Derivatives of cephalosporin containing their antibacterial composition, derivatives of 2-aminothiazoles as intermediate compounds and method of production thereof

 

(57) Abstract:

The invention relates to new derivatives of cephalosporin of the General formula I and II where R1selected from the group consisting of-N(O)ZR3, -NR4R5; Z is selected from the group consisting of-CH2(X)m-, -C(NR6)-; X is a sulfur atom; m = 0 - 1; R3- thiazolyl substituted by chlorine or amino group, and (CH2)T, where n = 1 to 6; T - guanidino; R4and R5each hydrogen; R6is hydrogen or may be a group which with the adjacent oxygen atom forms a protected hydroxyl group,2is hydrogen; each of G, H, L, and M - carbon; J is nitrogen; rings a, b, D and E are selected from the group consisting of thiazolyl and thiadiazolyl; R11is hydrogen; alk1- C1-6alkyl; alk2- C1-6alkyl, optionally substituted by a group selected from hydroxyl, amino, carboxamido; p is 0 to 1; R99selected from the group consisting of sulfur and SO2; q is 1; r = 1 - 3; R12- NR13R14group (a) or (b); R13-R17each hydrogen, or their pharmaceutically acceptable salts. Antibacterial composition having activity against methicillinsensitive, vancomycinflagyl or ampicillinulbactam bacteria, including Pharma is ing 2-aminothiazole General formula III, where Pg1is hydrogen or triphenylmethyl and Pg2triphenylmethyl. The method of obtaining the compounds of formula III by reacting the compounds of formula IIIA with gloriouse agent in an organic solvent. The technical result - obtaining new derivatives of cyclosporine. 5 C. and 20 C. p. F.-ly, 2 tab., 5 Il.

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This application is related to provisional patent application N 60/005389, filed October 12, 1995, which is incorporated into this whole description together with the drawings.

The present invention relates to new cephalosporin antibiotic, the method of their production and application. It is expected that these compounds have antibiotic activity against a broad spectrum of organisms including organisms which are resistant to conventional-lactam antibiotics.

Presents a survey designed to better understand the present invention, and neither it nor any of these links should not be taken as prior art against the present invention.

Over the past three decades for clinical use has become accessible to a wide range of antibiotics. One such class of antibiosis clinical use for the treatment of bacterial infections in mammals, since 1965, These cephalosporins demonstrate its antibacterial activity by inhibiting biosynthesis and composition of bacteria, and has proved to be extremely effective in the treatment of a wide range of bacterial infections. The cephalosporin with antibacterial activity are disclosed in U.S. patents 3992377 and 4256739.

Unfortunately, the widespread and indiscriminate use of these antibiotics has led to the rapid increase in the number of bacterial strains that have become resistant to these compounds. Most importantly, this resistance manifested clinically important microorganisms, which led to the limitation of currently available cephalosporin antibiotics. In particular, appeared resistant strains of Salmonella, S. pneumoniae, Enterobateriaceae and Pseudomonas, which negates the many steps taken to reduce mortality and morbidity as the result of bacterial infections.

Bacterial resistance to cephalosporins is developing in three main schemes: (a) production of-lactamases that can inactivate-laktamovogo ring of cyclosporine; (b) reducing the penetration of cyclosporine in bacteria due to the changes in the composition of cell walls back as binding, -lactams PBPS is necessary for the inhibition of biosynthesis of cell walls of bacteria. Some gram-positive bacteria, namely, metitsillinoustoychivye Staphylococcus aureus ("MRSA")b enterococci are highly resistant to-lactamase antibiotics. Such resistance MRSA is associated with the presence of high levels of unusual PBP, PBP2a, which is impervious, or little contact with-lactam antibiotics. Activity-lactam antibiotics against PBP2a-containing organisms, has been shown to be well correlated with the binding ability of the antibiotic and PBP2a. At the present time against MRSA bacteria mainly use, the glycopeptides vancomycin and teicoplanin. Antibacterial quinolone compounds and some carbapenems, such as imipenem was reported to be active against MRSA strains, but their use is limited because of the emergence of resistant MRSA strains.

Experimental compounds that can be used as anti-MRSA and anti-enterococcal bactericides include glycylcycline (see for example, R.-E. Sum et. al., J. Med. Chem., 37 (1994)), FK-037 (see for example, H. Ohki et. al. , J. Antibiotics 46: 359-361 (1993)), RP 59500 (see for example, S. K. Spangler et.al. Antimicro Agents Chemother 36:856-9(1992)), the complex evernimicin (see for example, W. E. Sanders et. al. Antimicro Agents Ch N 527686), 3- (Tesorillo)carbacephem (see for example, R. J. Terhansky et.al., J. Med. Chem. 36: 1971 (1993) and U.S. patent N 5077287) and arbekacin (S. Kondo, et. al. J. Antibiotics 46:531 (1993).

Recent advances in the field of the compounds, compositions and methods suitable for treating infections in mammals arising from bacteria resistant to-lactamase antibiotics described in the joint international application N WO 96/26966.

The present invention comprises compounds, compositions and methods effective in the treatment of infections in mammals arising from bacteria resistant to-lactamase antibiotics. The preferred connection must have a minimum inhibitory concentration (MIC) less than 50%, more preferably less than 10% and most preferably less than 1% of the MIC of Cefotaxime or imipenem for an organism that is resistant to beta-lactam, preferably methicillinsensitive staphylococcal or ampicillinulbactam Enterococcus body. Other preferred compounds must be able to prevent or reduce mortality in mice infected with resistant to beta-lactam body to a greater extent than is possible Cefotaxime or imipenem.

In one aspect of the present invention relative selected from the group consisting of-NHC(O)ZR3, -NR4R5;

Z is chosen from the group consisting of-CH2(X)m, -C(NOR6)-;

X represents a sulfur atom;

m = 0 or 1;

R3is thiazolyl substituted by chlorine or amino group, or (CH2)nT;

T represents guanidino;

n = 1 - 6;

R4-5each means hydrogen;,

R6represents hydrogen or may be a group which with the adjacent oxygen atom forms a protected hydroxyl group;

R6means hydrogen;

A, B, D, and E are selected from the group consisting of thiazolyl and thiadiazolyl;

examples of heterocyclic groups known in the chemistry; G, H, L and M are carbon;

J is nitrogen;

R11is hydrogen; alk1and alk2represent alkyl groups, and optionally and independently replaced by Deputy selected from the group consisting of hydroxyl, amino, carboxamido;

p takes on the values 0, 1;

R99selected from the group consisting of sulfur and SO2;

q = 1;

r = 1, 2, or 3;

R12is NR13R14,

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R13-R17each means hydrogen.

Not wanting to contact there are several new structural features of the present invention, deemed to contribute significantly improved functional characteristics. In particular, the chlorine substituents in the heterocyclic R3groups, apparently, 2-4 times improve value MICK compared to compounds in which there is no chlorinated heterocyclic R3groups.

Preferred pharmaceutically acceptable salts include (1) inorganic salts such as chloride, bromide, iodide, nitrate, phosphate, or sulfate; (2) carboxylates such as acetate, propionate, butyrate, malate or fumarate; (3) alkyl sulphonates such as methanesulfonate, aconsultant, 2-hydroxyethylsulphonic, n-propylsulfonyl or ISO - propylsulfonyl; and (4) such hydroxycarboxylic as lactate, malate and citrate.

In another embodiment, the present invention proposed a composition that includes such a number of compounds with the structure II, III, IV, V or VI, which is effective for the treatment of bacterial infections in mammals caused by bacteria that are resistant against-lactamase antibiotics.

In yet another embodiment, the present invention includes methods of treating bacterial infections in mammals caused by bacteria resistant to-lactamase Antibes what about the number of compounds with the structure II, III, IV, V or VI. Naturally, the compounds of the present invention also find use in the compositions and methods of treating mammals infected with bacteria that are susceptible to common-lactamase antibiotics.

In another embodiment, the present invention describes compounds and methods to obtain the intermediate compound VII, which can be used to obtain compounds with specific potential activity against methicillinsensitive Staphilococci and ampicillinulbactam Enterococci.

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Other characteristic features and advantages of the present invention will be apparent from the following description of the preferred options and from the claims.

Fig. 1-5 represent the preferred schemes for preparing compounds of the present invention.

Fig. 1 represents the scheme of obtaining cafema.

Fig. 2 represents a scheme to obtain C(7)-Deputy.

Fig. 3 represents a scheme for the preparation of 3-substituent.

Fig. 4 is a diagram of the final Assembly.

Fig. 5 is a diagram of removing the protection and education of salt.

The term "bacteria that are resistant to-lactam" refers to bacteria, L.

The term "methicillinsensitive bacteria" refers to bacteria that are resistant to methicillin. Examples of such bacteria are presented in table 1, or designated as MethR< / BR>
The term "methicillinsensitive bacteria" refers to bacteria that are sensitive to methicillin. Examples of such bacteria are presented in table 1 and marked as MethS.

In the present invention proposed compounds, methods and compositions that are effective in the treatment of bacterial infections, especially infections arising from bacteria that have developed resistance to conventional-lactamase antibiotics. More importantly, in the present invention proposed compounds, methods and compositions effective in the treatment of bacterial infections caused by bacteria that have developed resistance to conventional cephalosporin antibiotics.

The formation of compounds with the structure II

Compounds of the present invention can be easily obtained in accordance with the following schemes. Note, however, that other schemes of synthesis for the preparation of compounds of the present invention are possible and that the following diagrams are provided merely for example and are not limiting., is the quiet is usually used in practice (see, for example. Green and Wuts). Experts know that the choice of any specific protective group (for example, carboxyamide group) depends on the stability of the protected fragment in relation to the conditions of subsequent reaction.

Typically, the synthesis of cephalosporins of the present invention can be performed using well known methods and readily available materials (see, for example, March; Zarock, Comprehensive Organic Transformations (VCH Publishers, 1989); and G. I. Georg, The Organic Chemistry of - Lactams (VHC 1992), each of which is incorporated here by reference). As presented below in scheme 1, treatment of seventieth 1 need not necessarily protected thiolutin the nucleophile 2, using such standard techniques as those described by Farina et. al. J. Org. Chem. 54:4962 (1989) and in U.S. patent 4870168 Baker et. al. (both incorporated here by reference), leads to the production of 3-thio derivative 3. After subsequent removal of the protection with the use of well-known specialists of ways, receive a biologically active 4-carboxylate 4 (see diagram 1 at the end of the description).

Connection 1 is easily obtained from commercially available starting materials, for example, in the reaction of (7R)-7- [(phenylacetyl)amino]-3-hydroxy-3-cefem-4-carboxylic acid (Otsuka Chemical Co. Ltd., Otsuka J-3-caremy can be obtained by ozonolysis of 3-ectomesenchyme, using known methods (see Farina). Similarly, tiality nucleophile 2 can be obtained using known methods and commercially available starting materials.

Deputy R1can be any Deputy from the group previously described, and it can be either commercially available or can be obtained using known methods and starting materials (see, for example, March; Zarock). These groups can replace those that are present on the source materials, various well-known methods (see Barrett, J. C. S. Perkin 1, 1629 (1979) or Chauvette, J. Org. Chem. 36:1259 (1971) (both incorporated here by reference), for example, by transamination of an existing Deputy to obtain a desired substituent, or by hydrolytic removal of the existing Deputy, followed by reaction with an appropriate reactive form the desired substituent, for example, acylchlorides. And again, appropriate reagents, and methods should be obvious to the experts.

As a carboxyl group, R2can be such protective groups that are amenable to recovery of elimination, such as benzyl, para - or orthonitrophenyl, 2,2,2-trichloroethyl, allyl, cinnamyl, benzhydryl, 2-chlorallyl etc.

C. Synthesis of compounds of structure III

Compounds with the General structure III receive similarly, compounds of structure II. In most cases, the key step is the connection of substituted heterouncinata with reventilation 1 or functionally equivalent cafemom containing alternative tsepliaeva group C-(3). Compounds of structure III, in which the ring containing G, H, J, L, and M represents 4-pyridyl, can also be obtained by the method shown in Fig. 4.)

In accordance with the present invention, a therapeutically or pharmaceutically effective amount of a cephalosporin, and, specifically, compounds with structurally other infections, due to other-victimologie bacteria, such as vancomycinresistant or ampicillinulbactam bacteria), especially resistant S. aureus, in an amount effective for at least partial attenuation of infection. Especially important are infections caused by strains that have activity similar to the activity of these strains as S. aureus Col (MethR) (lac-), S. aureus 76 (MethR) (lac+), E. faecium ATCC 35667, or E. faecium ATCC 29212. And again, such compounds are also effective against bacteria that are sensitive to methicillin, vancomycin, and/or ampicillin, and therefore find use in such compositions and methods.

The compositions containing the compound (compounds) of the present invention can be entered for the prevention and/or therapeutic treatment. With therapeutic use of the composition is administered to a patient already suffering from the infection, as indicated previously, in a quantity sufficient to cure or at least partially suspending the symptoms of the infection. The number that enables it, is defined as "therapeutically effective amount or dose". Amounts that are effective for this purpose depend on the severity and course of the disease, the wound is In the case of prophylactic use, compositions containing compounds of the present invention, is administered to a patient susceptible to, or is at risk with respect to specific infections. This number is defined as a "prophylactically effective amount or dose". Used in this way, the exact number will again depend on the patient's condition, weight, etc.

Once there is improvement in the patient's condition, impose appropriate maintenance dose. Then the dose or frequency of administration, or both these factors can be reduced depending on the symptoms, to a level at which it remains superior condition. After symptoms decrease to the desired level, treatment can be discontinued. The patient, however, require intermittent treatment for a long time in case of recurrence of symptoms.

Typically, a suitable effective dose of a compound of the present invention is in the range from 0.1 to 1000 mg per day for the recipient, preferably in the range from 1 to 100 mg/day. The desired dose may be presented in the form of single, two, three, four or more subdot, administered at appropriate intervals throughout the day. Still to 100 mg of active ingredient in a unit dose form. Preferably the compounds of the present invention in amounts from about 2.0 mg/kg to 250 mg/kg of patient's weight and from about one to four times per day.

Although the active ingredient of the present invention can be entered separately, it is preferable that he attended as part of a pharmaceutical composition. Compositions of the present invention include at least one connection or the inhibitor of the present invention in a therapeutically or pharmaceutically effective dose together with one or more pharmaceutically or therapeutically acceptable carriers. Solid carriers include, for example, starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, as well as optionally other therapeutic ingredients. Liquid carriers include, for example, sterile water, polyethylene glycols, non-ionic surface-active agents, such edible oils as corn, peanut and sesame oils. Additionally, there may be included various adjuvant, such as those typically used in practice. Examples: flavouring agents, colouring agents, preservatives and antioxidants, such as vitamin E, ascorbic acid, BHT and BHA. Describes various other aspective introduction, for example, oral, intravenous, intraperitoneal or intramuscular and others. Pharmaceutically acceptable carriers include water, saline, buffers, and other described compounds, for example, the Merck Index, Merck and Co., Rahway, NJ. Usually the preferred routes of administration are intravenous and intraperitoneal. These pharmacological agents can be in various forms. These forms include, for example, solid, semi-solid and liquid dose forms such as tablets, pills, powders, liquid solutions or suspensions, liposomes, solutions for injection and infusion. The preferred form depends on the intended route of administration and therapeutic application. Usually use a pharmacologically acceptable salt of the compounds to facilitate preparation of the composition. Preferred salts include salts of sodium, potassium, arginine, glycine, alanine, threonine. They are produced preferably in an appropriate mixture of water with such a surface-active agent, as hydroxypropylcellulose.

Depending on the specific treatment conditions such agents can be introduced into the composition and injected systemically or locally. Description of methods of obtaining compositions and their administration can detect the orbital, transdermal, vaginal, or through the mucous through the intestines; the method comprises parenteral, intramuscular, subcutaneous, intramedullary, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections (listed simply as examples).

For injection, the agents of the present invention can be prepared in the form of aqueous solutions, preferably in physiologically compatible buffers such as the solution of Henk, ringer's solution, or physiological saline buffer. For transmucosally introductions to songs using agents that provide penetration through the barrier. Such agents promoting penetration, typically well known to the experts.

In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, for example, liquid oils, liquid paraffin, or liquid polyethylene glycols. In addition, can be added stabilizers.

Biological activity

In vitro antibacterial activity

Compounds of the present invention evaluated for their efficacy against some lactostasis (for example, methicillinsensitive, vancomycinflagyl and/ml) of each of the compounds in respect of each strain. MICK, the lowest concentration of antibiotic that inhibits growth of the test organism is determined using the agar dilution.

To determine the MIC for isolates of bacteria, the test compound is administered in a twofold dilution in the liquefied agar Mueller-Hinton (Mueller-Hinton). After curing, the number of different bacterial strains inoculant spot on the surface of the agar using a special device. After incubation overnight specify a threshold value MIC as the lowest concentration of drug that completely inhibits the growth regardless of, this refers only to one colony, or the entire lawn. The procedure used in these studies was standardized National Comittee for Clinical Laboratory Standards (NCCLS) in the form of NCCLS publication entitled Methods for Dilution Antimicrobial Susceptibility Tests (1991), which is incorporated here by reference.

Aliquots of antimicrobial agents produced in bateriafina phosphate saline solution (PBS) at a pH of 7.2. If necessary, as solubilizing agent use Tween 20 or DMSO. To facilitate solubilization test agent using standard methods centrifugation, treatment with ultrasound and orremove drugs. 1.28 mg/ml initial solution used with the subsequent highest working concentration of 128 µg/ml exercised by serial twofold dilution of 0.25 µg/ml of Each drug tested twice. Two-fold dilution of drugs is carried out in a sterile 50 ml ampoules with a finite amount of drug 5 ml After addition of 45 ml of molten agar is 10 fold dilution. Then two 25 ml plate is placed in a 15 x 150 mm square Petri dishes from the grill and leave to harden.

As a positive growth control using a control plate of comparative medicine, either Cefotaxime or vancomycin, or imipenem. The initial concentration of comparative antibiotics prepare and freeze at a temperature of -80oC. After preparation of the control plate, seal and store in the refrigerator up to 1 week before use, but the control plate with imipenem need to be prepared immediately prior to use. All test plates used within 24 hours after preparation.

Satisfactory results were obtained in cases where the AMF inoculum contains about 104colonelonic colonies are transferred into a vial with a nutrient broth and leave to rise for 4-6 hours at a temperature of 35-36oC to achieve logarithmic phase of growth. To PBS was added dropwise broth culture to achieve a standard turbidity of 0.5 McFarland equal to 108CFU/ml Is further diluted 10 times in PBS to achieve a working concentration of inoculum 107CFU/ml If 1 µl of assay inoculum applied to the surface of the agar, achieved concentration of about 104SOME on the stain.

For insulinopenia test plates use disposable sterile 1 µg loops, each isolate sown in designed for agrarian plate grill. In an alternative method of insulinopenia use the device with 48 steel spikes, which provides simultaneous insulinopenia many isolates. After the stain is dry, the plate is incubated at 35-36oC for 16-20 hours. And, finally, the end point is estimated as the minimum inhibitory concentration (MIC) of the antimicrobial agent.

New agents of the present invention are characterized by their high activity against S. aureus Col and Enterococci (E. faecium and E. faecalis). The strain of S. aureus Col PBP2a is a producer with a high level, whereas S. aureus Col 8A, its isogenic partner, gives little PBP2a.

Some compounds exhibit a wide stiu all tested agents, including Cefotaxime control. Thus, the compounds of the present invention are effective against Rura-producing bacteria. Some compounds show potential activity against enterococci. Some other compounds of the present invention are effective against E. coli in addition to gram-positive organisms.

Evaluation of antibacterial activity in vivo

Those compounds that have excellent activity in vitro, when compared with comparative antibiotics, to further evaluate the model in mice to lethal bacteremia of peritonitis.

Groups of 5 mice strain Swiss-Webster (Simonsen Gilroy, CA) each infect with intraperitoneal injection of 10 multiples of the increments of bacterial inoculum. This allows to estimate median lethal dose (LD50and LD100. For a preliminary assessment of the new antibiotic infect mice via intraperitoneal injection LD100the titer of bacteria. Two equal doses, administered at the time of bacterial contamination, and 2 hours later, groups of 10 mice in each treated with subcutaneous injection twice increments of the test drug and antibiotic known to Those of mice, which survive for 72 hours are considered to be long-lived. Full dose (MC/kg) drugs that protect 50% of mice in the group of death, considered as a secondary protective dose (ZV50). ZV50similarly determined for a number of pathogens. Then the quantitative results for the new drug is compared with the results obtained for comparative antibiotics

Groups of five mice each injected intraperitoneally six of ten-fold dilutions of inoculum, suspended in 0.5 ml of sterilized 7% hog gastric mucin (Sigma). The control group of mice injected only one mucin. The mice were observed for 72 hours. Those who remained alive after 72 hours are considered to be long-lived. Median lethal dose (LD50and 100% lethal dose (LD100determine in the probit test.

For studies of antibiotic effectiveness infect mice intraperitoneally with bacterial titers, which lead to LD100for the test strains. Two equal doses, administered at the time of bacterial contamination, and 2 hours later, groups of 10 mice in each treated with subcutaneous injection twice increments test antibiotic and man. Drug dose can be in the range of from 0.01 to 512 mg/kg If the drug is poorly soluble, for its solubilization you can use tween-20 or propylene glycol. Animals observed within 72 hours. 50% protective dose (ZV50) compute the MC/kg using probit analysis. ZV50represents the same thing as the 50% effective dose (ED50and 50% of a therapeutic dose (Leche.D50). Blood samples from the hearts of all animals that died, and from half of the animals that survived, grown on the infusion agar brain-heart. Animals, which have introduced protective dose of the test compounds remain alive within 72 hours, although they look may seem moderately ill or very ill during the observation period. Infected and received placebo control mice, as well as those who were introduced inefficient, that is, lower doses of the test drugs show a high degree of mortality. Most of these mice die during onset 6 to 48 hours. Those who remain alive after 72 hours, are considered long-lived.

The compound N

1. (7R)-7-[(phenylacetyl)amino] -3-(3-socioresidential-4-ylthio)- 3-cefem-4-carboxylate, salt triperoxonane kylptowxur acid

3. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3- (3-socioresidential-4-ylthio-3-cefem-4-carboxylate, salt triperoxonane acid

4. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3- (4-socioresidential-1,2,3-thiadiazole-5-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

5. (7R)-7-[(phenylacetyl)amino] -3-(4-socioresidential-5-ylthio)- 3-cefem-4-carboxylate, salt triperoxonane acid

6. (7R)-7-[(phenylacetyl) amino]-3-[4-(3-pyrrolidinedione)-1,2,2 - thiadiazole-5-ylthio-3-cefem-4-carboxylate, salt triperoxonane acid

7. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3- (4-socioresidential-5-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

8. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(cyclopentyloxy)- acetamido] -3-(3 - socioresidential-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

9. (7R)-7-[(phenylacetyl)amino] -3-(3-aminoethylthiomethyl-4-ylthio)- 3-cefem-4-carboxylate, salt triperoxonane acid

10. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- (3-aminoethylthiomethyl-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

11. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [(methylaminoethanol-4-yl)-2-(hydroxyimino) acetamido] -3-[(guanidinoacetate)-1,2,3-thiadiazole-5-ylthio] - 3-cefem-4-carboxylate, salt triperoxonane acid

13. (7R)-7-[(Z)-2-(aminothiazol-4-yl-2-(cyclopentyloxy)acetamido]- 3-(3-aminoethylthiomethyl-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

14. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- (3-guanidinoacetate-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

15. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino) acetamido] -3-(3-methylaminoacetaldehyde-4-ylthio)-3-cefem-4 - carboxylate, salt triperoxonane acid

16. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-aminoethylthiomethyl-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

17. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(acetamido hydroxyimino] -3- [3-(3-pyrrolidinedione)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

18. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(N-methylglycyl)-aminoethylthiomethyl-4-ylthio]-cefem-4-carboxylate, salt triperoxonane acid

19. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-amino-1,1-dimethylaminomethyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

20. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino)acetone is bromothiazole-4-yl)-2-(hydroxyimino)-acetamido] -3-(3-aminoethylthiomethyl-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

22. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)- acetamido] -3- [(methylenedianiline)-1,2,3-thiadiazole-5-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

23. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(2-foretokening) acetamido]-3-(3-aminoethylthiomethyl-4-ylthio)-3-cefem-4 - carboxylate, salt triperoxonane acid

24. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(glycyl)aminoethylthiomethyl-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

25. (7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- (3-(N-formimidoyl)aminoethylthiomethyl-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

26. (7R)-7-[(Z)-2-phenyl-2-(hydroxyimino)acetamido] -3-(3 - aminoethylthiomethyl-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

27. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)- acetamido] -3-[3-(3-aminopropyl)dimethylpyridin-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

28. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-(methylenedianiline)-1,2,3-thiadiazole-5-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

29. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl what usnei acid

30. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)- acetamido] -3-(3-aminoacridine-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

31. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)- acetamido] -3-(3-(N-formimidoyl) aminoethylthiomethyl-4-ylthio) -3-cefem-4-carboxylate, salt triperoxonane acid

32. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) -acetamido] -3-[3-(3-amino-2-hydroxyprop-1-altimeter) pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

33. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-(3-aminoethylthiomethyl-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

34. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl) -2-(hydroxyimino)acetamido] -3-(3-(3-N-formamidopyrimidine) pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

35. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)- acetamido] -3-[3- (glycyl)aminopropyldimethylamine-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

36. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)- acetamido] -3-(3-(2-aminopropan-1-altimeter)pyrid-4-ylthio)-3-cefem-4 - carboxylate, salt triperoxonane acid

37. (7R)-7-[(phenylacetyl)amino]-3-(4-(2-am is isothiazol-4-yl)-2-(hydroxyimino) acetamido]-3-(4-(2-aminoethylthiomethyl)-1,2,3-thiadiazole-5-ylthio) -3-cefem-4 - carboxylate, salt triperoxonane acid

39. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl] -2-(hydroxyimino)- acetamido] -3-(3-carboxamidotryptamine-4-ylthio)-3-cefem-4-carboxylic acid

40. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)- acetamido] -3-(3-(2-aminoethoxymethyl)pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

41. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)- acetamido] -3-(3-(2-N-methylaminomethyl)pyrid-4-ylthio)-3-cefem-4 - carboxylate, salt triperoxonane acid

42. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (hydroxyimino)-acetamido]-3-(3-(pyrrolidin-3-altimeter) pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

43. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(N-methylglycyl)aminoethylthiomethyl-4-ylthio]-3-cefem-4 - carboxylate, salt triperoxonane acid

44. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)- acetamido] -3-(3-(5-aminoethoxymethyl)pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

45. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-aminoethylethanolamine-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

46. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(Gelati

47. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-(3-aminopropylsilyl)pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

48. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)- 2-(hydroxyimino)acetamido] -3-(3-(4-amino-2-butyn-1-yl)pyrid-4 - ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

49. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-(2-aminopropylsilyl)pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

50. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-(4-amino-2-Z-butene-1-yl)pyrid-4-ylthio)-3 - cefem-4-carboxylate, salt triperoxonane acid

51. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-(3-aminopropyl)pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

52. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-(piperidine-4-altimeter)pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

53. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-aminoethylethanolamine-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

54. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-N - acetamidino the-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-(5S-5-N,N-dimethylcarbamoyl-3-ylthio-methyl) pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

56. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2RS-2-amino-3-hydroxyprop-1-altimeter) pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

57. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-(N-methylenedianiline)pyrid-4-ylthio)-3-cefem - 4-carboxylate, salt triperoxonane acid

58. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-(2R-2-N, N-dimethylcarbamyl-2-aminoethylthiomethyl)-pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

59. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-(2R-2-carboxamido-2-aminoethylthiomethyl)pyrid - 4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

60. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido]-3-(3-socioresidential-4-ylthio)-3-cefem-4 - carboxylate, salt triperoxonane acid

61. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)- acetamido] -3-(3-(N,N-dimethylcarbamodithioato) pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

62. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-(2-amino-2-methylpropionyl)pyrid-4-ylthio)-3-acetamido] -3-(3-(N-formalininactivated)pyrid-4-ylthio-3-cefem-4 - carboxylate, salt triperoxonane acid

64. (7R)-7-[(2)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-(N-formylamino)pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

65. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)- acetamido]-3-[3-(2R-2-amino-3-hydroxyprop-1-altimeter)pyrid-4-ylthio]- 3-cefem-4-carboxylate, salt triperoxonane acid.

(The numbering of the compounds corresponds to the numbering in MICK tables; data is shown for the infection methicillinsensitive organism S. aureus strain was ATSS 13709).

EXAMPLES

Hereinafter the present invention will be more fully described in connection with the following specific examples, which should not be construed in any way as limiting the scope of the present invention.

Example 1

(7R)-7-[(phenylacetyl)amino]-3-(4-hydroxymethyl-1,2,3-thiadiazole-5-ylthio)- 3-cefem-4-carboxylate, 4-methoxybenzyloxy ester

To a stirred solution of 1,3-dichloroacetone (6.85 g, 54 mmole) and ethyl-3-mercaptopropionate (to 13.9 ml, 108 mmol) in 150 ml of anhydrous tetrahydrofuran was added dropwise a triethylamine (15.0 ml, 108 mmol) at 0oC and stirred at room temperature for 24 hours. The solvent is evaporated, and the residue rachat over sodium sulfate and concentrated to dryness, getting to 17.4 g of crude 1,3-bis (2-ethoxycarbonylethyl) acetone.

A solution of 1,3-bis [(2-ethoxycarbonylethyl)thio]acetone (6,22 g, and 19.3 mmole), ethylcarbitol (2,40 g, 23.1 mmole) and a catalytic amount of n-toluensulfonate acid in anhydrous acetonitrile (50 ml) containing molecular sieves, stirred for 2 days at room temperature. The reaction is quenched with a mixture of water/ethyl acetate and filtered. The obtained filtrate is extracted with ethyl acetate. The organic extract was washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue is triturated with hexane, obtaining 7.2 g of 1,3-bis[(2-ethoxycarbonylethyl)thio] acetoacetanilide.

1H NMR (CDCl3) : 2,2-2,4 (m, 9H), 2,6-2,8 (m, 8H), 3,42 (s, 2H), 3,54 (s, 2H), 4,1-4,3 (m, 6H), 8,82 (Shir.s, 1H)

To a solution of the hydrazone (7.2 g, to 17.6 mmole) in 1,2-dichloroethane (20 ml) is added thionyl chloride (3.9 ml, 53 mmole) at 0oC and stirred over night at room temperature. The resulting mixture was concentrated to a volume of 10 ml, diluted with dichloromethane, washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, and then concentrated to dryness, obtaining 6,47 g of 5-[(2 - ethoxycarbonylethyl)thio] -4-[(2-ethoxycarbonylethyl)thiomethyl]-1,2,07 (s, 2H), 4,1 - 4,2 (m, 4H).

To a solution of 5-[(2-ethoxycarbonylethyl)thio] -4-[(2-ethoxycarbonylethyl)- thiomethyl]-1,2,3-thiadiazole (1.0 g, 3.0 mmole) in 40 ml dichloromethane add a few servings metallocarboranes acid at 0oC as long, until it vanishes source material. Then the resulting mixture was sequentially washed with saturated aqueous sodium thiosulfate, cold aqueous 1% sodium hydroxide and brine, and then concentrated to dryness. The oxidized product is treated triperoxonane anhydride (2 ml) for 30 minutes at room temperature. After removal triperoxonane anhydride under reduced pressure, the resulting mixture was stirred in a mixture of ethyl acetate/1% sodium hydroxide (30 ml/30 ml) for 30 minutes. An ethyl acetate layer is concentrated to a volume of 5 ml and add 10 ml of methanol. Batch add an excess of sodium borohydride (200 mg) at 0oC under stirring. After 30 minutes the reaction is quenched with diluted hydrochloric acid. The resulting mixture was extracted with ethyl acetate and concentrated. The residue is purified chromatographically on silica gel (1% methanol/dichloromethane) to obtain 225 mg of 5-[(2 - ethoxycarbonyl/ethyl)thio]-4 - hydroxymethyl-1,2,3-thiadiazole.

1H NMR (CDCl3) : of 1.27 (t, 3H, imethyl-1,2,3-thiadiazole (225 mg, of 0.91 mmole) in 20 ml of anhydrous ethanol is added 0.5 M sodium methoxide in methanol (1.6 ml). After 10 minutes, the resulting mixture was concentrated and triturated with dichloromethane to obtain tialata sodium. The solution tialata sodium and (7R)-7-[(phenylacetyl) amino]-3-tripterocalyx-3-cefem-4-carboxylate, 4-methoxybenzylthio of ester (500 mg, of 0.85 mmole) in 10 ml of tetrahydrofuran was stirred at 0oC for 30 minutes and add 50 ml of water. The reaction mixture was extracted with ethyl acetate and concentrated. The residue is purified chromatographically on silica gel (2% methanol/dichloromethane) to give 407 mg specified in the title compound.

1H NMR (CDCl3) : 3,22 (d, 1H, J = 18), of 3.46 (d, 1H, J = 18), 3,61 (d, 1H, J = 16), to 3.67 (d, 1H, J = 16), 3,81 (s, 3H), of 4.95 (d, 1H, J = 5), 5,02 (c, 2H), 5,23 (d, 1H, J = 12), 5,28 (d, 1H, J = 12), of 5.83 (DD, 1H, J = 5,8), 6,14 (d, 1H, J = 8), 6,86 (d, 2H, J = 9), of 7.2 to 7.4 (m, 7H).

Example 2

(7R)-7-[(phenylacetyl)amino] -3-(4-chloromethyl-1,2,3-thiadiazole-5-ylthio)- 3-cefem-4-carboxylate, 4-methoxybenzyloxy ester

To DMF (5 ml) is added thionyl chloride (85 ml; 1,71 mmole) and stirred for 30 minutes at room temperature. A solution of (7R)-7-[(phenylacetyl)amino] -3-(4-hydroxymethyl-1,2,3-thiadiazole-5-ylthio)-3 - cefem-4-carboxylate, 4-methoxybenzylthio of ester is camping extracted with ethyl acetate. The organic extract is washed with water and concentrated. The residue is purified chromatographically on silica gel (0.5% methanol/dichloromethane) to give 322 mg specified in the title compound.

1H NMR (CDCl3) : 3,20 (d, 1H, J = 18), 3,47 (d, 1H, J = 18), of 3.60 (d, 1H, J = 16), 3,66 (d, 1H, J = 16), 3,79 (s, 3H), of 4.95 (m, 3H), 5,22 (d, 1H, J = 12 in), 5.25(d, 1H, J = 12), to 5.85 (DD, 1H, J = 5,8), 6,53(d, 1H, J = 8), at 6.84 (d, 2H, J = 9), of 7.2 to 7.4 (m, 7H).

Example 3

(7R)-7-[(phenylacetyl)amino] -3-(4-socioresidential-1,2,3-thiadiazole-5 - ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

A solution of (7R)-7-[(phenylacetyl) amino]-3-(4-chloromethyl-1,2,3-thiadiazole-5 - ylthio)-3-cefem-4-carboxylate, 4-methoxybenzylthio of ester (70 mg, 0.12 mmole), thiourea (7,6 mg, 0.1 mmole) and sodium iodide (15 mg, 0.1 mmole) in 3 ml of dry acetonitrile was stirred at room temperature overnight. The resulting mixture was concentrated and triturated with dichloromethane to remove unreacted starting material. The residue is again dissolved in acetone (2 ml) and filtered. The resulting filtrate is concentrated to dryness, receiving 60 mg of (7R)-7-[(phenylacetyl) amino]-3-(4 - socioresidential-1,2,3-thiadiazole-5-ylthio)-3-cefem-4 - carboxylate, 4-methoxybenzylthio of ester, iodide (salt) in the form of a yellowish solid wisest, J = 15), 5,10 (d, 1H, J = 15), 5,28 (m, 3H), 5,88 (DD, 1H, J = 5, 8); 6,91 (d, 2H, J = 9), of 7.2 to 7.4 (m, 7H), 8,32 (d, 1H, J = 8).

A mixture of (7R)-7-[(phenylacetyl)amino]-3-(4-socioresidential-1,2,3 - thiadiazole-5-ylthio)-3-cefem-4-carboxylate, 4-methoxybenzylthio of ester, iodide (salt) (60 mg), anisole (0.1 ml) and 1 ml triperoxonane acid is stirred at 0oC for 30 minutes and then concentrated to dryness. The obtained residue sequentially triturated with dichloromethane (40 ml) and water (0.5 ml) to obtain 38 mg specified in the title compound.

1H NMR (DMSO-d6) : to 3.41 (d, 1H, J = 18), of 3.48 (d, 1H, J = 14), 3,55 (d, 1H, J = 14), of 3.69 (d, 1H, J = 18), a 4.86 (d, 1H, J = 15), 4,94 (d, 1H, J = 15), 5,14 (d, 1H, J = 5), 5,72 (DD, 1H, J = 5,8), a 7.1 to 7.3 (m, 7H), 9,18 (d, 1H, J = 8).

Example 4

(7R)-7-amino-3-(4-chloromethyl-1,2,3-thiadiazole-5-ylthio)-3-cefem-4 - carboxylate, 4-methoxybenzyloxy ester

To a solution of (7R)-7-[(phenylacetyl)amino]-3-(4-chloromethyl-1,2,3-thiadiazole - 5-ylthio)-3-cefem-4-carboxylate, 4-methoxybenzylthio of ester (604 mg, 1.68 mmole) and pyridine (0,271 ml, to 3.36 mmole) in dichloromethane (20 ml) was added dropwise a solution of patalenitsa phosphorus (208 mg, 2.68 mmole) in dichloromethane (10,7 ml) and stirred at -10oC for 2 hours. After cooling to -40oC add to 1.55 ml of Isobutanol and the resulting mixture was stirred for p is th the extract was washed with saturated aqueous sodium bicarbonate and concentrated. The residue is purified chromatographically on silica gel (10% methanol/dichloromethane) to give 599 mg specified in the title compound.

1H NMR (CD3OD) : 3,45 (d, 1H, J = 18), the 3.65 (d, 1H, J = 18), 3,76 (s, 3H), and 4.75 (1H, overlapped with water signal), to 4.98 (s, 2H), of 5.05 (d, 1H, J = 5), 5,23 (s,2H), PC 6.82 (d, 2H, J = 9), 7,26 (d, 2H, J = 9).

Example 5

4-chloro-3-hydroxymethyluracil

To a solution of 4-chloro-3-pyridinecarboxamide (140 mg, 1.0 mmole) in THF (1 ml) at 0oC add 1 ml of methanol, and then portioned add sodium borohydride (75 mg, 2.0 mmole). After an hour, add 0.15 ml of acetic acid and the reaction mixture is evaporated to dryness in a rotary evaporator at room temperature. The solid residue is treated chromatography on a column of silica gel (1% MeOH/dichloromethane) to obtain 60 mg (42%) specified in the title compound.

1H NMR (CDCl3) : 4,30 (Shir.s, 1H), 4,80 (s, 2H), 7,30 (d, 1H, J = 5), a 8.34 (d, 1H, J = 5), 8,62 (c, 1H).

Example 6

(7R)-7-[(phenylacetyl)amino] -3-(3-hydroxymethylene-4-ylthio) -3-cefem-4-carboxylate, 4-methoxybenzyloxy ester

To a solution of 4-chloro-3-hydroxymethylbilane (60 mg, at 0.42 mmole) in 1 ml DMF at room temperature under nitrogen atmosphere add thioacetate potassium (71 mg, 0,63 mmole). After stirring% MeOH/dichloromethane. Insoluble material is filtered and the obtained filtrate was concentrated in a rotary evaporator. The residue is dissolved in 3 ml of MeOH and added aqueous sodium hydroxide (0.5 ml, 3M). After reaction overnight at room temperature, the reaction mixture was acidified with 1 M hydrochloric acid, evaporated to dryness in a rotary evaporator and share between saturated sodium bicarbonate solution and ethyl acetate. The organic layer is dried over sodium sulfate and the solvent is removed in a rotary evaporator. The residue is dissolved in MeOH and added (7R)-7-[(phenylacetyl) amino] -3 - tripterocalyx-3-cefem-4-carboxylate 4-methoxybenzyloxy ester (240 mg, at 0.42 mmole), and then add dichloromethane. After reaction overnight at room temperature, the reaction mixture is divided between 5% sodium bicarbonate solution and ethyl acetate. In the purification on silica gel (Chromatotron, 2% MeOH/dichloromethane) receive specified in the title compound (60 mg, 25%).

1H NMR (CDCl3) : 3.15 in (d, 1H, J = 18), 3,55 (d, 1H, J = 18), 3,63 (d, 1H, J = 18), 3,68 (d, 1H, J = 18), of 3.78 (s, 3H), br4.61 (d, 1H, J = 13), of 4.66 (d, 1H, J = 13), of 5.05 (d, 1H, J = 5), to 5.08 (d, 1H, J = 13), the 5.25 (d, 1H, J = 13), of 5.89 (DD, 1H, J = 9.5) is, 6,76 (d, 2H, J = 8), 7,05 (m, 2H), 7,16 (d, 21H, J = 8), 7,32 (m, 5H), to 8.40 (d, 1H, J = 5), 8,48 (s, 1H).

1H NMR (CDCl3) : 3,17 (d, 1H, J = 18) and 3.59 (d, 1H, J = 18), 3,63 (d, 1H, J = 18), 3,68 (d, 1H, J = 18), of 3.77 (s, 3H), of 4.54 (d, 1H, J = 13), of 4.66 (d, 1H, J = 13), is 5.06 (d, 1H, J = 5), to 5.08 (d, 1H, J = 13), 5, 22 (d, 1H, J = 13), 5,90 (DD, 1H, J = 9.5) is, 6,76 (d, 2H, J = 8), to 6.95 (d, 1H, J = 9), 7,07 (d, 1H, J = 5), to 7.15 (d, 2H, J = 8), 7,30 (m, 5H), to 8.41 (d, 1H, J = 5), 8,45 (c, 1H).

Example 8

(7R)-7-[(phenylacetyl) amino]-3-(3-socioresidential-4-ylthio)- 3-cefem-4-carboxylate, 4-methoxybenzyloxy ester, hydrochloride (salt)

To a solution of (7R)-7-[(phenylacetyl) amino]-3-(3-chloromethylene-4-ylthio)-3 - cefem-4-carboxylate, 4-methoxybenzylthio of ester (52 mg, 0,087 mmole) in 0.4 ml of ethanol and 0.1 ml of dichloromethane added thiourea (7 mg, 0,095 mmole) at room temperature. After reaction overnight dissolve the t in vacuo to obtain the title compound (56 mg, 96%).

1H NMR (CDCl3/CD3OD) : 3,14 (d, 1H, J = 10), 3,53 (d, 1H, J = 10), to 3.58 (s, 2H), of 3.73 (s, 3H), and 4.40 (s, 2H), to 5.03 (d, 1H, J = 5), 5,12 (d, 1H, J = 9), further 5.15 (d, 1H, J = 9), of 5.75 (d, 1H, J = 5), 6,74 (d, 2H, J = 10), 7,10 (d, 1H, J = 5), 7,14 (d, 2H, J = 10), 7,25 (m, 5H), 8,30 (d, 1H, J = 5), 8,45 (c, 1H).

Example 9

(7R)-7-[(phenylacetyl) amino] -3-(3-socioresidential-4-ylthio)-3 - cefem-4-carboxylate, salt triperoxonane acid

To a solution of (7R)-7-[(phenylacetyl)amino]-3-(3-socioresidential-4-ylthio) -3-cefem-4-carboxylate, 4-methoxybenzylthio of ester hydrochloride (56 mg, 0,083 mmole) in 1 ml dichloromethane add 0.1 ml of anisole, and then add 1 ml of triperoxonane acid. After 30 minutes the reaction mixture was concentrated in a rotary evaporator, and the resulting residue triturated with ethyl ether. The residue is again washed, decanter fresh portions of ethyl ether and dried in vacuo to obtain the title compound (49 mg, 79%).

1H NMR (CD3OD) : 3,20 (d, 1H, J = 18), to 3.58 (d, 1H, J = 13), 3,62 (d, 1H, J = 13), 3,83(d, 1H, J = 18), 4,56 (d, 1H, J = 10), 4,60 (d, 1H,J = 10 in), 5.25 (d, 1H, J = 5), 5,78 (d, 1H, J = 5), 7,28 (m, 5H), the 7.43 (d, 1H, J = 5), to 8.45 (d, 1H, J = 5), 8,55 (c, 1H).

Example 10

(7R)-7-[(Z)-2-(N-triphenylimidazole-4-yl)-2-(triphenylphosphino) acetamido]-3-(4-chloromethyl-1,2,3 - thiadiazole-5-ylthio) -- (triphenylarsine) acetate sodium salt (2,11 g, 3,05 mmole) in 4 ml DMF add methanesulfonanilide (0,28 ml) at -60oC and stirred at the same temperature for 1.5 hours. Then this solution was added to a solution of (7R)-7-amino-3-(4-chloromethyl-1,2,3 - thiadiazole-5-yl) thio-3-cefem-4-carboxylate, 4-methoxybenzylthio of ester hydrochloride (920 mg, of 1.88 mmole) and diisopropylethylamine (0.4 ml) in DMF (2 ml) at -10oC and stirred for 1 hour. The reaction mixture was poured into ice water and the resulting precipitate collected by filtration. The filter cake purified through column chromatography with silica gel (0.5% methanol/dichloromethane) to give 558 mg specified in the title compound.

1H NMR (CDCl3) : of 3.07 (d, 1H, J = 18), 3,44 (d, 1H, J = 18), 3,81 (2H), 4,96 (2H), is 5.06 (1H), 6,07 (1H), gold 6.43 (s, 1H), 6,80 (Shir.s, 1H), to 6.88 (1H), 7,25 was 7.45 (40H).

Example 11

(7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- (4-socioresidential-1,2,3-thiadiazole-5-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

A solution of (7R)-7-[(Z)-2-(N-triphenylimidazole-4-yl)-2- (triphenylphosphino)acetamido] -3-(4-chloromethyl-1,2,3 - thiadiazole-5-ylthio)-3-cefem-4-carboxylate, 4-methoxybenzylthio of ester (221 mg, 0,19 mmole), sodium iodide (34 mg, 0,23 mmole) and thiourea (14 mg, of 0.18 mmole) in 10 ml acetone Lacetti layer washed with water and concentrated. The residue is triturated to obtain isothiouronium salt, which is treated similarly to the scheme of removal protection example 9, resulting in a gain of 27 mg specified in the title compound.

1H NMR (D2O) : 3,48 (d, 1H, J = 18), of 3.84 (d, 1H, J = 18), of 5.39 (s, 1H), 5,90 (s, 1H), 7,16 (s, 1H).

Example 12

4-etoxycarbonyl-5-[2-(phenylsulfonyl)ethylthio]thiazole

To a solution of tert-butoxide potassium (496 mg, 4.4 mmole) in 10 ml THF add solution ethylisothiocyanate (of 0.48 ml, 4.4 mmole) in 5 ml THF at -40oC and the reaction mixture continued to stir for 10 minutes. After the reaction solution has cooled down to -60oC, add a solution of carbon disulfide in 5 ml of THF. The obtained mixture is allowed to warm to 0oC and add 2-iodoethylene (4.4 mmole). Then the mixture is refluxed for 5 hours. After cooling it to room temperature, add water and ethyl acetate. The aqueous layer was brought to acidic pH with diluted hydrochloric acid and extracted with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude residue is purified chromatographically to obtain from the = 7), of 7.6 (t, 2H, J = 8), of 7.70 (t, 1H, J = 8), to 7.93 (d, 2H, J = 8), and 8,64 (s, 1H).

Example 13

4-hydroxymethyl-5-[2-(phenylsulfonyl)ethylthio]thiazole

To a solution of 4-etoxycarbonyl-5-[2-(phenylsulfonyl)ethylthio] thiazole (702 mg, 2 mmole) in 20 ml of THF added lithium borohydride (2M, 1 ml) and methanol (0.16 ml, 4 mmole) at -30oC. the Reaction mixture is allowed to slowly warm to room temperature and stirred over night. The solvent is removed under reduced pressure and the crude residue is treated chromatography, using as eluent dichloromethane and methanol to obtain the title compound (400 mg, 65%).

1H NMR (CDCl3) : 2,55 (s, 1H), 3.00 for (t, 2H, J = 6), 3,40 (t, 2H, J = 6), 4,71 (s, 2H), 7,6 (t, 2H, J = 7), to 7.68 (t, 1H, J = 7), of 7.82 (d, 2H, J = 7), and 8,80 (s, 1H).

Example 14

(7R)-7-[(Z)-2-(N-triphenylimidazole-4-yl)-2-(triphenylphosphino) acetamido] -3-(4-hydroxymethylimidazole-5-ylthio)-3-cefem-4-carboxylate, 4 - methoxybenzyloxy ester

To a solution of 4-hydroxymethyl-5-[2-(phenylsulfonyl)ethylthio]thiazole (39 mg) in 1 ml DMF added tert-piperonyl potassium (14 mg) and the mixture continued to stir for 2 hours. After the reaction solution was cooled to -40oC, add a solution of (7R)-7-[(Z)-2-(N-triphenylethylene delovogo of ester (104 mg) in 1.5 ml DMF. The resulting mixture was slowly heated to 0oC, quenched with diluted aqueous ammoniacloridegas and extracted with ethyl acetate and hexane. The solvent is removed under reduced pressure and the crude residue purified chromatography to obtain the title compound (61 mg).

1H NMR (CDCl3) : of 3.28 (q, 2H, J = 8), 3,82 (s, 3H), 4.72 in (q, 2H, J = 8 Hz), 4,98 (l, 1H, J = 4 in), 5.25 (q, 2H, J = 8), 5,96 (kV, 1H, J = 4), 6.42 per (s, 1H), 6,85 (s, 1H), 6,93 (d, 2H, J = 7), 7,20-7,42 (m, 33H) and 8.8 (s, 1H).

Example 15

(7R)-7-[(Z)-2-(N-triphenylimidazole-4-yl)-2- (triphenylphosphino)acetamido] -3-(4-chloromethylthiazole-5 - ylthio)-3-cefem-4-carboxylate, 4-methoxybenzyloxy ester.

To DMF (1 ml) is added thionyl chloride (0,016 ml) at 0oC and the resulting mixture was continued to stir at the same temperature for 30 minutes. The resulting solution was transferred by cannula into a solution of (7R)-7-[(Z)-2-(N-triphenylimidazole-4-yl)-2- (triphenylphosphino)acetamido] -3-(4-hydroxymethylimidazole-5 - ylthio)-3-cefem-4-carboxylate, 4-methoxybenzylthio of ester (61 mg) in 1 ml DMF and continue to stir at the same temperature for 1 hour. The reaction solution was diluted with ethyl acetate and hexane and washed with water. The solvent is removed under reduced pressure and si is P>H NMR (CDCl3) : up 3.22 (q, 2H, J = 12), of 3.80 (s, 3H), 4,78 (q, 2H, J = 8), 5,04 (d, 1H, J = 4), and 5.30 (q, 2H, J = 5), 6,00 (kV, 1H, J = 4), 6.42 per (s, 1H), 6,72 (s, 1H), 6,92 (d, 2H, J = 7), was 7.08 (d, 1H, J = 4), 7,20 was 7.45 (m, 32H) and of 8.95 (s, 1H).

Example 16

(7R)-7-[(Z)-2-(N-triphenylimidazole-4-yl)-2-(triphenylphosphino) acetamido] -3-(4-socioresidential-5-ylthio)-3-cefem-4-carboxylate, 4-methoxybenzyloxy ester

(7R)-7-[(Z)-2-(N-triphenylimidazole-4-yl)-2- (triphenylphosphino)acetamido] -3-(4-chloromethylthiazole-5 - ylthio)-3-cefem-4-carboxylate, 4-methoxybenzyloxy ester (43 mg) dissolved in 2 ml of acetonitrile, to which was added thiourea (4.5 mg) and sodium iodide (13 mg). The resulting mixture was stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude residue purified using flash chromatography to obtain the title compound (40 mg).

1H NMR (CDCl3/CD3OD) : 3,2 (q, 2H, J = 12), of 3.80 (s, 3H), 4,4 (q, 2H, J = 12), 5,02 (d, 1H, J = 4 in), 5.25 (q, 2H, J = 5); to 5.85 (d, 1H, J = 4), 6,45 (c, 1H), 6.90 to (d, 2H, J = 7), 7,2-7,4 (m, 32H) and 9.00 (c, 1H).

Example 17

(7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3-(4 - socioresidential-5-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

(7R)-7-[(Z)-2-(N-triphenylmethyl oxybenzoyl ester (40 mg) dissolved in 0.1 ml of anisole and 0.9 ml of dichloracetic acid. The resulting mixture was stirred at room temperature for 3 hours, and then precipitated by adding diethyl ether (100 ml). The precipitation is filtered and treated by high performance chromatography on HP-20 with the inverted phase to obtain the title compound.

1H NMR (D2O) : of 3.60 (q, 2H, J = 6), 4,60 (KB, 2H, J = 10), 5,20 (d, 1H, J = 4), 5,80 (d, 1H, J = 4), of 6.90 (s, 1H) and 9,13 (s, 1H) IR (KBr): 997, 1042, 1180, 1349, 1386, 1533, 1615, 1655 and 1768 cm-1.

Example 18

(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(triphenylphosphino)acetic acid

To a solution of (Z)-2-(2-aminothiazol-4-yl)-2-(triphenylphosphino)acetic acid (of 5.81 g, 13,47 mmole) in 30 ml DMF at room temperature add N-chlorosuccinimide (1.80 g, 13,47 mmole). After reaction overnight, the reaction mixture was poured into water (500 ml) and the precipitate filtered off, washed with water and then with ethyl acetate and dried in vacuo to obtain 4,43 (71%) specified in the title compound.

1H NMR (CDCl3) : 108,5, 125,6, 126,2, 126,6, 12,3, 134,7, 141,8, 146,5, 162,1, 163,3.

Example 19

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(triphenylphosphino) acetamido]-3-chloro-3-cefem-4-carboxylate diphenylmethylene ester

To a solution of 7-amino-what Olya) in dry THF (100 ml) is added pyridine (0,63 g, 10.0 mmole) at room temperature followed by the addition of (Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (triphenylphosphino) acetic acid (of 5.81 g, 13,47 mmole). The resulting suspension is cooled to -15oC and add additional pyridine (1.42 g, 22.5 mmole) followed by precapitalism petaluridae phosphorus (1.64 g, of 17.5 mmole), and the temperature of the reaction mixture at the same time supporting below -10oC. After 30 minutes the reaction add 200 ml of ethyl acetate, and then add water (150 ml). The aqueous layer was thoroughly extracted with ethyl acetate and the combined organic extracts dried over sodium sulfate and concentrated in vacuo to obtain the crude product, which was purified using flash chromatography on silica gel (ethyl acetate/hexane - 3/1) to obtain the title compound (lower than the 5.37 g, 65%)

1H NMR (CDCl3/CD3OD) : 3,35 (d, 1H, J = 18), 3,68 (d, 1H, J = 18), 5,07 (d, 1H, J = 5), 5,80 (Shir.s, 2H), 6,04 (DD, 1H, J = 9,5), 7,03 (s, 1H), 7,06 (d, 1H, J = 9), 7,22 - to 7.50 (m, 25H).

Example 20

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (triphenylphosphino)acetamido] -3-mercapto-3-cefem-4 - carboxylate diphenylmethylene ester

K the solution of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (triphenylphosphino)acetamido]-3-chloro-3-cefem-4-Carbo the second portion of the powdered hydrate sulphurous acid sodium (1.1 g, 19.6 mmole). After 15 minutes the reaction mixture was poured into 0.5 M monolatrist (about 100 ml), extracted with ethyl acetate and the organic layer washed thoroughly with water. After concentration in vacuum to get crude specified in the title product as a yellow foam (3.8 g 95%)

1H NMR (CDCl3/CD3OD) : 3,38 (d, 1H, J = 15), 4,43 (d, 1H, J = 15), of 5.03 (d, 1H, J = 5), 5,80 (d, 1H, J = 5), of 5.99 (Shir.s, 1H), 6,80 (s, 1H), 7,05 is 7.50 (m, 25H).

Example 21

3-chloromethyl-4-chloropyridine hydrochloride

Thionyl chloride (0,714 ml, 9,78 mmole) is added at room temperature to dry DMF (7 ml). After 30 minutes the resulting solution was transferred via cannula into a solution of 3-hydroxymethyl-4-chloropyridine (700 mg, 4,89 mmole) in 3 ml DMF. After 45 minutes, the product is precipitated by adding dry ether (100 ml), washed with ether and dried in vacuo to obtain 813 mg (84%) specified in the title compound.

1H NMR (CD3OD) : 5,00 (s, 2H), 8,31 (d, 1H, J = 5), 8,99 (d, 1H, J = 5), 9,18 (s, 1H).

Example 22

3-(N-tert-butoxycarbonylmethylene)-4-chloropyridin

To a solution of 3-chloromethyl-4-chloropyridine hydrochloride (513 mg, at 2.59 mmole) in 6 ml of DMF at room temperature is added sodium iodide (386 mg, at 2.59 mmole), diisopropylethylamine (1,12 ml, 6.47 mmole) and 2-(N-tert-butoxycarbonyl is. the content of inorganic fillers layer washed with water, dried over sodium sulfate and concentrated to obtain 750 mg of oily product (96%), which is used in the next stage without additional purification.

1H NMR (CDCl3) : USD 1.43 (s, 9H), 2,61 (m, 2H), 3,35 (m, 2H), 3,81 (s, 2H), 4,90 (Shir. s, 1H), 7,35 (d, 1H, J = 4), to 8.40 (d, 1H, J = 4), to 8.57 (s, 1H).

Example 23

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(triphenylphosphino) acetamido] -3-(3-N-tert-butoxycarbonylmethylene-4-ylthio)-3 - cefem-4-carboxylate diphenylmethylene ester

To a solution of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (triphenylphosphino)acetamido] -3-mercapto-3-cefem-4-carboxylate diphenylmethylene of ester (650 mg, 0,777 mmole) in 3 ml DMF added 3-(N - tert-butoxycarbonylmethylene)-4-chloropyridine (242 mg, 0,80 mmole) at room temperature. After reaction overnight, the reaction mixture is divided between water and ethyl acetate. The organic layer is washed thoroughly with water, dried over sodium sulfate and concentrated to obtain the crude product, which was purified using radial chromatography on silica gel (dichloromethane/methanol; volume/volume, 50/1) to obtain 220 mg specified in the title compound (26%).

1with, 1H), 5,94 (d, 1H, J = 5), to 6.80 (s, 1H), 6.90 to (d, 1H, J = 6), 7,00-7,22 (m, 25H), 8,01 (d, 1H, J = 6), 8,08 (s, 1H).

Example 24

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-(3-aminoethylthiomethyl-4-ylthio)-3-cefem-4-carboxylate, salt methanesulfonic acid

To a solution of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)- 2-(triphenylphosphino)acetamido] -3-(3-N-tert - butoxycarbonylmethylene-4-ylthio)-3-cefem-4 - carboxylate diphenylmethylene of ester (1.0 g, 0,907 mmole) in 10 ml of dichloromethane and 1.0 ml of anisole was added whenoC 13 ml triperoxonane acid. After 1.5 hours the reaction mixture was concentrated in vacuo at room temperature and the oily residue is dissolved in 98% formic acid (20 ml). After 4 hours at room temperature formic acid is removed in vacuo and the residue dissolved in water (25 ml). Nerastvorim material is removed by centrifugation, and the supernatant purified on a column of NR, elwira water and then with 0.1 M ammonium acetate, water, and in the end, elwira product with a mixture of acetonitrile-water (1/4). The obtained eluate concentrated to about 1/10 of the original volume and the resulting precipitate filtered, washed with water and dried in vacuum to obtain zwitterionic product (260 mg). Methansulfonate the water, 0,98 EQ) and acetonitrile (5 ml). After evaporating the resulting solution to dryness, the residue is dissolved in water (30 ml), centrifuged to remove nerastvorimogo material and the supernatant lyophilizer, getting mentioned in the title compound (274 mg, 44%).

1H NMR (D2O) : 3,11 (s, 3H), 3,19 (m, 2H), 3,52 (m, 2H), to 3.67 (d, 1H, J = 17), 4,22 (d, 1H, J = 17), to 4.33 (s, 2H), USD 5.76 (d, 1H, J-4), of 6.29 (d, 1H, J = 4), to 7.93 (d, 1H, J = 4), 8,78 (d, 1H, J = 4), 8,87 (C, 1H).

Example 25

3-(N-tert-butoxycarbonylamino)-4-chloropyridin

K suspension 4-chlorobenzylchloride (2 g) in 40 ml of dry THF added freshly prepared LDA (2.5 EQ) at -70oC and the resulting mixture was continued to stir at the same temperature for 4 hours. To this solution through the cannula add a solution of N,N'-di(tert-butoxycarbonyl)applied (2.5 g, 0.5 EQ.) in 10 ml of THF. The reaction mixture is allowed to warm to 0oC, quenched with water, and then extracted with ethyl acetate. The solvent is removed under reduced pressure and the crude residue purified using flash chromatography to obtain the title compound (0.95 g, 50%) as a solid white color.

1H NMR (CDCl3) : of 1.42 (s, 9H), 3.15 in (t, 2H, J = 7), to 3.38 (t, 2H, J = 7), of 4.95 (s, 1H), 7,32 (d, 1H, J = 6), 8,35 (d, 1H, J = 6) and at 8.60 (s, 1H).


To a stirring solution of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(triphenylphosphino) acetamido] -3-mercapto-3-cefem-4-carboxylate diphenylmethylene of ester (6.7 g, and 7.8 mmole) in 20 ml dry DMF, add 3-(N-tert-butoxycarbonylamino)-4-chloropyridine (2.3 g, 7,8 mmole) at -20oC. the Reaction mixture was left to slowly warm to room temperature and stirred over night. The reaction mixture was diluted with ethyl acetate and hexane and washed with water. The solvent is removed under reduced pressure and the crude residue purified chromatography to obtain the title compound (6 g; 68%) as a solid yellow color.

1H NMR (CDCl3) : of 1.40 (s, 9H), to 2.75 (t, 2H, J = 7), 3,10 (t, 2H, J = 7) and 3.15 (d, 1H, J = 14), 3,60 (d, 1H, J = 14), of 4.95 (s, 1H), 5,20 (d, 1H, J = 4), 5,90 (s, 2H), and 6.25 (q, 1H, J = 4), 6,85 (d, 1H, J = 4), make 6.90 (s, 1H), 7,15 to 7.4 (m, 26H), and 8.1 (s, 1H), 8,21 (d, 1H, J = 7).

Example 27

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)acetamido] - 3-(3-aminoacridine-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

To a solution of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)- 2-(triphenylphosphino)acetamido] -3-[3-(N-tert-butoxycarbonylamino) pyrid-4-thio]-3-cefem-4-carboxylate Ausnog acid and the resulting solution was stirred at room temperature for one hour. After removal of solvent, the residue is again dissolved in 20 ml of formic acid and stirred at room temperature overnight. The solvent is removed under reduced pressure. The residue is dried under high vacuum, then triturated with ethyl acetate. The obtained solid product is treated chromatography on a column of Amberchrom with reversed-phase (0.1% water triperoxonane acid/acetonitrile) to obtain the title compound (1.5 g, 48%).

1H NMR (D2O) : to 3.5-3.7 (m, 4H), and 3.8 (d, 1H, J = 14), and 4.4 (d, 1H, J = 14), of 5.84 (d, 1H, J = 4), to 6.4 (d, 1H, J = 4), the 7.65 (d, 1H, J = 6), 8,82 (d, 1H, J = 6) and of 9.02 (s, 1H). IR (KBr): 778, 1042, 1173, 1541, 1610, 1780, 3187 cm-1.

Example 28

(7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(triphenylethylene) acetamido] -3-(4-(2-tert-butoxycarbonylmethylene)-1, 2,3-thiadiazole-5-ylthio) -3-cefem-4-carboxylate, benzhydryl ester.

To a solution of 4-[(2-tert-butoxycarbonylamino) thiomethyl]-5-(2-ethoxycarbonylethyl)thio-1,2,3-thiadiazole (181 mg, of 0.44 mmole) in ethanol (5 ml) add sodium methoxide in methanol (0.55 M, 1 ml) and concentrated. The residue is triturated with a mixture of hexane-ethyl acetate (9:1), mixed with (7R)-7-[[(Z)-2-(2 - aminothiazol-4-yl)-2-(triphenylphosphino)acetyl] amino] -3 - chloro-3-zeranol and dichloromethane. The resulting solution

stirred at room temperature for 16 hours and concentrated. The crude residue is purified through column chromatography (3% methanol/dichloromethane) to give 100 mg specified in the title compounds

1H NMR (CDCl3) : of 1.46 (9H), 2,68 (2H), 3,19 (d, 1H, J = 18), to 3.33 (2H+1H), a 4.03 (2H), 4,88 (Shir.s, 1H), 5,09 (1H), 5,93 (Shir.s, 2H), 6,44 (s, 1H), 7,03 (1H), 7,20 was 7.45 (25H).

Example 29

(7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(hydroxyimino) acetamido]-3-(4-(2-aminoethylthiomethyl)-1,2,3-thiadiazole-5-ylthio) -3-cefem-4-carboxylate, salt dichloracetic acid

(7R)-7-[(Z)-2-(aminothiazol-4-yl)-2-(triphenylethylene) acetamido] -3-(4-(2-aminoethylthiomethyl)-1,2,3-thiadiazole-5-ylthio)-3-cefem-4 - carboxylate, diphenylmethylene ester (82 mg, 0,076 mmole) is dissolved in 0.8 ml dichloracetic acid containing 5% anisole and stirred at room temperature overnight. Add an excess of diethyl ether and the precipitate collected by filtration. The filter cake is cleaned by high-performance chromatography on HP-20 column with reversed phase, receiving 16 mg specified in the title compound.

1H NMR (DMSO-d6) : of 2.64 (2H), 2,90 (2H), 3,4 (1H, overlapped with water signal), 3,82 (d, 1H, J = 17), Android 4.04 (d, 1H, J = 15), 4,14 (d, 1H, J = 15), of 5.17 (d,oxymethyl)-4-chloropyridin

Two-phase mixture of 4-chloro-3-chloromethylpyridine hydrochloride (396 mg, 2 mmole), N-tert-butoxycarbonylmethyl (132 mg, 2 mmole) and benzyltriethylammonium (544 mg, 2 mmole) in 20 ml of toluene and 50% aqueous sodium hydroxide solution is intensively stirred at room temperature for 24 hours. The organic layer is taken and concentrated to obtain 490 mg specified in the title compound.

1H NMR (CDCl3) : of 1.46 (s, 9H), 3,39 (2H), the 3.65 (2H), with 4.64 (s, 2H), 4,90 (Shir.s, 1H), 7,33 (d, 1H, J = 5), 8,46 (d, 1H, J = 5), 8,64 (s, 1H).

Example 31

(7R)-7-[(Z)-2- (2-amino-5-chlorothiazole-4-yl)-2-(triphenylphosphino) acetamido] -3-(3-(2-tert-butoxycarbonylmethyl)pyrid-4-ylthio)-3 - cefem-4-carboxylate, diphenylmethylene ester

Almost in the same conditions as in example 26, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(triphenylphosphino) acetamido]-3-mercapto-3-cefem-4 - carboxylate diphenyl ester, is subjected to the interaction with 3-(2-N-tert-butoxycarbonylmethyl)-4-chloropyridine to obtain the title compound.

1H NMR (CDCl3) : of 1.42 (9H), 3,11 (d, 1H, J= 18), 3,24 (2H), 3,40 (2H), 3.46 in (d, 1H, J = 18), 4,30 (2H), a 4.83 (Shir.s, 1H), 5,17 (1H), 5,72 (Shir.s, 2H), 6,20 (1H), 6,99 (s, 1H), 7,25 was 7.45 (25H), of 8.28 (1H), with 8.33 (1H).

Example 32

1H NMR (D2O) : 3,35 (2H), 3.45 points (d, 1H, J = 18), 3,91 (2H), 4.00 points (d, 1H, J = 18), 5,52 (d, 1H, J = 5), 6,04 (d, 1H, J = 5), 7,73 (d, 1H, J = 6), to 8.57 (d, 1H, J = 6), 8,65 (s, 1H).

Example 33

3-(N-tert-butoxycarbonylmethylene)-4-chloropyridin

To a solution of 3-(N-tert-butoxycarbonylamino)thiomethyl)-4 - chloropyridine (302 mg, 1 mmol) in a mixture of solvents: ethyl acetate (10 mg) and methanol (5 ml) is added methanesulfonyl acid (144 mg, 1.5 mmole). Then add 3-chloroperoxybenzoic acid (700 mg) and the reaction mixture was stirred at room temperature for 5 hours. The reaction is quenched with a saturated aqueous sodium thiosulfate. The resulting solution was neutralized 10% sodium hydroxide and extracted with ethyl acetate. An ethyl acetate extract is dried over sodium sulfate and concentrated to dryness, obtaining 286 mg specified in the title compound.

1H NMR (CDCl(2-amino-5-chlorothiazole-4-yl)-2-(triphenylphosphino) acetamido] -3-(3-N-tert-butoxycarbonylmethylene-4-ylthio)- 3-cefem-4-carboxylate, diphenylmethylene ester

Almost in the conditions of example 26, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(triphenylphosphino) acetamido] -3-mercapto-3-cefem-4-carboxylate, diphenylmethylene ester is subjected to interaction with 3-(N-tert - butoxycarbonylmethylene)-4-chloropyridine to obtain the title compound.

1H NMR (CDCl3) : the 1.44 (9H), 3,20 (3H), 3,66 (3H), 4,48 (s, 2H), 5,19 (1H), 7,25 was 7.45 (25H), and 8.50 (s, 1H, J = 5), to 8.70 (1H).

Example 35

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)acetamido] - 3-(3-aminoethylethanolamine-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (triphenylphosphino)acetamido] -3-(3-N-tert - butoxycarbonylmethylene-4-ylthio)-3 - cefem-4-carboxylate diphenylmethylene ester is subjected to the reaction for the removal of protection in almost the same conditions as used in example 27, receiving specified in the title compound.

1H NMR (D2O) : 3,47 (d, 1H, J = 18), 3,70 (2H), 3,85 (2H), was 4.02 (d, 1H, J = 18), 5,07 (s, 2H), 5,52 (d, 1H, J = 5), 6,03 (d, 1H, J = 5), 7,79 (d, 1H, J = 6), 8,64 (d, 1H, J = 6), 8,76 (c, 1H).

Example 36

3-(4-N-tert-butoxycarbonylamino-1-yl)-4-chloropyridin

4-chloro-3-chloro who, the AK outlined in example 30, getting mentioned in the title compound.

1H NMR (CDCl3) : is 1.4-1.6 (9H, a mixture of retamero), 4,0 - 4,2 (2H), 7,32 (d, 1H, J = 5), 8,43 (d, 1H, J = 5), 8,53 (s, 1H).

Example 37

(7R)-7-[(Z)-2- (2-amino-5-chlorothiazole-4-yl)-2- (triphenylphosphino)acetamido] -3-(3-(4-N-tert - butoxycarbonylamino-1-yl)pyrid-4-ylthio)-3-cefem-4 - carboxylate, diphenylmethylene ester

Almost in the same conditions as in example 26, (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(triphenylphosphino) acetamido]-3-mercapto-3-cefem-4-carboxylate, diphenylmethylene ester, is subjected to the interaction with 3-(4-N-tert-butoxycarbonylamino-1-yl)-4-chloropyridine to obtain the title compound.

1H NMR (CDCl3) : 1,4-1,8 (9H), 3,10 (d, 1H, J = 18), 3,47 (d, 1H, J = 18), 3,85 (2H), 5,16 (1H), 5,62 (Shir.s, 2H), 6,13 (1H), 7,00 (1H), 7,2-7,5 (25 H), 8,35 (2H).

Example 38

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)acetamido] -3-(3-(4-amino-2-butyn-1-yl)pyrid-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (triphenylphosphino)acetamido] -3-(3-(4-N-Trent - butoxycarbonylamino-1-yl)-pyrid-4-ylthio)-3-cefem-4 - carboxylate, diphenylmethylene ester, is subjected to reaction removed inania.

1H NMR (CDCl3) : of 1.40 (s, 9H), 2,90 (m, 1H), 3,01 (m, 1H) and 3.59 (m, 2), 4,00 (d, 1H, J = 13), 4,22 (d, 1H, J = 13), and 5.30 (Shir.s, 1H), 7,40 (d, 1H, J = 4), to 8.45 (d, 1H, J = 4), to 8.57 (s, 1H).

Example 41

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)acetamido] - 3-(3-aminoethylethanolamine-4-ylthio)-3-cefem-4-carboxylate, salt triperoxonane acid

Almost in the same conditions as in example 43 (7R)-7- [(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(triphenylphosphino) acetamido]-3-mercapto-3-cefem-4-carboxylate diphenylmethylene ester is subjected to interaction with 3-(M-tert - butoxycarbonylmethylene)-4-chloropyridine to obtain (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (triphenylphosphino)acetamido] -3-(3-N-tert - butoxycarbonylmethylene-4-ylthio)-3 - cefem-4-carboxylate diphenylmethylene of ester, which then removes the protection in almost the same conditions used in example 35, getting mentioned in the title compound.

1H NMR (D2O) : 2,90 (s, 3H), 3,20-to 3.35 (m, 1H), 3,50 - 3,70 (m, 4H), of 4.00 (DD, 1H, J = 18,3), 4,55 (DD, 1H, J = 13, 3) and 4.65 (DD, 1H, J = 13.3-inch), the 5.51 (m, 1H), 6,02 (m, 1H), to 7.75 (m, 1H), at 8.60 (m, 2H).

Example 42

(7R)-7-{ [2-[N,N'-bis-(tert-butoxycarbonyl)guanidino] ethylthio]acetyl}-amino} -3-(4-chloromethyl-1,2,3-til-1,2,3-thiadiazole-5-ylthio)- 3-cefem-4-carboxylate 4-methoxybenzylthio of ester (485 mg, 0,794 mmole) and {2-[NwNw'bis-(tert-butoxycarbonyl)guanidino] ethyl}-teoksessa acid (329 mg, 0,873 mmole) is added phosphorus oxychloride (0,103 ml of 1.11 mmole) and diisopropylethylamine (0,55 ml, 3,18 mmole) and stirred at -10oC for 16 hours, water is added and the resulting mixture extracted with ethyl acetate. The organic extract was washed with aqueous sodium bicarbonate solution, and then concentrated. The residue is purified chromatographically on silica gel (1% methanol/dichloromethane) to give 440 mg specified in the title compound.

1H NMR (CD3OD) : the 1.44 (s, 9), of 1.47 (s, 9), and 2.79 (m, 2), 3,30 (2, overlaps with the signal of solvent), to 3.35 (d, 1, J = 18), only 3.57 (m, 2), to 3.64 (d, 1, J = 18), of 3.77 (3), 4,96 (s, 2), 5,15 (l, 1, J = 5), 5,20 (d, 1, J = 12), 5,23 (d, 1, J = 12), 5,77 (d, 1, J = 5), for 6.81 (d, 2, J = 9), 7,25 (d, 1, J = 8).

Example 43

(7R)-7-{[2-[N,N'-bis-(tert-butoxycarbonyl)guanidino]ethylthio]acetyl] amino}-3-(4-socioorganizational-1,2,3-thiadiazole-5-ylthio)-3-cefem - 4-carboxylate, 4-methoxybenzyloxy ester, iodide salt

A solution of (7R)-7-{ [2-[N, N'-bis-(tert-butoxycarbonyl)guanidino]ethylthio] acetyl]amino}-3-(4-chloromethyl-1,2,3-thiadiazole-5-ylthio)-3-cefem-4-carboxylate 4 - methoxybenzylthio of ester (200 mg, 0.24 mmole), thiourea (18 mg, 0.24 mmole) and sodium iodide (35 intronaut and triturated with dichloromethane. The residue is again dissolved in acetone (2 ml) and filtered. The resulting filtrate is concentrated to dryness, receiving 200 mg specified in the title compounds

1H NMR (CDCl3) : 1,45 (s, 18), of 2.81 (m, 2) and 3.15 (d, 1, J = 18), to 3.36 (d, 1, J = 15), 3,55 (d, 1, J = 15), 3,62 (m, 2), of 3.80 (s, 3), 3,83 (d, 1, J = 18), 4,80 (d, 1, J = 15), a 4.86 (d, 1, J = 15), to 5.08 (d, 1, J = 5), 5,23 (d, 1, J = 12), 5,27 (d, 1, J = 12), to 5.58 (DD, 1, J = 5, 8), 6,85 (d, 2, J = 9), 7,37 (d, 2, J = 9), 8,24 (d, 1, J = 8).

Example 44

(7R)-7-{ [(2-guanidinoacetic)acetyl] amino}-3-(4 - socioeconomically-1,2,3-thiadiazole-5-ylthio)-3-cefem-4-carboxylic acid, 2,2-dichloroacetate salt

A solution of (7R)-7-{ [2-[N,N'-bis-(tert-butoxycarbonyl)guanidino] ethylthio] acetyl]amino}-3-(4-socioeconomically-1,2,3-thiadiazole-5-ylthio)- 3-cefem-4-carboxylate, 4-methoxybenzylthio of ester iodide salt (200 mg) and 0.1 ml of anisole in 2 ml of dichloracetic acid is stirred at room temperature for 16 hours. The resulting mixture was precipitated with a mixture of diethyl ether/hexane, filtered and dried in vacuum to obtain 70 mg specified in the title compounds. Using almost the same methods that are disclosed in the preceding examples, additionally, you receive the following connections:

Example 45

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-aminoethyl the l-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-guanidinoacetic)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 47

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-N-(iminomethyl)aminoacylation)pyrid-4-ylthio] - 3-cefem-4-carboxylate, salt triperoxonane acid

Example 48

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-aminopropyl)pyrid-4-ylthio] -3-cefem-4 - carboxylate, salt triperoxonane acid

Example 49

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-guanidinopropionic)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 50

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [2-N-(iminomethyl)aminopropyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 51

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3-[3- (2-amino-2-carboxymethylthio)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 52

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-guanidino-2-carboxymethylthio)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 53

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-N-(iminomethyl)amino-2-carboxymethylthio) pyrid-4-ylthio] -3-cefem-4-CT what IDO] -3- [3-(2-amino-3-hydroxypropyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 55

(7R)-7-[(Z)-2- (2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3- [3-(2-guanidino-3-hydroxypropyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 56

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-N-(iminomethyl)amino-3-hydroxypropyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 57

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 58

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-guanidinoacetate)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 59

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-N-(iminomethyl)aminoethylthiomethyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 60

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-aminopropylsilyl)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 61

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-guanidinopropionic)pyrid-4-ylthio] -3 - cefem-4-carbox�] -3- [3-(2-N-(iminomethyl)aminopropylsilyl)pyrid-4-ylthio] -3 - cefem-4-carboxylate, salt triperoxonane acid

Example 63

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-amino-2-carboxamidotryptamine)pyrid-4-ylthio] -3-cefem - 4-carboxylate, salt triperoxonane acid

Example 64

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-guanidino-2-carboxamidotryptamine)pyrid-4-ylthio] -3 - cefem-4-carboxylate, salt triperoxonane acid

Example 65

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-N-(iminomethyl)amino-2-carboxamidotryptamine) pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 66

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3-[3- (2-amino-3-hydroxypropionate)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 67

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-guanidino-3-hydroxypropionate)pyrid-4-ylthio]-3-cefem-4 - carboxylate, salt triperoxonane acid

Example 68

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-N-(iminomethyl)amino-3-hydroxypropionate)pyrid-4-ylthio] -3 - cefem-4-carboxylate, salt triperoxonane acid

Example 69

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino 70

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-guanidinoacetic)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 71

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-N-(iminomethyl)-aminoacetic)pyrid-4-ylthio] - 3-cefem-4-carboxylate, salt triperoxonane acid.

Example 72

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (hydroxyimino)acetamido] -3-[3-(2-aminopropyl)pyrid-4 - ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 73

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (hydroxyimino)acetamido] -3-[3-(2-guanidinopropionic)pyrid-4 - ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 74

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (hydroxyimino)acetamido] -3-[3-(2-N-(iminomethyl) aminopropyl)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 75

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-amino-2 - carboxymethylthio) pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 76

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-guanidino-2-carboxymethylthio)pyrid-4-ylthio] - 3-cefem-4-carboxylate, �] -3-[3-(2-N-(iminomethyl)amino-2-carboxymethylthio) pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 78

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-amino-3-hydroxypropyl)pyrid-4-ylthio] - 3-cefem-4-carboxylate, salt triperoxonane acid

Example 79

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-guanidino-3-hydroxypropyl)pyrid-4 - ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 80

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (hydroxyimino)acetamido] -3-[3-(2-N-(iminomethyl)amino-3 - hydroxypropyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 81

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 82

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-guanidinoacetate)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 83

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-N-(iminomethyl)aminoethylthiomethyl)pyrid-4-ylthio] -3 - cefem-4-carboxylate, salt triperoxonane acid

Example 84

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)acetamido] - 3-[3 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)acetamido] -3- [3-(2-guanidinopropionic)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 86

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)acetamido] - 3-[3-(2-N-(iminomethyl)aminopropylsilyl)pyrid-4-ylthio] -3-cefem-4 - carboxylate, salt triperoxonane acid

Example 87

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[(3-(2-amino-2-carboxamidotryptamine) pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 88

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-guanidino-2-carboxamidotryptamine)pyrid-4-ylthio] - 3-cefem-4-carboxylate, salt triperoxonane acid

Example 89

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-N-(iminomethyl)amino-2-carboxamidotryptamine) pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 90

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-amino-3-hydroxypropionate)pyrid-4-ylthio] - 3-cefem-4-carboxylate, salt triperoxonane acid

Example 91

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino) acetamido] -3-[3-(2-guanidino-3-hydroxypropionate)pyrid-4-ylthio] - 3-cefem-4-carboxylate, salt triperoxonane acid

Example 92

(7R)-7-[(Z)-2-(2-Amio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 93

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3- [3-(2-aminoacetic)pyrid-4-ylthio] -3-cefem-4 - carboxylate, salt triperoxonane acid

Example 94

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3- [3-(2-guanidinoacetic)pyrid-4-ylthio] -3-cefem-4-caboxylate, salt triperoxonane acid

Example 95

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3- [3-(2-N-(iminomethyl)aminoacylation)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 96

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-aminopropyl)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 97

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3- [3-(2-guanidinopropionic)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 98

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3- [3-(2-N-(iminomethyl)aminopropyl)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 99

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3- [3-(2-amino-2-carboxymethylthio)pyrid-4-ylthio] -3-cefem-4-carboxylate, Sol is(2-guanidino-2-carboxymethylthio) pyrid-4 - ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 101

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-N-(iminomethyl)amino-2-carboxymethylthio)pyrid-4-ylthio] - 3-cefem-4-carboxylate, salt triperoxonane acid.

Example 102

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-amino-3-hydroxypropyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 103

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-guanidino-3-hydroxypropyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 104

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3-[3-(2-N-(iminomethyl)amino-3-hydroxypropyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 105

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cefem-4 - carboxylate, salt triperoxonane acid

Example 106

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3- [3-(2-guanidinoacetate)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 107

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening) acetamido] -3-[3-(EP 108

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-aminopropylsilyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 109

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-guanidinopropionic) pyrid-4-ylthio]-3-cefem-4 - carboxylate, salt triperoxonane acid

Example 110

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3-[3-(2-N-(iminomethyl)aminopropylsilyl)pyrid-4-ylthio] -3-cefem-4 - carboxylate, salt triperoxonane acid

Example 111

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3- [3-(2-amino-2-carboxamidotryptamine)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 112

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3- [3-(2-guanidino-2-carboxamidotryptamine)pyrid-4-ylthio] -3-cefem-4 - carboxylate, salt triperoxonane acid

Example 113

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3- [3-(2-N-(iminomethyl)amino-2-carboxamidotryptamine)pyrid-4-ylthio]-3 - cefem-4-carboxylate, salt triperoxonane acid

Example 114

(7R) -7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido]-3- [3-(2-amino-3-hydroxypropionate) who yl)-2-(2-foretokening) acetamido] -3-[3-(2-guanidino-3-hydroxypropionate) pyrid-4 - ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 116

(7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3- [3-(2-N-(iminomethyl)amino-3-hydroxypropionate)pyrid-4-ylthio] -3 - cefem-4-carboxylate, salt triperoxonane acid

Example 117

(7R)-7-[(Z)-2- (2 - amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-aminoacetic)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 118

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-guanidinoacetic)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 119

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-N-(iminomethyl)aminoacylation)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 120

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (2-foretokening)acetamido] -3-[3-(2-aminopropyl) pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 121

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (2-foretokening)acetamido] -3-[3-(2- guanidinopropionic)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 122

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido)-3-[3-(2-N-(im) - Rev. BR> (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-amino-2-carboxymethylthio)pyrid-4-ylthio] - 3-cefem-4-carboxylate, salt triperoxonane acid

Example 124

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2 - foretokening)acetamido]-3-[3-(2-guanidino-2 - carboxymethylthio)pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 125

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-N-(iminomethyl)amino-2-carboxymethylthio)pyrid-4-ylthio] - 3-cefem-4-carboxylate, salt triperoxonane acid

Example 126

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-amino-3 - hydroxypropyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 127

(7R)-7-[(Z)-2-(2-amino-chlorothiazole-4-yl)-2-(2-foretokening) acetamido]-3-[3-(2-guanidino-3-hydroxypropyl)pyrid-4-ylthio]-3-cefem-4 - carboxylate, salt triperoxonane acid

Example 128

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-N-(iminomethyl)amino-3-hydroxypropyl) pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 129

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) are the 30

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2 - foretokening)acetamido] -3-[3-(2-guanidinoacetate) pyrid-4-ylthio]-3-cefem-4-carboxylate, salt triperoxonane acid

Example 131

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-N- (iminomethyl)aminoethylthiomethyl)pyrid-4-ylthio] -3-cefem-4 - carboxylate, salt triperoxonane acid

Example 132

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido]-3-[3-(2-aminopropylsilyl)pyrid-4-ylthio]-3 - cefem-4-carboxylate, salt triperoxonane acid

Example 133

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido]-3-[3-(2-guanidinopropionic)pyrid-4-ylthio]-3 - cefem-4-carboxylate, salt triperoxonane acid

Example 134

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-N-(iminomethyl)aminopropylsilyl)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 135

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-amino-2-carboxamidotryptamine)pyrid-4-ylthio] -3 - cefem-4-carboxylate, salt triperoxonane acid

Example 136

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (2-foretokening)acetamido] -3-[3-(2-guanidino-2- >/BR>(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2- (2-foretokening)acetamido] -3-[3-(2-N-(iminomethyl) amino-2-carboxamidotryptamine)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 138

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-amino-3-hydroxypropionate)pyrid-4-ylthio] -3-cefem-4 - carboxylate, salt triperoxonane acid

Example 139

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-guanidino-3-hydroxypropionate)pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid

Example 140

(7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening) acetamido] -3-[3-(2-N-(iminomethyl)amino-3-hydroxypropionate) pyrid-4-ylthio] -3-cefem-4-carboxylate, salt triperoxonane acid.

Thus, it should be recognized that the compounds, methods and compositions of the present invention are effective against various-lactostasis strains of bacteria that pose an increased risk to public health.

Although certain options and examples were used for the disclosure of the present invention, the specialists should be obvious that without leaving the scope and essence of the present izobreteniya for links, including both patent and non-patent references, intentionally included here for reference.

Other variations fall within the scope of the presented claims.

1. The cephalosporin of the General formula

< / BR>
where R1selected from the group consisting of-NHC(O)ZR3, -NR4R5;

Z is selected from the group consisting of-CH2(X)mand-C(NOR6)-;

X is a sulfur atom;

m = 0 or 1;

R3- thiazolyl substituted by chlorine or amino group, and (CH2)nT, where n = 1 - 6, T - guanidino;

R4and R5each is hydrogen;

R6is hydrogen or can be the group which with the adjacent oxygen atom forms a protected hydroxyl group;

R2is hydrogen;

G, H, L and M are each carbon;

J - nitrogen;

R11is hydrogen;

alk1- C1-6alkyl;

alk2- C1-6alkyl, optionally substituted by a group selected from hydroxyl, amino, carboxamido;

p = 0 or 1;

R99selected from the group consisting of sulfur and SO2;

q = 1;

r = 1, 2, or 3;

R12is NR13R14,

< / BR>
where R13- R17each is hydrogen;

or its pharmaceutically acceptable salt.

2. The connection is inferred from 2-aminothiazol-4-yl and 2-amino-5-chlorothiazole-4-yl.

4. The compound or salt according to p. 3, where Z is - C(NOR6) and R6- hydrogen.

5. The compound or salt according to p. 1-4, with activity against methylcellosolve, vancomycinflagyl or ampicillinulbactam bacteria, as evidenced by its lower minimum inhibitory concentration compared with Cefotaxime or imipenem.

6. The compound or salt according to p. 1, where R1IS-NHC(O)ZR3Z - C(NOR6)-, R6is hydrogen, R3- thiazolyl, which may be substituted, as defined in paragraph 1, alk1- CH2p = 0 or 1, R99- sulfur, q = 1, alk2- CH2, r = 2 or 3, R12- NH2missing one of the groups (alk1)p(R99)q(alk2)rR12.

7. The compound or salt according to p. 6, where R3selected from the group consisting of 2-aminothiazol-4-yl and 2-amino-5-chlorothiazole-4-yl.

8. The compound or salt according to p. 6, which is (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)acetamido] -3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio] -3-cefem-4-carboxylate or its salt; (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] -3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio] -3-cefem-4-carboxylate or its salt; (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(gidron the azole-4-yl)-2-(hydroxyimino)acetamido] -3-[3-(2R-2-amino-2-carboxamidotryptamine)pyrid-4-ylthio] -3-cefem-4-carboxylate or its salt; (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)acetamido] -3-[3-(2S-2-amino-2-carboxamidotryptamine)pyrid-4-ylthio] -3-cefem-4-carboxylate or its salt; (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)acetamido] -3-[3-(2R-2-amino-3-hydroxypropionate)pyrid-4-ylthio] -3-cefem-4-carboxylate or its salt; (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(hydroxyimino)acetamido] -3-[3-(2S-2-amino-3-hydroxypropionate)pyrid-4-ylthio] -3-cefem-4-carboxylate or its salt; (7R)-7-[(Z)-2-(2-amino-5-chlorothiazole-4-yl)-2-(2-foretokening)acetamido] -3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio] -3-cefem-4-carboxylate or its salt or (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-foretokening)acetamido] -3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cefem-4-carboxylate or its salt.

9. Connection on p. 1 formula

< / BR>
or its pharmaceutically acceptable salt,

where R34- chlorine atom;

R53group NH2;

R2, R6, G, H, J, L, M, R11, alk1, p, R99, q, alk2r and R12have the values listed in paragraph 1.

10. The compound or salt according to p. 9, where R34is chlorine, R6- hydrogen, there is one group (alk1)p(R99)q(alk2)rR12, alk1- CH2p = 0 or 1, R99- sulfur, qH2.

11. The cephalosporin of the General formula

< / BR>
where R1selected from the group consisting of-NHC(O)ZR3and NR4R5;

Z is selected from the group consisting of-CH2(X)mand-C(NOR6)-;

X is sulfur;

m = 0 or 1;

R3- thiazole, substituted by chlorine or amino group, and the group (CH2)nT, where n = 1 - 6, T - guanidino;

R4and R5is hydrogen;

R6is hydrogen or may be a group which together with the adjacent oxygen forms a protected hydroxyl group;

R2is hydrogen;

rings A, B, D and E are selected from the group consisting of thiazolyl and thiadiazolyl;

R11is hydrogen;

alk1and alk2independently - CH1-6alkyl;

p = 0, 1, or 2;

R99- sulfur;

q = 1;

r = 1, 2, or 3;

R12- NR13R14where R13and R14is hydrogen,

and its pharmaceutically acceptable salt.

12. The compound or salt according to p. 11, where R1is-NHC(O)ZR3.

13. The compound or salt according to p. 12, where R3selected from the group consisting of 2-aminothiazol-4-yl and 2-amino-5-chlorothiazole-4-yl.

14. The compound or salt according to p. 13 where Z is-C(NOR6)-, and R6- hydrogen.

15. Connection ilosciowych bacteria, as evidenced by its lower minimum inhibitory concentration compared with Cefotaxime or imipenem.

16. Connection on p. 11 formula

< / BR>
or its pharmaceutically acceptable salt,

where R34- chlorine atom;

R53group NH2;

R2, R6, A, B, D, E, R11, alk1, p, R99, q, alk2r and R12have specified in the letter of 14 values.

17. The compound or salt according to p. 16, where R6is hydrogen, alk1- CH2p = 0 or 1, alk2- CH2, r = 2 or 3 and R12- NH2.

18. Antibacterial composition having activity against methicillinsensitive, vancomycinflagyl or ampicillinulbactam bacteria, including cephalosporin compound and a pharmaceutically acceptable carrier, characterized in that it contains as cephalosporin compounds or salts thereof an effective amount of the compounds according to paragraphs.1-17.

19. The composition according to p. 18, where these bacteria are methicillinsensitive staphylococcal or ampicillinulbactam Enterococcus body.

20. Derivatives of 2-aminothiazole General formula

< / BR>
where Pg1is hydrogen or triphenylmethyl;

Pg2- Trife giraudi reagent to a solution of compound

< / BR>
where Pg1is hydrogen or triphenylmethyl;

Pg2- triphenylmethyl.

22. The method according to p. 21, where gloriouse reagent selected from the group consisting of N-chlorosuccinimide, N-hariharan, N,N-dichloroethane, Trichloroisocyanuric acid, sodium salt dichloroisocyanurate acid, N-harptallica, sodium hypochlorite, calcium hypochlorite, sodium chlorite, sodium chlorate, tert-butylhypochlorite, sulfurylchloride, chlorine, HCl/m-chloroperoxybenzoic acid, HCl/hydrogen peroxide and dichlorodimethylsilane.

23. The method according to p. 22, where gloriouse reagent selected from the group consisting of N-chlorosuccinimide, N-chloritoid, and sodium hypochlorite.

24. The method according to p. 23, where gloriouse reagent is N-chlorosuccinimide, and the solution is prepared in an organic solvent.

25. The method according to p. 24, where the solvent is selected from the group consisting of DMF, acetonitrile, and THF.

 

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< / BR>
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< / BR>
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