Derivatives of cephalosporin and their pharmaceutically acceptable salts, pharmaceutical composition

 

(57) Abstract:

The essence of the invention: a cephalosporin derivative of the General formula (I) in which R means a hydrogen atom, a C1-C6-alkyl or C1-C6-haloalkyl; A and A' taken together represent a group of formula (II-V), which means a nitrogen atom or hydrogen, and X is a hydrogen atom, a halogen atom, a C1-C6-alkyl, C1-C6-alkoxyl, amino - or nitro-group, or their pharmaceutically acceptable salts and pharmaceutical composition containing as an active ingredient a cephalosporin derivative of the General formula (I) and a pharmaceutically acceptable carrier. General formula (I):

< / BR>
2 C. and 7 C.p. f-crystals, 1 table.

The invention relates to cephalosporin antibiotics, pharmaceutical compositions containing these antibiotics, and treatment of infectious diseases in humans and animals.

Cephalosporin antibiotics are bicyclic ring system, represented by the following formula, which is applied numbering system commonly used in conventional terminology system zeama:

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In the field of antimicrobial therapy is always required new chemotherapeutic agents. ness, many strains of Staph. aureus and Staph. epi (so-called resistant against methicillin strains of Staph. become significantly more resistant to available antimicrobial agents (see , for example, Phillips, J. and Cookson, B. J. Appl. Bacteriology. 61 (6) 1989).

To meet this need, continue surveys aimed at the development of these new tools. The invention provides a new antimicrobial agent against a broad spectrum of gram-positive and gram-negative microorganisms. Compounds according to the invention, especially useful against the methicillin-resistant strains of staphylococci.

The invention provides various 3-thiazole-tileflooring, useful as antibacterial agents. In particular, the invention provides 7-(2-aminothiazol-4-yl)-oximino-(or alkoxyimino)-acetylamino-3-optionally substituted, triazolone-3-cefem-4-carboxylic acid, useful as antibacterial agents.

The invention also provides for pharmaceutical compositions and therapeutic methods useful in the treatment of antimicrobial infections in humans and animals.

The invention provides compounds of formula (1):

< / BR>
in which R, l, C3-C6-cycloalkyl or C1-C6-haloalkyl and A and A' independently of one another are hydrogen, C1-C6-alkyl, nitro, amino, C1-C6-alkoxy, 5 - or 6-membered heterocycle containing nitrogen or sulphur, or phenyl; or A and A' together form a group of the formula:

,

in which X represents a hydrogen atom, halogen, C1- C6-alkyl, C1-C6-alkoxy, C1-C6- alkoxycarbonyl, amino, nitro or carboxy and Y is a nitrogen atom or carbon, or their pharmaceutically acceptable salts.

The term "pharmaceutically acceptable salt" encompasses those salts that are formed with the carboxylate anions and includes salts formed with organic and inorganic cations, such as counterions selected from alkali and alkaline earth metals (such as lithium, sodium, potassium, barium and calcium), ammonium salts, and educated by organic cations (such as dibenzyl-ammonium, benzylammonium, 2-hydroxyethylammonium, bis-(2-hydroxy-ethyl)-ammonium, phenylethylenediamine, dibenzylethylenediamine and similar cations). Other cations that fall under the definition of the above term, include protonated form is n, histidine, phenylglycine, lysine and arginine. In addition, any cvetelina form compounds represented by formula (1) formed of carboxylic acid and amino group, refers to this term. The preferred cation for the carboxylate anion cation is sodium. Further, the term includes salts, which are formed in a standard acid-base reactions with major groups (such as amino groups) and organic or inorganic acids. Such acids include hydrochloric, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, Mamonovo, muzinovy, D-glutamic, d-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicylic, methansulfonate, benzosulfimide, sorbic, picric, benzoic, cinnamic and like acids.

In the formula (1), the term "C1-C6-alkyl" denotes such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, amyl, tert-amyl, hexyl and the like. Preferred C1-C6-alkyl group is methyl.

The term "C2-C6alkenyl" means the lowest alkenyl straight or branched chain, such as vinyl, all is 2-C6-quinil" represents the lower alkylamino group with a straight or branched chain, for example, ethinyl, 1-PROPYNYL or propargyl.

The term "C3-C10-cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl or adamantyl.

The term "C1-C6-haloalkyl" means the above-mentioned C1-C6is an alkyl group that is substituted by one halogen, the "halogen" or "halogen" means chlorine atom, bromine, iodine or fluorine. Preferred fluorinated C1-C6-haloalkyl.

The term "C1-C6-alkoxy" refers to groups such as methoxy, ethoxy, 3-propoxy, butoxy and the like.

The term "halogen" includes fluorine atoms, bromine, chlorine and iodine.

The term "C1-C6-alkoxycarbonyl" refers to such groups as methoxycarbonyl, etoxycarbonyl, 3-propoxycarbonyl, 3-etoxycarbonyl, 4-tert-butyloxycarbonyl, 3-methoxycarbonyl, 6-methoxycarbonyl and the like.

The term 5 - or 6-membered heterocycle containing nitrogen or sulfur" refers to pyridine and thiophene, and may include more than nitrogen or sulfur and combinations thereof. Other examples include groups opasno the reaction scheme 1.

The original connection (A) (in which R represents a methyl), 2-(trityl)-amino--(methoxyimino)-4-trisiloxane acid can be obtained from the corresponding free amine (supplied by Aldrich Chemical Co. , Jnc., 940 West Saint Paul Avenue. Milwaukee, Wisconsin 53233), using methods well-known in the field of production-lactam. The original compound (B), or benzhydryl ester of 7-amino-3-Cryptor-methansulfonate-3-cefem-4-carboxylic acid, can be obtained using known methodology from the corresponding 3-enol-3-cafema and triftormetilfosfinov anhydride (Syn. Commun., 20 (14), 2185-2189 (1990).

In figure 1, the acid chloride of the compound (A) can be obtained by a known method, for example by interaction with chloride phosphoryla, and can react with the free amine (B) with the formation of 7-acyl-3-triflate (C). Titletype can then be entered by the interaction of the triflate (C) with the compound of the formula:

< / BR>
in the presence of a base such as sodium hydride. The final product of formula (1) can then be obtained by removing the amino - and carboxyamide groups. In scheme I triperoxonane acid and (CH3CH2)3SiH used to remove trailvoy and benzhydryl groups. Specialist in the field of diazolidinyl in the 3rd position of the kernel cafema (B) before the introduction of the 7-acyl functions, to get a useful intermediate compounds represented by the formula (2).

Alternative compounds may be obtained according to reaction scheme 2.

Figure 2 acetic acid (A), dissolved in dimethylformamide, treated with N-methylmorpholine and chloride accelerom. A mixture of 7-amino-3-lorzepam dissolved in dimethylformamide and treated bis-(dimethylallyl)-urea (BSU) and pyridine, mixed with acetic acid to obtain the compound (C). Then the compound (C) were treated with diphenyldiazomethane and titletype was administered in the presence of a base such as sodium hydride, with the formation of compound (D). Remove benzhydryl and trailing groups can be carried out as described in scheme 1.

The compounds of formula:

,

where A and A' together form a group of the formula:

< / BR>
and Y is a nitrogen atom, can be obtained according to reaction scheme 3.

Figure 3 3-aminopyridine acelerou di-tert-BUTYLCARBAMATE to enter tert-butoxycarbonyl protective group. (It should be borne in mind that the other two pyridineacetonitrile can be obtained by the known methods using aminopyridine isomers. ) Tert-butoxycarbonyl zasidannya treatment with saturated ammonium chloride. The obtained 3-tert-butoxycarbonylamino-4-tiapride was treated with a mixture of acetic acid and hydrochloric acid to obtain hydrochloride of 3-amino-4-mercaptopyridine. The desired 5-pyridine-thiazoleacetate can then be obtained by treating this compound with carbon disulfide in alkaline medium.

If A and A' together form a group of the formula:

,

the desired thiol of the formula:

< / BR>
can be obtained, as shown in figure 4.

Figure 4 2-chloro-3-nitropyridine treated with isothiocyanates potassium, to obtain 2-isocyanato-3-nitropyridine, which in turn hydrolyzing to obtain 2-mercapto-3-nitro-pyridine. The intermediate 3-nitrosoaniline then reactivated by treatment with a mixture of chloride of tin and hydrochloric acid to obtain 2-mercapto-3-aminopyridine. Desired pyridinethiol - dimercaptan then get alkaline catalytic condensation with carbon disulfide (KOH-CH3OH-CS2-H2O).

Examples of compounds falling under formula (1) are presented in the table.

In the formula (1) preferably R represents a C1-C6-alkyl or C1-C6halide alkyl. Preferably C1"I d-C1-C6-alkyl. Further preferred C1-C6-alkyl fluoride group is 2-floret-1-ilen group.

In the formula (1) is preferable that A and A' together form a group of the formula:

< / BR>
Further, it is preferable that Y is a nitrogen atom and A and A' taken together form a group of the formula:

< / BR>
for example, forming a compound of the formula:

< / BR>
or its pharmaceutically acceptable salt. Two other preferred compounds of the above formula are compounds in which R is the stands or 2-floret-1-yl.

The invention also provides a method of treating infectious diseases in humans and animals and pharmaceutical compositions suitable for administration by this method of treatment. therapeutic method according to the invention includes the introduction of a person or an animal is antibiotic effective non-toxic dose of a compound represented by the formula (1) or its pharmaceutically acceptable salt.

Is antibiotic effective amount is an amount ranging from 25 mg to 2 g of the Compound, salt or ester may be introduced in a single dose or multiple fractional doses during the day. The treatment is of Riem drugs may depend on such factors as the weight and age of the patient, specific pathogen infection, severity of infection, General health of the patient and individual tolerance to the antibiotic.

Cephalosporins may be introduced parenterally, subcutaneously, or rectally. As with other-lactamase antibiotics, the treatment method according to the invention can be used prophylactically to prevent infection after contact or to possible infection, such as preoperative. The antibiotic may be introduced by conventional methods, for example a syringe or dropper for intravenous infusion.

Pharmaceutically acceptable salts, as previously noted, can be a useful form of antibiotics to get antibiotic drugs.

The pharmaceutical compositions according to the invention contain is antibiotic effective non-toxic amount of the compound represented by formula (1) or its pharmaceutically acceptable non-toxic salts and pharmaceutically acceptable carrier.

Parenteral antibacterial agent composition for injection is prepared with water for injection, ringer's solution, physiological saline or glucose solution. The antibiotic may also Krasnogo means of formula (1) or its pharmaceutically acceptable salt, it can be preferably prepared in the form of a dry crystalline powder or in the form of lyophilized powder and placed in capsules. Such capsules can contain from 100 mg to 2 g of antibiotic per vial.

As a further aspect of the invention provides a new intermediate compounds of formula (2)

,

in which R0is amino or substituted amino group, R1is hydrogen or carboxyamide group and A and A' independently of one another represent hydrogen, C1-C6-alkyl, phenyl, nitro, amino, 5 - or 6-membered heterocycle containing nitrogen or sulfur; or C1-C6-alkoxy, or A and A' together form a group of the formula:

< / BR>
in which X represents hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxycarbonyl amino, nitro, or carboxy and Y is nitrogen or carbon.

In the formula (2) the term "carboxyamide group" refers to a group derived complex ester group of carboxylic acid, typically used to block or protect the carboxylic acid group at the time when the reaction is carried out on other functional groups of the compounds. Examples of such protective groups of the carboxylic acid include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl is nice, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, tert-butyldimethylsilyl, phenacyl, 2,2,2-trichlorethyl, -(trimethylsilyl)-ethyl, -/di-(n-butyl)-methyldecyl/-ethyl, para-toluensulfonate, 4-nitrobenzenesulfonyl-ethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)-prop-1-EN-3-yl, and the like radicals. The type carboxyamide group is not critical insofar as the derivative of carboxylic acid is stable to the conditions subsequent(s) reaction(s) in other provisions of the molecule and the protective group can be removed at the appropriate point without destroying the remainder of the molecule. In particular, it is important not to expose carboxyterminal molecule to strong nucleophilic bases or reducing conditions using a highly active metal catalysts, such as Raney Nickel. (Such harsh conditions off you should also avoid deleting mentioned here aminosidine groups.) Preferred protective groups are carboxylic acids are allyl, benzhydryl and para-nitroaniline group. Similar carboxyamide group used the technology for production of the cephalosporin, penicillin and peptide, m the Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N. Y., 1973, Chapter 5, and T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, N. Y., 1981, Chapter 5.

The term "protected amino group" used in connection with formula (2) concerns an amino group substituted by the group, usually used to block or protect amidofunctional in the process of interaction with other functional groups of the compounds. Examples of such aminosidine groups include the formyl group, trityloxy group, tert-butoxycarbonyl group, phthalimidopropyl, chloroacetyl, bromoacetyl and educationnow group, trichloroethylene group, a blocking group type of urethane, such as benzyloxycarbonyl, 4-phenylbenzoxazole, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxy, 3-chlorobenzylidene, 2-chlorobenzenesulfonyl, 2,4-dichlorobenzenesulfonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzenesulfonyl, 4-cyanobenzeneboronic, 2-(4-biphenyl)-isopropoxycarbonyl, 1,1-diffenret-1-jocstarbunny, 1,1-diphenylprop-1-jocstarbunny, 2-phenylprop-2-yl-oxycarbonyl, 2-(para-toluyl)-prop-2-jocstarbunny, cyclopentanecarbonyl, 1-methylcyclopentadienyl, cyclohexyloxycarbonyl, 1-methylcyclohexylamine is-(triphenylphosphino)-etoxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC") 2-(trimethylsilyl)-etoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)-prop-1-relaxerror, 5-benzisothiazolinone, 4-acetoxybenzoic, 2,2,2-trichlorocyanuric, 2-ethinyl-2-propoxycarbonyl, cyclopropanecarbonyl, 4-(decyloxy)-benzyloxycarbonyl, isobornylacitate, 1-piperidinylcarbonyl and the like; benzoylmethylecgonine group, 2-(nitro)-phenylsulfanyl group, a group of diphenylphosphinite and similar aminosidine group. The type aminosidine group is not critical, since the derivative of the amino group is stable to the conditions subsequent(s) reaction(s) in other provisions of the molecule and can be removed at the right time without destroying the remainder of the molecule. Preferred aminosidine groups are allyloxycarbonyl, phenoxyacetyl, tert-butoxycarbonyl, trityl. Similar aminosidine group used in the field of chemistry of cephalosporin, penicillin and peptide, are also included in the scope of the above mentioned terms. Other examples of groups belonging to these definitions, described by J. W. Bouton, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plemum Press, New York, N. Y., 1973, Chapter 2 and T. W. Greene, "Protective Groups in Organic Synthesis", Jo group of the formula:

< / BR>
Particularly preferably, when A and A' taken together form a group of the formula:

< / BR>
thus giving a compound of the formula:

< / BR>
The compounds of formula (2) are useful intermediates in obtaining antimicrobial agents of formula (1). The compounds of formula (2) can be obtained as shown in reaction scheme 1, substituting 3-triflate part of the molecule to the desired thiol of the formula:

,

using 7-protected amino-kernel.

The end products of the formula (1) can then be obtained from intermediates of formula (2) by removing protection 7-aminophenol, if necessary, with subsequent acylation of the desired acyl group, and further removing the amino - and carboxyamide groups.

Experimental part

Obtaining 1. 7 beta-amino-3-chloro-3-cefem-4-carboxylic acid

Indicated in the name of example, the connection can be obtained by the method of Chavvette described in U.S. patent N 4064343.

Getting 2. 3-(tert-butyloxycarbonyl)-aminopyridine

76,13 g (0,81 mmole) of 3-aminopyridine was dissolved in 500 ml of water with 150 ml of tert-butanol and 34 g of 0.85 mmole) of sodium hydroxide, cooled in an ice bath and was treated with 200 g (to 0.92 mmole) of di-tert-butylboronic. H is the return of ethyl acetate and water. The organic phase was separated and the remaining aqueous phase was extracted with ethyl acetate. The combined organic portions were dried over anhydrous sodium sulfate, concentrated in vacuo, purified Express chromatography and received 97 g (80%) of target compound indicated in the title of the example.

An NMR spectrum (hydrogen nuclei): (300 MHz, CDCl3), : a 8.34 (D., J = 1.5 Hz, 1H), compared to 8.26 (D. , J = 3 Hz, 1H), 7,97 (broad doublet, J = 6 Hz, 1H), 7.24 to of 7.70 (m, 1H), for 6.81 (broad singlet, 1H) and 1.51 (C., N).

IR spectrum (KBr, cm-1): 3167, 2986, 1716, 1598, 1545, 1407, 1566, 1288, 1233, 1154, 1017.

Mass spectrum: FDMS m/e 195 (M+).

UV-spectrum (ethanol) = 281 nm ( = 3350)

= 235 nm ( = 15200).

Getting 3. 3-(tert-butyloxycarbonyl)-amino-4-mercaptopyridine

10 g (51,5 mmole) of 3-(tert-butyloxycarbonyl)-aminopyridine was dissolved in 110 ml of tetrahydrofuran and cooled to -78oC under nitrogen. Then added in two portions 80 ml (120 mmol), 1.6 M in hexane n-utillity. Then the reaction mixture was cooled in an ice bath with acetate and allowed to dissolve the obtained solid substance. After about two hours the reaction mixture was cooled to -78oC and was treated with 2 g (7,8 mmole) of elemental sulfur. After about half an hour the reaction mixture was heated up on the raffia (50% mixture of hexane and ethyl acetate) was obtained 5,24 (45%) of target compound, the specified name.

Melting point: 170-171oC (decomposes).

An NMR spectrum on1H (300 MHz, DMSO-d6), : 12,88 (broad singlet, 1H), 8,95 (S., 1H), 8,45 (Shir.S., 1H), 7.62mm (Shir. doublet, J = 3 Hz, 1H), 7,44 (doctor , = 3 Hz, 1H), 1,49 (C., N).

IR spectrum (KBr, cm-1): 3239, 2978, 2885, 2741, 1721, 1608, 1530, 1492, 1436, 1384, 1213, 1161, 1085.

Mass spectrum: FDMS m/e 227 (M+).

UV-spectrum (ethanol): = 345 nm ( = 19600)

= 259 nm ( = 10200)

= 224 nm ( = 17200).

Getting 4. Hydrochloride 3-amino-4-mercaptopyridine

13,78 g (0,06 mmole) of 3-(tert-butyloxycarbonyl)-amino-4 - mercaptopyridine was dissolved with acetic acid (250 ml) and added to a cooled with ice to a solution of 3 N. hydrochloric acid in acetic acid, which was obtained by bubbling gaseous hydrogen chloride through glacial acetic acid (100 ml). After about 4 hours the resulting solid substance was filtered off, washed with diethyl ether, dried under vacuum and obtained 10.4 g (approximately 100% yield) of the target compound.

Melting point: above 200oC.

An NMR spectrum on1H (300 MHz, DMSO-d6, : 8,17 (S., 1H), 7,99 (D., J = 3 Hz, 1H), 7,81 (D., J = 3 Hz, 1H), ceiling of 5.60-4,00 (broad, 4H).

IR spectrum (KBr, cm-1): 3184, 3054, 2848, 1639, 1586, 1482, 1442, 1134, m ( = 13100)

Getting 5. 2-mercapto-5-pyridinethiol

13 g (0,198 mmole) of potassium hydroxide was dissolved in 32 ml of water and 154 ml of methanol. This solution was then processed and 3.8 ml (0,063 mmole) of carbon disulfide, followed by processing of 10.4 g (0.06 to mmole) of the hydrochloride of 3-amino-4-mercaptopyridine. After heating under reflux and stirring at leaving overnight, the reaction mixture was treated with activated charcoal and filtered through Hyflo Super CelTM. The filtrate was acidified with acetic acid, which causes the formation of solids. The obtained solid was dried in vacuum at 50oC for 3 h and at room temperature for 2.5 days, and received 8,19 g (81%) of target compound indicated in the title of the example.

Melting point: above 310oC (decomposes).

An NMR spectrum on1H (300 MHz, DMSO - d6), : 14.03 (broad singlet, 1H), 8,46 (S., 1H), 8,33 (D., J = 6 Hz, 1H), 7,75 (D., J = 6 Hz, 1H).

IR spectrum (KBr, cm-6): 3440 (broad band), 2650 (W), 2510 (Shir.), 1528, 1457, 1305, 1294, 1265, 1256, 1039, 1024, 815.

Mass spectrum: E1 MS m/e 168 (M+).

Getting 6. 2-isothiocyanato-3-nitropyridine

10 g of 2-chloro-3-nitropyridine, 8 g isothiocyanate potassium and 75 g of acetic acid were mixed and heated under reflux for 2 Wali water, was re-dissolved in ethyl acetate and 4 times washed with water. An ethyl acetate solution is then treated with activated charcoal, dried over anhydrous sodium sulfate, filtered, evaporated to dryness and received and 3.72 g of the target compound.

Melting point: 115-116oC.

An NMR spectrum on1H (300 MHz, CDCl3), : to 8.62 (m, 1H), they were 8.22 (D., J = 6 Hz, 1H), 7,46 (m, 1H).

Getting 7. 2-mercapto-3-nitropyridine

50 ml of ethanol was treated 612 mg of sodium at low temperature (ice bath) in anhydrous conditions. Then the reaction mixture was treated with 3.6 g (0.02 mmole) portions of the compound obtained according to example getting 6. The reaction mixture was stirred for 2 hours, diluted with 250 ml of water and evaporated in vacuum. Then the solution was acidified with acetic acid to pH 4.5, and formed a yellowish-red crystals. The target compound was filtered, washed with water, dried in a vacuum dessicator and received 1,1,

Melting point: 185-187oC (decomposes).

An NMR spectrum on1H (300 MHz, CDCl3), : 8,09 (D., J = 7 Hz, 1H), 7,89 (D. , J = 7 Hz, 1H), 6,84 (DD., J = 6 and 3 Hz, 1H).

IR spectrum (KBr, cm-1): 3119, 2872, 1611, 1577, 1527, 1349, 1330, 1240, 1141.

Mass spectrum EIMS m/e 126 (M+).

Getting 8. 2-measure the e and was treated with 100 g (about 0.53 mmole) tin chloride (SnCl2). Then the reaction mixture was treated with 14 g (of 0.11 mmole) of the compound obtained in example receiving 7) in portions and stirred 3 hours

Then the reaction mixture is evaporated until a solid residue was dissolved in 1 l of water and treated with gaseous hydrogen sulfide for 30 min. while heating on the steam bath. The obtained solid substance was filtered off, washed with warm water and poured. United water part evaporated to obtain a solid substance. The obtained solid is twice cooked with hot concentrated ammonium hydroxide. The obtained solid was filtered and unloaded, and a solution of ammonium hydroxide is evaporated to obtain a wet solid, which in turn translated into the water. The yellow-green target compound was filtered, washed with water, dried in vacuum over desiccant at 40oC and received 4,20 g (30% yield).

An NMR spectrum on1H (300 MHz, CDCl3and DMSO-d6), : 6,91 (m, 1H), 6,65 (D. , J = 5 Hz, 1H), 6,46 (m, 1H), 5,03 (S. 2N).

9. 2-mercapto-7-pyridinethiol

2.8 g (85%) potassium hydroxide was dissolved in 16 ml of water and 50 ml of methanol. Then was added 2.6 g of carbon disulfide and washed with 30 ml of methanol. Debavalya. After cooling, the reaction mixture was treated with activated charcoal and filtered through super CelTMby washing the filter residue with a small amount of methanol. Then the solution was acidified to pH 5.5 with acetic acid. The target compound precipitated from this solution in the form of a yellowish solid, which was dried at 60oC over the desiccant. The output was 3,29,

Melting point: 285-287oC (decomposes).

An NMR spectrum on1H (300 MHz, DMSO - d6), : scored 8.38 (DD., J = 3 and 1.5 Hz, 1H), to 7.61 (DD. , J = 4 and 1.5 Hz, 1H), 7,43 (DD., J = 5 and 3 Hz, 1H), 3.33 and (broad singlet, 1H).

IR spectrum (KBr, cm-1): 3040, 270oC 2540, 1597, 1523, 1399, 1311, 1302, 1274, 1132, 876.

Mass spectrum: E1 M/e 169 (M+1).

10. Ethyl ether /2-(triphenylmethyl)-aminothiazol-4-yl/-2-bromate-1-alexisinnocent acid

9.88 g (0.02 mmole) of ethyl-/2-(triphenylmethyl)-aminothiazol-4-yl/-ximeniaceae was dissolved in 20 ml of N,N'-dimethylformamide and treated of 8.28 g (0,06 mmole) of powdered potassium carbonate. After stirring for half an hour was added to 17.3 ml of 1,2-dibromethane and the reaction mixture was left overnight under stirring in argon atmosphere.

Then the reaction mixture was poured into 100 ml of a mixture of dichloro the ode and brine, was dried over anhydrous magnesium sulfate, filtered, evaporated in vacuum and got the oil. Liquid chromatography (25% mixture of hexane and dichloromethane gave 7,16 g (63,4%) of target compound.

Melting point: 55oC.

An NMR spectrum on1H (300 MHz, SDS3), : 7,32 (C., 15 NM), 6,52 (S., 1H), 4,55-to 4.46 (m, 2H), to 4.38 (sq, J = 4 Hz, 2H), 3,63-of 3.53 (m, 2H), of 1.37 (t, J = 4 Hz, 3H).

Elementary analysis:

calculated: C, 59, 58; H with 4.64; N 7,44

found: C 59,36; H br4.61; N 7,18.

Receipt 11. Ethyl-/2-(triphenylmethyl)-aminothiazol-4-yl/- 2-floret-1-yl-examinateur

Indicated in the name of example, the target compound was obtained by a method similar to that described in example 10, substituting 1-bromo-2-floridanum alkylating agent. The yield was 3.3 g

An NMR spectrum on1H (300 MHz, DMSO - d6), : 8,77 (S., 1H), 7,39 for 7.12 (m, 15 NM), 6,92 (S., 1H), 4,60 (t, J = 3 Hz, 1H), of 4.44 (t, J = 3 Hz, 1H), 4.26 deaths (that is , J = 3 Hz, 1H), 4,16 (t, J = 3 Hz, 1H), 3,90 (sq, J = 4 Hz, 2H), 1.06 a (t, J = 4 Hz, 3H).

Getting 12. /2-(triphenylmethyl)-aminothiazol-4-yl/-Z - floret-1-yl-oxaminoquine acid

2.5 g (5 mmol) of the compound obtained in example receiving 11, was dissolved in 20 ml ethanol and 5 ml (10 mmol) 2 N. sodium hydroxide.

After stirring for 2 h at 50oC Islami 1 N. hydrochloric acid. The aqueous layer was again extracted with chloroform and the combined chloroform phase was washed with water, brine and dried over anhydrous magnesium sulfate. Then the chloroform phase was evaporated in vacuum and received 1.52 g (63,9%) of target compound in the form of foam.

Melting point: 125, 33oC (decomposes).

An NMR spectrum on1H (300 MHz, CDCl3), : 9,70 (Shir.S., 1H), 7,30-7,22 (m, 15 NM), 6,52 (S., 1H) and 4.65 (t, J = 3 Hz, 1H), 4,49 (t, J = 3 Hz, 1H), 4,37 (t, J = 3 Hz, 1H), 4,27 (t, J = 3 Hz, 1H).

IR-spectrum (CDCl3cm-1): 3000, 1735, 1592, 1529, 1449, 1186, 1070, 1035.

Example 1. 7 -/(2-aminothiazol-4-yl)-(Z)-methoxybenzoyl/-amino-3-/2-(5 - pyridinemethanol)/-3-cefem-4-carboxylic acid

A. 7 beta/(2-triphenylmethyl)-aminothiazol-4-yl-(Z)-methoxybenzoyl/-amino-3-chloro-3-cefem-4-carboxylic acid

39,8 g (0,17 mmole) of 7-amino-3-chloro-3-cefem-4-carboxylic acid are suspended in 800 ml of N,N'-dimethylformamide and treated with 100 g (0,49 mole) bis-(dimethylallyl)-urea, then was heated at 50-65oC for one hour.

In another reaction vessel, 100 g (of 0.21 mmole) 2-(triphenyl-methyl)-aminothiazol-4-yl-(Z)-methoxybenzoate acid was dissolved in 800 ml of N, N'-dimethylformamide and cooled in an ice bath with acetone.

In the first reaction vessel, the reaction mixture was treated with 32 ml (0.40 mmole) of pyridine and transferred via cannula to the second reaction vessel within 50 minutes

Then the reaction mixture was poured into 2 l of a mixture of ice water, the resulting solid substance was dried in the air and got 116 g of compound indicated in the title of example A 1 (a mixture of 3:1,3:2).

An NMR spectrum on1H (300 MHz, DMSO - d6), : being 9.61 (D., J = 9 Hz, 1H), 8,83 (C. , 1H x 1/4), 8,80 (C., 1H x 3/4), 7,46-7,10 (broad multiplet, 15 NM), 6,83 (S., 1H), 6,68 (C., 1H x 1/4), 5,72 - to 5.66 (m, 1H x 3/4), the ceiling of 5.60 is 5.54 (m , 1H x 1/4), 5,23-5,17 (m, 1H x 1/4), 5,20 (doctor, J = 5 Hz, 1H x 3/4) of 4.83 (C., 1H x 1/4), 3,80 (C., 3H), 3,79 (AB sq, J = 20 Hz, 2H x 3/4).

B. Benzhydrylamine ether 7 -/2-(triphenylmethyl)-aminothiazol-4-yl-(Z)-methoxybenzoyl/-amino-3-chloro-3-cefem-4-carboxylic acid

The compound obtained in part a of example 1, was dissolved in 500 ml of methyl cyanide (CH3CN) and was treated with 10 g of highly pure diphenyldiazomethane and stirred at room temperature for approximately 2.5 days. Then the reaction mixture was rapidly cooled, acetic acid, and for the conversion of the reaction was concentrated in vacuo, using toluene to azeotrope of excess acetic acid. Cleaning Express chromatography (25% and 50% mixture of ethyl acetate-GN (300 MHz, DMSO-d6), : 9,60 (D., J = 6 Hz, 1H 8,80 (S. , 1H), 7,46-7,02 (broad m , 25N), 6,92 (C., 1H x 1/3), 6,88 (C., 1H x 2/3), 6,84 (C., 1H x 2/3), 6,78 (C., 1H x 2/3), 6,67 (C., 1H x 1/3), 5,76-5,70 (m , 1H x 1/3), 5,51-of 5.45 (m, 1H x 2/3), 5,76-5,70 (m, 1H x 1/3), 5,51-of 5.45 (m , 1H x 2/3), 5,12 (D., J = 4 Hz, 1H x 2/3), 3,79 (AB sq, J = 19 Hz, 2H x 1/3), of 3.77 (C., 3H).

C. Benzhydrylamine ether 7 -/2-(triphenylmethyl)-aminothiazol-4-yl-(Z)-methoxyimino/-acetyl-3-/2-(5-pyridinemethanol)/-3-cefem-4-carboxylic acid

92 mg (2.3 mmole, 60% in oil) of sodium hydride were washed with hexane and suspended in 50 ml of tetrahydrofuran and treated 390,9 mg (2.3 mmole) of 2-mercapto-5-pyridinethiol and heated. The solution was transferred via cannula to 5.7 g (2.3 mmole) of the compound obtained in part b of example 1, dissolved in 50 ml of tetrahydrofuran. Then the reaction mixture was treated with 15 ml of 1 N. hydrochloric acid and poured into a mixture of ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate. Was filtered and concentrated in vacuum, after column chromatography (75-90% mixture of ethyl acetate-hexane) and crystallized pure3-isomer (0.31 g, 34%).

An NMR spectrum on1H (300 MHz, DMSO - d6), : 9,70 (D., J= 9 Hz, 1H), 9,10 (S. , 1H), 8,79 (C., 1 H), of 8.47 (D., J = 7 Hz, 1H), 8,08 (D., J = 7 Hz, 1H), 7,38-7,03 (Shir. multiplet, 25N), 6,91 (S. 2 (wide), 3030, 2938, 1786, 1738, 1695, 1522, 1496, 1371, 1278, 1223, 1044, 700.

Mass spectrum: FABMS m/e 958 (M+).

Optical rotation: ()D= -133,33o, 589 nm, 5 mg of dimethyl sulfoxide.

Elementary analysis:

calculated: C 63,93; H 4,10; N 10,23

found: C 64,19; H 4,06; N 10,43.

D. Removing protection to obtain the target compound indicated in the title of the example 1.

0,42 g (438 mmol) of the compound obtained in part C, suspended with 7 ml of triethylsilane and 10 ml dichloromethane and treated with 5 ml triperoxonane acid and stirred at room temperature. Then the reaction mixture was concentrated in vacuo, using toluene to cause azeotropic mixture of excess triperoxonane acid. The obtained residue was purified by reversed-phase chromatography (10-20% of a mixture of methyl cyanide c water).

An NMR spectrum on1H (300 MHz, DMSO - d6), : 9,75 (D., J = 9 Hz, 1H), 9,18 (S. , 1H), 8,49 (D., J = 6 Hz, 1H), 8,19 (D., J = 6 Hz, 1H), 7,21 (broad singlet, 2H), of 6.71 (SD, 1H), 5,94 (DD., J = 6 Hz and 10 Hz, 1H), 5,35 (D., J = 6 Hz, 1H), 3,88 (AB sq, J = 15 Hz, 2H), 3,85 (C., 3H).

IR spectrum (KBr, cm-1): 3395, 1782, 1621, 1532, 1381, 1037.

Mass spectrum: FABMS m/e 550 (M+).

UV-spectrum (ethanol): = 286 nm ( = 22700)

= 231 nm ( = 34200).

Optical rotation ()D
< / BR>
Example 2. 7 -/(2-aminothiazol-4-yl)-(Z)-(2-floret-1-yl)-asiminoaei/-amino-3-/2-(5-pyridinemethanol)/-thio-3-cefem-4-carboxylic acid

An NMR spectrum on1H (300 MHz, DMSO - d6), : 9,70 (D., J = 10 Hz, 1H), 9,03 (S. , 1H), 8,39 (D., 1H, J = 5 Hz), 8,03 (D., J = 5 Hz, 1H), 7,20 (S., 2H), 6,72 (S., 1H), 5,73 (m, 1H), 5,19 (D., 1H, J = 7 Hz), of 4.67 (t, J = 5 Hz, 1H), 4,55 (t, J = 5 Hz, 1H), 3,63 (AB sq, J = 18 Hz, 2H).

IR spectrum (KBr, cm-1): 3420, 1774, 1668, 1663, 1653, 1617, 1534, 1388.

Mass spectrum: ("FAB) m/e 604 (M+1).

UV-spectrum (ethanol): = 288 nm ( = 21700)

= 232 nm ( = 31400).

Optical rotation: ()oDMCO= -89,22o.

Example 3. 7 -/(2-aminothiazol-4-yl)-(Z)-(2-floret - 1-yl)-asiminoaei/-amino-3-/2-(7-pyridinemethanol)/3-cefem-4-carboxylic acid

Output total 13% (of 22.8 mg).

An NMR spectrum on1H (300 MHz, DMSO - d6), : 9,68 (D., 1H, J = 10 Hz), 8,25 (D., 1H, J = 5 Hz), 8,14 (D., 1H, J = 10 Hz), 7,45 (m, 1H), 7,20 (S., 2H), 6,72 (S., 1H), 5,70 (m, 1H), 5,20 (D., 1H, J = 5 Hz), 4,70 (t, 1H, J = 5 Hz), 4,53 (t, 1H, J = 5 Hz), 4,30 (t, 1H, J = 5 Hz), 4,20 (t, 1H, J = 5 Hz), 3,63 (AB square, 2H, J = 15 Hz).

Mass spectrum ("FAB): m/e = 604 (M+1).

Example 4. 7 -/(2-aminothiazol-4-yl)-(Z)-(2-floret - 1-yl)-asiminoaei/-amino-3-(thiazol-2-yl)-thio-3-cefem-4-carboxylic acid

Yield 63 mg 5,70 (m, 1H), 5,20 (D., 1H, J = 5 Hz), of 4.66 (t, 1H, J = 5 Hz), 4,50 (t, 1H, J = 5 Hz), 4,28 (t, 1H, J = 5 Hz), 4,19 (t, 1H, J = 5 Hz), 3,50 (AB square, 2H, J = 15 Hz).

IR spectrum (KBr, cm-1): 3400, 1768, 1653, 1614, 1535, 1389, 1350, 1035.

Mass spectrum: ("FAB) m/e = 553 (M-1).

UV-spectrum (ethanol): = 284 nm ( = 14900)

= 231 nm ( = 21800)

Example 5. Sodium salt of 7-beta/2-aminothiazol-4-yl- (z)-(2-floret-1-yl)-asiminoaei/-amino-3/-(benzothiazol-2-yl)-thio/-3-cefem-4-carboxylic acid

An NMR spectrum on1H (300 MHz, DMSO - d6), : 9,67 (D., 1H, J = 10 Hz), 7,92 (D., 1H, J = 10 Hz), 7,78 (D., 1H, J = 10 Hz), 7,43-7,26 (m, 2H), 7,20 (S. , 2H), 6.73 x (S., 1H), to 5.66 (m, 1H), 5,15 (D., 1H, J = 5 Hz), 4,70 (t, 1H, J = 5 Hz), 4,20 (t, 1H, J = 5 Hz), 3,64 (AB square, 2H, J = 15 Hz).

Mass spectrum ("FAB): m/e = 603 (M+1).

Examples of ready-made forms of songs

Example 1. Hard gelatin capsules are prepared using the following ingredients. - Quantity (mg/capsule)

Active ingredient: 250

Starch, dried 200

Magnesium stearate - 10

Only 460 mg

Example 2. Tablets obtained using the following ingredients Quantity (mg/tablet)

Active ingredient: 250

Cellulose, microcrystalline - 400

Silica, crushed into fine powder - 10

Stearic acid - 5

Just.

Example 3. Prepared spray solution containing the following components: - Weight %

Active ingredient - 0,25

Methanol - 29,75

The propellant 22 (Chlorodifluoromethane) - 70.00

Total - 100,00

The active ingredient is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30oC and transferred to the filling device. In a stainless steel container placed the required amount of the drug and diluted with the remainder of the propellant. Then the container is installed metering valve.

Example 4. Tablets, each containing 60 mg of active ingredient are made as follows, mg:

Active ingredient - 60

Starch - 45

Microcrystalline cellulose - 35

Polyvinylpyrrolidone (as 10% solution in water) - 4

Magnesium stearate and 0.5

Talc - 1

Total - 150

The active ingredient, starch and cellulose are passed through a sieve USA 45 mesh and thoroughly mixed. With the obtained powder is mixed aqueous solution containing polyvinyl pyrrolidone, and the mixture is then passed through a 14 mesh sieve USA. Thus obtained granules are dried at 50oC and passed through a sieve 18 mesh US. Then to the granules on the mesh, and granules after mixing pressed on tabletirujut device, giving tablets each weighing 150 mg

Example 5. Capsules, each containing 80 mg of active ingredient are prepared from the following components, mg

Active ingredient - 80

Starch - 59

Microcrystalline cellulose - 59

Magnesium stearate - 2

Total - 200

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a sieve of 45 mesh (USA) and filled into hard gelatin capsules in the amount of 200 mg.

Example 6. Medical candles, each with a content of active ingredient 225 mg, prepared as follows, mg

Active ingredient: 225

Glycerides of saturated fatty acid - 2000

Total - 2225

The active ingredient is passed through a sieve of 60 mesh U.S. and suspendered in the glycerides of saturated fatty acids, previously melted using the minimum heat needed. The mixture is then poured into the form for medical candles nominal capacity of 2 g and left to cool.

Example 7. Suspension preparations, each containing 50 mg of active ingredient per 5 ml dose, are prepared as education is a thief benzoic acid 0.10 ml

Flavoring - gv

Coloring agent gv

Purified water to a total volume of 5 ml

The active ingredient is passed through a sieve of 45 mesh U.S. and is mixed with the sodium carboxymethyl cellulose and syrup with the formation of a homogeneous paste. Diluted partial amount of water and added with stirring a solution of benzoic acid, flavoring and coloring agent. Then add sufficient water to obtain the desired volume.

Example 8. Preparative form for intravenous use is prepared from the following components:

Active ingredient: 100 mg

Isotonic saline solution - 1000 ml

The solution of the above ingredients is usually administered intravenously to a patient at a rate of 1 ml per minute.

1. Derivatives of the cephalosporin of the General formula I

< / BR>
in which R is hydrogen, C1WITH6-alkyl or C1- C6-haloalkyl;

A and A1taken together form a group of the formula

< / BR>
or

< / BR>
where X is hydrogen, halogen, C1WITH6-alkyl, C1- C6-alkoxyl, amino - or nitro-group;

Y is nitrogen or carbon,

and their pharmaceutically acceptable salts.

3. Connection on p. 2, in which R is methyl or fluorine, WITH1- C6-alkyl.

4. Connection on p. 3, in which R 2-feratel.

5. Connection on p. 1, in which Y is nitrogen.

6. Connection on p. 5, in which A and A1taken together form a group of the formula

< / BR>
7. Connection on p. 6, in which R is methyl or vermeil.

8. Connection PP.1 7 as an antibiotic agent.

9. Pharmaceutical composition having antimicrobial activity, containing a cephalosporin derivative and pharmaceutically acceptable additives target, characterized in that as a cephalosporin derivative it contains an effective amount of the compounds of formula I or its pharmaceutically acceptable salt according to PP.1 7.

 

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