CZ20003506A3 - Cephalosporins containing cyclic aminoguanidine substituents intended for use as antibiotics - Google Patents

Abstract

A compound of formula I wherein R2 together with the nitrogen atom, k0 to which it is attached form cyclic aminoguanidine the group or derivative thereof and the other substituents are different meanings, is useful as a medicament.

Description

Technical field

The present invention relates to antibacterial compounds which are 7-acylamino-3- (cyclic aminoguanidine) methylencephalosporins, including compounds having a similar structure to the 3-cyclic aminoguanidines containing a triamino-methylidine group instead of an aminoguanidine group.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a compound of formula I

where

W is CH or N,

V is CH or NO,

R _x is hydrogen, acyl, carboxyl or alkyl,

R ₃ is a hydrogen atom or an ester group,

R ₂ is a group of formulas of the formula: -, -, -, -, -, -, -, -, -, -, -, -, -, · · · · · · · · · · · · · · · · · · · · · · · · ·

or where

X and Y are independently each C 2 -C 5 alkylene or C 2 -C 5 alkenylene group where one -C = C double bond is present or is at least 4 alkenylene carbon, where there are two -C = C- double bonds,

R ₄ is a hydrogen atom or an alkyl group,

_R is hydrogen, alkyl, or aminoiminomethyl group, • ···· ·· ·

_R is hydrogen, alkyl, cycloalkyl, amino, hydroxy, alkoxy, heterocyclyl or a group of formula -N = CHR _S wherein

R _a is an alkyl group, an aryl group or a heterocyclyl group, or

R _s and Rg together with the nitrogen atoms to which they are attached form a heterocyclyl group;

R's is an alkyl group,

R ₇ is hydrogen or

R 8 and R ₇ together with the nitrogen atom to which they are attached form a heterocyclyl group.

In formula I, R ₃ is a hydrogen atom or an ester group.

The ester group is an alkyl group; for example, unsubstituted alkyl or substituted alkyl, for example, aryl, such as benzyl, alkoxybenzyl, such as 4-methoxybenzyl, alkoxy, such as methoxymethyl; alkyloxycarbonyloxy; an alkyl group; an alkoxy group such as a glycyloxy group, a phenylglycyloxy group, for example a glycyloxymethyl group, a phenylglycyloxymethyl group; a heterocyclyl group such as a 5-methyl-2-oxo-1,3-dioxolen-4-yl group;

indanyl, phthalidyl, alkoxycarbonyloxy and ester groups which form, with the COO group, a physiologically hydrolyzable and acceptable ester, such as e.g.

· · «· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·································· ester groups known in the art of cephalosporins. Thus, the compound of formula I may be in the form of a physiologically hydrolyzable and acceptable ester. By physiologically hydrolyzable and acceptable esters according to the present invention is meant an ester group whose COO- group is esterified. and * hydrolysable under physiological conditions to produce an acid that is itself physiologically acceptable at the dose administered. Thus, the term is understood to mean a conventional form of a prodrug. The ester group may preferably be a group that is readily hydrolyzable under physiological conditions. These esters may preferably be administered orally. Parenteral administration may be used, and when the ester as such is an active compound or if the hydrolysis takes place in the blood.

In the compound of formula I:

Preferably, V is NO.

R _x is preferably a hydrogen atom or an alkyl group, for example a lower alkyl group, for example comprising an unsubstituted alkyl group and a substituted alkyl group; for example halogen, carboxyl, preferably halo ^; gene.

R ₂ is preferably a group of formula a), a '), c), d), d', e ') or f);

R ₄ is preferably a hydrogen atom or an alkyl group, for example a lower alkyl group.

X and Y are independently preferably alkylene or alkenylene, for example C 1 -C 4 alkylene or C 1 -C 4 alkenylene, such as C 2 -C 3 alkylene or C 2 -C 3 alkenylene 3 atoms • · • · AA · Α β ···

5α ΑΑΑΑΑΑΑΑ ΑΑ Α • Α Α · uhlíku uhlíku,,,,,,,, for example comprising an unsubstituted or substituted alkylene group or an alkenylene group, for example a halogen atom, an alkyl group, for example a lower alkyl group; cycloalkyl, carboxyl or alkylcarbonyl; preferably an alkyl group, for example including a hydroxyalkyl group, an aminoalkyl group; a carboxyl group and a (alkyl) carbonyl group containing a lower alkyl group.

_R is preferably hydrogen, alkyl, e.g. including unsubstituted alkyl and substituted alkyl groups, such as hydroxyl, carboxyl, amino, e.g. including lower alkylamino or di-lower alkylamino groups; a heterocyclyl group, for example including five and six membered rings, and containing one or two heteroatoms, for example one heteroatom, for example selected from the group consisting of oxygen, sulfur and nitrogen; a carboxylic, sulfonic or phosphoric acid ester, for example an alkyl or aryl ester, for example wherein the carboxylic acid moiety contains 1 to 12 carbon atoms and wherein the ester moiety contains 1 to 8 carbon atoms; or aminoiminomethyl group, for example of the formula / _Z N-Ru ^_C X ^X NR ₁₂ where R _X1 and R ₁₂ are independently hydrogen or alkyl, especially lower alkyl,

R ₆ is preferably hydrogen; amino, alkylamino, dialkylamino, wherein, for example, the alkyl moiety is unsubstituted;

- · · · · · · · · · · · · · ······································. or substituted, for example by hydroxyl, amino; arylamino; For example, R is _the group NR ₉ R _10, wherein R ₉ and R ₁₀ are independently hydrogen, alkyl, for example including a hydroxyalkyl, aminoalkyl, aryl;

an alkyl group, for example, including an unsubstituted alkyl group and a substituted alkyl group, for example a heterocyclyl group, for example containing 5 to 6 ring members and one or two heteroatoms, for example selected from the group consisting of nitrogen, oxygen and sulfur; including, for example, unsubstituted. heterocyclyl groups and substituted heterocyclyl groups; for example hydroxyl;

a hydroxyl group; alkoxy-, for example, including unsubstituted alkyloxy and substituted alkoxy, for example, hydroxyl, alkoxy, amino;

guanidino, for example wherein the amino groups are unsubstituted or substituted, for example, the terminal amino group is part of a heterocyclyl group;

amino, alkylamino, and dialkylamino, for example, lower-amino (alkyl) amino and lower-alkyl (dialkyl) amino;

an alkyl group, for example a lower alkyl group;

guanidino; wherein any amino group is unsubstituted or substituted, for example with an alkyl group;

hydroxyl, cycloalkyl, for example, including unsubstituted and substituted cycloalkyl, for example, amino; 9 9 9 9 9 9 9 9

Ί 9 9 9 99 9 9 99 9 '· 999999999999

4 4 4 4 4 44 5

44444444 44 4 4 44 44 heterocyclyl, for example including a heterocyclyl group having 5 to 6 ring members and one or two heteroatoms, for example selected from the group consisting of nitrogen, oxygen, sulfur; e.g. including unsubstituted heterocyclyl and substituted heterocyclyl groups such as alkyl, for example _R is a group of formula NR ₉ R ₁₀ wherein R ,, and _R10, together with the nitrogen atom to which they are attached form a heterocyclyl; or a group of formula -N = CHR _a , wherein R ₈ is preferably an aryl group, a heterocyclyl group, including a substituted and unsubstituted heterocyclyl group; for example alkyl; for example containing 5 or 6 ring members and one or two heteroatoms, for example selected from the group consisting of nitrogen, oxygen, sulfur;

_R and _R, where together with the nitrogen atoms ,, to which they are attached form a heterocyclyl group, it is preferably an alkylene group, an alkylene group containing 2-4 carbon atoms such as an alkylene group containing 2-3 carbon atoms;

R'e J ^es preferably an alkyl group, for example a lower alkyl group;

When _R and R ₇ together with the nitrogen atom to which they are bonded form hetercyklylovou group hetercyklylová group preferably contains 5 to 7 ring members and one or two heteroatoms, for instance chosen from the group consisting of nitrogen, oxygen, sulfur .

In another embodiment, the invention provides a compound of formula Ia.

• • •

4 4

Ia wherein W, R _{1 Z} R _3, R _s and _Rg are as defined above.

In another embodiment, the invention provides a compound of formula 1b

N lb

N- (CH _{Z) m}

R 'where. W, R _{1 Z} R _3, R _s and _Rg are as defined above and m is 1 or 2 respectively.

In another embodiment, the present invention provides 7 - {[(5-amino-1,2,4-thiadiazol-3-yl) - (Z) - (fluoromethoxyimino) acetyl] amino} -3 {[(3-ethyl-2) methylimino-imidazolidin-1-yl) imino] methyl} -3cephem-4-carboxylic acid, for example in the form of its hydrochloride.

As used herein, unless otherwise indicated, the term "compound of formula I, Ia and Ib" includes the compound in any form, for example, in the form of a salt and in the form of a free base. Thus, the present invention includes ^; compound in the form. the free base or, for example, if such a form exists, in the form of a salt, for example in the form of an acid addition salt, an internal salt, a quaternary salt and / or in the form of a solvate, for example in the form of a hydrate. The salt may be a pharmaceutically acceptable salt of a compound of formula I, Ia and Ib, such as metal salts or ammonium salts. Metal salts include, for example, sodium, potassium, calcium, barium, aluminum salts, preferably sodium or potassium salts. Ammonium salts include, for example, salts with trialkylamine, procaine, dibenzyl, and dibenzyl.

Inem φφ φφ amine and benzylamine. The free compound of formula I, Ia and Ib can be converted to the salt form and vice versa.

In another embodiment, the present invention provides a compound of Formula I, Ia and Ib in free form and in salt form, for example in the form of an acid addition salt or a metal salt; and the compound of formula I, Ia and Ib, for example, in free form or in salt form, in solvate form.

Unless otherwise indicated, carbon-containing groups may contain up to 20 carbon atoms, for example an alkyl group includes, for example, a straight or branched group having 1 to 20 carbon atoms, for example an alkyl group having 1 to 8 carbon atoms, such as an alkyl group having 1 to 6 and lower alkyl. A lower alkyl group includes, for example, an alkyl group having 1 to 4 carbon atoms, such as an alkyl group having 1 to 2 carbon atoms. A cycloalkyl group includes, for example, a cycloalkyl group having 3 to 7 carbon atoms, in particular a cycloalkyl group having 3, 5 or 6 carbon atoms. An acyl group includes an alkylcarbonyl group and an arylcarbonyl group, for example, an acyl group containing 1 to 5 carbon atoms. 12 carbon atoms, for example an acyl group having 1 to 6 carbon atoms, such as an acyl group having 1 to 4 carbon atoms. Aryl includes phenyl, naphthyl, for example phenyl. The heterocyclyl group includes heterocyclyl. a group containing 4 to 7, for example 5 to 6 ring members and 1 to 3 nitrogen, sulfur and / or oxygen (N, O, S) atoms, including, for example, a fused heterocyclyl group such as a benzthiazolyl group. The amino group includes a free amino group, for example in the form of a salt, an alkylamino group, a dialkylamino group and an arylamino group, and for example a protected amino group.

9

9

9 '9

9 9 9

Guanidino includes guanidino where the 3-nitrogen atoms are unsubstituted or independently substituted, for example, with an alkyl group.

Unless otherwise indicated, any of said groups may be unsubstituted or substituted, for example, one or more times, for example, by those conventional in β-lactam chemistry, for example, alkyl, for example CF3, aryl, alkoxy, halogen, hydroxyl, carboxyl a sulfonic acid derivative such as SO 3 H, a phosphoric acid derivative, an acyl group, an amino group; guanidino, heterocyclyl, for example pyridyl, oxo, thiono, mercapto, alkyl- or arylthio, imino, alkylimino, GHO.

The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. '

The present invention includes a compound of formula I in any isomeric form in which it may exist. For example, the configuration in group -C = VR where VR _{FS x} is NO, may be syn [(Z)] and anti [(E)] and is preferably syn · [(Z)]. For example, geometric isomers can be obtained, for example, during the preparation of a compound of formula I, for example due to the presence of a double bond -CX '= CX''- where X' and X '' are groups having different meanings. carbon atoms, for example during the preparation of a compound of formula I and the corresponding stereoisomeric forms of the compound of formula I can be obtained, for example mixtures of individual stereoisomers, for example racemates or pure isostereomeric forms. Mixtures of isomers may be separated.

·· ··

I · · · · · · · · · · · · · · · · · · ·

The present invention includes a compound of formula I in any tautomeric form. For example, a compound of formula I wherein ϊ »

R ₂ is a group of formula a) wherein _R is hydrogen, or

R ₂ is a group of formula (d) wherein R _s or R _s is a hydrogen atom may exist in tautomeric form, as described, for example, below:

and)

N

NH • NH

Rg

I ⁶

NH • w N w

HNd)

N -

AND.

• N N I

R

-NH N I

R,

R,

R _e '6'N

Ν NH ¹ Y /% y • NH ^N

In another embodiment, the present invention provides a compound of formula Ip

H ₂ N

, N - R.

2p ip where

W _p is CH or N, ··· · ·

V _p is = CH- or = N-0-,

R _1p is hydrogen, acyl, carboxyl, unsubstituted alkyl. a group, or an alkyl group substituted with a halogen atom or a carboxyl group,

R _3p is a hydrogen atom, an ester-forming group or a cation,

R ₂ is a group of formula

R,

6p ^Rsp ^ N ^ ^R7p

R _r . \ R. "® ^P ^ N 7p \ p \

Ν '

and)

(b)

C)

Y "

E)

-Ν N - R

-Ν 'N - R

5p

R,

5p '6p \

-Ν N ^R 4p ^R 5p ^6pX Nv i ^Y p

-N N \ p \

4p

G)

-Ν N <X ^Y p where X _p and Y _p are the same or different and each represents - (CH ₂ ) _and -, where n is 2 to 5, and optionally one or two CH ₂ - are replaced by -CH = CH- and optionally one or more hydrogen atoms is replaced by a halogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a carboxyl group or an ethoxycarbonyl group,

R _4p is hydrogen, alkyl or hydroxyalkyl,

R _Sp is a hydrogen atom, an alkyl group, a (poly) hydroxyalkyl group, or an aminoalkyl group, wherein optionally the alkyl groups are further substituted with functional groups, for example radical 44 or

4 4 4 4 4 9 99 • 9 9

49 44 carboxylic acid, phosphoric acid residue, sulfonic acid residue

R _Sp is hydrogen, alkyl, hydroxyalkyl, aminoalkyl, amino, hydroxyl, alkoxyalkyl, cycloalkyl, N = CHR _{and p} , wherein

R _p is aryl or heteroaryl, or -NR ₁₀ R _9p wherein

R _9p and R _10p are the same or different and are each a hydrogen atom, an alkyl group, a hydroxyalkyl group or an aryl group or together with the nitrogen atom represent a saturated, unsubstituted 5 or 6 ring heterocycle having one or two nitrogen atoms and / or oxygen atoms and

R _7p is hydrogen, or

R _7p and R _Sp together with the nitrogen atom represent a 5- to 7-membered heterocycle containing one or two nitrogen atoms and / or oxygen atoms, provided that when W _p is CH, V _p is = N-O-, R _1p is hydrogen or methyl, R _2p is a group of formula (d) and R _3p is a hydrogen atom, R _5p and R _Sp are simultaneously a group other than a hydrogen atom or a methyl group, in free form or, if any, in in the form of acid addition salts, inner salts, quaternary salts or hydrates.

A compound of formula I may be prepared, for example. so,. as set forth below, and in the examples and, for example, analogously to methods common in β-lactam chemistry.

In another embodiment, the present invention provides a process for preparing a compound of formula I, comprising reacting a compound of formula

II

»ΦΦ ΦΦ · · φ φ φ φ φ · · · φ φ φ φ Φ Φ φ φ φ φ φ φ φ φ φ φ · · · · · h _{2 2 2 2 2 2} 2φ φ

wherein W, V and R _x are as defined above and

a) R _b is a hydroxyl group and R _c a. R _d together represent a bond, or

β) R _d is a hydrogen atom, a cation, an ester-forming group or a silyl group and R _b and R _c together represent oxo, in free form or in the form of an acid addition salt with an amine of formula ¹¹¹ r ₂ - nh ₂ iii wherein R ₂ is as defined above, for example, the desired (reactive) groups may be protected by protecting groups which are, for example, common in β-lactam chemistry, which may be cleaved under the reaction conditions or upon completion of the reaction described above. A compound of formula I wherein R ₃ is a hydrogen atom may be converted to a compound of formula I wherein R ₃ is an ester group, for example a carboxylic ester group, and vice versa, for example, by methods analogous to conventional methods. The compound of formula I can be isolated from the reaction mixture by conventional methods, for example analogous to conventional methods.

The compounds of formula I can be prepared, for example, as follows:

φ φ • • · · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

The compound of formula II can be reacted in a solvent which is inert under the reaction conditions, for example in a polar solvent, for example water or a mixture of water with a lower alcohol or dioxane or in a dipolar aprotic solvent, for example dimethylformamide, dimethylsulfoxide, dimethylacetamide, preferably dimethylacetamide. or mixtures of these solvents, such as those described above, for example mixtures of dimethylacetamide with an alcohol or water, for example at -20 to 50 ° C with a compound of formula III. A suitable, for example optimum pH may be adjusted, for example, by the addition of a base or an acid, for example an inorganic or organic acid. The compound of formula I obtained can be isolated from the reaction mixture, for example in an analogous manner to conventional methods, for example by adding an anti-solvent, to the reaction mixture or, for example, by chromatography. If appropriate, any group, for example a reactive group, may be protected from the reaction, for example by silyl protecting group technology in a suitable solvent, for example a solvent inert under the reaction conditions, for example halogenated hydrocarbons, for example dichloromethane. nitriles, such as acetonitrile, ethers, for example tetrahydrofuran, or dipolar aprotic solvents, for example dimethylformamide, including mixtures of individual solvents, for example as defined above. Protecting groups can be cleaved, for example, by methods for removing protecting groups, for example, by conventional methods.

The starting materials are known or can be prepared by conventional methods, for example analogously or, for example, as described in the examples. Starting compounds, for example in the free form or in the form of salts, for example in the form of the hydrochloride, of the formula

16 NR ₆ p '*' HSl * u N N-R ' _s ií h, n - yy

ί Int

R7 or

Int. φφ nh ₂ -n = ^ or or

R ''

R

AND

NI

R

III

Int ⁶ R ⁷ h ₂ nn or \ °

N ^h 2N-N-Z

IV,

Int r · N- ⁴ V

Int or

or

N ^z

Λ.

H ₂ N — Ν N

VII

Int R ¹ -R 8 where Y 'is an alkylene group, for example an alkylene group having 2 to 3 carbon atoms,

R _'is hydrogen, alkyl nebo'alkyliminoskupina; for example, unsubstituted alkyl, alkyl substituted by hydroxyl, carboxyl, amino, for example, including amino, alkylamino, and dialkylamino;

a heterocyclyl group, for example containing 5 or 6 ring members and one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, for example nitrogen, for example piperidino, pyrrolidino; · «· · · · · · · · · · · · I · i · i · i · i · i · i · i · · Ganidino;

pyridylmethylimino;

R 'is _a hydrogen, alkyl, hydroxy, alkoxy, cycloalkyl, amino or heterocyclyl;

for example alkylamino, hydroxyalkylamino, phenylamino; unsubstituted. alkyl, heterocyclyl-substituted alkyl, e.g. containing 5 to 6 ring members and containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, e.g. nitrogen, e.g. piperazino, piperidino, pyridino, morpholino, a pyridoxal group; including unsubstituted heterocyclyl and substituted heterocyclyl, such as alkyl;

amino, for example, amino, alkylamino, dialkylamino, hydroxyalkylamino, (di) aminoalkylamino; · Hydroxy, hydroxyalkoxy; alkoxy, for example hydroxyalkoxy, alkoxyalkoxy, aminoalkoxyalkoxy;

guanidino, for example wherein the amino groups are unsubstituted or substituted, for example by an alkyl group; for example guanidino, wherein the terminal amino group is part of a heterocyclic ring system, for example, containing 5 or 6 ring members and one or two heteroatoms selected from

IQ · · · · · A ········

A group consisting of a nitrogen atom, an oxygen atom, a sulfur atom, at least a nitrogen atom;

an alkyl group, for example a lower alkyl group;

a heterocyclyl group, for example containing 5 to 6 ring members and containing one or two heteroatoms, for example selected from the group consisting of nitrogen, sulfur, oxygen; C 3 -C 7 cycloalkyl, for example unsubstituted cycloalkyl or substituted cycloalkyl with amino;

R ' ₇ and R' ₈ are independently hydrogen, carboxyl, alkoxycarbonyl, or alkyl; for example a lower alkyl group such as an unsubstituted alkyl group and a substituted alkyl group such as a hydroxyl group;

^Zzz R, R '''' ₆ are independently alkyl, for example lower alkyl group; or

^Zzz R 6 and R '''' ₅ together with the nitrogen atom to which they are bonded form a heterocyclyl group, for example, containing 5 to 6 ring members and containing one or two heteroatoms, e.g., selected from the group consisting of nitrogen, oxygen , sulfur atom; at least a nitrogen atom;

R 1 ^of 5 is an alkyl group, for example a lower alkyl group; or

R '' ₅ and R ^zzz s are an alkylene group, an alkylene group containing 2-3 carbon atoms;

R ^zzzz and R ^zzzzz are independently an alkyl group, for example a lower alkyl group;

• ·

Rzfz / z / g _and r '' _? together with the nitrogen atom to which they are attached form a heterocyclyl group, for example, containing 5 or 6 ring members and one or two heteroatoms, for example selected from the group consisting of nitrogen, oxygen, sulfur, for example nitrogen;

R ' ₄ and R' _g are independently alkyl, for example lower alkyl; and

Hal 'is a halogen atom, for example a chlorine atom, a bromine atom;

with the proviso that the compound of formula _Iin , wherein R ' _s , R' ₇ and R ' _a are hydrogen and R' _s is hydrogen, 2- (N-morpholino) ethyl, 3- (N, N- dimethylamino) -propyl; (2-hydroxyethyl) amino or 2-hydroxyethyl is excluded.

In another embodiment, the present invention provides a compound of formula I _Int , II _Int , III _Int , IV _Int , V _Int or VI _Int , wherein, the residues are as defined above, with the conditions set forth above.

The compounds of formula (I) of the present invention, designated as "active compounds of the invention, exhibit pharmacological activity and further have low toxicity and are therefore useful as pharmaceuticals. In particular, the active compounds of the present invention exhibit antimicrobial, for example antibacterial, activity against, for example, gram-negative and gram-positive bacteria, for example gram-positive bacteria such as Pseudomonas, for example Pseudomonas aeruginosa; Escherichia, for example Escherichia coli; Enterobacter, for example Enterobacter cloacae; Klebsiělla,. for example Klebsiella edwardsii, Klebsiella pneumoniae; Enterococcus, for example Enterococcus faecalis; Moraxella, for example Moraxella catarrhalis; Streptococcus, for example Streptococcus pneumoniae, Strepto-

coccus .pyogenes; and Staphylococcus, for example Staphylococcus aureus; in vitro, in an agar dilution test according to the National Commitee for Clinical Laboratory Standards (NCCLS) 1993, Document M7A3VO1.13, No. 2; The active compounds exhibit an MIC (g / ml) in an agar dilution test of about <0.0125 to> 25.6. The active compounds of the present invention exhibit a surprisingly broad spectrum of activity.

For example, the MIC (µg / ml) of the compound of Example 48 against, for example, the E. coli strain ATCC 35218 and ATCC 10536 was found to be <0.0125; and is <0.0125 against Enterobacter cloacae strains.

The active compounds of the present invention are therefore suitable for the treatment of microbial, for example bacterial diseases.

According to another embodiment, the present invention provides a compound of claim 1 for use as a medicament, preferably as an antimicrobial, such as an antibiotic. In another embodiment, the present invention provides a compound according to claim 1. for use in the preparation of a medicament for the treatment of microbial diseases, for example diseases caused by bacteria selected from the group consisting of Pseudomonas, Escherichia, Enterobacter, Klebsiella, Enterococcus, Moraxella, Streptococcus and Staphylococcus.

In another embodiment, the present invention provides a method of treating microbial diseases, which comprises administering an effective amount of a compound of Formula I to a patient in need thereof.

44 44 44 44

4 4 4 4 4 ·

4 4444444 4

4 444

44 44 44

For such an indication, the appropriate dosage will, of course, vary depending upon, for example, the compound of Formula I employed, the patient, the mode of administration, and the nature and severity of the condition being treated. In general, however, satisfactory results in higher mammals are obtained at a daily dose of 0.05 to 5 g, for example 0.1 to 2.5 g, of an active compound of the invention suitably administered, for example, in divided doses up to four times a day.

The active compound of the present invention may be administered by any suitable route, for example orally, for example in the form of tablets or capsules, or parenterally in the form of injection solutions or suspensions, for example in an analogous manner, such as ceftazidime.

Compound 7 - {[(5-amino-1,2,4-thiadiazol-3-yl) - (Z) - (fluoromethoxyimino) acetyl] amino} -3 - {[(3-ethyl-2-methylimino-imidazolidine) -yl) imino] methyl} -3-cephem-4-carboxylic acid (a compound of Example 48) is a preferred compound of the present invention for use as an antimicrobial agent.

For example, it has been found that the MIC (µg / ml) of the compound of Example 48 (tested as the hydrochloride) against, for example, Klebsiella edwardsii, ATCC 10896 strain is about 0.8, while ceftazidime, for example, exhibits a MIC (µg / ml) of about 1, 6. It is therefore clear that for the treatment of microbial diseases, for example bacterial diseases, higher mammals, for example humans, may be administered the preferred compounds of the present invention by similar methods at similar dosages to those commonly used for cefezididime.

The compounds of formula I may be administered in the form of pharmaceutically acceptable salts, for example in the form of acid addition salts or basic addition salts, or in the corresponding free forms. Means, optionally in the form of a solvate. These forms of kind of activity like free forms.

···· ·· show the same

The present invention also provides pharmaceutical compositions comprising a compound of Formula I in the form of a pharmaceutically acceptable salt or in free form, together with at least one pharmaceutical carrier or diluent. Such compositions may be prepared in conventional manner.

The present invention, in other embodiments, provides a compound of Formula I for use as. a medicament for the treatment of microbial diseases caused by Pseudomonas, Escherichia, Enterobacter, Klebsiella, Moraxella, Enterococcus, Streptococcus, Staphylococcus;

the use of a compound of formula I, or the use of a pharmaceutical composition comprising a compound of formula I as a medicament, and

a method of treating microbial diseases, comprising administering to a patient in need thereof an effective amount of a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In the following examples which illustrate the present invention, all temperatures are given in degrees Celsius.

The following abbreviations are used:

t-BOC = N-tert-butyloxycarbonyl

BOC anhydride = di-tert-butyl dicarbonate

Example 1

To a mixture of 0.2 g of 1,2-diamino-4,5-dihydro-1H-imidazole as dihydrochloride, 0.73 ml of 2N hydrochloric acid solution, 0.57 ml of dimethylacetamide and 0.57 ml of water is added 0.57 ml. g- (1,4,5a, 6-tetrahydro-3-hydroxy-1,7-dioxo-3H, 7H-azeto [2,1-b] furo [3,4-d] [1,3] thiazine -6-yl) -2- (5-amino-1,2,4-thiadiazol-3-yl) - (Z) -2- (fluoromethoxyimino) acetic acid, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was poured into 150 ml of acetonitrile with stirring. The precipitate was filtered off, washed and dried. There was obtained 7 - {[(5-amino-1,2,4-thiadiazol-3-yl) - (Z) (fluoromethoxyimino) acetyl] amino} -3 - {[(2-amino-4,5-dihydro- 1 H-imidazol-1-yl) imino] methyl} -3-cephem-4-carboxylic acid as the tri-hydrochloride as a yellow powder. For further purification, the crude obtained is dissolved in water, applied to a chromatography column (LiChroprep RP-18®, Merck) and eluted with water or a water / methanol mixture. Fractions containing the desired compound (as determined by HPLC) were combined and lyophilized.

In an analogous manner to that described in Example 1, the compounds described in Table 1 below, which are examples (Ex.) 2 to 83, are obtained. These are compounds of formula I wherein VR 1 = NOCH ₂ F; W is defined in Table 1; R ₃ = hydrogen; and _R2 = a compound of formula a), wherein _R and _R are as defined in Table 1, and X = _{-CH2 CH2} -; in the form of salts as defined in Table 1:

Table 1:

Ex. 'w Salt 2 N H -nh-ch ₃ 2HCl 3 N H -NH-C ₆ H _s 2HCl 4 N H ch ₃ 2HCl 5 N H - Ν N — CH. \ _ / 3HC1 6 N H - <J 2HCl 7 N H -CH ₂ CH -r / \ NH W 3HC1

A A A A A A A A A A A A AA AA AA AA

Ex. w ^R s R _e Salt 8 N -CH ₂ CH ₂ OH H 2HCl 9 N H -ch ₂ ch ₂ -nh-c ₂ h ₅ 3HC1 10 N H -CH ₂ CH ₂ -N (CH ₃ ) ₂ 3HC1 11 N H -ch ₂ ch ₂ -nh ₂ HCl 12 N H -nh-ch ₂ ch ₂ oh HCl 13 N H - (CH ₂ ) ₃ -NH ₂ HCl 14. N H - CH ₂ GH ₂ -NH-CH ₂ CH ₂ OH 3HC1 15 Dec N -CH ₂ CH ₂ OH -ch ₂ ch ₂ -n ^-^ nh HCl 16 N H -CH ₂ - \ h HCl 17, N H -ch ₂ ch ₂ - ^ \ N— ' 3HC1 18 N H - CH ₂ CH ₂ - O - CH ₂ CH ₂ OH HCl 19 Dec N H OH 2HCl 20 May N H / —Y -N 0 \ _y 2HCl 21 N H - (CH ₂ ) ₄ -NH ₂ HCl 22nd N H -ch ₂ ch ₂ oh HCl 23 N H - (CH ₂ ) _with -NH ₂ 3HC1 24 . N H '- / NH ₂ - CH, -CH 2, HCl 25 N H ΛΛ —CH ₂ CH ₂ -N N HCl 26 N H CH, ^13- CH, -C-NH, ² 1, ^{2 and} ₃ 3HC1 27 Mar: N H -c ₂ h ₅ 2HCl 28 N H -c ₃ h ₇ 2HCl 29 N H -ch ₂ ch ₂ -o-ch ₂ ch ₂ -o- 2HCl

• 9 9 9 9

9999 9999 · * 9 8

Ex. W Rs R _s Salt ch ₂ ch ₂ -nh ₂ 30 N H - (CH _{2) 3} -NH- _CH3 3HC1 31 N H - (CH ₂ ) ₃ -NH-CH ₂ CH ₂ OH HCl 32 N H - (CH _{2) 3} -N (CH _{3) 2} 3HC1 33 N -CH ₂ CH ₂ OH - (CH ₂ ) ₃ -NH ₂ HCl 34 N -ch ₂ ch ₂ oh - (CH ₂ ) 3 -NH-CH 3 HCl 35 ' N -ch ₂ ch ₂ oh - (ch ₂ ) ₃ -nh-ch ₂ ch ₂ oh HCl 36 N -ch ₂ ch ₂ oh - (CH ₂ ) ₃ -N (CH ₃ ) ₂ HCl 37 N -ch ₂ ch ₂ oh -N (CH _{3) 2} HCl 38 N H -ch ₂ ch ₂ ch ₂ oh 2HCl 39 N -CH ₂ CH ₂ OH . CH ₃ 2HCl 40 N H -ch ₂ -ch (oh) -ch ₂ nh ₂ 2HCl 41 N H -ch ₂ ch ₂ -n (CH ₂ CH ₂ NH ₂ ) ₂ 2HCl 42 N H x> NH -CI-LCI-LCH -—- N - Cf 2 2 2 »» ^M nh ₂ 3HC1 43 N -CH ₂ CH ₂ OH -C ₂ H _s 2HCl 44 N H - (CH ₂ ) 3 -NH- (CH ₂ ) ₃ -nh ₂ 2HCl 45 N H 3HC1 46 N -C ₂ H ₅ H 2 HCl 47 N H -CH ₂ -CH (OH) -CH ₂ OH 2HCl 48 N -c ₂ h _p . ch ₃ HCl  49 N -c ₂ h _p - (CH ₂ ) ₃ -N (CH ₃ ) ₂ HCl 50 N -c ₂ h ₅ - (CH ₂ ) ₃ -NH ₂ HCl 51 N -C ₂ H _s nh ₂ 3HC1 52 N -ch ₂ ch ₂ oh ^NH 2 HCl 53 N H NH - (CH ₂ ) _{3 -} NH - C 1 - N - 4HC1

99

9f 9 * 9

9 9 9

9 9 9

99

99

9 9

9 9

999

9 · · 9 · · 9 ·

9

9999 9999

Ex. . w R _s • R ₆ Salt 54 N H - N - CH - (CH ₂ ) ₃ -NH 4 NH-CH ₃ 2HCl 55 N ch ₃ H 2HCl 56 N ch ₃ ch ₃ . 2HCl 57 • N • ch ₃ -c ₂ h ₅ 2HCl 58 N ch ₃ 3HC1 59 N ch ₃ -CH ₂ CH ₂ OH HCl 60 N -ch ₂ ch ₂ oh -ch ₂ ch ₂ oh HCl 61 N -CH ₂ CH ₂ - N (C ₂ H _{s) 2} η 2HCl 62 N - (ch ₂ ) ₃ - n (ch ₃ ) ₂ H 2HCl 63 N , H -CH ₂ CH ₂ -N (C ₂ H ₅ ) ₂ 2 HCl 64 N -CH ₂ CH ₂ - N (C ₂ H _{s) 2} ch ₃ 2 HCl 65 N -ch ₂ ch ₂ - n (ch ₃ ) ₂ H 2HCl 66 N H (-O-CH ₂ —ς -ONa N) / OH 67 N H P H ₂ N HCl 68 N H h ₂ n HCl 69 N -ch ₂ ch ₂ ch ₃ 2HCl 70 N -ch ₂ ch ₂ ch ₃ ch ₃ 2HCl 71 N N-CH (CH ₃ ) ₂ —C ^X NH-CH (CH ₃ ) ₂ H 3HC1

• φ

ΦΦ φ φ φ φ φ φ · · φ φ φ • φ

Ex. • W Rs Salt 72 N ^ ch ₃ -CH ^x ch ₃ H 2HCl 73 N —CH ₂ CH ₂ -N \ H 2HCl 74 N - (ch ₂ ) ₃ -ch ₃ ch ₃ 2HCl 75 N - (CH ₂ ) ₃ -CH ₃ H 2HCl 76 N CH ₂ CH ₂ -N \ y ¹ . ch ₃ 2HCl 77 N --ch ₂ ch ₂ -i / ~ H 2HCl 78 N -ch ₂ cooh H 2HCl 79 N - (CH ₂ ) ₄ -CH ₃ H 2HCl 80 N - (CH ₂ ) ₅ -CH ₃ H 2HCl 81 N - (CH ₂ ) ₆ -CH ₃ H 2HCl 82 N -CH ₂ CH ₂ - 2HCl 83 N -ch ₂ ch ₂ ch ₂ - 2HCl

Example 84

In an analogous manner to that described in Example 1, compound I is prepared wherein VR _x = N-OCH ₂ F; R ₃ = -CH ₂ -O-CO-C (CH ₃ ) ₃ ; W = N and _R2 = a compound of formula a) wherein _R = -C ₂ H _{5, R} = 'CH ₃ and X = -CH ₂ CH ₂ -; in the form of the hydrochloride.

In an analogous manner to that described in Example 1, the compounds described in Table 2 below, which represent Examples (Ex.) 8.5 to 90, are prepared. These are compounds of Formula I wherein W = N; VR ₃ = N-OCH ₂ F; R ₃ = hydrogen; and R ₂ = a compound of formula a '), wherein R 5 &_lt; R ₆ , R ₆ ' and Hal are as defined in Table 2 and X - -CH ₂ CH ₂ -; in the form of salts as defined in Table 2:

·

9

9

9

9 • 9

999 9

98 • 9 9 9

9 · 9

9 9 9

9 999

9 9

9 9

Table 2:

Ex. r ₅ ^R 6 R '« Hal Salt 85 -c ₂ h ₅ ch ₃ ch ₃ Cl HCl 86 ch ₃ ch ₃ ch ₃ - Cl HCl 87 -c ₂ h ₅ ch ₃ -C ₂ H _s Cl HCl 88 -ch ₂ ch ₂ ch ₃ ch ₃ ch ₃ Cl HCl 89 -ch ₂ ch ₂ - ch ₃ Cl HCl 90 -ch ₂ ch ₂ ch ₂ -, ch ₃ Cl HCl

In an analogous manner to that described in Example 1, the compounds described in Table 3, which are examples (Ex.) 91 to 97, are prepared. These are compounds of Formula I wherein W = N; VR _x = N-OCH ₂ F; R ₃ = hydrogen and _R2 = a compound of formula a) wherein _{R, R} and X are as defined in Table 3; in the form of salts as defined in Table 3:

Table 3:

Ex. X r ₅ ^R s Salt 91 - CH - CH - ch ₃ H H 2HCl 92 -CH - CH- CH ₃ H ch ₃ 2HCl 93 - CH, -CH- i. ch ₃ H - (CH ₂ ) ₃ -nh ₂ HCl 94 —Ch ₂ -chčh ₃ H - (CH ₂ ) ₃ -NH ₂ HCl 95 CH, —ch ₂ —c— ch ₃ H H 2HCl 96 ch ₃ —ch ₂ —c— ch ₃ H CH ₃ . 2HCl

ΦΦ · φ φ · · · · · ·

Ex. X R _s r ₆ Salt 97 -CH = CH- ch ₃ ch ₃ HCl

In an analogous manner to that described in Example 1, the compounds described in Table 4 below, representing Examples (Ex.) 98 to 100, were prepared. These are compounds of formula I wherein VR _x = NOH; R ₃ = hydrogen; W is defined in Table 4; and _R2 = a compound of formula a), wherein _R and _R are as defined in Table 4, and X = _{-CH2 CH2} -; in form ^{1 of the} salt defined in Table 4:

Table 4:

Ex. W ^R s Salt 98 CH H - (CH ₂ ) ₃ -NH ₂ HCl 99 CH H -ch ₂ ch ₂ -nh ₂ HCl 100 ALIGN! CH -C ₂ H ₅ ch ₃ HCl

Ananlogickým manner as described in Example 1, was prepared by the compounds described in Table 5 below represent examples (Ex.) 101 to 115. These are compounds of formula I where _one VR. = NOCH ₂ F; W = N; R ₃ = hydrogen; and _R2 = a compound of formula d), wherein R _s, R ₆ and Y are as defined in Table 5; in the form of salts as defined in Table 5:

Table 5:

Ex. Y ^R 5 r ₆ Salt 101 -ch ₂ ch ₂ - H -N = CH-C ₅ H _S 2HCl 102 -ch ₂ ch ₂ - H -CH ₂ CH ₂ OH HCl 103 -ch ₂ ch ₂ - H H HCl 104 -ch ₂ ch ₂ ch ₂ - H H 2 HCl 105 -ch ₂ ch ₂ - H -CH ₂ CH ₂ -NH ₂ HCl 106 -ch ₂ ch ₂ - H -n = chR ^ n-ch _s 2HCl

44 44 ·· 44 ·· · · 4 4 44 4 4 · 4 4

4 444 4 4 4 4 4 • 4 4 4 4 444 4 4 4 4 4 • 4 4 4 4 4 4 4 4

4444 4444 44 44 44 44

Ex. Y ^R s ^r 6 Salt 107 -ch ₂ ch ₂ - ch ₃ ch ₃ 2HCl 108 -ch ₂ ch ₂ - H -c ₂ h ₅ 2HCl 109 '-ch ₂ ch ₂ - H ch ₃ 2HCl 110 -ch ₂ ch ₂ - H -ch ₂ ch ₂ ch ₃ 2HCl 111 -ch ₂ ch ₂ - H ^ ch ₃ - CH 'ch, 2HCl 112 -ch ₂ ch ₂ -. / CH ₃ —CH 2 CH ₃ / CH ₃ - CH ₃ OH 2HCl 113 —CH-CH, - 3ch ₃ H H 2HCl 114 - CH-CHj— COOCH, H H HCl 115 —Ch-ch ₂ - ch ₂ oh H H HCl

In an analogous manner as described in Example 1, the compounds described in Table 6 below, representing Examples (Ex. 116-118), are obtained. These are compounds of Formula I wherein VR _x and W are as defined in Table 6; R ₃ = hydrogen; and _R2 = a compound of formula f), wherein R ₄ = CH _{3, R} is as defined in Table 6 and Y = -CH ₂ CH ₂ -; in the form of salts as defined in Table 6:

Table 6:

Ex. w vr ₃ ^R 6 Salt 116 CH n-och ₃ ch ₃ 2HCl 117 CH N-OH ch ₃ 2HCl 118 N N-OCH ₂ F ch ₃ 2HCl

Example 119

In an analogous manner as described in Example 1, a compound of formula I is obtained wherein W = Ν '; VR _x = N-OCH ₂ F; R ₃ = hydrogen conductor.

A •

AND

AA A A

AA AA ··

AAA A

A A · ·

And AAA A

AA AA A * ku; and R _a = a compound of formula (c), wherein R _s and R together with the nitrogen atom to which they are attached form a group of formula

N NH and X = -CH ₂ CH ₂ ; in the form of the hydrochloride.

Example 120

In an analogous manner as described in Example 1, a compound of formula I is obtained wherein W = N; VR _x = N-OCH ₂ F; R ₃ = hydrogen; and _R2 = a compound of formula d), wherein R _s and R ₆ = hydrogen; in the form of the dihydrochloride.

Substituted 1,2-diamino-4,5-dihydro-1H-imidazoles are obtained as follows:

Example A

a. 5 g of 1-benzylideneamino-imidazolidin-2-thione are suspended in

0 ml of methanol and treated with 1.7 ml of methyl iodide. The resulting mixture was heated at reflux for about 1 hour and the solvent was evaporated. 1-Benzylideneamino-2-methylthio-4,5-dihydro-1H-imidazole is obtained as the hydroiodide as a solid, to which is added 120 ml of water and 70 ml of ion exchange resin in the form of chloride (Amberlite IRA-400 (Cl ) ^R ). The mixture was stirred at room temperature for about 2 hours, filtered and lyophilized. 1-Benzylideneamino-2-methylthio-4,5-dihydro-1H-imidazole hydrochloride is obtained as a lyophilisate.

b. 1 g of L-benzylideneamino-2-methylthio-2-imidazoline in 10 ml methanol was treated with 0.33 ml of NH ₃ (28% in H ₂ 0). The resulting mixture was heated to reflux for about 5 hours and the precipitate formed was filtered off. The solvent was evaporated from the filtrate. The residue was treated with acetonitrile. Gets φ · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ · φ φ φ φ φ • •

φ • ΦΦΦ φφ φ φ φ φ

φ

The channel precipitate is filtered off and dried. 2-amino-1-benzylideneamino-4,5-dihydro-1H-imidazole hydrochloride is obtained as a solid.

c. Benzaldehyde was distilled off from a mixture of 0.89 g of the 2-amino-1-benzylideneamino-4,5-dihydro-4-imidazole hydrochloride salt in 5.9 ml of 2N hydrochloric acid by distillation with steam. The solvent was evaporated from the remaining mixture. Solid 1,2-diamino-4,5-dihydro-ΙΗ-imidazole is obtained as the hydrochloride.

Example B

A mixture of 0.79 g of 1-benzylideneamino-2-methylthio-4,5-dihydro-1H-imidazole hydrochloride in 10 ml of methanol with 0.18 ml of hydrazine hydrate was stirred at room temperature for 6 hours. The solvent was evaporated from the obtained mixture and the residue was treated with acetonitrile. The 1-benzylidene-amino-2-hydrazino-4,5-dihydro-1H-imidazole precipitate was filtered off and dried.

Example C

a. 0.58 g of 1- (β-aminoethyl) imidazolidine-2-thione in 25 ml of dichloromethane is treated with 0.96 g of BOO anhydride. The resulting mixture was stirred at room temperature for 4 hours and the solvent was evaporated. Solid 1- [β- (t-BOC-aminoethyl)] imidazolidin-2-thione is obtained.

b. A mixture of 0.5 g of β- (t-BOC-aminoethyl)] imidazolidine-2-thione in 20 ml of methanol and 0.32 g of methyl iodide was heated at reflux for 1 hour and the solvent was evaporated. 1 [β- (t-BOC-aminoethyl)] - 2-methylthio-4,5-dihydro-1H-imidazole is obtained as the hydroiodide and stirred in 20 ml of water and the anion exchange resin as chloride (6 ml). IRA-400 (Cl) ^R ) at room temperature for about 1 hour. The anion exchange resin is filtered from the mixture obtained and the filtrate obtained is lyophilized.

9 9 9 • 9

. ··· · 9 · ·

1- [β- (t-BOC-aminoethyl)] - 2-methylthio-4,5-dihydro-1H-imidazole is obtained as lyophilisates. *

c. A mixture of 1.06 g of 1- [β- (t-BOC-aminoethyl)] - 2-methylthio-4,5-dihydro-1H-imidazoline in 25 ml of methanol and 0.2 g of hydrazine hydrate was heated for 2 hours. at reflux, and the solvent was evaporated. Solid 1- [β- (t-BOC-aminoethyl)] - 2-hydrazino-4,5-dihydro-1H-imidazole is obtained.

Example D and ·. The pH of a solution of 1.59 g of 1-benzylideneamino-4,5-dihydro-2-methylamino-1H-imidazole as hydrochloride in 40 ml of water was adjusted to 12.0 with 2M sodium hydroxide. The resulting mixture was extracted with dichloromethane. The organic phase is dried over sodium sulphate and evaporated. 1-Benzylideneamino-4,5-dihydro-2-methylamino-1H-imidazole is obtained as a powder.

b. A mixture of 1 g of 1-benzylideneamino-4,5-dihydro-2-methylamino-1H-imidazole in 30 ml of acetonitrile with 1.26 g of propyl iodide was heated at reflux for about 8 hours. The resulting mixture was stirred at room temperature overnight. The 1-benzylideneamino-2-methylimino-3-propyl-imidazolidine precipitate in the form of the hydroiodide is filtered and dried.

c. A mixture of 0.70 g of 1-benzylideneamino-2-methylimino-3-propyl-imidazolidine as hydroiodide in 20 ml of water with 10 ml of anion exchange resin (Amberlite IRA-400 (Cl) ^R ) was stirred for 3 hours at The anion exchange resin was filtered off and the filtrate was treated with 3.6 ml of 2M hydrochloric acid. The benzaldehyde is distilled off from the obtained mixture by steam distillation. The solvent was evaporated from the remaining mixture. 1-Amino-2-methylimino-3-propyl-imidazolidine is obtained as the hydrochloride as an oil.

• · • ·

Example.Ε

a. A mixture of 0.89 g of 1-benzylideneamino-2-methylimino-3-propyl-imidazolidine as hydroiodide in 20 ml of water with 10 ml of anion exchange resin in the form of chloride (Amberlite IRA-400 (Cl) ^R ). After stirring at room temperature for about 3 hours, the anion exchange resin is filtered off and the pH of the filtrate is adjusted to 12.6 with 2M sodium hydroxide. The 1-benzylideneamino-2-methylimino-3-propyl-imidazolidine precipitate was filtered off, dried and the product was obtained as a powder.

b. A mixture of 0.51 g of 1-benzylideneamino-2-methylimino-3-propyl-imidazolidine in 15 ml of acetonitrile with 0.36 g of methyl iodide was heated at reflux for 1 hour and the solvent was evaporated. The residue was treated with acetonitrile and the solvent was evaporated. There was obtained (1-benzylideneamino-3-propyl-imidazolidin-2-ylidene) -dimethylammonium iodide as a powder.

Solid (1-amino-3-propyl-imidazolidin-2-ylidene) -dimethylammonium chloride in the form of the hydrochloride was obtained in an analogous manner to that described in Example D, c.

Example P

A mixture of 0.72 g of 2- (3-aminopropylimino) -imidazolidin-1-yl-benzylidenamine in 15 ml of absolute ethanol with 0.53 g of S-methylisothiourea chloride was refluxed for 4 hours and the solvent was evaporated. The residue is dissolved in 4 ml of 2M hydrochloric acid and 4 ml of water, applied to a chromatography column (LiChroprep RP-18 ^R , Merck) and eluted with water. Fractions containing 2- (3-guanidino-propylimino) -imidazolidin-1-yl-benzylidenamine hydrochloride (as determined by HPLC) were combined. From the mixture obtained after addition of 2M hydrochloric acid, distillation is carried out by distillation.

JJ I φ φ · · · · s s s s s s φ φ φ φ φ s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s The solvent was evaporated from the remaining mixture. Solid 2- (3-guanidinopropylimino) imidazolidin-1-yl-amine is obtained as the dihydrochloride salt.

Example G

a. A mixture of 2.61 g of 2- (3-amino-propylimino) -imidazolidin-1-yl-benzylidenamine in 25 ml of dichloromethane with 0.48 g of methyl isothiocyanate was stirred at room temperature for about 90 minutes and the solvent was evaporated. The residue is treated with 40 ml of water and the pH of the mixture is adjusted to 1.00 with 2M hydrochloric acid. The precipitated 1- [2- (1-Benzylideneamino-imidazolidin-2-ylideneamino) -propyl] -3-methylthiourea was filtered, dried and isolated as a powder.

b. A mixture of 1.79 g of 1- [2- (1-benzylideneamino-imidazolidin-2-ylideneamino) -propyl] -3-methylthiourea as hydrochloride in 30 ml of methanol with 0.52 ml of methyl iodide was heated at reflux for 3 hours. The solvent was evaporated and the residue was stirred with 80 ml of water and 30 ml of anionic ion exchange resin in the form of chloride (Amberlite IRA-400 (Cl) ^R ) for about 2 hours. The ion exchange resin is filtered from the mixture obtained and the filtrate is lyophilized. There was obtained 1 - [(1-benzylideneamino-imidazolidin-2-ylideneamino) -propyl] -3-methyl-2-methyl-isothiourea as the hydrochloride as a lyophilisate.

c. A mixture of 1 g of 1 - [(1-benzylideneamino-imidazolidin-2-ylideneamino) propyl] -3-methyl-2-methyl-isothiourea as hydrochloride with 0.54 ml of methylamine (33% solution in absolute ethanol). ) and 30 ml of methanol are heated at reflux for 7 hours and the solvent is evaporated. The residue was dissolved in 4 mL of 2M hydrochloric acid and 6 mL of water, applied to a chromatography column (LiChroprep RP-18 ^r , Merck) and eluted with water / methanol. Fractions containing 2- [3- (N, N ^x -dimethylguanidino) -propyl-propyl 4 4 4 4 4 4 4

Jo · ···· ♦ ······· imid * * * ♦ imid imid imid imid imid]]]]]]]] imid imid imid imid imid imid imid imid imid imid imid imid imid imid imid imid imid imid imid imid imid imid of the hydrochloride (as determined by HPLC) were combined and lyophilized.

d. From a solution of 0.5 g of the 2- [3- (N, N'-dimethylguanidino) -propylamino] -imidazolidin-1-yl-benzylideneamine derivative as hydrochloride in 2.1 ml of 2M hydrochloric acid is distilled with steam distills benzaldehyde. Evaporation of the solvent from the residue gave 2- [3- (Ν, Ν-dimethylguanidino) -propylamino] imidazolidin-1-yl-amine as the dihydrochloride.

Example H

0.99 ml of Ν, N'-diisopropylcarbodiimide in 10 ml of dichloromethane are added dropwise over 30 minutes to a solution of 1 g of 2-amino-1-benzylideneamino-4,5-dihydro-id-imidazole in 20 ml of dichloromethane, The mixture was stirred at room temperature for about 6 days and the solvent was evaporated. The residue was dissolved in 6 ml 2M hydrochloric acid and 4 ml water, applied to a chromatography column (LiChroprep RP-18 ^r , Merck) and eluted with water. Fractions containing 1-benzylideneamino-3- (N, N'-diisopropyl-guanidino) -2-iminoimidazolidine (determined by HPLC) were combined and lyophilized.

b. Solid 1-amino-3- (Ν, N'-diisopropylguanidino) -2-imino-imidazolidine dihydrochloride is obtained by removal of benzylaldehyde from 1-benzylideneamino-3- (Ν, N-diisopropylguanidinó) -2 imino-imidazolidine analogously in a manner as described in Example G, d.

Example I

a. A mixture of 3 g of 2 - [(1-benzylideneamino-4,5-dihydro-1H-imidazol-2-yl) amino] ethanol in 50 ml of methylene chloride with 1.22 ml of thionyl chloride is stirred at room temperature for 1 hour. The 2 (2-chloro-ethylimino) -imidazolidin-1-yl-benzylidenamine precipitate was filtered and evaporated. UJ

9 9 9 9 9 9 9 9 9 9 99 99 99

b. A mixture of 3.7 g of 2- (2-chloro-ethylimino) -imidazolidin-1-yl-benzylidenamine in 50 ml of absolute ethanol with 2.25 ml of N-ethyldiisopropylamine was heated at reflux for 22 hours, the solvent was evaporated and the residue was is treated with acetonitrile. There was obtained solid 2,3,5,6-tetrahydroimidazo [1,2a] imidazol-1-ylbenzylidenamine as the hydrochloride salt.

c. Solid 2 _of 3,5,6-tetrahydro-imidazo [1,2a] imidazol-1-ylamine hydrochloride is obtained by removing benzylaldehyde from 2,3,5,6-tetrahydro-imidazo [1,2a] imidazole- 1-yl-benzylidenamine in the hydrochloride form in an analogous manner to that described in Example G, d.

Example J

a. A mixture of 4 g of hydrazinoacetaldehyde diethyl acetal in 40 ml of ethanol is stirred with 1.97 g of methyl isothiocyanate for about 4 hours at room temperature, the solvent is evaporated to give 2- (2,2-diethoxy-ethyl) -4-methyl-thiosemicarbazide. in crystalline form.

b. A mixture of 4 g of 2- (2,2-diethoxy-ethyl) -4-methylthiosemicarbazide and 2.82 g of methyl iodide in 40 ml of methanol was heated at reflux for 90 minutes and the solvent was evaporated. 4.53 g of 2- (2,2-diethoxy-ethyl) -3,4-dimethyl-isothiosemicarbazide is obtained as the hydroiodide which is dissolved in water and stirred with a strongly basic ion-exchange resin in the form of chloride (Amberlite IRA 400 ( Cl) ^R ) 2.5 hours. The ion exchange resin is. the filtrate is lyophilized. 2- (2,2-Diethoxy-ethyl) -3,4-dimethyl-isothiosemicarbazide was obtained as the hydrochloride as an oil.

c. A mixture of 2 g of 2- (2,2-diethoxy-ethyl) -3,4-dimethyl-isothiosemicarbazide as hydrochloride in 20 ml of ethanol with 0.91 ml of methylamine (33% solution in absolute ethanol) is stirred for 26 hours. · • • • • φ φ φ

φ φ φ φ ΦΦΦ at room temperature. 0.91 g of benzylaldehyde is added. The mixture was stirred for 21 hours, the solvent was evaporated and the residue was treated with diethyl ether. 1- (Benzylideneamino) -1- (2,2-diethoxyethyl) -2,3-dimethylguanidine was obtained as the hydrochloride salt.

d. A mixture of 1.39 g of 1- (benzylideneamino) -1- (2,2-diethoxyethyl) -2,3 dimethylguanidine hydrochloride with 5 ml of concentrated hydrochloric acid was stirred at room temperature for about 30 minutes. The pH of the mixture was adjusted to 6.4 with 1N sodium hydroxide solution. The resulting mixture was extracted with diethyl ether. The pH of the aqueous solution was adjusted to 12 with 1N sodium hydroxide solution. The resulting mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate, the solvent was evaporated, yielding benzylidene (3-methyl-2-methylimino-2,3-dihydro-imidazol-1-yl) -amine as an oil.

e. From 384 mg of benzylidene- (3-methyl-2-methylimino-2,3-dihydro-imidazol-1-yl) -amine in 10 ml of water and 3.55 ml of 2N hydrochloric acid, benzylaldehyde was removed in an analogous manner to described in Example G, d. to give 3-methyl-2-methylimino-2,3-dihydro-imidazol-1-ylamine as the dihydrochloride as an oil.

Example K

a. 0.6 ml of CS ₂ is added dropwise with stirring to a solution of 1.7 g of potassium hydroxide in 6 ml of water and 14 ml of ethanol. The resulting mixture was heated. The mixture was heated at reflux for 4 hours with 1.47 g of (R, S) -2,3-diamino-1-propanol as the dihydrochloride salt. The pH of the mixture was adjusted to 2 with 6N hydrochloric acid and the solvent was evaporated. The residue is treated with ethanol and methanol.

The potassium chloride precipitate was filtered off. From the filtrate ·

The solvent is evaporated to give a solid (R, S) -4-hydroxymethylimidazolidine-2-thione. .

b. A mixture of 1.4 g of (R, S) -4-hydroxymethyl-imidazolidin-2-thione in 25 ml of methanol with 1.8 g of methyl iodide is heated at reflux for 2 hours, the solvent is evaporated to give 2, 2. 26 g of (R, S) -2-methylthio-4,5j-dihydro-1H-imidazol-4-yl) -methanol as the hydroiodide which is dissolved in 4 ml of water and applied to a column packed with a strongly basic ion-exchange resin in chloride (Amberlite IRA 400 ^R ) and eluted with water. Fractions containing (R, S) -2-methylthio-4,5-dihydro-1H-imidazol-4-yl) -methanol as hydrochloride. (determined by HPLC) were combined and lyophilized.

c. A mixture of 1.54 g of (R, S) -2-methylthio-4,5-dihydro-1H-imidazol-4-yl) methanol as its hydrochloride was dissolved in methanol with 462 mg of hydrazine hydrate and stirred for 1 day at room temperature. The solvent was evaporated and the residue was dissolved in ethanol and treated with ethereal hydrochloric acid. (R, S) -2-Hydrazono-imidazolidin-4-yl) -methanol was obtained as the dihydrochloride as a crystalline solid.

Example L

a. 2.8 6 ml CS ₂ was added dropwise to 7.9 g potassium hydroxide in 30 ml water and 64 ml ethanol with stirring. The resulting mixture was heated to reflux with 6.0 g of DL-2,3-diaminopropionic acid hydrochloride for 4 hours. The mixture is adjusted to pH 2 with 6N hydrochloric acid and the solvent is evaporated. The solid (R, S) -2-thioxo-imidazolidine-4-carboxylic acid was obtained and stirred overnight with 150 ml of methanol with the addition of 5 ml of 1N ethereal hydrochloric acid. The potassium chloride precipitate was filtered off. The solvent is evaporated from the filtrate and

(R, S) -2-thioxo-imidazolidine-4-carbose solid xylic acid methyl ester.

b. Mixture. 6 g of (R, S) -2-thioxo-imidazolidine-4-carboxylic acid methyl ester in 100 ml of methanol and 4 g of methyl iodide are heated under reflux for 2 hours, the solvent is evaporated and 5 g of methyl ester of R, S) -2-methylthio-4,5-dihydro-im-imidazole-4-carboxylic acid as the hydroiodide as a solid which was dissolved in 30 ml of water. 3 g of sodium carbonate are added in portions to the obtained solution. The aqueous solution was extracted with dichloromethane, the organic phase was dried over sodium sulfate and the solvent was evaporated. (R, S) -2-methylthio-4,5-dihydro-1H-imidazole-4-carboxylic acid methyl ester is obtained.

c. A mixture of 1.36 g of (R, S) -2-methylthio-4,5-dihydro-1H-imidazole-4-carboxylic acid methyl ester in 15 ml of methanol with ‘710 mg of hydrazine as monohydrochloride and 1 ml of water was stirred over. overnight at room temperature and the solvent was evaporated. The solid is obtained as a hydrochloride salt of (R, S) -2-hydrazonoimidazolidine-4-carboxylic acid.

In an analogous manner, the compounds of

Example M to Example

Compounds of the formula as described in Examples A to L with Examples M to CZ, which are described below:

CK

4 4 4 4 4 4

4 4

Where R _s and which is

R _g are defined in Table 7 below in the form of a salt as defined in Table 7 below (Ex. = Example):

Table 7:

Ex. ^R S ^R s Salt M H -nh-ch ₃ HCl N H -NH-C ₆ H _s 2HCl 0 H ch ₃ 2HCl P H -CH ₂ CH ₂ - 2HCl Q -CH ₂ CH ₂ OH H 2 HCl R H -CH ₂ CH ₂ -NH-C ₂ H _s 2HCl WITH H -CH ₂ CH ₂ -N (CH ₃ ) ₂ 2HCl T H -ch ₂ ch ₂ -nh ₂ 2HCl at H -nh-ch ₂ ch ₂ oh 2HCl in H - (CH ₂ ) ₃ -nh ₂ 2HCl w H - CH ₂ CH ₂ -NH- CH ₂ CH ₂ OH 2HCl X -CH ₂ CH ₂ OH -CH ₂ CH _{2 -} 1 H 2HCl Y H -CH ₂ - <^ / NH 2HCl of H -ch ₂ ch ₂ - ^ \ N— 2HCl AA H - ch ₂ ch ₂ - 0 - CH ₂ CH ₂ OH 2HCl AB H 'OH 2HCl AC H Z “Λ - N 0 \ _y 2HCl AD H - (CH ₂ ) ₄ -NH ₂ 2HCl AE H -ch ₂ ch ₂ oh 2HCl AF H - (ch ₂ ) ₆ -nh ₂ 2HCl

· 9 9 *

9,999 9 9 9 * 9

9 99 9 99999 99 9 • 9 99 9 9 9 · 9

99999999 99 «9 9 * 99

Ex. ^R s ^R ' Salt AG H / NH ₂ —ch ₂ ch xh ₃ 2HCl AH H -CH.CH ₇ -l / 0 ^{2 2} 2HCl AI H CH, 1 —CH, —c — NH, ² 1, ^{2 and} ₃ 2HCl AJ —N - CH — CHj Cl ” -nh ₂ 2HCl AK H - / \ -ch ₃ 2HCl AL H - < 2HCl AM H -C ₂ H _s 2HCl AN H -c ₃ h ₇ 2HCl AO H - ch ₂ ch ₂ - 0 - ch ₂ ch ₂ - 0 - ch, ch ₂ -nh ₂ 2HCl AP H - (CH _{2) 3} -NH-CH ₃ 2HCl AQ H - (ch ₂ ) ₃ -nh-ch ₂ ch ₂ oh 2HCl AR H - (CH ₂ ) ₃ -N (CH ₃ ) ₂ 2HCl AS -CH ₂ CH ₂ OH - (ch ₂ ) ₃ -nh ₂ . 2HCl AT -ch ₂ ch ₂ oh - (CH _{2) 3} -NH-CH ₃ 2HCl AU -CH3CH3OH. - (CH ₂ ) ₃ -nh-ch ₂ ch ₂ oh 2HCl AV -CH ₂ CH ₂ OH - (CH ₂ ) ₃ -N (CH ₃ ) ₂ 2HCl AW -ch ₂ ch ₂ oh -N (.ch _{3) 2} 2HCl AX H - (CH ₂ ) ₃ -OH , 2HCl AY -CH ₂ CH ₂ OH ch ₃ 2HCl AZ H -ch ₂ -ch (oh) -ch ₂ -nh ₂ 2HCl BA H -ch ₂ ch ₂ -n (CH ₂ CH ₂ NH ₂ ) - ₂ 2HCl BB ' -CH ₂ CH ₂ OH -c ₂ h ₅ 2HCl BC H -ch ₂ ch ₂ -nh- (ch ₂ ) ₃ -nh ₂ 3HC1

φ φ • φ φ φ · φ φ φ φ φ φ φ φ φ φ • · · · · · φ φ φ · · · · · · · · φ φ φ • ΦΦΦ φφφφ

Ex. R _s Rs Salt BD Η ^nhj 3HC1 ΒΕ -c ₂ h ₅ H 2HCl BF Η -CH ₂ -CH (OH) -CH ₂ OH / 2 HCl BG -c ₂ h ₅ ch, 2HCl ΒΗ -c ₂ h ₅ - (CH ₂ ), -N (CH ₂ ) ₂ 2HCl ΒΙ -c ₂ h ₅ - (CH ₂ ) ₃ -NH ₂ 3 HCl BJ -C ₂ H _s 3HC1 ΒΚ . -CH ₂ CH ₂ OH 3HC1 BL H NH - (CH ₂ ) 1 -NH-CH ₃ - (NH) 3HC1 ΒΜ ch, H 2HCl ΒΝ, ch ₃ CH, 2HCl ΒΟ  ch, -C ₂ H _s . 2HCl ΒΡ ch, 3HC1 BQ CH, -ch ₂ ch ₂ oh 2HCl BR -CH ₂ CH ₂ OH -ch ₂ ch ₂ oh 2 HCl BS -CH ₂ CH ₂ -N (C ₂ H _{s) 2} H 2HCl ΒΤ - (CH ₂ ) ₃ -N (CH ₂ ) ₂ H 2HCl BU H -CH ₂ CH ₂ -N (C ₂ H ₅ ) ₂ - 2HCl BV -CH ₂ CH ₂ -N (C ₂ H ₅ ) ₂ CH, 2HCl BW -CH ₂ CH ₂ -N (CH ₂ ) ₂ H 2HCl ΒΧ H 0 HCl - CH - ₍ --OH - ⁷ ). OH

Φ φ ► ► φ φ φ φ φ φ φ · · · · φ φ φ φ φ φ φ φ φ φ φ

Ex. ^R 5 r ₅ Salt BY H / nh ₂ 3HC1 ΒΖ -CH ₂ CH ₂ CH ₃ Η 2HCl CA -CH (CH _{3) 2} H 2HCl CB —CH ₂ CH ₂ -N \ H 2HCl CC - (CH ₂ ) ₃ -CH ₃ ch ₃ 2HCl CD. - (CH ₂ ) ₃ -CH ₃ H 2 HCl CE ~ ch ₂ ch ₂ -N \ ch ₃ 2HCl CF —CH ₂ CH ₂ - / / 3 H 2HCl CG -ch ₂ -cooh H 2HCl CH - (CH ₂ ) ₄ -CH ₃ H 2 HCl Cl - (CH ₂ ) _s -CH ₃ Η 2HCl CJ - (CH ₂ ) _s -CH ₃ . H 2HCl CK -ch ₂ ch ₂ ch ₂ - 2HCl

5 * ·························· ·· «··· <* 9999 9999 99 99 99 99

Example CL to Example CP

Compounds of formula cr. +.

N + ^R 6

H ₂ N — Ν N — R _s a ') where R _s , R _s and R' _e are defined in Table 8 below in the form of the salts defined in Table 8 below (Ex = Example):

Table 8:

Ex. R ₅ r ₅ R ' ₆ Salt Cl -c ₂ h ₅ ch ₃ ch ₃ HCl CM ch ₃ ch ₃ ch ₃ HCl CN -C ₂ H _s . -C ₂ H _s ch ₃ HCl WHAT -ch ₂ ch ₂ - ch ₃ HCl CP -ch ₂ ch ₂ ch ₂ - CH ₃ HCl

Example CQ to Example CU

Compounds of formula

FL

ON.

H ₂ N — Ν M - R _p

and)

ΦΦ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

φ φ

φ φ φ φ φ φ φ φ φ φ φφ φ φ φ φ φφφ φ • Φ φφ • · φ · φ φ φ φ φ φ φ φφ φφ wherein _R · R _e and X are as defined in Table 9 below in sol form defined in Table 9 below (Ex = Example):

Table 9:

Ex. r ₅ X Salt CQ H ch ₃ - CH ₃ -CH ₃ 2HCl CR H H —Ch ₂ —ch — ch ₃ 2HCl CS H - (CH ₂ ) ₃ -NH ₂ —Ch ₂ —ch — ch ₃ 3HC1 CT H ch ₃ ch ₃ —ch ₂ -c-. ch ₃ 2HCl CU H H ch ₃ —ch ₂ -ch ₃ 2HCl

Example CV to Example CX

Compounds of formula

Rq i ^{6 ν} ~ Ίnh ₂ -n = (

(d) where R _s and R _s are defined in Table 10 below in the form of salts as defined in Table 10 below (Ex = Example):

9

9 ·

· · · 9 · 9 · • 9 9 9 9 9

9,999,999

9

9900 9900 99 99

Table.10 :.

• ·

• · • · ··

Ex. ^R 5 Salt CV -ch ₂ ch ₂ ch ₃ H HCl CW -CH (CH _{3) 2} H HCl cx -CH (CH _{3) 2} -CH (CH _{3) 2} HCl

Example CY

Compound of formula

Rg / R _?

H ₂ N-N '

C), where R _s and R ₇ together with the nitrogen atom to which they are attached form a group

N NH in the form of the dihydrochloride.

Example CZ

Compound of formula

R,

6 \

Nh ₂ nn

f) r ₄ ⁿ

DA is prepared from 1-ethyl-3z 1-methyl-3z 1-propyl-3z 1-nitroso-499 99 99 99 99 99 99 9 9 9 9 9999 9

. 9 99 999999 99 9

9 99 99999

9999 9999 99 99 99 99 R = ₄ · CH ₃ and _R = CH ₃ as the hydrochloride.

Example DÁ

A cold mixture of 68.5 mL (about -5 °) of 2N sulfuric acid with 4 g of 1- (2-hydroxyethyl) -3-nitrosoimidazolidin-2-thione is treated with 3.42 g of zinc powder, the resulting mixture is stirred for about 15 minutes and filtered. The filtrate is treated with 2.88 ml of benzylaldehyde and stirred at room temperature for about 1 hour. 1-Benzylideneamino-3- (2-hydroxyethyl) imidazolidin-2-thione precipitated, filtered, washed with diethyl ether and dried

In an analogous manner to that described in the example

1-benzylideneamino-3-ethyl-imidazolidin-2-thione nitrosoimidazolidin-2-thione,

1-benzylideneamino-3-methyl-imidazolidin-2-thione nitrosoimidazolidin-2-thione,

1-benzylideneamino-3-propyl-imidazolidin-2-thione nitrosoimidazolidin-2-thione,

1-benzylideneamino-4-methyl-imidazolidin-2-thione methyl-imidazolidin-2-thione, and 1-benzylideneamino-4,4-dimethyl-imidazolidin-2-thione from 4,4-dimethyl-3-nitroso-imidazolidine-2- thion.

Example DB

To an ice-cold mixture of 6.81 g of 1-ethyl-imidazolidin-2-thione and 3.6 g of NaNO ₂ in 440 ml of dichloromethane was added dropwise 63 ml of 1M hydrochloric acid and the resulting mixture was stirred for 10 minutes. The two-phase system is divided. The organic phase was washed with water, dried over sodium sulfate and the solvent was evaporated. Solid ethyl 3-nitrosoimidazolidin-2-thione is obtained.

AA ·· AA ·· ··

AAAA · · A «A A · A 'A'. A A · A · A · A

A A A A A AAA A A A A A

A A A A A A AA A

AAAA AAAA «AA AA At AA

The following compounds were prepared in an analogous manner to that described in Example DB:

1-methyl-3-nitrosoimidazolidine-2-thione from 1-methyl-imidazolidine-2-thione,

3-nitroso-1-propyl-imidazolidin-2-thione from 1-propylimidazolidin-2-thione,

4-methyl-1-nitroso-imidazolidin-2-thione from 4-methylimidazolidin-2-thione; and

4,4-dimethyl-1-nitrosoimidazolidin-2-thione from 4,4-dimethylimidazolidin-2-thione.

1 H-NMR spectra of compounds (Ex. = Example), unless otherwise indicated, in perdeuterodimethylsulfoxide

Př.l 3.58 and 4.64, AB-quartet, J = 18 Hz, 2H, _S-CH2; From 3.68 to 4.10, m, 4H, _N-CH2; 5.3.4, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.81, d, J = 55 Hz, 2H, CH ₂ F; 5.95, dd, J = 5 Hz and 8 Hz, 1H, S-lactam-H; 7.87 s,

1H, CH = N; 9.11, br, 1H, NH; 9.85, d, J = 8Hz, 1H, NH

Pr.2: 3.20 to 4.28, m, 9H, 4H of _N-CH2 and 2H of _S-CH2 and 3H of CH _3; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.82, d, J = 55 Hz, 2H, CH ₂ F;

5.96, dd, J = 5Hz. and J-8 Hz, 1H, S-lactam-H; 7.92, s, 1H, CH = N; 8.34, b, 2H, NH; 8.97, b, 1H, NH; 9.86, d, J = 8 Hz, 1H, NH

Př.3: 3.52 and 4.54, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3,67-4,25 m

4Ή, N-CH ₂ ; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55Hz, ·

2H, CH ₂ F; 5.93, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 6.85 6.92, m, 3H, CH-aromatic; 7.20-7.30, m, 2H, CH-aromatic;

7.93, s, 1H, CH-N; 8.28, b, 2H, NH; 8.5l š, š, IH, NH; 9,84, d,

J = 8Hz, 1H, NH-. ite

Φ Φ · · · · · · φ φ φ «« «φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Example 4: 2-, 97, d, J = 5 Hz, 3H, CH ₃ , 3.56 and 4.55, AB-quartet, J = 18 Hz, 2H, S-CH ₂ ; From 3.70 to 4.15, m, 4H, _N-CH2; 5.32, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.81, d, J = 55 Hz, 2H, _CH2 F; 5.96, dd, J = 5 Hz and J = 8 Hz, IH, β-lactam-H; 7.88, s, 1H, CH-N; 8.33, b, 2H, NH; 8.71, d, J = 5Hz, 1H, NH; 9.75, S, 1H, NH; 9.86, d, J = 8Hz, 1H, NH

Ex. 5: 2 83, s, 3H, CH _3; 3,00 -3,30, m, 6H, _N-CH2; 3.40 - 4.20, m, 7H, H of _S-CH2 and 6H From _N-CH2; 4, 44, part of AB-quartet, J = 18 Hz, IH, _S-CH2; 5,30 d, J = 5Hz, IH, β-lactam-H; 5.82, d, J = 55 Hz, 2H, CH ₂ F; 5.96, dd, J = 5 Hz and J = 8 Hz, IH, β-lactam-H; 7,91,

s, 1H, CH = N; 8.34, s, 2H, NH; 9.87, d, J = 8 Hz, 1H, NH

Př.6: 0.60 to 0.92, m, 4H, CH ₂ -cycloprop. ; 2.50-2.54, m, 1H, CH-C; 3.51 and 4.59, AB-quartet, J = 18 Hz, 2H, _S-CH2; From 3.70 to 4.10, m, 4H, _N-CH2; 5.31, d, J = 5 Hz, 1H, [beta] -lactam-H; .5,79, d, J = 55 Hz, 2H, CH ₂ F; 5.95, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 7.88, s, 1H, CH-N; 9.85, d, J = 8Hz, 1H, NH

Pr.7: 3.38 to 4.18, m, 17H, 16H of _N-CH2 and H of _S-CH2; 4.60, part of AB-quartet, J = 18 Hz, IH, _S-CH2; 5.32, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.80, d, J = 55 Hz, 2H, CH ₂ F; 5.96, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 7.92, s, IH, H = N; 8.30, br, 2H, NH; 9.86, d, J = 8Hz, 1H, NH

To Example 8: 3.45 to 3.70, m, 5H, 4H of _N-CH2 and H of _S-CH2; 3.72 4.10, m, 4H, _N-CH2 and _O-CH2; 4.59, part of AB-quartet, J = 18 Hz,

H, _S-CH2; 5.32, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.80, d, J = 55Hz,

2H, CH ₂ F; 5.96, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H ;. 7,90 s,

1H, CH = N; 8.33, S, 2H, NH; 9.86, d, J = 8Hz, 1H, NH

PR.9: 1.2 0, t, J = 5 Hz, 3H, CH _3; 0 from 2.90 to 3.2, m, 4H, _N-CH2; 3.40-4.10, m, 7H-,

6H from N-CH ₂ and IH from S-CH ₂ ; 4.60, part of AB-quartet, J = 18 Ηζ, ΙΗ, SCH ₂ ; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F;

9 9 9 9

9 9 9 9 9 9

9

99 99 99

1 H, CH = N;

NH »· 99 · <

• · · · ·

9 9

9 9 9

9 9

5.94, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 7.89, s, 8.28, br, 2H, NH; 9.00, b, 1H, NH; 9.84, d, J = 8Hz, 1H,

Ex. 10: 2, 85, s, 6H, CH ₃ ; 3.35, s, 2H, _N-CH2; 3,48 - 7H, 6H od _N-CH2 and 1H from _S-CH2; 4.61, part of AB-Quartet, 1H, _S-CH2; 5.32, d, J = 5 Hz, 1H, β-lactam-H; 5,80, d, 2H, CH ₂ F; 5.96, dd ,. J = 5. Hz and J = 8 Hz, 1H, [beta] -lactam-H;

1 H, CH = N; 8.31, S, 2H, NH; 9.86, d, J = 8Hz, 1H, NH

4.15, m, J = 18Hz, J = 55Hz, 7.89, s,

Př.ll: 3.05, s, 2H, _N-CH2; From 3.45 to 3.68, m, 3H, 2H of _N-CH2 and 1H of _S-CH2; From 3.70 to 4.15, .m, 4H, _N-CH2; 4.52, part of AB-quartet,

J = 18 Hz, 1H, _S-CH2; 5.24, d, J = 5 Hz, 1H, [beta] -lactam-H; .5,81, d, J = 55 Hz, 2H, CH ₂ F; 5.84, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 8.09, S, 1H, CH-N; 8.30, S, 2H, NH; 9.81, d, J = 8Hz, 1H, NH

Pr.12: 2.90, s, 2H, _N-CH2; From 3.40 to 3.61, m, 3H, 2H of _O-CH2 and 1H of _S-CH2; 3.63 - 4.20, m, 4H, _N-CH2; 4.50, part of AB-quartet ,. J = 18 Hz, 1H, _S-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.82, d, J = 55 Hz, 2H, CH ₂ F; 5.92, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 8.07, s, 1H, CH = N; 8.23, S, 2H, NH; 9.77, d, J = 8Hz, 1H, NH

Př.13: 1.72 to 1.92, m, 2H, _CH2; 2.85, s, 2H, _N-CH2; 3,38 w

2H, _N-CH2; 3.54 and 4.51, AB-quartet, J = 8 Hz, 2H, _S-CH2; 3.68 4.14, m, 4H, _N-CH2; 5.21, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d,

J = 55 Hz ', 2H, CH ₂ F; 5.79, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H;

8.04, s, 1H, CH-N; 8.26, b, 2H, NH; 9.77, d, J = 8Hz, 1H, NH

Př.14: 3.10, s, 2H, _N-CH2; 3.20, s, 2H, _N-CH2; 3.55 and 4.64, ABq, J = 18 Hz, 2H, _S-CH2; 3.62 - .4,15 m, 8H, 6H of _N-CH2 and

2H of _OCH2; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d, J = 55Hz,

2H, CH ₂ F; 5.94, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 7.87, s, 1H, CH-N; 9.84, d, J = 8Hz, 1H, NH

Pr.15: 3.30 to 4.30, m, 22H, 18H of _N-CH2 and 2H of _O-CH2 and 2H of

_S-CH2; 5.25, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55Hz, 2H, _ · A · Α ·· · · · · · · ·

AAAAA

A AAAA

A A A A A A

CH ₂ F; 5, -75, dd, J = 5Hz and J = 8Hz,

OH,

S-lactam-H; 8.15, s, 1H,

CH = N; 8.26, b, 2H, NH; 9.77, d, J = 8 Hz, 1H, NH

Pr.16: 1.18 to 1.50, m, 2H, _CH2 -C; From 1.68 to 1.98, m, 3H, _CH2-C and CH-C; 2.70-2.98, m, 2H, _N-CH2; From 3.10 to 3.38, m, 4H, _N-CH2; 3.53 and 4.53, ABq, J = 18 Hz, 2H, _S-CH2; From 3.62 to 4.15, m, 4H, _N-CH2; 5.3, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.77, d, J = 55 Hz, 2H, CH ₂ F; 5.93, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 7.88, s, 1H, CH = N; 9.83, d, J = 8Hz, 1H,

NH

Př.17: 3.20 to 4.10, m, 9H, 6H of _N-CH2, ¹H from _S-CH2 and 2H of CH ₂ C; 4.38, part of AB-quartet, J = 18 Hz, H, s-CH _2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F; 5.90, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 7.87, s, 1H, CH = N; 7.90-8.20, m, 2H, CH-aromatic; 8.45-8.60, m, 1H, CH-aromatic; 8.78-8.90, m, 1H, CH-aromatic; 9.83, d, J = 8 Hz, 1H, NH; 10.17, b, 1H, OH

Př.18: 3.40 to 3.70, m, 9H, 6H of _O-CH2 and 2H of _N-CH2 and IH from SCH _2; From 3.72 to 4.12, m, 4H, _N-CH2; 4.55, part of AB-quartet, J = 18 Hz, H, s-CH _2; 5.32, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.96, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 7,89,

S, 1H CH = N; 9.63, S, 1H, NH; 9,87, d, J = 8 Hz, 1 H, NH Př.19 ; 3.50 and 4.45, AB-quartet, J = 18 Hz , 2H, _S-CH2; 3.70 - 4,12, m, 4H, _N-CH2; 5.28, d, J = 5Hz, OH, β-lactam-H; 5,78, d, J = 55 Hz ', 2H CH ₂ F; 5.93, dd, J = 5 Hz and J = 8 Hz, 1 H, β-lactam- H; 7,84, S, IH, CH = N; 8.30, s, 2H, NH _2; 9 , 52, s, 1H, NH; 9,83, d,

J = 8Hz, 1H, NH; 11.86, S, 1H, OH

Pr.20: 2.80 -3.02, m, 4H, O-CH _2; From 3.42 to 4.18, m, 9H, 8H of _N-CH2 and IH of _S-CH2; 4.50, part of AB-quartet, J = 18 Ηζ, ΙΗ, S-CH ₂ ; 5.31, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d, J = * 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 7.86, s, 1H, CH = N; 8.29, b, 2H, NH; 9.32, w, ΙΗ, ΝΗ; 9.85, d, J = 8Hz, 1H, NH; 10,16, w, lH, OH · · · · · · · · · · · · · · · · · · · ·

Př.21 :, 1.59, s, 4H, CH ₂ -C; 2.80, 6H, 2H, N-C 1 H 4 H, 32 S, 2H, W- CH ₂ ; 3.53 and 4.53, AB-quartet, J = 18 Hz, 2H, _S-CH2; From 3.68 to 4.12, m, 4H, _N-CH2; 5.24, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.81, d, J = 55 Hz, 2H, CH ₂ F; 5.80, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 8,05,

S, 1H, CH-N; 8.31, S, 2H, NH; 9.80, d, J = 8Hz, 1H, NH

Př.22: 3.35, s, 2H, _N-CH2; 3.42-3.62, m, 3H, 2H of _OCH2 and H of _S-CH2; From 3.65 to 4.10, m, 4H, _N-CH2; 4.46, part of AB-quartet, J = 18 Ηζ, ΙΗ, S-.CH _2; 5.31, d, J = 5 Hz, IH, S-lactam-H; 5.80, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and J = 8 Hz, 1H, [beta] -lactam-H; 7.86, s, 1H, CH-N; 8.30, S, 2H, NH; 9.60, S, 1H, NH; 9.84, d, J = 8Hz, 1H, NH

Př.23: 1.28, s, 4H, _C-CH2; 1.52, s, 4H, _C-CH2; 2.76, s, 2H, _N-CH2; 3,25,

S, 2H, _N-CH2; 3.50 and 4.45, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3.62 '4.10, m, 4H, _N-CH2; 5.30, d, J = 5 Hz, IH, β-lactam-H; 5.80, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and J = 8 Ηζ, ΙΗ, β-lactam-H; 7.85, s, 1H, CH-N; 8.10, b, 3H, NH; 8.30, b, 2H, NH; 9.84, d, J = 8Hz, 1H, NH

Př.24: l, 25, d, J = 5 Hz, 3H, CH _3; From 3.35 to 3.68, m, 4H, 2H of _N-CH2 and H of N-CH and H of _S-CH2; 3.70-4.20, m, 4H, _N-CH2; 4.56, part of ABq, J = 18 Hz, IH, _S-CH2; 5.24, d, J = 5?,?,? -Lactam-H; 5.81, d, J = 55 Hz, 2H, CH ₂ F; 5.84, dd, J = 5 Hz and J = 8 Hz, 1H, beta-lactam-H; 8.09, s, 1H, CH-N; 8.30, br, 2H, NH; 9.81, d, J = 8Hz, 1H, NH

Ex.25: 2,92 - 3.60 , m 5H, 4H od _N-CH2 and H of _S-CH2; 3,62 - 4.15, m, 12H, 8H from _N-CH2 and 4H of _O-CH2; 4.35, part AB- quartet, J = 18 Hz, IH, _S-CH2; 5.16, , d, J = 5Hz , IH, β-lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F; 5,72, dd, J = 5Hz and J = 8Hz, IH, β- lactam-H; 8.10 í s, IH, CH = N; 8,25, S, 2H, NH; 9.76, d, J = 8Hz,

IH,. NH

Ex 26: 1.35, s, 6H, CH ₃ ; From 3.48 to 4.15, m, 7H, 6H of _N-CH2 and H of _S-CH2; 4.74, part of AB-quartet, J = 18 Hz, IH, _S-CH2; 5.32, d, · 99 99 * 99 * 9 99

9 ·· 9 · 9 9 9 9 ·

9 9999 999 «9 9 9 9 9 999 9 9 9 9 9 • 9 99 9 · 9 9 • 999 9909 99 99

J = 5 Hz, 1Η, β-lactam-H; 5.81, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd,

J = 5 Hz and J = 8 Hz, 1H, β-lactam-H; 7.90, s, 1H, CH = N; 9,86, d,

J = 8Hz, 1H, NH; 10.26, b, 1H, OH

Př.27: 1.16, t, J = 7 Hz, 3H, CH _3; 3.33, q, J = 7 Hz, 2H, CH _2;

3.54 and 4.53, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3.68 - 4.12, m,

4H, _N-CH2; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55Hz,

2H, CH ₂ F; 5.94, dd, J = 5 and 8 Hz, 1H, [beta] -lactam-H; 7.87, s, 1H, CH = N; 8.28, b, 2H, NH; 8.68, b, 1H, NH; 9.84, d, J = 8Hz, 1H, NH

Ex 28: 0.87, t, J = 7 Hz, 3 H, CH ₃ ; 1.55, h, J = 7 Hz, 2H, CH _2; 3,24, t,

J = 7 Hz, _N-CH2; 3.52 and 4.54, AB-quartet, J = 18 Hz, 2H, _S-CH2; 4.12, 3.65, m, 4H, _N-CH2; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d,

J = 55 Hz, 2H, CH ₂ F; 5.93, dd, J = 5 and 8 Hz, 1H, [beta] -lactam-H; 7.87,

S, 1H, CH = N; 8.29, S, 2H, NH; 8.68, b, 1H, NH; 9.84, d, J = 8Hz,

1 H, NH

Ex.2 9; 2.90-3.05, m, 2H, _N-CH2; 3.40 - 4.18, m, 15H, 6H of _N-CH2 and 8H od O-CH ₂ and IH of _S-CH2; 4, 55, part of AB-Quartet, J = 18 Hz, 1 H, _S-CH2; 5.33, d, J = 5Hz, 1H, β-lactam-H; .5,80, d, J = 55Hz, 2H,

CH ₂ F; 5.95, dd, J = 5 and 8 Hz, 1H, [beta] -lactam-H; 7.90, s, 1H, CH = N; 8.26, S, 2H, NH; 8.77, b, 1H, NH; 9.82, d, J = 5Hz, 1H, NH

Př.30: 1.72 to 2.02, m, 2H, CH _2; 2.54, s, 3H, N-CH _3; 2.94, s, 2H, NCH _2; From 3.34 to 3.64, m, 3H, 2H of _N-CH2 and IH of _S-CH2; 3.70-4.10, m, 4H, _N-CH2; 4.55, part of AB-quartet, J = 18 Hz, H, s-CH _2; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.80, d, J = 55 Hz, 2H, CH ₂ F; 5.92, dd, J = 5 and 8 Ηζ, ΙΗ, β-lactam-H; 7.87, s, 1H, CH = N; 8.28, b, 2H, NH; 8.88, S, 1H, NH; 9.84, d, J = 8, ΙΗ, NH

Př.31: 1.80-2.05, m, 2H, CH _2; 2.88-3.12, m, 4H, _N-CH2; 3.40, s, 2H, _N-CH2; 3.53 and 4.51, AB-quartet, J = 18 Hz, 2H, _S-CH2; .3,62-4,12, m, 6H, 4H of _N-CH2 and 2H of _O-CH2 ; 5.30, d, J = 5 Hz, 1 H, β-lactam-H, 5.77, d, J = 55 Hz, ·· ¢ 0 φφ φφ · · · · · · 4 ΦΦΦ 4 Φ Φ φ • • 4 4 4 4 4 4 4 4 φ φ

2Η, CHjF-; 5.82, dd, J = 5 and 8Hz, I H, β-lactam -% ‘&, θΓ,, * ϊ · · * CH = N; 8.30, br, 2H, NH; 9.80, d, J = 8Hz, 1H, NH

Př.32: 1.82-2.10, m, 2H, CH _2; 2.75, s, 6H, _N-CH3; 3,00-3,18 m

2H, _N-CH2; From 3.32 to 3.48, m, 2H, _N-CH2; 3.54 and 4.54, AB-quartet, J = 18 Hz, 2H, _S-CH2; From 3.68 to 4.12, m, 4H, _N-CH2; 5.30, d, J = 5?,?,? -Lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.92, dd, J = 5 and 8 Hz, 1H, [beta] -lactam-H; 7.86, s, 1H, CH = N; 8.30, br, 2H, NH; 8.85, b, 1H,

NH; 9.84, d, J = 8Hz, 1H, NH

Př.33: 1.78 to 2.02, m, 2H, CH _2; 2,95-3-75, m, 11H, 10H of _N-CH2 and

¹H from _S-CH2; 4.10-4.35, m, 2H, O-CH _2; 4.65, part of AB-Quartet,

J = 18 Hz, H, s-CH _2; 5.27, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d,

J = 55 Hz, 2H, CH ₂ F; 5.82, dd, J = 5 and 8 Hz, 1H, [beta] -lactam-H; 8.24, b, 2H, 1H from CH = N and 1H from NH; 8.32, b, 1H, NH; 9.77, d, J = 8Hz,

1 H, NH Ex.34: 1 , 82 - 2.02, m, 2H, CH ₂ ; 2.55, s, 3H, N-CH _3; 2.88 - 3.02 ,, m, 2H, _N-CH2; 3.48 - 4.22, m, 12H, 8H of N-CH ₂ and 2H of 0- _CH2 and 2H from _S-CH2; 5.27, d, J = 5 Hz, 1H, β-lactam-H; 5,78, d, J = 55Hz 2H, CH ₂ F; 5.82, dd, J = 5 and 8 Hz, 1 H, β-lactam-H; 8,10,

s, 1H, CH = N; 8.28, b, 2H, NH; 9.78, d, J = 8Hz, 1H, NH

.35: 1.82 to 2.08, m, 2H, _CH2; 2.85 - 3,10 m 4H, _N-CH2; 3.38 4.22, m, 14H, 8H of N-CH2 and 4H of N-CH2 _{; O-CH2} and 2H of _S-CH2; 5.17, J = 5 Hz, 1 H, β-lactam-H; 5,80, d, J = 55Hz 2H, CH ₂ F; 5,82, J = 5 and 8 Hz, 1H, β-lactam-H; 8,08, s, 1H, CH = = N; 8.27, w, 2H, ; 9.75, d, J = 8Hz, 1H, NH

Př.36: 1.82 to 2.12, m, 2H, _CH2; 2.77, s, 6H, _N-CH3; 3.00 3.22, m, 2H, _N-CH2; From 3.45 to 4.12, m, 12H, 8H of _N-CH2 and 2H of 0CH ₂ and 2H of _S-CH2; 5.20, d, J = 5?, 1H,? -Lactam-H; 5,82, d,

J = 55 Hz, 2H, CH ₂ F; 5.85, dd, J = 5 and 8 Hz, 1H, [beta] -lactam-H; 8.09, s, 1H, CH = N; 8.30, br, 2H, NH; 9.78, d, J = 8Hz, 1H, NH • · φ φ '

Př.37: 2.72, s, 6Η, N-CH _3; From 3.42 to 4.08, m, 9H, .6H of _N-CH2 and 2H of _O-CH2 and 1H of _S-CH2; 4.56, part of AB quartet, J = 18 Hz, 1H, _S-CH2; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 and 8 Hz, 1H, [beta] -lactam-H; 7.84, s, 1H, CH-N; 8.24, b, 2H, NH; 9.77, d, J = 8Hz, 1H, NH

Př.38: 1.55 to 1.82, m, 2H, _CH2 -C; 3.30-3.65, m, 5H, 2H of _N-CH2 and 2H of _O-CH2 and 1H of _S-CH2; 3.70-4.10, m, 4H, _N-CH2; 4.51, part

AB-quartet, J = 18 Hz, 1H, _S-CH2; 5.32, d, J = 5 Hz, 1H, [beta] -lactamH; 5.8, d, J = 55 Hz, 2H, CH ₂ F; 5.95, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.88, s, 1H, CH-N; 8.32, b, 2H, NH; 8.74, m, 1H, OH; 9.73, br, 1H, NH; 9.87, d, J = 8Hz, 1H, NH

Př.39: 3.20, d, J = 5 Hz, 3H, N-CH _3; From 3.45 to 4.05, m, 9H, 6H of _N-CH2 and 2H of _O-CH2 and 1H of _S-CH2; 4.34, part of AB-quartet, J = 18 Hz, lH, _S-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F; 5.95, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.89, s, 1H, CH-N; 8.33, b, 2H, NH; 8.58, d, J = 5 Hz, 1H, NH; 9.86, d, J = 8Hz, 1H, NH

Př.40: 2.65 to 3.05, m, 2H, _N-CH2; 3.25-3.45, m, 2H, _N-CH2; 3.54 and 4.55, AB-quartet, J = 18 Hz, 2H, _S-CH2; From 3.65 to 4.12, m, 5H, 4H of _N-CH2 and 1H of O-CH; 5.21, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.80, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 8.05, S, 1H, CH-N; 8.29, b, 2H, NH; 9.78, d; J = 8 Hz, 1 H, NHΦΦ

Př.41: 2.80-3.20, m, 10H, _N-CH2; 3.40-3.65, m, 3H, 1H of _S-CH2 and 2H of _N-CH2; From 3.70 to 4.05, m, 4H, _N-CH2; 4.45, part of AB-quartet, J = 18 Hz, 1H, _S-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F; 5.85, d, J = 5 Hz, 1H, [beta] -lactam-H; 7.93, s, 1H, CH-N

Př.42: 1.65-1.92, m, '2H, _CH2 -C; 3.12-3.32, m, 2H, N-CH _Z; 3,40-3,58,

3H, 2H of _N-CH2 and 1H of _S-CH2; From 3.62 to 4.12, m, 4H, _N-CH2; 4.55, part of ABq, J = 18 Hz, lH, _S-CH2; 5.29, d, J = 5Hz, 1H, β-lactam-H; 5.78, d, • ·

J = 55 Hz, 2H, CH ₂ F; 5.92, dd, J = 5 Hz and 8 Ηζ, ΙΗ, β-lactam-H; 7.87 * s',

1 H, CH = N; 9.86, d, J = 8Hz, 1H, NH; 10.01, b, 1H, NH

Př.43: 1.20, t, J = 7 Hz, 3H, CH _3; From 3.45 to 4.22, m, 12H, 8H of _NCH2 and 2H of _O-CH2 and 2H of _S-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactamH; 5.78, d, J = 55Hz. 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, [beta], [beta] -lactam-H; 7.91, S, 1H, CH-N; 8.29, b, 2H, NH; 8.61, m, 1H, OH; 9.84, d, J = 8 Hz, 1H, NH

Př.44: 1.82-2.08, m, 4H, CH ₂ -C; 2.82-3.10, m, 6H, N-CH _2; 3.3 5-3,65 m,

3H, 2H of _N-CH2 and 1H of _S-CH2; From 3.70 to 4.12, m, 4H, _N-CH2; 4.55, part of ABq, J = 18 Ηζ, ΙΗ, _S-CH2; 5.30, d, J = 5Hz, 1H, β-lactam-H; 5.78, d, J = 55 Hz, 2H CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 8.01, S, 1H, CH-N; 8.30, S, 2H, NH; 9.78, d, J = 8 Hz, 1H, NH

Př.45: 1.30 to 1.70, m, 4H, CH ₂ -C; From 1.85 to 2.10, m, 4H, CH ₂ -C;

2, 85-3.10, m, 1H, CH- C; 3,40 - 3,55, m, 2H, 1H of CH and 1H from WITH- CH ₂ ; 3.56 - 4.10, m, 4H, _N-CH2; r 4.59 , part of AB-Quartet, J · = 18 Hz , 1H, _S-CH2; 5.29 , d, J = 5 Hz ΙΗ, β · -lactam-H; 5.78, d, J- = 55 Hz , 2H, CH ₂ F; 5,94, dd, J = 5 Hz and 8 Hz, 1H, β-lactam-H; 7,85, with, 1H CH = N; 8,30 Š 6H, NH; 9,88., d, J = = 5 Hz, 1 H, NH; 10,01, with, 1H , NH Ex .46: 1.15, t, J = 7 Hz, 3H, _CH3; 3.4.0 3.62, m, 3H, 2H; CH ₂

and 1H of _S-CH2; From 3.70 to 4.10, m, 4H, _N-CH2; 4.55, part of AB-quartet, J = 18 Hz, 1H, _S-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.81, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.85, S, 1H, CH-N; 8.30, br, 2H, NH; 9.83, d, J = 8 Hz, 1H, NH

Př.47: 3.20-4.10, m, 10H, 6H of _N-CH2 and 2H of _O-CH2 and 1H of O-CH and 1H of _S-CH2; 4.55, part of AB- quartet, J = 18 Hz, 1H, _S-CH2; 5.30, d, J = 5?,?,? -Lactam-H; 5,8Í, d, J = 55 Hz, 2H, _CH2 F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, β-lactam-H; 7.87, s, 1H, CH-N; 8, 28, b, 2H, NH; 8.68, br, 1H, OH; 9.47, b, 1H, OH; 9.84, d, J = 8 Ηζ, ΙΗ, ΝΗ • • · »»

Př.48: 1.18, t, J = 7 Hz, 3H, CH _3; 3.16, d, J = 5 Hz, 3H, N-CH _3; From 3.45 to 3.68, m, 3H, 2H of _N-CH2 and H of _S-CH2; From 3.70 to 4.10, m, 4H, _N-CH2; 4.29, part of AB-quartet, J = 18 Hz, IH, _S-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.81, d, J = 55 Hz, 2H, CH ₂ F; 5.96, dd, J = 5 Hz and 8 Hz, 1H, β-lactam-H; 7.87, s, 1H, CH-N; 8.29, b, 2H, NH; 8.66, d, J = 5Hz, 1H, NH; 9.84, d, J = 8Hz, 1H, NH

Př.49 1.16, t, J = 7Hz / 3H, CH _3; 1.88 - 2,10 , m, 2H, _CH2 -C; 2,78, s, 6H, _N-CH3; 3.00 - 3.20, m, 2H, _N-CH2; 3.40 - 4.20 m, 10H, 8H of _N-CH2; 2H of _S-CH2; 5.17, d, J = 5 Hz IH, β-lactam-H; 5,80, d, J = 55 Hz, 2H, CH ₂ F; 5,82, dd, J = 5 Hz and 8 Hz, IH, β-

lactam-H; 8.05, s, 1H, CH-N; 8.28, b, 2H, NH; 9.74, d, J = 8Hz,

1H, NH

Pž.50: 1.20, t, J = 7 Hz, 3H, CH _3; From 1.75 to 2.00, m, 2H, _CH2 -C; From 2.90 to 3.60, m, 9H, 8H of _N-CH2 and H of _S-CH2; 4.08 - 4.38, m, 2H, _N-CH2; 4.65 ', part of AB-quartet, J = 18 Hz, IH, _S-CH2; 5.28, d, J = 5 Hz, 1H, β-lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F; 5.84, dd, J = 5 Hz and 8 Hz, 1H, β-lactam-H; 8 ,: 24, b, 2H, IH of CH = N and IH of NH; 8.37, b, 1H, NH; 9.77, d, J = 8 Hz, 1 H, NH

Př.51: l, 14 t, J = 7 Hz, 3H, CH _3; 1.30-1.75, m, 4H, CH ₂ -C; 1.88-2.12, m, 4H, CH ₂ -C; 2.88-3.10, m, H, N-CH; 3.40 to 4.22, m, 9H, 6H of _N-CH2 and H of N-CH and 2H of _S-CH2; 5.28, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, 'd, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.93, S, 1H, CH-N; 8.27, b, 5H, NH; 9.85, d, J = 8Hz, 1H, NH

Př.52: 1.25-1.70, m, 4H, CH ₂ -C; 1.85-2.12, m, 4H, CH ₂ -C; 2,88-

3,10 m 1 H, N-CH; 3.4 5-4,28, , m, 11H, 6H from N- CH ₂ a IH from N-CH and 2H from _O-CH2 and 2H from _S-CH2; 5.15, d, J = 5 Hz IH, β-lactam-H; 5,81, d, J = 55Hz 2H, CH ₂ F; 5,74,. dd, J = 5Hz and 8 Hz, IH, β- lactam-H Z 8/18 _Z 's / 3H, IH od CH = N and 2H from NH; 8,28, S, 3H, NH;

9.79, d, J = 8Hz, 1H, NH

4 4 44

44 444444 44 4

4,444 4,444

Př.53: 2.72 -2.92, m, 2H, _CH2 -C; 3.10-3.30, m, 6H, N-CH3;

From 3.32 to 3.60, m, 3H, 2H of _N-CH2 and 1 H of _S-CH2; 3.62 - 4.15, m,

8H, _N-CH2; 4.59, part of AB-quartet, J = 18 Hz, IH, _S-CH2; 5.29, d,

J = 5 Hz, 1H, β-lactam-H; 5,81 ,. d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd,

J = 5 Hz and 8 Hz, 1H, β-lactam-H; 7.86, s, 1H, CH-N; 8.08, w, 2H,

NH; 8.28, b, 2H, NH; 8.59, b, 1H, NH; 8.96, S, 1H, NH; 9,84, d,

J = 8Hz, 1H, NH

Př.54: 1.70 to 1.92, m, 2H _of CH ₂ -C; 2,76, d, J = 4 Hz, 6H, _N-CH3; From 3.10 to 3.25, m, 2H, _N-CH2; 3.27 - 3.42, m, 2H, _N-CH2; 3.41 a * 4.51, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3.70 - 4.10, m, 4H, N- CH ₂ ; 5.17, d, J = 5Hz, IH, β- lactam-H; 5,73, dd, J = 5 Hz and 8 Hz, '* 1H, β-lactam-H; 5.78, d, J = ⁵⁵ Hz, 2H, CH ₂ F ; 7.72, br, 2H, NH;

8.04, s, 1H, CH-N; 8.26, b, 2H, NH; 8.60, br, 1H, NH; 9.76, d, J = 8Hz, 1H, NH

Př.55: 3.04, s, 3H, N-CH _3; 3.53 and 4.54, AB-quartet, J = L8 Hz, 2H, _S-CH2; From 3.68 to 4.04, m, 4H, N-CH _2; 5.29, d, J = 5 Hz, IH, β-lactam-H; 5,7.9, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.85, s, IH, CH = N; 8.29, b, 2H, NH; 9.83, d, J = 8, Ηζ, ΙΗ

Př.56: 3.16, s, 3H, N-CH _3; 3.17, s, 3H, N-CH _3; 3.57 and 4.32, ABq, J = 18 Hz, 2H, _S-CH2; From 3.68 to 4.08, m, 4H, _N-CH2;. 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F; 5.95, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.86, s, 1H, CH-N; 8.30, br, 2H, NH; 8.64, b, 1H, NH; 9.84, d ,. J = 8Hz, 1H, NH

Př.57: l, 21, t, J = 7 Hz, 3H, CH _3; 3.10, s, 3H, N-CH _3; From 3.48 to 4.10, m, 7H, 6H of _N-CH2 and H of _S-CH2; 4.20, part of AB-quartet, J = 18 Hz, IH, _S-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.95, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H ;. 7.89, s, 1H, CH-N; 8.30, br, 2H, NH; 8.69, br, 1H, NH; 9.84, d, J = 8Hz,

IH, NH • · · * · · · · · · · υ υ υ φ φ φ φ φ φ φ φ φ φ φ φ

Ex.58:. 1.30-1.75, m, 4Η, CH ₂ -C; 1.88-2.12, m, 4Η, CH ₂ -C * 2 * * * 8 5-3,02 m *

1 H, N-CH; 3.07, s, 3Η, CH3; 3.45 to 4.21 m, 7Η, 4Η of _N-CH2 and H from

N-CH and 2H of _S-CH2; 5.28, d, J = 5 Hz, 1H, [beta] -lactam-H; 5,80, d,

J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H;

7.91, s, 1H, CH-N; 8.31, b, 3H, NH; 9.85, d, J = 8Hz, 1H, NH

Ex.59: 3.14, s, 3H, CH3; From 3.50 to 4.10, m, 9H, 6H of _N-CH2 and 2H of _O-CH2 and H of _S-CH2; 4.25, part of AB-quartet, J = 18 Hz, IH, .SCH _2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55Hz, 2H,

CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.89, s, IH,

CH = N; 8.23, b, 2H, NH; 9.75, d, J = 8Hz, 1H, NH

Př.60: 3.48 to 4.10, m, 13H, 8H of _N-CH2 and 4H of _O-CH2 and H from

_S-CH2; 4.20, part of AB-quartet, J = 18 Hz, IH, _S-CH2; 5.13, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.72, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 8.16, s, 1H,. CH = N; 8.24, b, 2H, NH; 9.76, d, J = 8Hz, 1H, NH

Ex 61: 1.24, t, J = 7Hz, 6H, CH 2; From 3.05 to 3.45, 'm, 6H, _N-CH2; 3.54 and 4.55, AB-quartet, J = 18 Hz, 2H, _S-CH2; From 3.70 to 4.10, m, 6H, _N-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.80, d, J = 55 Hz, 2H, CH ₂ F; 5.96, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.86, s, 1H, CH-N; 8.28, b, 2H, NH; 9.83, d, J = 8Hz, 1H, NH; 10.89, S, IH,

NH

Př.62: 1.90 to 2.14, m, 2H, _CH2 -C; 2.73, d, J = 4 Hz, 6H, N-CH3;

From 3.00 to 3.20, m, 2H, _N-CH2; From 3.32 to 4.10, m, 7H, 6H of _N-CH2 and H of _S-CH2; 4.60, part of AB-quartet, J = 18 Hz, IH, _S-CH2; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.86, s, 1H, CH-N; 8.30, br, 2H, NH; 9.83, d, J = 8Hz, 1H, NH; 10.97, b, 1H, NH

Ex.63: 1.24, t, J = 7Hz, 6H, CH3; From 3.05 to 3.40, m, 6H, _N-CH2; 3.53 'and 4.56, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3.70 4.18, m 999 9 9 9

6H, _N-CH2; 5.30 , d, J = 5Hz, 1 H, β-lactam-H; 5,79, d, J = 55 Hz, 2H, CH ₂ F; 5,94, dd, J = 5 Hz a 8 Hz, 1 H, β-lactam-H; 7.87 s, OH, CH = N; 8.28 W, 2H, NH; 9.02 s, 1H, NH; 9,84, d, J = 8Hz, OH,

NH; 10.26, b, 1H, NH; 10.89, S, 1H, NH

Př.64; l 21 t, J = 7 Hz, 6H, CH _3; 3.08-3.30, m, 7H, 4H of N-CH2 and 3H of N-CH2 _;

N-CH _3; 3.32 -3.50, m, 2H, _N-CH2; 3.58 and 4.24, AB-quartet, J = 18 Hz, 2H,

_S-CH2; From 3.75 to 4.10, m, 6H, _N-CH2; 5.12, d, J = 5Hz, 1H, β-lactam-H; 5.70, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F; 8.15, s, 1H, CH = N; 8.23, b, 2H, NH; 9.75, d, J = 8Hz, 1H, NH

Ex 65: 2.79, d, J = 4 Hz, 6H, N-CH ₃ ; From 3.32 to 3.48, m, 2H, _N-CH2;

3.53 and 4.56, AB-quartet, J = 18 Hz, 2H, _S-CH2; From 3.68 to 4.04, m, 6H, _N-CH2; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.86, s, 1H, CH = N; 8.28, b, 2H, NH; 9.84, d, J = 8Hz, 1H, NH; 10.95, w, lh,

NH

Př.66 (in DMSO-d ₆ / CF ₃ COOD): 3.50 and 4.31, AB-quartet, J = 18 Hz,

2H, _S-CH2; From 3.75 to 4.20, τη, 4H, _N-CH2; 5.17, s, 2H, _OCH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.33, s, 1H, CH; 7.87, s, 1H, CH = N; 8.32, s, 1H, CH; 9.84, d, J = 8Hz, 1H, NH

Př.67: 1.10 to 2.20, m, 8H, CH ₂ -C; 3.12-3.40, m, 1H, N-CH;

3.55 and 4.55, AB-quartet, J = 18 Hz, 2H, _S-CH2; From 3.65 to 4.18, m, 5H, 4H of _N-CH2 and Ih, from N-CH; 5.23, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.84, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 8.10, s, 1H, CH = N; 8.27, b, 3H, NH; 9.82, d, J = 8Hz, 1H, NH

Př.68: 1.10 to 2.20, m, 8H, CH ₂ -C; 3.18-3.40, m, 1H, N-CH;

3.55 'and 4.59, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3,68 - 4,20, m, so · · φ · • • φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ · · φ · φ φ

5Η, 4Η from N-CH ₂ and 1Η from N-CH; 5.21., D, J = 5 Hz, better, "* i? -I * acts-ft *;

5.78, d, J = 55 Hz, 2H, CH ₂ F; 5.80, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 8.07, s, 1H, CH-N; 8.26, b, 3H, NH; 9.77, d, J = 8Hz,

1H, NH

Př.69: 0.88, t, J = 7 Hz, 3H, CH _3; 1/40 - 1.70, m, 2H, _CH2 -C; From 3.30 to 3.48, m, 2H, _N-CH2; 3.53 and 4.55, AB-quartet J = 18 Hz 2H, _S-CH2; From 3.65 to 4.08, m, 4H, _N-CH2; 5.29, d, J = 5 Hz, 1 H, β- lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.93, dd, J = 5 Hz and 8 Hz,

1H, β-lactam-H; 7.85, s, 1H, CH-N; 8.29, b, 2H, NH; 9.84, d, J = 8Hz, 1H, NH

Př.70: 0.90, t, J = 7 Hz, 3H, CH _3; From 1.48 to 1.72, m, 2H, _CH2 -C;

3.16, d, J = 5Hz, 3H, N-CH _3; 3.32 -3.50, m, 2H, _N-CH2; 3, 58 a 4,25, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3.70 - - 4, 1.0,. m, 4H , N- CH ₂ ; 5.28, d, J = 5 Hz, 1H, β-lactam-H; 5,79, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = = 5 Hz and 8 Hz, 1H, β-lactam-H; 7.87, with, 1H, CH = N; 8.29, b, 2H , NH; 8.71 , d, J = 5Hz, 1 H, NH; 9,84, d, J = 8

Hz, 1 H, NH

Př.71: 1.00 to 1.44, m, 12H, CH _3; 3.54 and 4.59, AB-quartet, J = 18 Hz, 2H, SCH _2; From 3.75 to 4.30, m, 6H, 4H of _N-CH2 and 2H of N-CH; 5.32, d, J = 5Hz, 1H, β-lactam-H; 5.80, d, J = 55 Hz, 2H, CH ₂ F; 5.98, dd, J = 5 Hz and 8 Ηζ, ΙΗ, β-lactam-H; 8.00, s, 1H, CH = N; 8.30, b, 2H, NH, 9.53, b, ΙΗ, ΙΗ; 9.86, d, J = 8 Hz, 1H, NH; 10,39, br, 1H, NH; 10.78, S, 1H, NH

Ex.72: 1.19, d, J = 7 Hz, 6H, CH ₃ ; 3.53 and 4.55, AB-quartet, J-18 Hz, 2H, _S-CH2; 3.65 - 4,02, m, 4H, _N-CH2; 4,15 - 4,32 m 1H, N-CH; 5,29, d, J = 5 Hz, 1H, β-lactam-H; 5,80, d, J = 55Hz 2H, CH ₂ F; 5,94, dd , J = 5 Hz and 8 Hz, 1H, β-lactam-H; 7.85 s, 1H, CH = N; 8,28, SX WITH, 2H, NH; 9,83, d, J = 8 Hz 1 H, NH Ex.73: 1.30 1,90, m, 6H, CH ₂ -C; 2.82 - 3.05, m, 2H, N- -CH ₂ ;

From 3.24 to 3.65, 5H, 4H of _N-CH2 and 1H of _S-CH2; 3.75 - 4.10, m, 6H, ·· ···· # # AAA · «· A · A · AA · · A AA ΑΑΑΑΑΑΑ AA A • AAA

A · A · AA ··

_N-CH2; Fourth, 58, part of AB-quartet, J = 18 Hz, H, s-CH _2; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.80, d, J = 55Hz,. 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.85, s, 1H, CH = N; 8.29, b, 2H, NH; 9.84, d, J = 8 Hz, 1H, [beta] -lactam-H; 10.95, b, 1H, NH

Př.74: 0.90, t, J = 7 Hz, 3H, CH _3; From 1.25 to 1.42, m, 2H, _CH2 -C;

From 1.50 to 1.70, m, 2H, _CH2 -C; 3.16, d, J = 5 Hz, 3H, N-CH _3; 3.40 3.50, m, 2H, _N-CH2; 3.58 and 4.25, AB-quartet, J = 18 Hz, 2H, SCH _2; From 3.70 to 4.12, m, 4H, _N-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactamH; 5.78, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.87, s, 1H, CH = N; 8.29, b, 2H, NH; 8.69, d, J = 5Hz, 1H, NH; 9.84, d, J = 8, ΙΗ, NH

Př.75: 0.90, t, J = 7 Hz, 3H, CH _3; 1.20-1.40, m, 2H, _CH2 -C; 1.45-1.65, m,

2H, _CH2 -C; 3.35-3.50, m, 2H, _N-CH2; 3.53 and 4.55, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3.70-4.10, m, 4H, _N-CH2; 5.30, d, J = 5?,?,? -Lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5Hz. and 8 Hz, 1 H, β-lactam-H; 7.85, s, 1H, CH = N; 8.29, b, 2H, NH; 9.84, d, J = 8Hz, 1H, NH

Př.76: 1.30-1.90, m, 6H, _CH2 --C; From 2.85 to 3.08, m, 2H, _N-CH2; 3.20, d, J = 5 Hz, 3H, N-CH _3; 3.30-3.70, m, 5H, 4H of _N-CH2 and IH from S-. CH ₂ ; From 3.75 to 4.10, m, 6H, _N-CH2; 4.21, part of AB-quartet, J = 18 Hz, H, s-CH _2; 5.28, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.88, s, 1H, CH = N; 8.26, b, 2H, NH; 9,11 ,. d, J = 5 Hz, 1H, NH; 9.84, d, J = 8Hz, 1H, NH

Př.77: 1.78 to 2.10, m, 4H, CH ₂ -C; 3.00-3.20, m, 2H, _N-CH2, -3.40 to 3.65, m,

5H, 4H of _N-CH2 and IH of _S-CH2; 3.80-4.10, m, 6H, _N-CH2; 4.59, part of AB-quartet, J = 18 Hz, 1 H, β-lactam-H; 5.30, d, J = 5 Ηζ, ΙΗ, β-lactamH; 5.80, d, J = 55 Hz, 2H, _CH2 F; 5.93, dd, J = 5 Hz and 8 Hz, Ih β-lactam-H; 7.86, s, 1H, CH = N; 8.28, b, 2H, NH; 9.84, d, J = 8Hz, 1H, NH

 • AAA AAA AA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

A AAAA AAAA

AAAAAAA

A A AA AA AAA A

AAAA AAAA «AA AA AA

Př.78: 3.54 and 4.54, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3.62-4.18, m, 4H,

_N-CH2; 4.34, s, 2H, _N-CH2; 5.33, d, J = 5 Hz, 1H, [beta] -lactam-H; 5,81, d,

J = 55. Hz, 2H, CH ₂ F; 5.96, dd, J = 5 Hz and 8 Ηζ, ΙΗ, S-lactam-H; 7.93, s,

IH, CH = N; 8.3 O, w, 2H, NH; 9.86, d, J = 8 Ηζ, ΙΗ, ΝΗ

Př.79: 0.87, t, J = 7 Hz, 3H, CH _3; From 1.18 to 1.40, m, 4H, CH ₂ -C;

From 1.42 to 1.68, m, 2H, _CH2 -C; From 3.30 to 3.50, 2H, _N-CH2; 3.53 and 4.54,

AB-quartet, J = 18 Hz, 2H., _S-CH2; 3.70 - 4,10, m, 4H, _N-CH2; 5.30, d, J = 5Hz, IH, S-lactam-H; 5.79, d , J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5Hz and 8 Hz, IH, S- lactam-H; 7,85, s, IH, ' CH = N; 8.26, b, 2H, NH; 8 , 70, S, 2H, NH; 9,83, d, J = 8Hz , 1H, NH

Př.80: 0.86, t, J = 7 Hz, 3H, CH _3; From 1.20 to 1.40, m, 6H, _CH2 --C; From 1.42 to 1.70, m, 2H, _CH2 -C; From 3.38 to 3.51, m, 2H, _N-CH2; 3.54 and 4.54, AB-quartet, J = 18 Hz, 2H, _S-CH2; From 3.70 to 4.10, m, 4H, _NCH2; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F ;. 5.93, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.86, s, 1H, CH-N; 8.25, b, 2H, NH; 8.77, br, 2H, NH; 9.79, d, J = 8Hz, 1H, NH

Př.81: 0.85, t, J = 7 Hz, 3H, CH _3; From 1.12 to 1.38, m, 8H, CH ₂ -C; From 1.40 to 1.68, m, 2H, _CH2 -C; From 3.35 to 3.62, m, 3H, 2H of _N-CH2 and H of _S-CH2; From 3.70 to 4.10, m, 4H, _N-CH2; 4.55, Part of AB-quartet, J = 18 Hz, IH, _S-CH2; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.93, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7,85 ,. s, 1H, CH = N; 8,27 ,. S, 2H, NH; 9.84, d, J = 8Hz, 1H, NH

Př.82: 3.50 to 3.78, m, 5H, 4H of _N-CH2 and H of _S-CH2; 4.00 4.48 m, 5H, 4H of _N-CH2 and H of _S-CH2; 5.32, d, J = 5 Hz, 1H, Slaktam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.90, S, 1H, CH-N; 8.28, b, 2H, NH; 9.83, d, J = 8Hz, 1H, NH; 10.07, bs, 1H, NH

Př.83: 1.90 to 2.05, m, 2H, _CH2 -C; From 3.28 to 3.46, m, 4H, _N-CH2;

3.54 'and 4.45, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3.68 - 4.10, m,

· 99 99 99

9 9 9 9 9

9 9 9 9 9

99 99 99999 99 9

9 9 9 · · ·

4H, _N-CH2; 5.31, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.7 9 *, '** d *, * ”j = 5 * 5' Hz,

2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz ,. 1 H, β-lactam-H; 7.87, s, 1H,

CH = N; 8.30, br, 2H, NH; 9.26, S, 1H, NH; 9.84, d, J = 8 Hz, 1H, NH

Př.84: 1.10 to 1.30, m, 12H, CH _3; 3.17, d, J = 5 Hz, 3H, N-CH _3;

From 3.48 to 3.70, m, 3H, 2H of _N-CH2 and IH, _S-CH2; 3.75 - 4.00, m,

4H, _N-CH2; 4.37, part of AB-quartet, J = 18 Hz, H, s-CH _2; 5.32, d,

J = 5 Hz, 1 H, β-lactam-H; 5.65, part of the doublet, 1H, CH ₂ F; 5.80 6.08, m, 4H, CH ₂ from ¹H F by ¹H and S-lactam-H and 2H of _O-CH2; 7.79, s, 1H, CH = N; 8.44, br, 1H, NH; 8.65, d, J = 5 Hz, 1H, NH; 9.86, d, J = 8 Hz, 1H,

NH

Př.85: l, 21, t, J = 7 Hz, 3H, CH _3; 3.14, s, 6H, _N-CH3; 3.30-3.55, kv, J = 7Hz, 2Ή, N-CH ₂ ; 3.61, part of AB-quartet, J = 18 Hz, 1H, _S-CH2; 3704.20 m, 5H, 4H of _N-CH2 and 1Ή of _S-CH2; 5.28, d, J = 5 ', ΙΗ, β-lactam-H; 5.79, d, J = 55. Hz, 2H, CH ₂ F; 5.95, dd, J = 5 Hz and 8 Ηζ, ΙΗ, βlactam-H; 7.94, s, 1H, CH = N; 8.31, b, 2H, NH; 9.84, d, J = 8, Ηζ, Ηζ

Př.86: 3.12, s, 3H, N-CH _3, 3.14, s, 6H, _N-CH3; 3.61, part of ABq, J = 18Hz, H, s-CH _2; From 3.70 to 4.18, m, 5H, 4H of _N-CH2 and IH of _S-CH2; 5.29, d ,. J = 5 Hz, 1 H, β-lactam-H; 5.79, d, J = 55Hz,

2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.92, s, 1H,

CH = N; 8.32, b, 2H, NH; 9.84, d, J = 8Hz ,. 1 H, NH

Př.87: '1.12-1.30, m, 6H, CH _3; 3.09, s, 3H, N-CH _3; 3.32-4.20, m, 10H, 8H;

_N-CH2 and 2H of _S-CH2; 5.28, d, J = 5 Ηζ, ΙΗ, β-lactam-H; 5.78, d, J = 55

Hz, 2H, CH ₂ F; 5.95, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.95, s, 1H,

CH = N; 8.31, b, 2H, NH, 9.84, d, J = 8Hz, [delta], [delta]

Př.88: 0.92, t, J = 7 Hz, 3H, CH _3; From 1.50 to 1.75, m, 2H, _CH2 -C;

3.14, s, 6H, _N-CH3; From 3.30 to 3.50, m, 2H, _N-CH2; 3.61, part of ABq, J = 18Hz, H, s-CH _2; From 3.72 to 4.18, m, 5H, 4H of _N-CH2 and

¹H from _S-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5,80 ,. d, J = 55Hz,

# · # ♦ ♦ »» »» »» 4 4 4 4 • 4 4 4 • • 4 4 • • 4 • 4 4 • • • 4 4 9 • 9 4 4 9 4 9 9

Itt 4449 44 49 44 44

2H, CH ₂ E; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.94, s, 1H, CH-N; 8.30, br, 2H, NH; 9.84, d, J = 8Hz, 1H, NH

Ex.89: 3.28, s, 3H, N-CH _3; 3,42 - 3,72 m 5H, 4H of _N-CH2 and H from _S-CH2; 3.90 4.50, m, 5H, 4H av N-CH ₂ and IH Of _S-CH2; 5,29, d, J = 5Hz, IH, β-lactam-H; 5,80, d, J = 55 Hz, 2H, CH ₂ F; 5,95,

dd, J = 5 Hz and 8 Hz, 1H, β-lactam-H; 7.91, s, 1H, CH-N; 8.30, br, 2H, NH; 9.85, d, J = 8Hz, 1Ή, NH

Př.90: 1.90 to 2.12, m, 2H, _CH2 -C; From 3.20 to 3.60, m, 8H, 4H of NCH ₂ and 3H from NCH ₃ and H of _S-CH2; From 3.62 to 4.15, m, 5H, 4H of _N-CH2 and H of _S-CH2; 5.27, d, J = 5. Hz, IH, β-lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.91, s, 1H, CH-N; 8.31, S, 2H, NH; 9.84, d, J = 8Hz, 1H, NH

Př.91 (diaisostereomerní mixture): 1.20-1.40, m, 3H, CH _3; 3.30-3.65, m, 2H, H of N-CH and H of _S-CH2; 3.95-4.30, m, 2H, _N-CH2; 4.53, part

AB-quartet, J = 18 Hz, H, _S-CH2; 5,30 d, J = 5 Hz, IH, β-lactam- H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.93, dd, J = 5 Hz and 8Hz, IH, β- lactam-H; 7,83, p 1H, CH = N; 9.27 w, IH, NH; 9, 84, d, J = 8Hz,

1H, NH

Ex 92 (diaisostereomeric mixture): 1.20 d, J = 5 Hz, 3H, N-CH ₃ ; 3.30 - 3.70, m,

1.40, m, 3H, 2H, 1H of N-CH

CH ₃ ; 2.94, and IH.of S-

CH ₂ ; From 3.90 to 4.30, m, 2H, _N-CH2; l 4.49, part of AB-Quartet, J = 18 Hz, H, _S-CH2; 5.31, d, J = 5Hz, IH, β-lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, IH, β-lactam-H; 7.83 , s, IH, CH = N; 8.30, br, 2H, NH; 8.65 d, J = 5 Hz, 1H, NH; 9.84 , d, J = 8 Hz, 1 H, NH

Př.93: 1.32, d, J = 6Hz, 3H, CH _3; From 1.70 to 1.98, m, 2H, _CH2 -C; From 2.75 to 2.98, m, 2H, _N-CH2; From 3.25 to 3.65, m, 4H, 2H of _N-CH2 and H of N-CH and H of _S-CH2; From 4.05 to 4.35, m, 2H, _N-CH2; 4.53, part of AB-quartet, J = 18 Hz, IH, _S-CH2; 5.22, d, J = 5 Hz, 1H, [beta] -lactam67

Η; 5.78, lactam-H d, J = 55 Hz, 2H, CH ₂ F; 5.80, 8.01, s, 1H, CH-N; 8.28, bdd, J = 5 Hz and 8, 2H, NH; 9,78,

ΦΦ φ ΦΦ * * * * *

ΦΦΦΦ φφ φφ

Hz, ΙΗ, βd, J = 8Hz,

NH, NH

ΦΦ φφ φ φ «

Φ Φ 4

Φ.

Ex.94: 1.28, d, J = 6Hz, 3Η, CH ₃ ; From 1.70 to 1.92, m, 2H, _CH2 -C; From 2.72 to 3.00, m, 2H, _N-CH2; From 3.22 to 3.72, m, 4H, 2H of _N-CH2 and 1H of N-CH and 1H of _S-CH2; From 3.90 to 4.35, m, 2H, _N-CH2; 4.49, part of AB-quartet, J = 18 Hz, 1H,; _S-CH2; 5.19, d, J = 5 Hz, 1H, [beta] -lactamH; 5.76, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 5.78, d, J = 55Hz,

2H, CH ₂ F; 8.07, s, 1H, CH-N; 8,27, S, 2H, NH; 9.77, d, J = 8Hz, - 1H, NH Př.95 (in CDC1 ₃ / CD ₃ OD = 1/1): 1.46, S, 3H, CH _3; 1,48, s, 3H, CH _3; 3.55 and 4.32, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3,71, AB-system, J = 4 Hz and 10 Hz, 2H, _N-CH2; 5.18, d, J = 5 Hz 1H, β-lactam-H; 5.75, d, J = 55 Hz, 2H, CH ₂ F; 5,94, d, J = 5 Hz 1H, β-lactam-H;

8.10, s, 1H, CH-N

Ex 96 (in CDCl ₃ / CD ₃ OD = 1/1): 1.46, S, 3H, CH ₃ ; 1.48, s, 3H, CH _3;

2.84, s, 3H, N-CH _3; 3.56 and 4.36, AB-quartet, J = 18 Hz, 2H, SCH _2; 3.76, s, 2H, _N-CH2; 5.19, d, J = 5 Hz, [beta], [beta] -lactam-H; 5.78, d, J = 55 Hz, 2H, _CH2 F; 5.92, d, J = 5Hz, 1H, β-lactam-H; 8.06, s, 1H, CH = N

Př.97: 3.17, s, 3H, N-CH _3; 3.58, s, 3H, N-CH _3; 3.65 and 4.25, AB-quartet, J = 18.2 Hz, 2H, _S-CH2; 5.28, d, J = 5 Hz, 1H, [beta] -lactamH; 5.78, d, J = 58 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8.1 Hz, [beta], [beta] -lactam-H ;. 7.05, d, J = 2.8 Hz, 1H, imidazole-H; 7.61, d, J = 2.8 Hz, 1H, imidazole-H; 8.61, s, 1H, CH-N; 9.90, d, J = 8.1 Hz, 1H, NH

Př.98 (in D ₂ O): 1.84, s, 2H, CH ₂ -C; 2.84, s, 2H, _N-CH2; 3.34, s, 2H, _N-CH2;

3.56 and 4.40, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3.68 to 4.10, m, 4H, _N-CH2; 5.13, d, J = 5 &lt; 1 &gt;, ΙΗ, [beta] -lactam-H; 5.71, d, J = 5 Hz, 1H, [beta] -lactam-H; 6.64, S, 1H, thiazole-H; 7.97, s, 1H, CH-N.

9 9 99 99 99 99 · 9 99 9 9 99 9

9,999,999

9999 999 · 9 99 9 »

9 ··· 9999 ·· 99 99 9.9

Př.99 (.in D ₂ 0): 3.45-3.68, m, 3H, 2H of _N-CH2 and IH of _S-CH2; 3704.10, m, 4H, _N-CH2; 4.40, part of AB-quartet, J = 18 .Hz, Ih _S-CH2; 5.16, d, J = 5 Hz, Ih β-lactam-H; 5.75, d, J = 5 Hz, 1H, [beta] -lactam-H; 6.65, s, 1H, thiazole-H; 7.95, s, 1H, CH = N

Př.100: l, 18, t, J = 7 Hz, 3H, CH _3; 3.15, s, 3H, N-CH _3; From 3.42 to 3.68, m, 3H, 2H of _N-CH2 and IH of _S-CH2; 3.70-4.10, m, 4H, _N-CH2; 4.25, part of AB- quartet, J = 18 Hz, lH, _S-CH2; 5.12, d, J = 5 Hz, 1 H, β-lactam-H, 5.69, dd, J = 5 Hz and 8 Hz, 1 H, β-lactam-H; 6.65, s, 1H, thiazole-H; 7.14, b, 2H, NH; 8.14, s, 1 H, CH = N; 8.42, w, 1 H, NH; 9.45, d, J = 8 Ηζ, ΙΗ, ΝΗ

Př.101; A.4,47 3.58, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3.85 4.00, m, 2H, _N-CH2; From 4.15 to 4.30, m, 2H, N-CH _second; 5.35, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.81, d, J = 55 Hz, 2H, CH ₂ F; 5.98, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 7.37-7.56, m, 3H, CH-aromatic; 7.85 7.95, m, 2H, CH-aromatic; 7.99, s, 1H, aromatic-CH = N; 8.34, S, 2H, NH; 8.74, s, 1H, CH = N; 9.82, s, 1H, NH; 9.88, d, J = 8Hz, 1H, NH

Př.102; From 3.45 to 3.97, m, 9H, 6H of _N-CH2 and 2H of _O-CH2 and IH from SCH _2; 4.43, part of AB-quartet, J = 18 Hz, H, s-CH _2; 5.32, d, J = 5Hz; 1H, β-lactam-H; 5.8, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 8.62, s, 1H, CH = N; 8.81, s, 1H, NH; 9.86, d, 1H, NH

Př.103; 3.51 and 4.36, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3.71, s, 4H, _N-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55. Hz, 2H, CH ₂ F; 5.95, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 8.26, b, 2H, 1H of CH = N and 1H of NH; 9.83, d, J = 8Hz, 1H, NH.

Př.104; 1,90 m 2H, CH ₂ -C; 3.33, b, 4H, N- CH ₂ ; 3.50 and 4.45, AB-quartet, J = 18 Hz, 2H, _S-CH2; 5.28, d, J = 5 Hz, 1H, β-lactam- H; 5.77, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz. 8 Hz, 1H, β-

 * 5.

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 8.30, b, 3Η, 1Η of CH = N and 2H of NH; 8.4 * 2 * 2H * NH *;

* 9 9 9

9 9 9

9 9 9

9 9 9

99

9.85, d, J = 8Hz, 1H, NH

Př.105: 3.11, s, 2H, _N-CH2; 3.51 and 4.39, AB-quartet, J = 18 Hz, 2H, _S-CH2; From 3.60 to 3.95, m, 6H, _N-CH2; 5.30, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.77, d, J = 55Hz. 2H, CH ₂ F; 5.96, dd, 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 8.12, b, 2H, NH; 8.28, b, 2H, 1H from NH and 1H from CH = N; 8.70, br, 2H, NH; 9.82, d, J = 8Hz, 1H, NH

Př.106: 3.56 and 4.45, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3,75-4,25 m

4H, _N-CH2; 4.30, s, 3H, CH _3; 5.33, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F; 5.98, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 8.18, s, 1H, pyrid.-CH = N; 8.30, br, 2H, NH; 8.66 and 9.07, m, each 2H, CH-aromatic; 8.95, s, 1H, CH-N; 9.85, d, J = 8Hz, 1H, NH

Př.107: 3.15, s, 6H, _N-CH3; From 3.55 to 3.82, m, 5H, 4H of _N-CH2 and 1H from SCH _2; 3.95, part of AB-quartet, J = 18 Hz, 1H, _S-CH2; 5.29, d, J = 5?,?,? -Lactam-H; 5.81, d, J = 55 Hz, 2H, _CH2 F; 5.92, dd, J = 5 and 8 Ηζ, ΙΗ, βlaktam-H; 8.73, s, 1H, CH = N; 9. 87, d, J = 8, ΙΗ, ΝΗ.

Př.108: l, 12, t, J = 7 Hz, 3H, CH _3; 3.42, q, J = 7 Hz, 2H, _N-CH2; 3.51 a

4.38, AB-quartet, J = 18 Hz, 2H, _S-CH2; 3.60-3.90, m, 4H, _N-CH2; 5.32, d, J = 5 Hz, 1H, [beta] -lactam-H; . 5.81, d, J = 55 Hz, 2H, CH ₂ F; 5.95, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 8.31, b, 2H, NH; 8.64, s, 1H, CH-N; 8.80, br, 1H, NH; 9.86, d, J = 8Hz, 1H, NH; 12.83, s, 1H, OH

Př.109: 2.98, s, 3H, N-CH _3; 3.51 and 4,

2H, _S-CH2; From 3.60 to 3.88, m, 4H, _N-CH2; lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F; Hz, 1H, β-lactam-H; 8.30, b, 2H, NH;

38, AB-quartet, J = 18 Hz, 5,30 d, J = 5 Hz, 1 H, β- 5.94, dd, J = 5 Hz and J = 8 8.61, s, 1 H, CH = N; 8, 79,

S, 1H, NH; 9,84, d, J = 8Hz, 1H, NH; 12.83, s, 1H, OH. Ex.110: 0.87, t, J = 7Hz, 3H, CH _3; 1.45 - 1.70, m, 2H, _CH2 -C; 3.25 - 3.40, m, 2H, _N-CH2; 3.51 a 4.39, AB-quartet, J = 18 Hz,

· 44 44 44 99 94

4 4 4 4 4 9 4 4 4 4 4 .4 9 9 4 9 4 9 9 4

4 9 94 499 4 4 44 «« · · · · · · · · · · · · · · · · · · · · ·

2H, _S-CH2; 3.60 -3.90, m, 4H, _N-CH2; 5.30, d, J = 5 Hz, 1H, lactam-H; 5.79, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd? J = 5 Hz and 8 Hz,

1H, S-lactam-H; 8.28, b, 2H, NH; 8.61, s, 1H, CH = N; 8.77, š,

1H, NH; 9.84, d, J = 8Hz, 1H, NH; 12.76, s, 1H, OH

Př.lll: 1.00 to 1.32, m, 6H, CH _3; 3.51 and 4.39, AB-quartet, J = 18 Hz, 2H, SCH _2; 3.60-3.90, m, 4H, _N-CH2; 4.08-4.30, m, 1H, N-CH; 5.30, d, J = 5Hz,

1 H, β-lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and

J = 8 Hz, 1 H, β-lactam-H; 8.32, b, 2H, NH; 8.66, s, 1H, CH = N;

8.78, S, 1H, NH; 9.86, d ,. J = 8Hz, 1H, NH; 12,84 ,. s, 1H, OH

Př.112: 1.16, d, 12H, CH _3; 3.40-3.90, m, 6H, 4H of _N-CH2 and 2H from SCH _2; 4.67, h, 2H, N-CH; 5.21, d, J = 5 ', ΙΉ, β-lactam-H; 5.82, d, J = 55

Hz, 2H, CH ₂ F; 5.84, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 8.26, b, 2H, NH;

8.54, s, 1H _/ CH = N; 9.80, d, J = 8Ηζ, ΙΗ, ΝΗ

Př.113 (diaisostereomerní mixture): 1.27, d, J = 6Hz, 3H, CH _3; 3.20

3.38, m, 1H, N-CH; 3.52 and 4.37, AB-quartet, J = 18 Hz, 2H, SCH _2;. 3.75 to 3.92 m, ¹H, ¹H from _N-CH2; 4.08-4.30, m, 1H, 1H

_N-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.79, d, J = 55Hz, 2H,

CH ₂ F; 5.93, dd, J-5 Hz and 8 Hz, 1H, [beta] -lactam-H; 8.29, b, 2H, NH;

8.38, s, 1H, CH = N; 9.84, d, J = 8 Hz, 1H, NH _s

Př.114: 3.52 and 4.42, AB-quartet, J = 18.2 Hz, 2H, _S-CH2; 3.79, s, 3H, _OCH3, 3.83 and 4.02, q , I H, J = 5.5 Hz and 10.0 Hz and wide triplet, I H,

J = 10.4 Hz, _N-CH2; 4.79, kv, 1H, J = 5.5 Hz and 10.4 Hz, N-CH; 5.32, d, J = 5

Hz, 1H, β-lactam-H; 5.80, d, J = 58 Hz, 2H, CH ₂ F .; 5.94, dd, J = 5 Hz and 8.2

Hz, 1 H, β-lactam-H; 8.44, S, 1 H, CH = N; 9.87, d, J = 8.2 Ηζ, ΙΗ, ΝΗ.

Ex.115: 3.4-3.9, m, 5H, I H from NCH and I H from NCH ₂ and 2H from O-CH ₂ and

¹H from SCH _2, 4.40, m, Ih _N-CH2; 4.43, part of AB-quartet, J = 18 Hz,

Ih _S-CH2; 5.31 d, J = 4.6 Hz, 1H, [beta] -lactam-H; 5.80, d, J = 55Hz,

2H, CH ₂ F; 5.94, dd, J = 4.6 Hz and 8.1 Hz, 1H, [beta] -lactam-H; 8,40 s,

1H, CH = N; 9.86, d, J = 8.1 Hz, 1H, NH

Př.llS (in D ₂ 0): 3.11, s, 3H, N-CH _3; 3.28, S, 3H, 'N-Ch'' ₃ '; ** 58 * 3 '3.71, m, 3H, 2H of _N-CH2 and H of _S-CH2; From 3.78 to 3.89, m, 2H, NCH _2; 3.96, s, 3H, O-CH _3; 3.97, part of AB-quartet, J = 18 Hz, IH,

_S-CH2; 5.22, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.76, d, J = 5 Hz, 1H, [beta] -lactam-H; 7.04, s, 1H, thiazole-H; 7.98, S, 1H, CH = N

4 4 4 · 4 4 4 4 4 4 4 44 444444 44 4

4

3,10 s, 3H, N-CH _3; 3,29, S, 3H, N-CH _3; 3.50 av N-CH ₂ and IH Of _S-CH2; 3.75 -3.89 m 2H, AB-Quartet, J = 18 Hz, 1 H, S -CH ₂ ; 5,22, d, J

Hz, IH, β-lactam-H; 5.78, d, J = 5 Hz, 1H, [beta] -lactam-H; 7.02, s, 1H, thiazole-H; 7.98, S, 1H, CH-N

Př.118 (in DMSO-d _s / D ₂ O): 3.12, s, 3H, N-CH _3; 3.30, s, 3H, N-CH _3; From 3.52 to 3.72, m, 3H, 2H of _N-CH2 and H of _S-CH2; From 3.76 to 3.91, m, 2H, _N-CH2; 4.01, part of AB-quartet, J = 18 Hz, IH, _S-CH2; 5.22, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.77, d,. J = 55 Hz. 2H, CH ₂ F; 5.83, d, J = 5 Hz, 1H, [beta] -lactam-H; 8.06, s, 1H, CH-N

Př.119: 3.31, s, 4H, _N-CH2 -piperazine; From 3.52 to 4.30, m, 10H, 4H of _N-CH2 and 4H of piperazine _{N-CH2-imidazole} and 2H of _S-CH2; 5.29, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.82, d, J = 55 Hz, 2H, CH ₂ F; 5.90, dd, J = 5 Hz and J = 0 Hz, 1H, β-lactam-H; 7.98, s, 1H, CH-N; 8.30, br, 2H, NH; 9.82, d, J = 8Hz, 1H, NH

Př.120 (diaisostereomerní mixture): l, 15 l, 60 m, 4H, CH ₂ -C; l, 62 l, 85 m, 2H, _CH2 -C; From 1.88 to 2.22, m, 2H, _CH2 -C; 3.20-3.40, m, 2H, N-CH; 3.52 and 4.31, respectively. 3.55 and 4.39, AB-quartet, J = 18 Hz, 2H, _S-CH2; 5.31, d, J = 5 Hz, 1H, [beta] -lactam-H; 5.78, d, J = 55 Hz, 2H, CH ₂ F; 5.94, dd, J = 5 Hz and 8 Hz, 1H, [beta] -lactam-H; 8.28, b, 2H, NH; 8.41, S, 1H, CH-N; 8.78, br, 1H, NH; 9.15, b, 1H, NH; 9.84, d, J = 8Hz, 1H, NH

Ex. A: 3.38 - 3.58 and 3.60 - 3.80, m, 4H, N-CH ₂ φ * · · · '

·. ·········.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Ex. Β (in CDCl₃) 3.60 to 3.75 and 3.76 to 3.92, m, 4Η, _N-CH2; 7.22

7.48, m, 4H, 3H of CH-aromatic and 1H of CH = N; 7.52 -7.68 m

2H, CH-aromatic

Ex. C: 1.39, b, 9H, CH3; 2.98-3.20 and 3.22-3.40 and 3.42-3.55 and

3.57-3.78, m, 8H, _N-CH2

Ex. D (in D ₂ O) : 0,80, t, J = 7 Hz, 3H, CH ₃ ; 1.53 , hex, J = 7 Hz, 2H, CH ₂ -C; 2,99, s, 3H, N-CH3; 3.25 , t, J = 7 Hz, 2H, _N-CH2; 3,40 - 3,65, m, 4H, n-ch ₂ Ex. E (in D ₂ O) : 0,79, t, J = 7 Hz, 3H, CH ₃ ; 1.52. , hex, J = 7 Hz, 2H, CH ₂ -C; 2,97, s, 6H, N-CH _3; 3.15 , t, J = 7 Hz, 2H, _N-CH2; 3,48 - 3,75, m, 4H, n-ch ₂

Ex. F (in D ₂ 0): 1.68 to 1.90, m, 2H, _CH2 -C; 3.08-3.32, m, 4H,

_N-CH2; From 3.42 to 3.70, m, 4H, _N-CH2

Př.G (in D ₂ O): from 1.70 to 1.90, m, CH ₂ -C; 2.73, S, 6H, N-CH3; 3.10 3.30, m, 4H, _N-CH2; From 3.40 to 3.70, m, 4H, _N-CH2

Ex. H (in D ₂ O): 1.21, d, J = 7 Hz, 12H, CH ,; From 3.70 to 3.96, m, 4H, _N-CH2; 3.98-4.18, m, 2H, N-CH

Ex. I (D ₂ O): from 3.28 to 3.48, m, 4H, _N-CH2; From 3.82 to 4.00, m, 4H, _N-CH2

Ex. J (in CDCl3): 3.12, s, 3H, N-CH3; 3.57, s, 3H, N-CH3; 6.95 and 6.99, AB-quartet, J = 2 Hz, 2H, N-CH

Ex. K (in D ₂ O): 3.30-3.60 ,, m, 3H, 2H of _O-CH2 and H of _N-CH2; 3.78, t, J = 10 Hz, IH, N-CH _2; 4.14, m, 1H, N-CH

Ex. L: 3.61, kv, J = 5, 4 Hz and 10.3 Hz, 1H, N-CH; 3,87, s, 3H, 0- CH ₃ , 4.10, t, J = 10.3 Hz, H, N-CH _2; 4.56, kv, J = 5.4 Hz and 10.6 Hz, IH, N-CH ₂

· - · 4 4 ♦ ♦ 4 4 4 4 4 · · Φ «φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φφ and 2H of _N-CH2; 3,66-3,78 m

Ex. M: from 3.33 to 3.50, .m, 5H, 3H of _N-CH3, 2H, _N-CH2

Ex. N: 3.40 to 3.64 and 3.66 to 3.92, m, 4H, _N-CH2; 6.75-6.92, m, 3H, CH-aromatic; 7.15-7.40, m, 2H, CH-aromatic

Ex. O: 2.85, d, J = 5 Hz, 3H, CH _3; From 3.40 to 3.56 and 3.58 to 3.72, m, 4H, _N-CH2; 8.18, d, J = 5Hz, 1H, NH

Ex. P (in D ₂ O): 3.41-3.81, m, 16H, 8H from N-CH ₃ -piperazine and 4H from N-CH ₂ -imidazole and 4H from N-CH ₂

Ex. Q: 3.35 to 3.58, m, 4H, _{N-CH2-imidazole;} From 3.60 to 3.72, m, 4H, 2H of _N-CH2 and 2H of _O-CH2; 7.14, s, 2H, NH ₂

Ex. R: 1.24, t, J = 7 Hz, 3H, CH _3; 2.85 - 3.15, m, 4H, _N-CH2; 3,42 - 3.78 'm, 6H, 4H of _N-CH2 - imidazole and 2H from _N-CH2; 8,30, t, J = 6 Hz, 1 H, NH; 9.20, b, 1H, NH; 9.46, w, 2H, nh ₂ Ex. WITH (in D ₂ O): 2.87, s, 6H, CH _3; 3.28 - 3.40, m, 2H; _N-CH2 ; 3.51.

- 3.75, m, 6H, 4H of _N-CH2 and 2H of imidazole _N-CH2

Ex. T (D ₂ O): from 3.08 to 3.26, m, 2H, _N-CH2; From 3.43 to 3.76, m, 6H, N 4H'od _{imidazole-CH2} and 2H of _N-CH2

Ex. In: from 2.68 to 2.91, m, 2H, _N-CH2; From 3.30 to 3.76, m, 6H, 4H of NCH ₂ and 2H from imidazole _O-CH2

Ex. V (D ₂ O): from 1.78 to 2.00, m, 2H, _CH2 -C; From 2.89 to 3.14, m, 2H, _N-CH2; From 3.25 to 3.32, m, 2H, N-CH _second; From 3.45 to 3.71, m, 4H, _N-CH2 imidazole

Ex. W (vDjO): 3.07 to 3.29, m, 4H, _N-CH2; From 3.45 to 3.69, m, 6H, 4H of _N-CH2 and 2H of imidazole _N-CH2; From 3.70 to 3.79, m, 2H, _O-CH2

Ex. X (in D ₂ O): 3.15-3.80, m, 20H, N-CH ₂ and O-CH ₂ ·· ·· ··

1 · • 9 9 ·

9,999 9 9

Ί4

Ex. Y (in D ₂ 0): 1.20 to 1.50, m, 2H, _CH2 -C; 1.72

CH ₂ -C and CH-C; 2.71 -3.72, m, 10H, _N-CH2

9900 9900 99 99

2.00, m, 3H, 1 · 4 · 4

. Z: 3.12 - 3.41, m, 2H, _N-CH2; 3.43 - 3,90, m, .6H, _N-CH2; 88 - 8.08, m, 1H, pyr-H; 8,10 - 8,20, m, IH, CH-aromatic; 40, W, IH, NH; 8.50 - 8 , 68, m, IH, CH-aromatic; 8.71 - 90, m, IH, CH-aromatic; 9.38, b , IH, NH

Ex. AA: 3.28 to 3.72, m, 12H, _N-CH2 and _O-CH2; 8.09, t, J = 6 Hz, 1H, NH, 8.86, br, 1H, NH

Ex. AB (in D ₂ 0): 3.40 to 3.78, m, 4H, _{N-CH2-imidazole}

Ex. AC: 2.66 to 2.90, m, 4H, O-CH _2; From 3.38 to 3.88, m, 8H, _N-CH2

Ex. AD (in D ₂ O): from 1.46 to 1.76, m, 4H, C-CH ₂ -C; From 2.82 to 3.02, m, 2H, _N-CH2; From 3.08 to 3.30, m, 2H, _N-CH2; From 3.40 to 3.74, m, 4H, _N-CH2 imidazole

Ex. AE 3.20 3.40 - m, 2H, _N-CH2; From 3.42 to 3.78, m, 6H, _{N-CH2-imidazole} and O CH _2; 8.14, t, J = 6Hz, 1H, NH; 8.99, br, 1H, NH

Ex. AF (in D ₂ O): 1.13 - 1.38, m, 4H, CH ₂ -C; From 1.40 to 1.68, m, 4H, CH ₂ -C; From 2.78 to 2.98, m, 2H, _N-CH2; From 3.02 to 3.22, m, 2H, _N-CH2; From 3.40 to 3.68, m, 4H, _{N-CH2-imidazole}

Ex. AG (in D ₂ O): 1,22, d, J = 6 H 2 O, 3H, CH ₃ ; 3,25 - 3.75, m, 7H, N-CH ₂ a N-CH Ex. AH: 2,95 - 4,18, m, 16H, _N-CH2 and _O-CH2; 8.43 s, 1H, NH;

9.42, b, 1H, NH

Ex. AI (in D ₂ O): 1.37, s, 6H · CH _3; 3.48, s, 2H, _N-CH2; 3.50 3.95 m, 4H, _{N-CH2-imidazole;} 7.35-7.51, m, 3H, CH-aromatic; 7.66, s, 1H, CH-N; 7.70 - 7.82, m, 2H, CH-aromatic 9 · »· φ · φ · φ · · ·

Ex. AJ (-V _DMSO-d6 / D ₂ O): from 4.00 to 4.22 and 4.28 to 4.48, m, 4H, _N-CH2; 4.53, s, 3H, CH _3; 8.14, s, 1H, CH-N; 8.48-8.62 and 8.92-9.10, m, 4H, CH-aromatic

Ex. AK (in D ₂ O): 2.87, s, 3H, CH _3; 2.90-3.80, m, 12H, 8H from NCH ₂ -piperazine and 4H from N-CH ₂ -imidazole

Ex. Al: 0.58 to 0.82, m, 4H, CH ₂ -C; From 2.55 to 2.72, m, lH, CH-C; 3.50-3.82, m, 4H, _N-CH2

Ex. AM: 1.10, t, J = 7 Hz, 3H, CH _3; 3.27, p, J = 7 Hz, 2H, _N-CH2; From 3.42 to 3.78, m, 4H, _N-CH2; 8.30, t, J = 7Hz, 1H, NH; 9.06, S, 1H, NH

Ex. AN: 0.86, t, J = 7 Hz, 3H, CH _3; 1.48, h, J = 7 Hz, 2H, CH _2; 3.16, p, J = 7 Hz, 2H, _N-CH2; From 3.40 to 3.72, m, 4H, _N-CH2; 8.30, t, J = 7Hz, 1H, NH; 9.03, b, 1H, NH

Ex. AO (in D, O): 3.08, t, J = 5 Hz, 2H, _N-CH2; 3.33, t, J = 5Hz,

2H, N-1 ZH ₂ ; 3.42 - 3.71, m, 12H, 4H od _N-CH2 and 8H of _O-CH2 Ex. AP (in D ₂ O): 1.89, p, J = 7.5 Hz, 2H CH _2; 2.61, s, 3H, N-CH _3; 3,00, t, J = 7.5 Hz, 2H, _N-CH2;. 3,25, t, J = 7.5Hz, 2H, _N-CH2; 3,42 - 3,72 m 4H, _N-CH2 Ex. AQ (in D ₂ O): 1.89, p, J = 7.5 Hz, 2H, CH _2; 2.92 - 3.15, m, 4H,

_N-CH2; 3.23, t, J = 7.5 Hz, 2H, _N-CH2; From 3.42 to 3.68, m, 4H, _N-CH2;

3.69, m 4H, _N-CH2

2H, O-CH ₂ 1.82 - 2.02 m, 2H, CH ₂ ; 2,79, s, 6H, N-CH _3; , 2H, 1 _N-CH2; 3,24, t, J = 7Hz, 2H, _N-CH2; 3,43 - 1,84, , p, J = 6Hz, 2H, CH ₂ ; 3,13 - 3,43, m, 8H,

6H of N-CH and 2H of _O-CH2; 3.68 - 3.84, m, 4H, N-CH ₂ • ··· ·· · 4

Ex. AT (in D ₂ 0): 1.85-2.12, m, 2H, _CH2; 2.64, s, 3H, CH _3; 2.95 3.12, m, 2H, _N-CH2; From 3.30 to 3.42, m, 2H, _N-CH2; 3.50 - 3.78, m,

8H, 6H from N-CH ₂ and 2H from O-CH ₂ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Ex. AU (in D ₂ O): from 1.84 to 2.08, m, 2H, _CH2; From 2.98 to 3.18, m, 4H, _NCH2; 3.30 to 3.42 m., 2H, _N-CH2; From 3.48 to 3.82, m, 10H, 6H of _N-CH2 and 4H of _O-CH2

Ex. AV (in D ₂ O): 1.95-2.20, m, 2H, _CH2; 2.88, s, 6H, _N-CH3; 3,12-3,28 m

2H, _N-CH2; From 3.38 to 3.50, m, 2H, _N-CH2; From 3.58 to 3.83, m, 8H, 6H of _N-CH2 and 2Ή from O-CH ₂

Ex. AW (in D ₂ O): 2.67, s, 6H, _N-CH3; From 3.49 to 3.80, m, 8H, 6H of _N-CH2 and 2H of _O-CH2

Ex. AX (in D ₂ O): 1.69, p, J = 7 Hz, 2H, _CH2 -C; 3,19, t, J = 7 Hz, 2H, _N-CH2; 3.40 - 3.64, m, 6H, 4H of _N-CH2 and 2H of _O-CH2 Ex. AY (in D ₂ O): 3.03, s, 3H, N-CH _3; 3.48, t, J = 5Hz / 2H Z N- CH ₂ ; 3.52 3.6 2, m, 4H, _N-CH2; 3.70, t, J = 5 Hz, 2H, _O-CH2 Ex. AZ (in D ₂ O): From 2.70 to 3.40, m, 4H, _N-CH2; 3.42 - 3.75, m, 4H,

_N-CH2; 3.85-4.10, m, 1H, O-CH

Ex. ' BA (in D ₂ O): from 3.20 to 3.75, m, 16H, _N-CH2

Ex. BB (in D ₂ O): 1.10, t, 'J = 7 Hz, 3H, CH _3; From 3.30 to 3.80, m, 10H, 8H of _N-CH2 and 2H of _O-CH2

Ex. BC (in D ₂ O): 1.78 to 2.18 m, 4H, CH ₂ -C; 2.85 - 3.18 m 6H, _N-CH2; From 3.20 to 3.38, m, 2H, _N-CH2; 3.40 - 3.78, m, , 4H, _N-CH2 Ex. BD (in D ₂ O): from 1.20 to 1.60, m, 4H, CH ₂ -C; 1.80 - 2.20 m, 4H, CH ₂ -C; 2.98-3.40, m, 2H, N-CH; 3.42 - 3.72, m, 4H, _N-CH2 Ex. BE (in D ₂ O) j 1.05, t, J = 7 Hz, 3H, _CH3; 3,22, kv, J = 7Hz, 2H, _N-CH2; From 3.40 to 3.68, m, 4H, _N-CH2

WS ·· ··; i. · · ··· · ⁷⁷ · · ·: ·: ··: · ::: ί «······· ·· · ·· ··

Ex. BF (in D ₂ 0): 3.06 to 3.34, m, 2H, _N-CH2; From 3.36 to 3.66, m, 6H, 4H of _N-CH2 and 2H of _O-CH2; 3.68-3.82, m, 1H, O-CH

Ex. BG (in D ₂ O): 1.07, t, J = 7Hz, 3H, _CH3; 2.98 , with, 3H, N -CH ₃ ; 3.34, kv, J = 7Hz, 2H, _N-CH2; 3.42 - 3.58, m, 4H, n-ch ₂ Ex. BH (in D ₂ O): 1.05, t, J = 7Hz, 3H, _CH3; 1.88 - 2,12, m, 2H, CH ₂ -C; 2.78, s, 6H, N -CH ₃ ; 2.98 - 3.35, m, 4H, _N-CH2; ' 3, 40 - 3.70, m, 6H, _N-CH2 Ex. BI (in D ₂ O): 1.22, t, J = 7Hz, 3H, _CH3; 1.72 - 1,95, m, 2H, CH2-C; 2.95 - 3.18, m, 2H, _N-CH2; 3.20-3.40, m, 6H, N-CH 2 i 3.60 - 3.80, m, 2H, _N-CH2 Ex. BJ (in D ₂ O): 1.10, t, J = 7Hz, 3H, _CH3; 1,25 - 1,60, m, 4H,

CH ₂ -C; From 1.82 to 2.20, m, 4H, CH ₂ -C; 3.00-3.20, m, 1H, N-CH; 3.29, q, J = 7 Hz, 2H, _N-CH2;, 3.42 to 3.68, m, 4H, _N-CH2; 3.85, 4.10, m, 1H, N-CH

Ex. BK (in D ₂ O): from 1.25 to 1.60, m, 4H, CH ₂ -C; 1.85 - 2, , 20, m, 4H, CH ₂ -C; 2.96-3.25, m, 1H, N-C H; 3.30 - 3.40, m, 2H, N- CH _2; 3,50 - 3.78, m, 6H, 4H of _N-CH2 and 2H of _O-CH2; 4.02 ~ ⁴ , 22 , m, 1 H, N-CH Ex. BL (in D ₂ O): from 1.65 to 1.95, m, 2H, _CH2 -C; 3.05 - 3, 38, m, 8H, _N-CH2; From 3.40 to 3.82, m, 8H, _N-CH2 Ex. BM (D ₂ O): 2.84, s, 3H, N-CH _3; 3.40 - 3.65, m, 4H, N-C h ₂

Ex. BN (in D ₂ O): 2.98, s, 3H, N-CH _3; 3.0, s, 3H, N-CH _3; 3.42 - 3.58, m,

4H, _N-CH2

Ex. BO (in D ₂ O): 1.13, t, J = 7 Hz, 3H, CH _3; 2.96, s, 3H, N-CH _3; From 3.40 to 3.60., M, 6H, _N-CH2

···· · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Ex. BP (D ₂ O): 1.25-1.60, m, 4H, CH ₂ -C; From 1.85 to 2.18, m, 4H, CH ₂ -C; 2.93, s, 3H, N-CH _3; 3.02-3.25, m, 1H, N-CH; From 3.40 to 3.68, m, 4H, _NCH2; 3.88-4.10, m, 1H, N-CH

Ex. BQ (D ₂ O): 2.95, s, 3H, N-CH _3; 3.42-3.70, m, 8H, 6H of _N-CH2 and 2H of _O-CH2

Ex. BR (D ₂ O): 3.25-3.82, m, 12H, 8H from N-CH ₂ and 4H from O-CH ₂

Ex. BS (D ₂ O): 1, 22, t, J = 7Hz, 6H, CH ₃ ; 3.10 -3.28 m 4H, N- CH ₂ ; 3, 30 - 3.42 , M, 2H, _N-CH2; 3.50 - 3.75, m, 6H, _N-CH2 Ex. BT (in D ₂ O): 1.88 - 2.08, m, 2H, CH ₂ -C; 2.83, s, 6H, N-CH _3; 3.05 - 3,20 m 2H, _N-CH2; 3,25 - 3.38, m, 2H, _N-CH2; 3,46 -

3.70, m, 4H, _N-CH2

Ex. BU (in D ₂ O) 1.20, t, J = 7 Hz, 6H, CH _3; 3.22, q, J = 7 Hz, 4H, _N-CH2; From 3.26 to 3.38, m, 2H, _N-CH2; From 3.48 to 3.74, m, 6H, _N-CH2

Ex. BV (in D ₂ O): 1.24, t, J = 7 Hz, 6H, CH _3; 3.07, s, 3H, N-CH _3; From 3.12 to 3.92, m, 12H, _N-CH2

Ex. BW (in D ₂ O): 2.87, s, 6H, _N-CH3; From 3.30 to 3.48, m, 2H, _N-CH2; From 3.50 to 3.78, m, 6H, _N-CH2

Ex. BX (v D ₂ O): From 3.55 to 3.82, m, 4H, _N-CH2; 5,00, s, 2H, O-CH _2; 7.10 , S, 1 H, CH; 7.99, S, 1H, CH Ex. BY (v D ₂ O): From 1.10 to 1.54, m, 4H, CH ₂ -C; 1,56 - 1/84, m, 2H, CH ₂ - < 3; 1,8 6-2 18, m, 2H, _CH2 -C; 3,10 - 3,46 m, 2H, N-CH; 3.48 - 3,7 0, tn, 4H, _N-CH2 Ex. POI (v D ₂ O): 0.79, t, J = 7 Hz, 3H, CH _3; 1,51, hex, J = 7 Hz, 2H, CH ₂ -C; 3,15, t, J = 7 Hz, 2H, _N-CH2; 3,40-3,70, m, 4H, n-ch ₂ Ex. CA (v D ₂ O): 1.11, d, J = 7 Hz, 6H, CH _3; 3,40 - 3,62, m, 4Η,

_N-CH2; 3.72-3.92, m, 1H, N-CH

 «·» «« «« «« «

Ex. CB (in D ₂ 0): 1.22 to 2.00, m, 6H, _CH2 --C; 2.80 _N-CH2; From 3.20 to 3.82, m, 10H, -N-CH ₂

3.08, m, 2H,

Ex. CC (in Djo): 0.80, t, J = 7 Hz, 3H, CH _3; 1.10-1.38, m, 2H, _CH2 -C; 1401.58 m, 2H, _CH2 -C; 3.00, s, 3H, N-CH _3; From 3.20 to 3.38, m, 2H, NCH _2; From 3.40 to 3.68, m, 4H, _N-CH2

Ex. CD (in D ₂ O): 0.80, t, J = 7 Hz, 3H, CH _3; 1.08 - 1.32, m, 2H,

CH ₂ -C; From 1.36 to 1.62, m, 2H, _CH2 -C; From 3.08 to 3.30, m, 2H, _N-CH2; From 3.40 to 3.70, m, 4H, _N-CH2

Ex. CE (in D ₂ O): from 1.10 to 1.90, m, 6H, _CH2 --C; From 2.78 to 3.04, m, 5H, 2H of _N-CH2 and 3H of _N-CH3; From 3.20 to 3.90, m, 10H, _N-CH2

Ex. CF (in D ₂ O): from 1.75 to 2.22, m, 4H, CH ₂ -C; 2.92 - 3.18, m, 2H,

_N-CH2; From 3.32 to 3.48, m, 2H, _N-CH2; From 3.48 to 3.78, m, 8H, N-CH _second . Ex. CG (D ₂ O): 3.4 8 -3.72, m, 4H, _N-CH2; 4,11, s, 2H, CH ₂ Ex. CH (D ₂ O): 0.79 t, J = 7 Hz, 3H, CH _3; 1,08 - .1,40 m, 4H, CH ₂ - C; 1.42 - 1.68, m, 2H, _CH2 -C; 3.10 - 3.32, m, 2H, _N-CH2; 3,40 - 3.70, m, 4H, _N-CH2 Ex. Cl (D ₂ O): 0.75, t, J = 7 Hz, 3Ή, CH _3; 1,08 - . 1.32, m, 6H, .CH ₂ - C; 1.48 - 1.60, m, 2H, _CH2 -C; 3.10 - 3.25, m, 2H, _N-CH2; 3,40 - 3.68, m, 4H, _N-CH2 Ex. CJ (D ₂ O): 0.90, t, J = 7 Hz, 3H, CH _3; 1.20 - 1.48, m, 8H, CH ₂ - C; 1.52 - 1.75, m 2H, _CH2 -C; 3.25 - 3.40, m, 2H, _N-CH2; 3,52 - « 3.80, m, 4H, _N-CH2 * Ex. CK (D ₂ O): 1.8 - 2.02, m, 2H, _CH2 -C; 3.10 - 3.38, m, 4H, N- CH ₂ ; 3.4 0 - 3.65, m ., 4H, _N-CH2 Ex. CL (in D ₂ O): 1, 09, t, J = 7 Hz, 3H, CH _3; 2, 98, s, 6H, _N-CH3;

3.26, q, J = 7 Hz, 2H, _N-CH2; From 3.48 to 3.75, m, 4H, _N-CH2

I ·············

J ················· · · · ·, ·································

Ex. CM - (in D ₂ O): 2.90, s, 3H, N-CH _3; 2.99, s, 6H, _N-CH3; 3.45 3.75, m, 4H, _N-CH2

Ex. CN (in D ₂ O): from 1.00 to 1.22, m, 6H, CH _3; 2.94, s, 3H, N-CH _3;

From 3.12 to 3.45, m, 4H, _N-CH2; From 3.50 to 3.72, m, 4H, _N-CH2

Ex. CO (in D ₂ O): 3.1, s, 3H, N-CH _3; 3.20-3.42, m, 4H, _N-CH2; From 3.75 to 4.02, m, 4H, _N-CH2

Ex. CP (in Djo): 1.72 to 2.02, m, 2H, _CH2 -C; From 2.95 to 3.30, m, 7H, 3H of _N-CH3 and 4H of _N-CH2; From 3.32 to 3.70, m, 4H, _N-CH2

Ex. CQ (in D ₂ O): 1.17, d, J = 6Hz, 3H, CH _3; 2.75, s, 3H, N-CH _3;

3.05-3.28, m, 1H, N-CH; From 3.60 to 4.10, m, 2H, _N-CH2

Ex. CR (in D ₂ O): 1.17, d, J = 6Hz, 3H, CH _3; 3.12-3.30, m, 1H,

N-CH; From 3.68 to 4.05, m, 2H, _N-CH2

Ex. CS (in D ₂ O): l, 2, d, J = 6 Hz, 3H, CH _3; From 1.72 to 2.12, m, 2H _CH2-C; 2.88 · *

3.10, m, 2H, N-CH ₂ ; 3,12-3,4-5, m, 3H, 2H of _N-CH2 and 1H od N-CH; 4.15, m, 2H, n-ch ₂ Ex. CT (v CDC1 ₃ / CD ₃ OD = 1/1): 1.40, s, 6H, CH _3; 2,90, with, 3H, N- CH ₃ ; 3,58, S, 2H, _N-CH2 Ex. CU (v CDC1 ₃ / CD ₃ OD = 1/1): 1.40, s, 6H, CH _3; 3,54, with, 2H, N- CH ₂ Ex. CV: 0, 84, t, J = 7 Hz, 3H, CH _3; 1.49, hex, J =  7 Hz, 2H, . CH ₂ -C; 3.16, t, J = 7 Hz, 2H, _N-CH2; 3.42 - 3.72, m, 4H, N-CH ₂ Ex. CW (v D ₂ O): 1.14, d, J = 7 Hz, 6H, CH ₃ ; 3.50 - 3, 92, m, 5H, 4H from N-CH ₂ and 1H of N-CH Ex. CX: 1, 12, d, 12H, CH _3; 3.50, s, 4H, _N-CH2; 4,88, h, 2H, N-

CH

ΦΦ · · · φ φ • • • φ φ φ φ · · · · · φ φ φ φ φ φ φ · · · · · · · φ φ φ φ φ φ φ φ

Ex. CY: 3.17, b, 4Η, N-CH ₂ -piperazine; 3.40 to 3.58 3.68 and 3.88, m, 4H, _{N-CH2-imidazole;} 3.98, s, 4H, _N-CH2; 9.16, b, 1H, NH; 10.01, s, 2H, NH ₂

Ex. CZ (in D ₂ O): 3.05, s, 3H, N-CH _3; 3.20, s, 3H, N-CH _3; 3.45 3.54, m, 2H, _N-CH2; From 3.66 to 3.76, m, 2H, _N-CH2

Ex. DB (in CDC1 _3): 1.26, t, J = 7 Hz, 3H, CH _3; 3.70-4.00, m, 6H, N-CH,

Claims (16)

PATENTOVÉ RO KY -Jro A compound of formula I wherein W is CH or N, V is CH or NO, R ₃ is hydrogen, acyl, carboxyl or alkyl, R ₃ is a hydrogen atom or an ester group, R ₂ is a group of formula R, AA · AA AAAA A · AA A A · · A A A A A A A A A AA or where X and Y are independently C 2 -C 5 alkylene or C 2 -C 5 alkenylene wherein one -C = C- double bond is present or, in the case of an alkenylene group containing at least 4 carbon atoms, where two -C = C- double bonds are present, R ₄ is a hydrogen atom or an alkyl group, _R is hydrogen, alkyl, or aminoiminomethyiová group, _R is hydrogen, alkyl, cycloalkyl, B is amino, hydroxyl, alkoxy, heterocyclyl or -N = CHR _a , wherein R ₈ is an alkyl group, an aryl group or a heterocyclyl group; or R _s and R ₆ together with the nitrogen atoms to which they are bonded are heterocyclyl *, *. R ' _s is an alkyl group, R ₇ is hydrogen, or _R and R together with the nitrogen atom to which they are bonded form a heterocyclyl group. AND ····························· 9.9 99 9 9900 9900 99 99 2. A compound of formula la la wherein W, R _X, R _3, R _s and Rg are as defined claim 1. A compound of formula 1b N- _{(CH2) m} lb R _e cations W, et al _R and _R are as defined above and m is 1 or 2 9i 4- 7 - {[(5-Amino-1,2,4-thiadiazol-3-yl) - (Z) - (fluoromethoxyimino) acetyl] amino} -3 - {[(3-ethyl-2-methyliminoimidazolidine) -1-yl) imino] methyl} -3-cephem-4-carboxylic acid. A compound according to any one of claims 1 to 4 in free form. A compound according to any one of claims 1 to 4 in the form of a salt. A compound according to any one of claims 1 to 6 in the form of solvates. A compound of formula Ip N85 «♦ · · 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85 85. h ₂ n ^V P- ^R 1P -C-CO-NH N —R. ip 2p COOR 3p where W _p is CH or N, V _p is = CH- or = NO-, R _1p is a hydrogen atom, an acyl group, a carboxyl group, an unsubstituted alkyl group, or an alkyl group substituted with a halogen atom or a carboxyl group, R _3p is a hydrogen atom, an ester-forming group or a cation, R ₂₀ is a group of the formula '6p ^{R 6} ' _N '' ^{R 'P'} R, 6p \. and) (b) C) (d) Y. E) -Ν N - R 6p \ ‘Sp -Ν N - R Sp -Ν N -Ν 'N 5 _P R, Sp \. R. 6p \. ^Y py -Ν N G) -Ν N -Ν N ^R <p ^R 5P TO. 4p ^Λ Ρ where X _p and Y _p j sou same or different and each are group - (CH ₂ ) _n -, where n is number 2 to 5, and optionally one or two groups ch ₂ - j sou replaced group -CH = CH- a optionally one one or more hydrogen atoms are replaced by a halogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a carboxyl group or an ethoxycarbonyl group,. · · Φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ · · · · · · · · · · · · · · · · R _4p is hydrogen, pina, alkyl or hydroxyalkyl Skurat _Sp is hydrogen, alkyl, (poly) hydroxyalkyl or aminoalkyl where the alkyl groups are optionally further substituted. a functional group such as a carboxylic acid residue, a sulfonic acid residue or a phosphoric acid residue, R _gp is hydrogen, alkyl, hydroxyalkyl, aminoalkyl, amino, hydroxy, alkoxyalkyl, cycloalkyl, N = CHR _8p , wherein R _8p . is aryl or heteroaryl, or -NR _9p R ₁₀ wherein R _8p and R _10p are the same or different and are each a hydrogen atom, an alkyl group, a hydroxyalkyl group or an aryl group or together with the nitrogen atom represent a saturated, unsubstituted heterocycle containing 5 or 6 ring members with one or two nitrogen atoms and / or oxygen atoms and R _7p is hydrogen, or R _7p and R _Sp together with the nitrogen atom are a 5- to 7-membered heterocycle containing one or two nitrogen atoms and / or oxygen atoms, provided that when W _p is CH, V _p is = N-O-, R _1p is a hydrogen atom or a methyl group, R _2p is a group of formula (d) and R _3p is a hydrogen atom, R _5p and R _gp are simultaneously other than a hydrogen atom or a methyl group, in free form or, where such forms exist, in the form of acid addition salts, inner salts, quaternary salts or hydrates. 9. A process for preparing a compound of formula I wherein t e r i z comprises reacting a compound of formula II wherein W, V and R _x are as defined above and a) R _b is a hydroxyl group and R _c and R _d together represent a bond, or β) R _d is a hydrogen atom, a cation, an ester-forming group or a silyl group, and R _b and R _c together represent oxo, in free form or in acid addition salt form, with an amine of formula III R2-NH _second Wherein R ₂ is as defined above. The compound of claim 1 for use as a medicament. The compound of claim 1 for use in the preparation of a medicament for the treatment of microbial diseases. 12. A pharmaceutical composition comprising a compound of formula I in the form of a pharmaceutically acceptable salt or in free form together with at least one pharmaceutical carrier or diluent. A compound according to claim 1 for use according to claim 11 in the treatment of microbial diseases caused by bacteria selected from the group consisting of Pseudomonas, Escherichia, Enterobacter, Klebsiella, Moraxella, Etherococcus, Streptococcus, Staphylococcus. «99 99 99 99 9 9 9 9 9 9 9 9 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9,999,999 9 9 99 9 9, 99 Use of a compound of formula I according to claim 1 or use of a composition according to claim 13 as a medicament. 15. A method of treating microbial diseases comprising administering to a patient in need thereof an effective amount of a compound of Formula I. A compound of formula NR _S AND. R. Hal ' AND⁺ /^R h₂n-n n-r '₅ NH - N - N - R R 'llnt R 'or τ or ₅ NH ₂ or ₂ -N = ( ΝInt Η Int R R '.R'i h ₂ nn or ÍV,, Int R ₆ -N ⁶ Nh ₂ nn ~ / \ r · NV, int or Y ' H ₂ N — Ν 'N H.N — N N Z, γ · VI R ' ₇ or ^lnt R'' VII Int R · ^R, 7 where Y 'is an alkylene group, R ' _s is a hydrogen atom, an alkyl group or an alkylimino group, R 'is _a hydrogen, alkyl, hydroxy, alkoxy, cycloalkyl, amino or heterocyclyl, • AAA · A · A · A · A · A A A A A AAA A A A A AAAAAAAA AA * * A A · A A A A A A A A A A A A AA Η. R ' ₇ and R' ₈ are independently hydrogen, carboxyl, alkoxycarbonyl or alkyl, R ''' _e and R'''' ₆ are. independently of one another an alkyl group, or R '' _s and R ''' _s together with the nitrogen atom to which they are attached are a heterocyclyl group, R '' _s . is an alkyl group, or R ' ₅ and R ' g together are an alkylene group, R '' _s and R '''' g are independently alkyl, R ^{'a /, //} g and R' 7 together with ^a nitrogen atom to which they are bonded are heterocyclyl, R _'4 and R' ·· '·'_<s are independently an alkyl group, and Hal '' is a halogen atom, with the proviso that the compound of formula I _int , wherein R ' _s , R' ₇ and R ' ₈ are hydrogen and R''g is hydrogen, 2- (N-morpholino) ethyl group. pina, 3- (Ν, Ν-dimethylamino) propyl; (2-hydroxyethyl) -. An amino or 2-hydroxyethyl group is excluded.