2H, CH^; 0.84 (m broad 2H, CH2J 1.50 (s, 3H, C-CHj); 1.52 (s, 3H, C-CH3); 2.61 (m broad 1H, N-CH); 3÷53 and 4.53 (AB quartet, J=18.2 Hz,,2H, :S CH2); 5.31 .(d, J=?5.0 ;Hz, . 1H, β-lactam-H); 5.96 (dd, J=5.0 and 8.2 Hz, 1H, β-lactam-H); 6.90 (s, 1H, CH thiazol); 8.10 (s broad 2H, NH); 8.34 (s, 1H, CH=N); 8.60 (s broad 1H, NH); 9.70 (d, J=8.2 Hz, 1H, NH); 12.08 (s, 1H, OH). 106 (300 MHz, DMSO-d6): 1.50 (s, 3H, C-CH3); 1.52 (s, 3H, C-CH3); 2.87 (broad 6H, N-CH3); 3.54 and 4.51 (AB quartet, J=18.1 Hz, 2H, S-CH2); .33 (d, J=5.0 Hz, 1H, β-lactam-H); 5.96 (dd, J=5.0 and 8.1 Hz, 1H, β-lactam-H); 6.91 (s, 1H, CH thiazol); 8.06 (s broad 1H, NH); 8.30 (s broad IH, NH); 8.62 (s, 1H, CH=N); 9.71 (d, J=8.4 Hz, 1H, NH); 1 1.76 (s, IH, OH). 107 (300 MHz, DMSO-de): 1.51 (s, 3H, C-CH3); 1.53 (s, 3H, C-CH3); 1.8-2.0 (m, 4H, C-CH2); 1.8-2.0 (m, 4H, N-CH2); 3.54 and 4.55 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.31 (d, J=5.0 Hz, IH, β-lactam-H); 5.95 (dd, J=5.0 and 8.3 Hz, IH, β-lactam-H); 6.90 (s, IH, CH thiazol); 7.70 (s broad NH); 7.93 (s broad NH); 8.63 (s, IH, CH=N); 9.62 (d, J=8.2 Hz, IH, NH); 9.75 (s, IH, NH); 1 1.71 (s, IH, OH). 108 (300 MHz, CD3OD): 8.59 (s, IH, CH=N); 6.94 (s, IH, CH); 5.95 (d, J=5.0 Hz, IH, CH); 5.29 (d, J=5.0 Hz, 1 H, CH); 4.02 (s, 3H, OCH3); 4.34 and 3.61 (AB quartet, J=18.0 Hz, 2H, SCH2); 2.73 (s, 3H, SCH3). 109 (300 MHz, DMSO-d6): 0.64 (m broad 2H, CH2 cyclopr); 0.84 (m broad 2H, CH2 cyclopr); 2.62 (m broad IH, N-CH cyclopr); 3.54 and 4.51 (AB quartet, J=18.1 Hz, 2H, S-CH2); 4.66 (s, 2H, 0-CH2); 5.30 (d, J=5.0 Hz, I H, β-lactam-H); 5.93 (dd, J=5.0 and 8.1 Hz, IH, β-lactam-H); 6.93 (s, Case 970-9827 87 IH, CH thiazol); 8.09 (broad 2H, NH); 8.35 (s, IH, CH=N); 8.58 (broad, IH, NH); 9.77 (d, J=8.0 Hz, IH, NH); 12.04 (s, IH, OH). (300 MHz, DMSO-d6): 2.87 (s, 6H, N-CH3); 3.56 and 4.50 (AB quartet, - J=18.0 Hz, 2H, S-CH2); 4.67 (s, 2H, 0-CH2); 5.32 (d, J=5.0 Hz, IH, 4actam-H); 5.92 (dd, J=5.0 and 8.1- Hz, ;lH,^=lactam-H); 6.94 (s, .IH, CH thiazol); 8.1 (broad IH, NH); 8.35 (broad IH, NH); 8.63 (s, IH, CH=N); 9.80 (d, J=8.1 Hz, IH, NH); 1 1.77 (s, IH, OH). (300 MHz, DMSO-d6): 1.93 (broad, 4H, C-CH2); 3.47 (broad, 4H, N-CH2); 3.55 and 4.54 (AB quartet, J=17.9 Hz, 2H, S-CH2); 4.67 (s, 2H, 0-CH2); 5.30 (d, J=5.0 Hz, IH, β-lactam-H); 5.92 (dd, J=5.0 and 7.9 Hz, IH, β-Iactam-H); 6.94 (s, IH, CH thiazol); 7.96 (broad 2H, NH); 8.62 (s, IH, CH=N); 9.79 (d, J=7.8 Hz, IH, NH); 1 1.72 (s, IH, OH). (300 MHz, DMSO-de): 3.62 and 4.67 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.37 (d, J=5.1 Hz, IH, β-lactam-H); 5.96 (dd, J=5.1 and 7.9 Hz, IH, β-lactam-H); 6.83 (s, IH, CH thiazol); 7.7-7.9 (m, IH, CH aromatic); 8.1-8.3 (m, IH, CH aromatic); 8.4-8.6 (m, IH, CH aromatic); 8.8-8.9 (m, IH, CH aromatic); 8.97 (s, IH, CH=N); 9.79 (d, J=7.9 Hz, IH, NH); 9.85 (s, IH, NH); 10.37 (s, IH, NH); 12.31 (s, IH, OH). (300 MHz, DMSO-d6): 1.1-1.3 (m, 2H, CH2 cyclopr); 1.2-1.4 (m, 2H, CH2 cyclopr); 1.9-2.0 (m, IH, CH2 cyclopr); 3.54 and 4.49 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.32 (d, J=5.1 Hz, IH, β-lactam-H); 5.93 (dd, J=5.1 and 8.0 Hz, IH, β-lactam-H); 6.76 (s, IH, CH thiazol); 8.59 (s, IH, CH=N); 9.07 (s, IH, NH); 9.23 (s, IH, NH); 9.67 (d, J=8.0 Hz, IH, NH); 1 1.92 (s, IH, OH); 13.27 (s, IH, OH). 1 14 (300 MHz, DMSO-d^: 1.59 (broad, 6H, C-CH2); 3.53 (broad 4H, N-CH2); 3.6 and 4.52 (AB quartet, J=18.4 Hz, 2H, S-CH2); 5.29 (d, J=5.0 Hz, IH, β-lactam-H); 5.89 (dd, J=5.0 and 7.6 Hz, IH, β-lactam-H); 6.82 (s, IH, Case 970-9827 88 CH thiazol); 8.16 (s 2H, NH); 8.60 (s, IH, CH=N); 9.75 (d, J=7.6 Hz, IH, NH); 11.94 (s, IH, OH); 12.30 (s, IH, OH). 115 (300 MHz, DMSO-ds): 3.5 and 4.53 (AB quartet, J=17.9 Hz, 2H, S-CH2) . 3.4-3.7 (m, 8H, N-CH2); 5.31 (d, J=5.0 Hz, IH, β-lactam-H); 5.90 (dd, J=5.0 and 7.9 Hz, IH, β-.lactam-H);.6.82. (s, lH,.CH thiazol); 8.08 (s. IH, CH=0); 8.38 (broad 2H, NH); 8.62 (s, IH, CH=N); 9.75 (d, J=7.9 Hz, IH, NH); 12.18 (s, IH, OH); 12.28 (s, IH, OH). (300 MHz, DMSO-d^O): 2.81 (s, 6H, N-CH3); 2.92 (s, 3H, C=N-CH3); 3.54 and 4.58 (AB quartet, J=18.1 Hz, 2H, S-CH2); 3.6 (broad, 2H, N-CH2); 3.97 (broad, 2H, N-CH2); 5.30 (d, J=4.8 Hz, IH, β-lactam-H); .90 (d, J=4.8 Hz, IH, β-lactam-H); 6.81 (s, IH, CH thiazol); 8.55 (s, IH, CH=N). (300 MHz, DMSO-d( D20): 2.91 (s, 3H, C=N-CH3); 3.19 (s, 9H, N-CH3); 3.29 (broad, 2H, N-CH2); 3.56 and 4.48 (AB quartet, J=18.1 Hz, 2H, S-CH2); 3.82 (broad, 2H, N-CH2); 5.31 (d, J=5.0 Hz, IH, β-lactam-H); .90 (d, J=5.0 Hz, IH, β-lactam-H); 6.84 (s, IH, CH thiazol); 8.56 (s, IH, CH=N). 118 (300 MHz, DMSO-d6): 3.61 and 4.59 (AB quartet, J=18.0 Hz, 2H, S-CH2); 5.35 (d, J=5.1 Hz, IH, β-lactam-H); 5.59 (dd, J=5.1 and 7.9 Hz, IH, β-lactam-H); 6.82 (s, IH, CH thiazol); 6.9-7.1 (m, IH, CH aromatic); 7.2-7.4 (m, 2H, CH aromatic); 8.74 (s, IH, CH=N); 9.31 (s IH, NH/OH); 9.76 (s IH, NH/OH); 9.78 (d, J=7.9 Hz, IH, NH); 12.25 (s, IH, OH); 13.03 (s, IH, OH). 1 19 (300 MHz, DMSO-d6): 2.30 (s, 3H, C-CH3); 3.59 and 4.57 (AB quartet, J=18.1 Hz, 2H, S-CH2); 3.67 (s, 3H, N-CH3); 5.34 (d, J=5.1 Hz, IH, β-lactam-H); 5.94 (dd, J=5.1 and 8.0 Hz, IH, β-lactam-H); 6.13 (d, Case 970-9827 89 J=3.9 Hz IH, CH Pyrrol); 6.77 (s, IH, CH thiazol); 6.86 (d, J=3.9 Hz IH, CH Pyrrol); 8.66 (s, IH, CH=N); 9.25 (s IH, NH); 9.46 (s IH, NH); 9.70 (d, J=8.0 Hz, IH, NH); 1 1.96 (s, IH, OH); 12.90 (s, IH, OH). 120 (300 MHz, DMSO-d6): 3.71 and 4.12 (AB quartet, J=17.9 Hz, 2H, S-CH2); 5.32 (d, J=5.1 Hz^ lH, β-Jactam-H); .91..(dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.84 (s, IH, CH thiazol); 7.9-8.0 (m, 2H, CH aromatic); 8.66 (s, IH, CH=N); 8.8-8.9 (m, 2H, CH aromatic); 8.8 (broad IH, NH); 9.76 (d, J=8.0 Hz, IH, NH); 12.17 (s, IH, OH); 12.37 (s, IH, OH). 121 (300 MHz, DMSO-de): 3.22 (s, 6H, N-CH3); 3.54 and 4.55 (AB quartet, J=18.5 Hz, 2H, S-CH2); 3.6 (broad, 4H, N-CH2); 4.0 (broad, 4H, N-CH2); .30 (d, J=5.0 Hz, IH, β-lactam-H); 5.91 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.82 (s, IH, CH thiazol); 8.73 (s, IH, CH=N); 9.75 (d, J=7.6 Hz, IH, NH); 12.30 (s, IH, OH); 12.76 (s, IH, OH). 122 (300 MHz, DMSO-de): 2.76 (s, 3H, N-CH3); 3.1-3.3 (broad, 2H, N-CH2); 3.4-3.6 (broad, 2H, N-CH2); 3.5-3.7 (broad, 2H, N-CH2); 3.55 and 4.53 (AB quartet, J=18.1 Hz, 2H, S-CH2); 4.2-4.4 (broad, 2H, N-CH2); 5.31 (d, J=5.0 Hz, IH, β-Iactam-H); 5.90 (dd, J=5.0 and 7.8 Hz, IH, β-lactam-H); 6.82 (s, IH, CH thiazol); 8.66 (s, IH, CH=N); 9.77 (d, J=7.8 Hz, IH, NH); 11.74 (s, IH, NH); 12.36 (s, IH, OH); 12.56 (s, IH, OH). 123 (300 MHz, DMSO-d6): 2.90 (d, J=4.7 Hz 3H, N-CH3); 3.34 (s, 3H, N-CH3); 3.55 and 4.59 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.30 (d, J=5.0 Hz, IH, β-lactam-H); 5.91 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.81 (s, IH, CH thiazol); 8.09 (s, IH, CH=N); 8.25 (s, 2H, NH); 8.37 (s, IH, NH); 9.72 (d, J=7.9 Hz, IH, NH); 12.14 (s, IH, OH). 124 (300 MHz, DMSO-d6): 2.81 (d, J=4.3 Hz 6H, N-CH3); 3.2-3.4 (m broad 2H, N-CH2); 3.56 and 4.55 (AB quartet, J=18.0 Hz, 2H, S-CH2); 3.7-3.9 (m broad 2H, N-CH2); 5.30 (d, J=4.9 Hz, IH, β-lactam-H); 5.9 (dd, J=4.9 90 and 7.9 Hz, IH, β-lactam-H); 6.82 (s, IH, CH thiazol); 8.3 (broad, NH); 8.38 (s, IH, CH=N); 8.47 (broad, NH); 9.76 (d, J=7.9 Hz, IH, NH); .84 (s, IH, NH); 12.31 (s, 2H, OH). (300 MHz, DMSO-d6): 2.82 (d, J=4.5 Hz 6H, N-CH3); 3.2-3.3 (m broad 2H, N-CH2); 3.40 (s, 3H, N-CH3); 3.56 and 4J3 (AB quartet, J=18.3 Hz, 2H, S-CH2); 3.8-3.9 (m broad 2H, N-CH^; 5.29 (d, J=5.0 Hz, IH, β-lactam-H); 5.91 (dd, J=5.0 and 7.8 Hz, IH, β-lactam-H); 6.82 (s, IH, CH thiazol); 8.1 1 (s, IH, CH=N); 8.68 (s, 2H, NH); 8.74 (m broad IH, NH); 9.77 (d, J=7.9 Hz, IH, NH); 10.91 (s, IH, OH); 12.32 (s, IH, OH). (300 MHz, DMSO-d6): 3.60 and 4.56 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.32 (d, J=5.0 Hz, IH, β-lactam-H); 5.92 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.83 (s, IH, CH thiazol); 6.8-6.9 (m, IH, CH aromatic); 7.1-7.2 (m, IH, CH aromatic); 7.3-7.4 (m, IH, CH aromatic); 8.23 (s, IH, CH=N); 8.37 ( 2H, NH/OH); 8.51 (s, IH, CH=N); 9.78 (d, J=7.9 Hz, IH, NH); 12.27 (s, IH, OH). (300 MHz, DMSO-de): 3.53 and 4.49 (AB quartet, J=18.1 Hz, 2H, S-CH2); 5.29 (d, J=5.0 Hz, IH, β-lactam-H); 5.89 (dd, J=5.0 and 7.9 Hz, IH, β-lactam-H); 6.79 (s, IH, CH thiazol); 7.93 (broad, 2H, NH); 8.37 (broad, IH, CH=N); 9.73 (d, J=7.8 Hz, IH, NH); 12.15 (s, IH, OH). (300 MHz, DMSO-d6): 3.25 (broad, 4H, N-CH-); 3.31 (s, 3H, N-CH2); 3.62 and 4.27 (AB quartet, J=18.0 Hz, 2H, S-CH2); 3.74 (broad, 4H, N-CH2); 5.30 (d, J=5.0 Hz, IH, β-lactam-H); 5.89 (dd, J=4.9 and 7.9 Hz, IH, β-lactam-H); 6.79 (s, IH, CH thiazol); 8.1 1 (s, IH, CH=N); 9.03 (broad, IH, NH); 9.31 (broad, IH, NH); 9.67 (d, J=7.9 Hz, IH, NH); 9.87 (s, 2H, NH); 12.07 (s, IH, OH). (300 MHz, DMSO-d6): 0,70 (m; 4H, -CH2-CH2-); 3,05 (m, IH); 3,51 and 4,49 (AB quartet, J=18 Hz, 2H, SCH2); 4,38 (s, 3H, 0-CH3); 5,24 (d, Case 970-9827 91 J=4,9 Ηζ,Ι Η, β-lactam-H); 5,84 (dd, J=7,9 Hz and 4,9 Hz, IH, β-lactam- H); 6,86 (s, IH, thiazolyl-H); 8,19 (d, J=3,9 Hz, IH); 8,21(s, IH, CH=N); 9,72 (d, J=8,0 Hz, IH, NH);11 ,58 (s, IH). 130 (300 MHz, CD3CN + D20): 1,26 (t, J=7 Hz, 3H); 1,68 (sextet, J=7 Hz, 2H); 1,93 (quintet, J=7 Hz,;2H); 3,93 (t, J=7,l Hz, 2H); 3,95 (s, 3H, O- CH3); 3,98 and 4,57 (AB quartet, J=18 Hz, 2H, SCH2); 5,59 (d, J=4,9 Hz, IH, β-lactam-H); 6,18 (d, J=4,9 Hz, IH, B-lactam-H); 7,40 (s, IH, thiazolyl-H); 8,63 (s, IH, CH=N). (300 MHz, D20): 0,74 (m, 2H); 0,88 (m, 2H); 2,58 and 2,38 (two singu- lets, 3H, SCH3); 2,68 (m, IH); 3,45 and 3,94 (AB-system, broad, 2H, SCH2); 3,95 (s, 3H, 0-CH3); 5,23 (d, J=4,7 Hz, IH, β-lactam-H); 5,75 (d, J=4,7 Hz, IH, B-lactam-H); 7,03 (s, IH, thiazolyl-H); 8,36 (s, broad, IH, CH=N). (300 MHz, D20): 0,82 (t, J=7,3 Hz, 3H); 1,29 (sextet, J=7 Hz, 2H); 1,56 (quintet, J=7 Hz, 2H); 2,61 and 2,46 (two singulets, 3H, SCH3); 3,46 (t, J=7,l Hz, 2H); 3,55 and 4,01 (AB quartet, J=18 Hz, 2H, SCH2); 3,98 (s, 3H, 0-CH3); 5,25 (d, J=4,9 Hz, IH, β-lactam-H); 5,78 (d, J=4,9 Hz, IH, β-lactam-H); 7,05 (s, IH, thiazolyl-H); 8,39 (s, IH, CH=N). (300 MHz, DMSO-d6): 2,68 (m, 2H); 3,73 (m, 2H); 3,57 and 4,23 (AB quartet, J=18 Hz, 2H, SCH2); 3,96 (s, 3H, 0-CH3); 5,29 (d, J=4,9 Hz, IH, β-lactam-H); 8,48 (dd, J=8 Hz and J=4,9 Hz, IH, B-lactam-H); 6,91 (s, IH, thiazolyl-H); 8,24 (s, IH, CH=N); 9,20 (s, IH); 9,90 (d, J=8,0 Hz, IH NH). (300 MHz, DMSO-d6+ D20): 0,68 (m, 2H); 0,84 (m, 2H); 2,91 (m, IH); 3,62 and 4,22 (AB quartet, J=18 Hz, 2H, SCH2); 5,28 (d, J=4,9 Hz, IH, β-lactam-H); 5,85 (d, J=4,8 Hz, IH, β-lactam-H); 7,06 (s, IH, thiazolyl- H); 8,23 (s, IH, CH=N).

Case 970-9827 92 135 (300 MHz, DMSO-d6): 0,89 (t, J=7 Hz, 3H); 1 ,29 (sextet, J=7 Hz, 2H); I, 54 (quintet, J=7 Hz, 2H); 3,51 and 4,47 (AB quartet, J=18 Hz, 2H, SCH2); 3,52 (m, 2H); 5,24 (d, J=4,8 Hz, IH, B-lactam-H); 5,85 (dd, J=7,9 Hz and 4,8 Hz, IH, β-lactam-H); 6,69 (s, IH, thiazolyl-H); 8,21 (s/ - IH, CH=N); 8,47 (m, IH); 9,55 (d, J=7,9 Hz, IH, NH); 1 1 ,44 (s, IH); I I , 54 (s, IH). 136 (300 MHz, DMSO-d6): 2,77 (s,3H, NCH3); 3,0-3,2 (m, 4H); 3,35-3,6 (m, 4H); 3,63 and 4,03 (AB quartet, J=18 Hz, 2H, SCH2); 3,95 (s, 3H, OCH3); 5,26 (d, J=4,9 Hz, IH, β-lactam-H); 5,84 (dd, J=7,9 Hz and J=4,9 Hz, IH, β-lactam-H); 6,85 (s, IH, thiazolyl-H); 8,40 (s, IH, CH=N); 9,69 (d, J=8,0 Hz, IH, NH); 1.1,67 (s, IH). (300 MHz, DMSO-d6): 3.59 and 4.54 (AB quartet, J = 18.2 Hz, 2H, SCH2); 3.66 (d, J = 4 Hz, 3 H, NHCH3); 3.95 (s, 3 H, 0-CH3); 5.26 (d, J = 5 Hz, 1 H, B-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, β-lactam-H); 6.95 (s, 1 H, thiazolyl-H); 7.96 (s, 1 H, CH=N); 8.4 (d, J = 4 Hz, NHCH3); 9.84 (d, J = 8 Hz, NH). (300 MHz, DMSO-d6): 1,43 (s, 9H, -OC(CH3)3); 3.62 and 4.02 (AB quartet, J = 17.8 Hz, 2H, SCH2); 5.25 (d, J = 4.9 Hz, IH, β-lactam-H); .83 (dd, J = 4.9 and 8,0 Hz, IH, β-lactam-H); 6,93 (s, IH, thiazolyl-H); 8,20 (s, IH, CH=N); 9,69 (d, J = 8,0 Hz, IH, NH). (300 MHz, DMSO-d6): 3.21 (broad singulet, 4 H); 3.89 (broad singulet, 4 H); 3.50 and 4.53 (AB quartet, J = 18.1 Hz, 2H, SCH2); 5.27 (d, J = 5 Hz, 1 H, B-lactam-H); 5.77 (d, J = 58 Hz, 2H, -CH2F); 5.90 (dd, J = 5 Hz and 8.2 Hz, B-lactam-H); 8.66 (s, 1 H, CH=N); 9.85 (d, J = 8.2 Hz, NH). 140 (300 MHZ, DMSO-d6): 1.02 (t, J=7.4 Hz, 3H, C-CH3); 2.32 (qd, J=7.4 and 7.5 Hz, 2H, C=C-CH2-C); 3.52 and 4.15 (AB, J=17.7 Hz, 2H, S- CH2); 5.17 (d, J=5.2 Hz, IH, β-lactam-H); 5.73 (dd, J=5.2 and 8.8 Hz, Case 970-9827 93 1H, β-lactam-H); 6.48 (s, 1H, CH thiazol); 6.61 (t, J=7.5 Hz, 1H, C=CH-C); 8.93 (s, 1H, CH=N); 9.14 (d, J=8.8 Hz, 1H, NH). 141 (90 MHz, DMSO-d6): 2.3 (s, 3 H, CH3); 1.8 to 2.1 (m, 1 H); 3.95 (s, 2H, - SCH2); 3.9 (s, 3 H, 0-CH3); 5.35 (d, J = 5 Hz, 1 H, β-lactam-H); 5.9 (dd, J = 5 Hz and 8 Hz B-lactam-H); 6.95 (s, 1 fl, thiazolyl-H); 8.65 (s, 1-H, CH=N); 9.9 (d, J = 8 Hz, NH). 142 (90 MHz, DMSO-d6): 2.3 (s, 3 H, thiazolyl-CH3); 4.0 (s, 3 H, 0-CH3); 3.75 and 4.3 (AB quartet, J = 18 Hz, 2H, SCH2); 5.4 (d, J = 5 Hz, 1 H, β-lactam-H); 5.95 (dd, J = 5 Hz and 8 Hz, B-lactam-H); 6.7 (s, 1 H, thiazolyl-H); 7.05 (s, 1 H, thiazolyl-H); 8.55 (s, 1 H, CH=N); 9.95 (d, J = 8 Hz, NH). 143 (90 MHz, DMSO-de): 2.25 (s, 3 H, thiazolyl-CH3); 3.60 (s, 3 H, N-CH3); 3.7 and 4.15 (AB quartet, J = 18 Hz, 2H, SCH2); 3.95 (s, 3 H, 0-CH3); .35 (d, J = 5 Hz, 1 H, β-lactam-H); 5.85 (dd, J = 5 Hz and 8 Hz, 8- lactarn-H); 6.7 (s, 1 H, thiazolyl-H); 7.02 (s, 1 H, thiazolyl-H); 8.15 (s, 1 H, CH=N); 9.95 (d, J = 8 Hz, NH). 144 (300 MHz, DMSO-d6): 2.83 (d, 3H, NCH3); 3.55 and 4.23 (AB quartet, J = 19.8 Hz, 2H, SCH2); 3.84 (s, 3H, =N-OCH3); 5.21 (d, J = 5.5 Hz, 1H, B-lactam-H); 5.70 (dd, J = 5.5 Hz and 9 Hz, β-lactam-H); 6.77 (s, 1H, thiazolyl-H); 9.28 (s, 1 H, CH=N); 9.63 (d, J = 9 Hz, 1H, NH). 145 (300 MHz, DMSO-d6): Diastereomer A: 1.25 (d, J = 6 Hz, 3H); 1.24 (d, J = 6 Hz, 3H); 1.53 (d, J = 5.4 Hz, 3H, -0(CH3)CH-0-); 2.9 (d, J = 4,9 Hz, 3H, NCH3); 3.62 and 4.61 (AB quartet, J = 18.3 Hz, 2H, SCH2); 3.94 (s, 3H, =N-OCH3); 4.75 to 4.84 (m, 1 H, -0-CH(CH3)2); 5.34 (d, J = 5 Hz, 1H, B-lactam-H); .94 (dd, J = 5 Hz and 7.8 Hz, β-lactam-H); 6.9 (q, J = 5.3 Hz, 1 H, - 0(CH3)CH-0-); 6.92 (s, 1 H, thiazolyl-H); 8.3 (s, 1 H, CH=N); 9.96 (d, J Case 970-9827 94 = 7.8 Hz, 1H, NH).

Diastereomer B: 1.24 (d, J = 6 Hz, 3H); 1.22 (d, J = 6 Hz, 3H); 1.51 (d, J = 5.5 Hz, 3H, -0(CH3)CH-0-); 2.9 (d, J = 4,9 Hz, 3H, NCH3); 3.60 and 4.65 (AB quartet, J = 18.3 Hz, 2H, SCH^); 3.93 (s, 3H, =N-OCH3); 4.75 - to 4.84 (m, 1 H, -0-CH(CH3)2); 5.30 (d, J = 5 Hz, 1H, β-lactam-H); 6.04 (dd, J = 5 Hz and 7.6 Hz, β-lactam-H); 6.8 (q, J = 5.3, 1 H,-0(CH3)CH- O-); 6.92 (s, 1 H, thiazolyl-H); 8.14 (s, 1 H, CH=N); 9.95 (d, J = 7.6 Hz, 1H, NH). 146 (300 MHz, DMSO-d6): Diastereomer A: 1.25 (d, J = 6 Hz, 6H); 1.50 (d, J = 5.4 Hz, 3H, - 0(CH3)CH-0-); 2.18 (s, 3H, CH3CO); 3.76 and 4.48 (AB quartet, J = 17.9 Hz, 2H, SCH2); 4.7 to 4.9 (m, 1 H, -0-CH(CH3)2); 5.31(d, J = 4.8 Hz, 1H, B-lactam-H); 5.88 (dd, J = 4.8 Hz and 7.6 Hz, β-lactam-H); 6.87 (q, J = 5.3 Hz, 1 H, -0(CH3)CH-0-); 7.1 (s, 1 H, thiazolyl-H); 8.28 (s, 1 H, CH=N); 9.93 (d, J = 7.6 Hz, 1H, NH).

Diastereomer B: 1.23 (d, J = 6 Hz, 6H); 1.49 (d, J = 5.4 Hz, 3H, - 0(CH3)CH-0-); 2.17 (s, 3H, CH3CO); 3.70 and 4.38 (AB quartet, J = 18 Hz, 2H, SCH2); 4.7 to 4.9 (m, 1 H, -0-CH(CH3)2); 5.28 (d, J = 4.8 Hz, 1H, β-lactam-H); 5.83 (dd, J = 4.8 Hz and 7.6 Hz, B-lactam-H);6.80 (q, J = 5.2, 1 H,-0(CH3)CH-0-); 7.1 (s, 1 H, thiazolyl-H); 8.18 (s, 1 H, CH=0); 9.91 (d, J = 7.6 Hz, 1H, NH). 147 (300 MHz, DMSO-d6 ) Diastereomer A: 1.26 (d, J = 6.2 Hz, 6H); 1.53 (d, J = 5 Hz, 3H, - 0(CH3)CH-0-); 2.29 (s, 6H, 2 aryl-CH3); 3.60 and 4.54 (AB quartet, J = 18.5 Hz, 2H, SCH2); 4.75 to 4.84 (m, 1 H, -0-CH(CH3)2); 5.34 (d, J = 5 Hz, 1H, B-lactam-H); 5.97 (dd, J = 5 Hz and 7.7 Hz, β-lactam-H); 6.91 (q, J = 5.3 Hz, 1 H, -0(CH3)CH-0-); 6.92 (s, 1 K,' thiazolyl-H); 7.12 and 7.49 (AB quartet, J = 8 Hz, 2 x 4 aromatic-H); 8.34 (s, 1 H, CH=N); 9.69 (d, J = 7.7 Hz, 1H, NH).

Diastereomer B: 1.24 (d, J = 6.2 Hz, 6H); 1.52 (d, J = 5.5 Hz, 3H, - Case 970-9827 95 0(CH3)CH-0-); 2.29 (3. 6 H, 2 Aryl-CH3); 3.59 and 4.51 (AB quartet, J = 18.4 Hz, 2H, SCHj); 4.75 to 4.84 (m, 1 H, -0-CH(CH3)2); 5.31 (d, J = Hz, IH, β-lactam-H); 5.93 (dd, J = 5 Hz and 7.7 Hz, β-lactam-H); 6.83 (q, J = 5.3, 1 H,-0(CH3)CH-0-); 6.84 (s, 1 H, thiazolyl-H); 7.12 and 7.49 , (AB quartet, J = 8 Hz, 2 x 4 aromatic-H); 8.24 (s, 1 H, CH=N); 9.69 (d, J = 7.7 Hz, IH, NH).

A) a) (D20 + DC1): 3.62 (AB quartet, J=16Hz, 2H, S-CH2); 5.10 (2d, J=5Hz, 2H, β-lactam-H); 6.20 (s, broad, IH, 0-CH-O).

A) c) (DMSO-d6): 3.55 and 3.73 (AB quartet, J=18Hz) resp. 3.70 (s), (2H, S-CHj); 3.87 (s, 3H, N-0-CH3), 5.1 1 (d, J=5Hz, β-lactam-H); 5.87 (m, IH, β-lactam-H); 6.20 resp. 6.26 (s, IH, O-CH-0); 6.77 resp. 6.78 (s, IH, thiazolyl-H);7.27-7.35 (m, 15H, Ar-H); 9.6 (s, broad, IH, NH-thiazolyl); 9.72 resp. 9.74 (d, J=8Hz, IH, NH). ' A) d) (DMSO-de): 3.58 and 3.76 (AB quartet, J=18Hz) resp. 3.72 (s), (2H, S-CH2); 3.88 (s, 3H, N-0-CH3), 5.15 (d, J=5Hz, β-lactam-H); 5.94 (dd, J=8Hz and 5Hz, IH, β-lactam-H); 6.21 resp. 6.28 (s, IH, O-CH-O); 6.81 resp. 6.82 (s, IH, thiazolyl-H); 9.77 resp. 9.78 (d, J=8Hz, IH, NH).

B) c) (CDC13): 3.2- 3,5 (m, 2H, S-CH2); 5.05 (d, J=5Hz, β-lactam-H); 6,0 (dd, J= 5 and 8Hz, IH, B-lactam-H); 6.4 (s, IH, O-CH-O); 7-7.4 (m, 30H, Ar-H).

B) d) (DMSO-d6): 3.72 (m, 2H, S-CH2); 5.15 (d, J=5Hz, B-lactam-H); 5.95 (dd,J=8Hz and 5Hz, IH, B-lactam-H); 6.3 (broad s, IH, O-CH-O); 6.8 (s, IH, thiazolyl-H); 9.75 (d,J=8Hz, IH, NH).

C) (300 MHz, DMSO-d6): 3.55 and 3.77 (AB quartet, J=18Hz) resp. 3.71 (s), (2H, S-CH2); 5.14 (d, J=5Hz, β-lactam-H); 5.97 (m, IH, β-lactam-H); 5,79 (d, J=55 Hz, 2H, -CH2F); 6.20 resp. 6.27 (s, IH, O-CH-O); 9.81 resp. 9.84 96 Case 970-9827 AVA (d, J=8Hz, IH, NH). (300 MHz, DMSO-d6): 2.20 resp. 2.21 (s, 3H, 0=C-CH3); 3.63 and 3.80 (AB quartet, J=18 Hz) resp. 3.76 (s) (2H, S-CHJ; 5.20 (d, J=5Hz, IH, β-lactam-H); 6,00 (dd, J=8Hz and 5Hz, IH, β-lactam-H); 6,23 resp. 6,29 (s, IH, O-CH-O); 7.16 resp. 7.17 (s, IH, CH thiazol); 10,04 resp. 10,05 (d, J=8Hz, IH, NH). (300 MHz, DMSO-d6): 3.58 and 3.79 (AB quartet, J=18.2Hz) resp. 3.75 (s) (2H, S-CH2); 5.17 (d, J=5Hz, IH, β-lactam-H); 5.94 (dd, J=8Hz and 5Hz, IH, β-lactam-H); 6,21 resp. 6,28 (s, IH, 0-CH-O); 6.85 resp. 6.86 (s, IH, CH thiazol); 9.74 (d, J=8Hz, IH, NH); 12.38 (s, IH, OH). (300 MHz, DMSO-d6): 1.4 (2s, 6H, C-(CH3)2); 1.5 (s, 9H, C-(CH3)3);3.6 and 3.7 (AB quartet, J=18 Hz) resp. 3.7 (s) (2H, S-CH2); 5.2 (d, J=5Hz, IH, B-lactam-H); 5.9 (dd, J=8Hz and 5Hz, IH, B-lactam-H); 6,2 resp. 6,3 (s, IH, O-CH-O); 6.8 (s, IH, CH thiazol); 7.2-7.5 (m, 15H, CH aromatic); 9.6 (d, J=8Hz, IH, NH). (300 MHz, DMSO-d6): 1.48 resp. 1.50 (s, 6H, 3.60 and 3.77 (AB quartet, J=18 Hz) resp. 3.74 (s) (2H, S-CH2); 5.19 (d, J=5.2Hz, IH, B-lactam-H); 6,01 (dd, J=8.5Hz and 5.2Hz, IH, β-lactam-H); 6,23 resp. 6,29 (s, IH, O-CH-O); 6.87 resp. 6.88 (s, IH, CH thiazol); 9.67 (d, J=8.5Hz, IH, NH). (300 MHz, DMSO-d6): 1.00 (t, J=7.5 Hz, 3H, C-CH3); 1.47 (s, 9H,0-C(-CH3)3); 2.27 (qd, J=7.5 Hz, 2H, C=C-CH2-C); 3.57 and 3.74 (AB quartet, J=18,3 Hz) resp. 3.73 (s) (2H, SrCH2); 5,U (d, J=5.1 Hz, IH, β-lactam-H); 5.88 (dd, J=8.5 Hz and 5.1 Hz, I H, β-lactam-H); 6,22 resp. 6,26 (s, IH, O-CH-O); 6.56 (t, J=7.5 Hz, IH, C=CH-C); 7.05 (s, IH, CH thiazol); 8.80 resp. 8.81 (d, J=8.4 Hz, IH, NH). 97 Case 970-9827 WA (300 MHz, DMSO-d^: 2.7 (s, 3H, S-CH3); 3.5-3.6 (m, 4H, N-CH2); 3.7-3.8 (m, 2H, N-CH2); 3.8-3.9 (m, 2H, N-CH2); 8.1 (s, 1H, CH=0); 9.6 (broad, 2H, NH). (300 MHz, DMSO-dg): 3.42 (s, 4H, N-CH2); 3.4-3.6 (m, 4H, N-CH2); 4.8 (broad, 2H, NH); 7.9 (broad, 2H, NH); 8.1 (s, 1H, CH=0); 9.5 (broad, 1H, NH). (300 MHz, DMSO-de): 3.1-3.2 (s, 4H, N-CH2); 3.7-3.8 (m, 4H, N-CH2); 4.8 (broad, 2H, NH); 8.0 (broad, 2H, NH); 9.6 (broad, 1H, NH); 10.0 (broad, 2H, NH). (90 MHz, D20): 1,2 ppm (t, 3H); 1,9 - 2,1 ppm (m, 4H); 3,3 - 3,7 ppm (m, 6H). (90 MHz, DMSO-d6): 2,9 ppm (d, J = 5 Hz, 3H, NCH3), 3,4 - 3,8 ppm (m, 8H), 7,55 ppm (broad quartet, 1 H, NH). (90 MHz, D20): 1,3 ppm (s, 9H). (90 MHz, DMSO-d6 + D20): 2,8 ppm (s, 3H, NCH3); 3,4 - 3,65 ppm (m, 4H); 4,0 - 4,4 ppm (m, 4H). (300 MHz, DMSO-d6): 2.74 (s, 3H, C=N-CH3); 3.15 (s, 9H, N(CH3)3); 3.49 (m broad, 2H, N-CH2); 3.64 (m broad, 2H, N-CH2); 4.8 (broad, 2H, NH); 7.8 (broad, 3H, NH). (90 MHz, DMSO-d6): 2,85 ppm (s, 3H, NCH3); 3,2 - 3,65 ppm (m, 8H); 8,1 ppm (s, 1H, CH=0). 98 Case 970-9827 AVA (90 MHz, DMSO-d6 + D20): 2,85 ppm (s, 3H, NCH3); 3,2 - 3,5 ppm (m, 4H); 3,5 -3,9 ppm (m, 4H). (300 MHz, D20): 2.84 (s, 3H, N-CH3); 3.3-3.4 (m, 2H, N-CH2); 3.7-3.8 (m, 2H, N-CH2). (90 MHz, DMSO-d6): 2,65 ppm (s, 3H, S-CH3); 3,35 ppm (s, 6H, NCH3)2); 3,65 - 4,0 ppm (m, 4H); 4,0 - 4,3 ppm (m, 4H), 9,45 ppm (broad singulet, 1H, NH).

Q) b) (90 MHz, DMSO-d6): 3,3 ppm (s, 6H, NCH3)2); 3,5 - 3,8 ppm (m, 4H); 3,8 - 4,2 ppm (m, 4H).

R) a) (90 MHz, DMSO-d6): 2,55 ppm (s, 3H, SCH3); 3,45 ppm (s, 3H, NCH3).

R) b) (90 MHz, DMSO-d6): 3,15 ppm (s, 3H, NCH3); 3,2 - 3,28 ppm (m, 2H); 3,28 - 3,35 ppm (m, 2H); 3,4 - 3,55 ppm (m, 4H); 5,18 ppm (broad singulet, 2H); 8,05 (s, 1H, -CH=0); 8,1 - 8,3 (broad singulet, 2H).

R) c) (300 MHz, DMSO-d6): 3,16 ppm (m, 3 + 4 H); 3,63 ppm (m, 4H); 6,7 ppm (broad singulet, 5H); 8,5 (broad singulet, 1H); 10,0 ppm (broad singulet, 2H).

S) (300 MHz, DMSO d6): 2.55 (s, 2H, N-CH2); 5.92 (s, 2H, NH).

T) (300 MHz, DMSO d6): 0.5 (m, 2H, CH2); 0.7-0.8 (m, 2H, CH2); 2.4-2.5 (m, IH, N-CH); 4.7 (broad, 2H, NH); 7.5 (broad, -2H, NH); 8.2 (broad, 1H, NH); 8.9 (broad, IH, NH).

U) (300 MHz, DMSO d^: 2.7 (s, 3H, N-CH3); 4.7 (broad, 2H, NH); 7.7 99 Case 970-9827/WA (broad, 1H, NH); 9.2 (broad, IH, NH/OH); 9.8 (broad, 1H, NH/OH).

V) (300 MHz, DMSO d6): 2.79 (d, J=4.8Hz 6H, N(CU^ 3.20 (s, 3H, N- - CHj); 3.2 (m, 2H, N-CH2); 3.6 (m, 2H, N-CH2); 4.7 (very broad, 2H, NH); 7.7 (broad, 2H, NH); 10.4 (broad, IH, NH).

W) (300 MHz, D20): 6.75-6.85 (m, IH, CH aromatic); 6.9-7.0 (m, IH, CH aromatic); 7.1 -7.15 (m, IH, CH aromatic); 7.7 (s, IH, CH=N).

X) (300 MHz, D20): 2,0 (m, IH); 2,47, 2,35 (s, s, together 3H, -SCH3); 0,84 (m, 2H); 0,69 (m, 2H).

Y) (300 MHz, D20): 3,36 (t, J=7 Hz, 2H); 2,51 , 2,43 (s, s, together 3H, - SCH,); 1,55 (quintet, J=7 Hz, 2H); 1,29 (sextet, J=7 Hz, 2H); 0,85 (t, J=7 Hz, 3H).

Z) (90 MHz, DMSO-d6): 3,65 ppm (s, 3H, NCH3).

AA) a) (300 MHz, DMSO d6): 2.19 (s, 3H, C-CH3); 3.84 (s, 3H, N-CH3); 5.84 (d, J=3.8Hz IH, C=CH); 6.58 (d, J=3.8Hz lHz, C=CH); 8.76 (s, IH, NH); 8.93 (s, IH, NH).

AA) b) (300 MHz, DMSO d6): 2.3 (s, 3H, C-CH3); 2.75 (s, 3H, S-CH3); 3.65 (s, 3H, N-CH3); 6.2 (d, J=4Hz IH, C=CH); 7.1 (d, J=4Hz lHz, C=CH); 10.6 (s, broad 5H, NH).

AA) c) (300 MHz, DMSO d6): 2.2 (s, 3H, C-CH3); 3.1 (s, 3H, N-CH3); 5.95 (d, J=4Hz IH, C=CH); 6.5 (d, J=4Hz lHz, C=CH); ?,2 (very broad 5H, NH).

AB) (300 MHz, DMSO d^O): 6.75-6.85 (m, IH, CH aromatic); 7.00-7.05 (m, IH, CH aromatic); 7.05-7.10 (m, IH, CH aromatic). 100 Case 970-9827/WA (300 MHz, DMSO cyD20): 8.24 (s, IH, CH=N); 5.20 (d, J=5.2 Hz, IH, β-lactam-H); 4.07 (d, J=5.2 Hz, IH, β-lactam-H); 3.89 and 3.61 (ABq, J=17.8 Hz, 2H, SCH2). (300 MHz, DMSO d6/CD3C02D+CF3COOD): 8.67 (s, IH, CH=N); 5.38-5.40 (2d, 2H, 26-lactam-H); 4,01 (s, 3H, CH3-0); 3,98-4.00 (ABq, 2H, SCH2). (300 MHz, DMSO d^: 8.14 (s, IH, CH=N); 5.33 (d, J=5.6 Hz, IH, CH); 4.80 (d, J=5.6 Hz, IH, CH); 3.88 and 3.58 (ABq, J=17.8 Hz, 2H, SCH2). (300 MHz, DMSO d6): 7.96 (s, IH, CH=N); 5.17 (d, J=5.2 Hz, IH, CH); 5.02 (d, J=5.2 Hz, IH, CH); 3.96 and 3.47 (ABq, J=17.7 Hz, 2H, SCH2). (300 MHz, DMSO d^: 8.35 (s, IH, CH=N); 5.31 (d, J=5.1 Hz, IH, CH); 5.14 (d, J=5.1 Hz, IH, CH); 4.28 and 3.84 (ABq, J=17.9 Hz, SCH2). (300 MHz, DMSO d6): 8.41 (s, IH, CH=N); 5.34 (d, J=5.1 Hz, IH, CH); 5.18 (d, J=5.1 Hz, IH, CH); 4.37 and 3.80 (ABq, J=17.9 Hz, SCH2). (300 MHz, DMSO d6): 8.61 (s, IH, CH=N); 5.36 (d, J=5.1 Hz, IH, CH); 5.18 (d, J=5.1 Hz, IH, CH); 4.42 und 3.71 (ABq, J=18.0 Hz, SCH2); 2.74 (s, 3H, SCH3). (300 MHz, DMSO d6): 8.52 (s, IH, CH=N); 5.36 (d, J=5.1 Hz, IH, CH); 5.21 (d, J=5.1 Hz, IH, CH); 4.46 and 3.79 (ABq, J= 17.7 Hz, 2H, SCH2); 2.95 (s, 3H, N-CH3). (300 MHz, DMSO d6): 8.51 (s, IH, CH=N); 7.56-6.84 (m, 10H, 2Ph); 5.28 (d, J=4.8 Hz, IH, CH); 5.00 (d, J=5.1 Hz, IH, CH); 4.13 and 3.93 (ABq, J=16.8 Hz, 2H, SCH2).

Claims (6)

Claims : 101 141442/2

1. A compound of formula in free form, in the form of a salt and/or in the form of a solvate, wherein R] denotes hydrogen or an ester moiety Rxx denotes a group wherein Rx is a group of formula / \ / \ N N— CHO or N NH or - NH - (CH2)2 - N (CH3)3 \ / \ / Ry is NH and is CH3; or Rx is - SCH3 Ry is a group of fo: = N - C4H9 141442/2 102 and R, is hydrogen; or Rx is the group Ry is oxygen and z is hydrogen.

2. A compound of formulae Via according to claim 1 in free form.

3. A compound of formulae Via according to claim 1 in salt form.

4. A compound of formulae Via according to claim 2 in acid addition salt form.

5. A compound of formulae Via according to claim 3 in metal salt form. /

6. A compound of formulae Via according to any one of claims 2 to 5 in solvate form. For the Applicants, REINHOLD CORN AND PARTNERS B