New derivatives of benzoxazinone and medicine based on them

 

(57) Abstract:

The invention relates to new derivatives of benzoxazinone General formula (I), where R1means N or carboxyethyl, R2represents hydrogen or alkyl, and R3is a different derivatively of amino acids, dipeptides and hydrazones acid groups, respectively, their conjugates with active substances, such as residues from a number of penicillin. The proposed compounds are geterotsiklicheskikh protected derivatives of catechol and effective against strains of gram-negative bacteria, as siderophores. Also disclosed is a medicinal preparation on the basis of the compounds of formula (I). 2 C. and 12 C.p. f-crystals, 2 PL.

The invention relates to new derivatives of benzoxazinone, and their conjugates with biologically active substances, for example antibiotics. These compounds are effective as siderophores in gram-negative bacteria, i.e., they are able to supply the bacteria with iron, in the form of conjugates with active substances, for example with antibiotics (as "siderophore conjugates-antibiotics"), to deliver the latest in transportation of iron in bacteriathat decrease in resistance to antibiotics, due to poor penetration. Compounds according to the invention represent a preliminary stage of formation of chelates with iron, respectively geterotsiklicheskikh protected catecholic compounds, i.e. they can be enzymatically converted by corresponding derivatives of catechol. Thus, they can have an impact on biological metabolism involving iron and impact in different ways on the associated disease. The invention is intended for pharmaceutical research and application in industrial scale.

Derivatives of benzoxazinone formula I with the following alternates to the present time have not been described in the literature. These compounds are in principle acylated derivatives of catechol, one acyl component which is included in benzoxazinone ring.

It is known that certain categorie patterns in natural siderophore as structural elements forming iron complexes play an important role ("Iron Transport in Microbes, Plants and Animals, ed. Winkelmann G., van D. Helm, J. B. Neilands, V. Ch.-Verlagsgesellschaft Weinheim, 1987); an example is enterobactin, siderophore of E. coli and other bacterial strains, the trimer of N-(icrobiol. Lett. 62 (1990), 5).

N-(2,3-dihydroxybenzoic)glycine was detected as siderophore in B. subtilis (Ito T., Neilands J. B. Journ. Amer. Soc. 80 (1958), 4645). Some catecholamine derivatives of amino acids were synthesized, for example, N-(2,3-dihydroxybenzyl)-L-threonine (Kanai F., Kaneko T., Morishima, H. , Isshiki, K. , Takita T., Takeuchi T., Umezawa H. Journ. Antibiot. 38 (1985), 39), N2N6bis(2,3-dihydroxybenzyl)-L-lysine (Corbin J. L., Bulen, W. A. Biochemistry, 8 (1969), 757; McKee J. A., Sharma S. K., Miller, M. J. BioconjugateChem.,2(1991)281)PI2N6bis(2,3-dihydroxybenzoic)lysyl-N6-(2,3-dihydroxybenzoic)lysine (A. Chimiak, Neilands J. B. Structure and Bonding, 58 (1984), 89). It was further established that different strains of bacteria certain benzhydrazide Glyoxylic acid derivatives oksanalove acid, etc. can serve as siderophores (Reissbrodt R., L. Heinisch, Mollmann, U., Rabsch, W., H. Ulbricht BioMetals, 6 (1993), 155).

Various categorie compounds were obtained by combining with a-lactam, which helped to achieve a significant increase in antibacterial effectiveness of these antibiotics due to their delivery on bacterial transport pathways of iron in bacterial cells (for example, Arisawa M., Sekine Y., Shimizu, S., Takano, H., P. Angehrn, Then R. L. Antimicrob. Agents Chemother. 35 (1991), 653). To date, however, none of the compounds of this polucheniya new synthetic siderophores, which would be capable of forming conjugates with antibiotics.

On the other hand, siderophore as chelates with iron have the potential to affect biological metabolism involving iron and thereby have a different way impact on the associated disease. Thus, in particular, siderophore desferrioxamine (Desferal) is successfully used for diseases associated with the transfer of iron (e.g., thalassemia). Derivatives of benzoxazinone without substituent in position 8, not derivatively from katholou, for example, 3-carboxymethyl-2,4-dioxopentanoate known (see, for example, A. Lespagnol, Lespagnol Ch., Bernier J. L., J. C. Cazin, M. Cazin Bull. Soc. Pharm. Lille 4, (1972), 179-185). To obtain a derivative benzoxazine from alloxanthine and amine components in the model HC1 removal and methanol hitherto not been described.

The invention is intended for the development of new derivatives of benzoxazinone and their applications. The aim of the invention is to obtain the corresponding compounds suitable for delivery of biologically active substances, for example antibiotics, bacterial transport pathways of iron in bacterial cells. In addition, using etelecom, which in one way or another can affect the biological metabolism involving iron and related diseases. The inclusion katholou patterns in heterocyclic structure benzoxazine should provide links in their acylated form, first of all its conjugates with antibiotics, which are compared with the free catecholate would have improved pharmacological properties and which, accordingly, as pharmacological forms of migration could contribute to the actual penetration Catholic connections.

The basis of the invention was based on the task to obtain new derivatives of benzoxazinone intended for use as siderophores, respectively biological chelates with iron.

According to the invention this problem is solved with the help of new derivatives of benzoxazinone General formula I

< / BR>
in which R1represents H, Isoalkyl or Coolkill, R2represents H, alkyl, halogen, and R3represents the following placeholders:

a) R3means-Z-CHR4-COR5where

Z represents a group

< / BR>
R4who appoints (CH2)nSOKH, where X denotes OA, where a represents H, alkyl, alkali metal ion or ammonium ion, respectively, substituted ammonium ion, or where X represents the residue of the active substance, primarily the remainder of antibiotic associated through IT - or NH-group, and where n denotes 1 to 10,

or R4means (CH2)n-Y, where Y is benzoxazinones a radical of the formula

< / BR>
where R1and R2have the above values, and both benzoxazinones radicals can be identical or different, and n can mean 1-10,

and R5means OA, where a has the above values,

or R5represents the balance of the active substance, primarily the remainder of antibiotic associated through IT - or NH-group,

or R5means NH-CHR8-COR9where R8represents H, alkyl, phenyl or substituted phenyl, and R9means OA, where a has the above values, or R9represents the balance of the active substance, primarily the remainder of antibiotic associated through IT - or NH-group,

or R5represents a group

< / BR>
(this group is an R17)

where X and Y are specified>/BR>n means 1 to 10 and m means 1-2, or

b) R3means CHR4-COR5where R4and R5have the above values, or

in R3represents a group

< / BR>
(this group is an R18)

where R10and/or R11mean H, alkyl, phenyl or substituted phenyl, n means 1-10, a COR9and R12can be in all possible positions, R9has the above significance, and R12represents H, alkyl, halogen, hydroxy, alkoxy, benzoxazinones radical Y or

R12represents a group

< / BR>
(this group is an R19)

where R1, R2have the above values, R14, R15have the same meaning as R1, R2and n can mean 1-10, or

g) R3represents a group

< / BR>
(this group is an R20)

where R13and COR9can be in all possible positions, and R13represents H, alkyl, halogen, hydroxy, alkoxy or benzoxazinones radical Y, and

R9has the above significance, and R means 0-2, or

d) R3represents a group

< / BR>
(this gasthauses a R22)

where R9has the above significance, and R16represents H, alkyl, phenyl or substituted phenyl, or

e) R3represents the balance of the active substance, primarily the remainder of antibiotic associated through IT - or NH-group.

In the above formulas, as well as in the subsequent acyl represents primarily remotemachine or branched C1-C6alkanoyl or remotemachine or branched C1-C6alkoxycarbonyl; remotemachine or branched alkyl and remotemachine or branched alkoxy, including designations such as remotemachine or branched alkoxycarbonyl, which are primarily remotemachine or branched C1-C8alkyl, respectively, WITH1-C8alkoxy; substituted phenyl is a phenyl, substituted remotemachine or branched alkyl, halogen, especially CL or F, remotemachine or branched alkoxygroup, a hydroxyl group, a carboxyl group, remotemachine or branched alkoxycarbonyl and halogen-substituted by alkyl. Substituted ammonium ion is, for example, the metal may be, for example, the sodium ion or potassium.

The remainder of the active substance is, for example, the remainder of any acceptable antibacterial active substances with a free NH - or HE-group, with the remainder for this NH - or Oh group can be esterified, respectively amitirova compound of formula I. the Relationship between catholisim derivative and an antibiotic can be carried out both directly and using a conventional binder groups, such as aminocarbonyl acid, hydroxycarbonate acids, diamines or diols. The term antibiotic is meant, for example, containing the corresponding NH - or HE-group-lactam, such in particular as a cephalosporin, such as cephalexin, cephalo-Smoking or claforan or penicillin, such as ampicillin, amoxicillin, or derived O-allamatriciana, or a derivative of tetracycline, for example aminopenicillin or type antibiotic aminoglycosides, macrolides, quinolones, or carbapenems.

In the case of asymmetric C-atoms corresponding D - and L-forms, enantiomers and diastereoisomers and racemates, respectively, mixtures of enantiomers and diastereomers are also subject of the present invention.

Wasalaam, in particular under physiological conditions, esters.

Proposed according to the invention the compounds of formula I, where R5or R9mean IT, get the reaction of condensation of 2,3-decyloxybenzoate with the appropriate amine components, such as amino acids, dipeptides or aminobenzene acid, sodium bicarbonate solution according to scheme 1 (see the end of the description).

During the reaction Coolkenno group in R1can be split hydrolytically, as a result can form compounds with R1that represents N. These connections can be re-allievate, for example, to compounds where R1is Salkil.

The compounds of formula I, where R5or R9IT means, can be obtained on the same principle and also according to reaction scheme 2 (see the end of the description), namely the interaction of the respective aminopropionic, for example 2,3-dihydroxybenzoate, with alkylamino esters of Harborview acid in alkaline medium.

The proposed compounds of formula I, where R3, R5, R9, respectively, X represents the residue of the active substance, for example a residue of an antibiotic, poulnabrone using pentachloride phosphorus tetrachloride, get the corresponding chloride, after which the latter is subjected to interaction with the active substance or antibiotic containing free HE - or NH-group and do not necessarily commonly used for these purposes, a bridging group, such as, for example, remains diaminocarbenes acid, hydroxycarbonic acid, respectively diamine or diol, in an appropriate solvent, such as tetrahydrofuran, or

b) the compound of formula I, where a is N, for example, by the method of mixed anhydrides first subjected to interaction with the ether Harborview acid and tertiary amine, such as triethylamine, and then with the corresponding active substance containing the free NH - or HE-group and do not necessarily commonly used for these purposes, a bridging group, such as, for example, remains diaminocarbenes acid, hydroxycarbonic acid, respectively diamine or diol, together with the corresponding tertiary amine, such as triethylamine, in an appropriate solvent, e.g. tetrahydrofuran.

The compounds of formula I with a carboxyl group can be represented in the form of free acids, in the form of their salts or in the form of easily degradable, especially under physiological conditions, scrapping recrystallization or by chromatography methods.

The compounds of formula I according to the invention, and in particular connections without the rest of the active substances are different strains of gram-negative bacteria siderophore efficiency. Due to this, these compounds can be used as growth factors for specific cultures of bacteria.

Tests siderophore efficiency according to DIN 58940 was carried out with different indicator mutants of bacteria that due to the lack of their own systems of transfer of iron did not show under test conditions no tendency to increase. After addition of the test substances as foreign siderophores we can say that it promotes growth. The indicator mutants in the biosynthesis of the corresponding siderophores, such as pyoverdine, pyochelin, enterobactin, aerobactin, yersiniabactin, or, for example, the biosynthesis of aromatic hydrocarbons blocked or there are no receptors enterobactin, pyochelin, respectively pyoverdine, and also other important components for bacterial iron transport (for example, membrane proteins Cir, Fiu, FepA protein Topv). Therefore, in conditions of iron deficiency, these mutants either do not grow or grow very li: AB 2847, Salmonella typhimurium: enb-7, TA 2700, Yersinia enterocolitica WAH 5030. As control strains of Pseudomonas and Y. enterocolitica was used ferrioxamine E, for strains of Salmonella - ferrioxamine G and enterobactin, and for E. coli - Ferrara. The subjects of the substance was used in each case in an amount of 5 µg/disc.

The growth zone indicator mutants (diameter in mm), which was determined depending on the impact of the respective test substances are presented in table 1.

Due to their properties as bacterial siderophore compounds of General formula I can serve as vectors, respectively, as penetration accelerators for antimicrobial antibiotics and other biologically active substances, in other words, they are capable of conjugates with antibiotics or other active ingredients to deliver these last transport pathways of iron in the cell of microorganisms and thereby to increase their effectiveness. Consequently, the compounds of General formula I, where R3, R5, R9, respectively, X represents the residue of the active substance, in particular-lactam, have an antibacterial effect, including partly also against bacteria resistant to other-lactams, prunescu of the whole molecule. To identify the antimicrobial effectiveness test conducted in microrasbora, defining in this way according to the standard DIN 58940 minimum inhibiting concentration (MIC) on the following strains of bacteria: Pseudomonas aeruginosa SG 137, NCTC 10662, ATSS 27853, E. coli ATCC 25922, Klebsiella pneumoniae ATCC 10031, Stenotrophomonas maltophilia GN 12873 and Staphylococcus aureus SG 511. The test results presented in table 2. According to the obtained data of the tested compounds exhibit high antibacterial effect, partly superior to that of comparative substances of azlocillin and ampicillin. By varying the iron content in the test environments and using mutants to transport iron, found the dependence of antibacterial action against bacterial iron transport.

Compounds of General formula I, in particular compounds without residue of the active substance, and in the presence of acid groups, their salts and split under physiological conditions esters due to their properties as siderophores, respectively chelates with iron suitable for use as a drug for diseases caused by disorders of metabolism involving iron. Compounds of General formula I, where R3, R5, R9according to the in the presence of acid groups, their salts and split under physiological conditions esters due to their antibacterial efficiency can be used as drugs against bacterial infections in humans and useful animals.

In these diseases the compounds of formula I can be used either individually or in the form of pharmaceutical preparations with a physiologically acceptable known from the prior art excipients or fillers, and in principle you can use all the usual pharmaceutical forms.

EXAMPLES

Example 1

Obtaining (8 methoxycarbonylamino-2,4-dioxopentanoate-3-yl)acetic acid (formula I, where R1means of SOON3, R2means N, R3means of CH2COOH)

A solution of 2.75 g of glycine in 175 ml of 0.5 M sodium hydrogen carbonate solution was cooled in an ultrasonic bath to 0-5oC. With stirring was added dropwise at 0-5oWith 10.5 g of 2,3-di-(methoxycarbonylamino)of benzoyl chloride dissolved in 20 ml of absolute tetrahydrofuran. Formed after 1 h cloudy solution was filtered and the tetrahydrofuran drove away. The obtained substance was filtered through a vacuum filter and washed with a small amount of cold water. For purification, the substance was re-dissolved in 0.5 M solution of sodium bicarbonate, filtered and precipitated with concentrated hydrochloric acid. The result obtained colorless crystals with temsilcisi-2,4-dioxopentanoate-3-yl)acetylglycine (formula I, where R1means of SOON3, R is H, R3means CH2CONHCH2COOH)

The compound was obtained analogously to example 1 from glycylglycine and 2,3-di-(methoxycarbonylamino)of benzoyl chloride in aqueous sodium bicarbonate solution. Thus obtained colorless crystals with a melting point 195-198oAfter recrystallization from water to yield 70% of theory.

Example 3

Obtaining (8 methoxycarbonylamino-2,4-dioxopentanoate-3-yl)acetyl-L-alanine (formula I, where R1means of SOON3, R2means N, R3means of CH3N-CH(CH3)-COOH)

The compound was obtained analogously to example 1 from glycyl-L-alanine and 2,3-di-(methoxycarbonylamino)of benzoyl chloride in aqueous sodium bicarbonate solution. Thus obtained colorless crystals with a melting temperature of 180-185oAfter recrystallization from ethyl ester of acetic acid to yield 70% of theory.

Primer 4

Obtaining (8-hydroxy-2,4-dioxopentanoate-3-yl)acetyl-L-alanine (formula I, where R1means N, R2means N, R3means CH2CONH-CH(CH3)-COOH)

Connection received from the mother liquor formed in the selection (8-methoxycarbonyl clonicel/water = 1/1 from 0.05% triperoxonane acid). Thus obtained colorless crystals with a melting point 203-204oAfter recrystallization from ethyl ester of acetic acid to yield 20% of theory.

Example 5

Obtaining (8 methoxycarbonylamino-2,4-dioxopentanoate-3-yl)acetyl-L-leucine (formula I, where R1means of SOON3, R2means N, R3means of CH2N-CH(COOH)-CH2CH(CH3)2)

The compound was obtained analogously to example 1 from glycylglycine and 2,3-di-(methoxycarbonylamino)of benzoyl chloride in aqueous sodium bicarbonate solution. The selection was performed in the immediate extraction of the mixture obtained after acidification with hydrochloric acid, ethyl ester acetic acid, repeated washing of the thus obtained solution with water, drying with sodium sulfate and removal of solvent under vacuum. After preparative GHUR (eluent: acetonitrile/water = 1/1 from 0.05% triperoxonane acid) and recrystallization from water obtained colorless crystals with a melting point 179-181oWith the release of 60% of theory.

Example 6

Obtaining (8-hydroxy-2,4-dioxopentanoate-3-yl)acetyl-L-leucine (formula I, where R1means N, R2means N, R3means CH2CONH-CH(FROM the home to the thrill/water = 1/1 from 0.05% triperoxonane acid) as the second product from the reaction mixture, formed in obtaining (8 methoxycarbonylamino-2,4-dioxopentanoate-3-yl)acetyl-L-leucine (product of example 5). After recrystallization from ethyl ether-acetic acid obtained colorless crystals with a melting point 204-207oWith the release of 25% of theory.

Example 7

Getting 2-L-(8-methoxycarbonyl-2,4-dioxopentanoate-3-yl)propionic acid (formula I, where R1means of SOON3, R2means N, R3means CH(CH3)-COOH)

The compound was obtained analogously to example 4 from L-alanine and 2,3-di-(methoxycarbonylamino)of benzoyl chloride in aqueous sodium bicarbonate solution. After preparative GHUR (eluent: acetonitrile/water = 2/3 from 0.05% triperoxonane acid) received a colorless foamy substance with the release of 50% of theory.

Example 8

Obtain L-(8-methoxycarbonyl-2,4-dioxopentanoate-3-yl)phenylacetic acid (formula I, where R1means COOH3, R2means N, R3means6H5-CH-COOH)

The compound was obtained analogously to example 4 from L-phenylalanine and 2,3-di-(methoxycarbonylamino)of benzoyl chloride in aqueous sodium bicarbonate solution. After preparative GHUR (eluent: acetonitrile/water = 1/1 from 0.05% trip-184oWith the release of 50% of theory.

Example 9

Getting 4-[(8-methoxycarbonyl-2,4-dioxopentanoate-3-elimina)methyl] benzoic acid (formula I, where R1means of SOON3, R2means N, R3means N = CH-C6H4-COOH(R))

To a solution of 0.3 g of 4-[(2,3-dihydroxybenzoic)hydroconseil]benzoic acid in 2 ml of 2n. sodium liquor and 3 ml of water under stirring was added at 0oWith 2 ml of methyl ether of Harborview acid. The mixture was stirred for 30 min, then acidified with hydrochloric acid. The crude product was dissolved in hot dimethylformamide, the solution was filtered and the product is again besieged with water. Subsequent purification was performed by preparative GHUR (eluent: acetonitrile/water = 1/1 from 0.05% triperoxonane acid). The result obtained colorless crystals with a melting point of 232-234oC.

Example 10

Obtaining N-[(8-methoxycarbonyl-2,4-dioxopentanoate-3-yl)acetyl] ampicillin (formula I, where R1means of SOON3, R2means N, R3means of CH2-CO-R5and R5is a N-ampicillino-)

a) Getting (8 methoxycarbonylamino-2,4-dioxopentanoate-3-yl)acetylcho is 1 g pentachloride phosphorus in 5 ml of absolute carbon tetrachloride was carefully heated to complete the education model HC1 (30 min). The resulting solution was filtered and the filtrate was concentrated. The residue was re-dissolved in hot carbon tetrachloride, the acid chloride was besieged anhydrous petroleum ether and dried under vacuum. In this way received 0,81 g of product (86% of theory) with a melting point of 80-82oC.

b) a Solution of 0,78 g of sodium salt of ampicillin in 12 ml of 80% tetrahydrofuran was cooled to -5oC. Then, with stirring, to the solution was added in portions to 0.63 g of 8-methoxycarbonyl-2,4-dioxopentanoate-3-Elaterid. The mixture was stirred for 1 h at 0oC and for 1 h at 20oWith, and then was evaporated under vacuum. The residue was mixed with 50 ml water and 50 ml ethyl ester of acetic acid. Then slightly acidified (pH 3) 1M hydrochloric acid and washed three times with an aqueous solution of sodium chloride. The organic phase was separated, dried over sodium sulfate and concentrated to a volume of 20 ml, the Residue was mixed with petroleum ether, receiving 0,92 g (74% of theory) of a derivative of ampicillin in the form of a white powder.

Example 11

Obtaining N-[(8-methoxycarbonyl-2,4-dioxopentanoate-3-yl)acetyl] amoxicillin (formula I, where R1means of SOON3, R2means N, R3OZNA the ml of 80% tetrahydrofuran were mixed from 0.22 ml of triethylamine and cooled to -5oC. Then, with stirring, to a solution of the portions was added 0.45 g (8 methoxycarbonylamino-2,4-dioxopentanoate-3-yl)acetylchloride (receiving according to example 8). The mixture was stirred for 1 h at 0oC and for 1 h at 20oWith, and then was evaporated under vacuum. The residue was mixed with 40 ml water and 40 ml ethyl ester of acetic acid. Then slightly acidified (pH 3) 1M hydrochloric acid, shaken and washed with an aqueous solution of sodium chloride to the complete lack of acid. The separated organic phase was dried over sodium sulfate, almost completely evaporated and mixed with petroleum ether. In this way received a derivative of amoxicillin in the form of a white powder with a yield of 80% of theory.

Example 12

Obtaining N-[(8-methoxycarbonyl-2,4-dioxopentanoate-3-yl)acetylglycine] ampicillin (formula I, where R1means of SOON3, R2means N, R3means CH2-CONH-CH2-COR5, a R5is a N-ampicillino-)

0,352 g (8 methoxycarbonylamino-2,4-dioxopentanoate-3-yl)acetylglycine (receipt see example 2), 140 μl of triethylamine and a catalytic amount of dimethylaminopyridine was dissolved in 5 ml of absolute tetrahydrofuran and the solution at -20 is whether for 30 min at -20oWith, then added 0,357 g of ampicillin sodium salt in 5 ml of 80% tetrahydrofuran. Then was stirred for 1 h at -20oC and for 1 h at +20oWith, and then was evaporated under vacuum. The residue was mixed with ethyl ether, acetic acid and water and carefully acidified using 1M hydrochloric acid. The organic phase was separated, washed three times with sodium chloride solution, dried over sodium sulfate and partially evaporated. The addition of petroleum ether was besieging a derivative of ampicillin, which was purified by preparative GHUR (eluent: acetonitrile/water = 1/1 from 0.05% triperoxonane acid).

Example 13

Obtaining N-[(8-methoxycarbonyl-2,4-dioxopentanoate-3-yl)acetyl-L-alanyl] ampicillin (formula I, where R1means of SOON3, R2means N, R3means of CH2-NH-CH(CH3)R5and R5is a N-ampicillino-)

The connection is carried out analogously to example 12 from (8 methoxycarbonylamino-2,4-dioxopentanoate-3-yl)acetyl-L-alanine (receipt see example 3) and the sodium salt of ampicillin. Purification was performed by preparative GHUR (eluent: acetonitrile/water = 1/1 from 0.05% triperoxonane acid), getting this way the hydroxy-2,4-dioxopentanoate-3-yl)acetyl-L-leucyl] ampicillin (formula I, where R1means of SOON3, R2means N, R3means CH2-CONH-CH(COR5)-CH2CH(CH3)2and R5is a N-ampicillino-)

The compound was obtained analogously to example 12 from (8 methoxycarbonylamino-2,4-dioxopentanoate-3-yl)acetyl-L-leucine (receipt see example 5) and the sodium salt of ampicillin. Purification was performed by preparative GHUR (eluent: acetonitrile/water = 2/3 from 0.05% triperoxonane acid), receiving a colorless solid with a yield of 60% of theory.

Example 15

Obtaining N-[(8-methoxycarbonyl-2,4-dioxopentanoate-3-yl)acetyl] -O-n-propiomelanocortin (formula I, where R1means of SOON3, R2means N, R3means CH2COR5, a R5represents N-(O-n-propionyl)amoxicillin-)

0,385 g of N-[(8-methoxycarbonyl-2,4-dioxopentanoate-3-yl)acetyl] amoxicillin (receipt see example 11) was dissolved in 25 ml of tetrahydrofuran and the solution was cooled to -78oC. With stirring was added first to 0.34 ml of triethylamine, and then 0.16 ml of propionitrile. The reaction mixture was stirred for 30 min at -60oC and for 1 h at 20oC. and Then was evaporated under vacuum and the residue is dnim solution of sodium chloride to the complete lack of acid. The separated organic phase was dried over sodium sulfate, almost completely evaporated and mixed with petroleum ether. In this way received a derivative of amoxicillin in the form of a white powder with a yield of 40% of theory.

Example 16

Getting 4-(8-methoxycarbonyl-2,4-dioxopentanoate-3-yl)benzoic acid (formula I, where R1means of SOON3, R2means N, R3means6H4-COOH(R))

The compound was obtained analogously to example 1 from 4-aminobenzoic acid and 2,3-di-(methoxycarbonylamino)of benzoyl chloride in an aqueous solution of sodium bicarbonate. After recrystallization from ethyl ether-acetic acid obtained colorless crystals with a melting point 236-240oWith the release of 80% of theory.

Example 17

Obtaining 2L,6-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanoic acid (formula I, where R1means of SOON3, R2means N, R3means CHR4-COOH, a R4means (CH2)4Y)

The compound was obtained analogously to example 5 from L-lysine and 2 mol. equivalents of 2,3-di-(methoxycarbonylamino)of benzoyl chloride in an aqueous solution of sodium bicarbonate in the form of a colorless foamy substance.

1means of SOON3, R2means N, R3identical to R20where R13means H, COR9in position 4, and R9is a N-ampicillino (Na-salt), R is 0)

a) Obtaining 4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl chloride

Connection received similar substance 10A) of the substance 16 and pentachloride phosphorus tetrachloride. In this way received a colorless oil with a yield of 65% of theory.

b) Obtaining N-[4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl]ampicillin

Connection received similar substance 10B) of 4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl chloride and sodium salt of ampicillin. Thus obtained white powder with a yield of 85% of theory.

C) Sodium salt: a Solution of 0.25 g of N-[4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl] ampicillin in ethyl ether acetic acid under cooling with ice and stirring was mixed with a solution of 0.083 g 2-ethylhexanoate sodium ethyl ester of acetic acid. After precipitation of the product with petroleum ether was filtered. Purification was performed by preparative GHUR (eluent: acetonitrile/water). If this is lexi-2,4-dioxo-1,3-benzoxazin-3-ylmethyl)benzoic acid (formula I, where R1means of SOON3, R2means N, R3identical to R20where R13means H, COR9in position 4, and R9IT means, p is 1)

The compound was obtained analogously to substance 5 of 4-(aminomethyl)benzoic acid and 2,3-di-(methoxycarbonylamino)of benzoyl chloride in an aqueous solution of sodium bicarbonate. After recrystallization from ethyl ether-acetic acid obtained colorless crystals with a melting point of 220-222oWith the release of 65% of theory.

Example 20

Obtaining the sodium salt of N-[4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-ylmethyl)benzoyl] ampicillin (formula I, where R1means of SOON3, R2means N, R3identical to R20where R13means H, COR9in position 4, and R9is a N-ampicillino (Na-salt), R is 1)

a) Obtaining 4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-ylmethyl)of benzoyl chloride

Connection received similar substance 10A) of the substance 19 and pentachloride phosphorus tetrachloride. In this way received a colorless oil with a yield of 95% of theory.

b) Obtaining N-[4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-ylmethyl)benzoyl] ampicillin

C) Sodium salt: Getting were performed similarly to the substance 18 of N-[4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-ylmethyl)benzoyl] ampicillin and 2-ethylhexanoate sodium ethyl ester of acetic acid. Thus obtained white powder with a yield of 60% of theory.

Example 21

Obtain 3,5-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoic acid (formula I, where R1means of SOON3, R2means N, R3identical to R20where R13means Y at position 3, COR9in position 5, and R9IT means, p is 0, R2matter listed above)

The compound was obtained analogously to substance 5 of the 3.5-diaminobenzoic acid and 2 mol. equivalents of 2,3-di-(methoxycarbonylamino)of benzoyl chloride in an aqueous solution of sodium bicarbonate. After recrystallization from ethyl ether-acetic acid obtained colorless crystals with a melting point 164-166oWith the release of 65% of theory.

Example 22

Obtaining the sodium salt of N-[3,5-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl]ampicillin (formula I, where R1means of SOON3, RSUP>9represents-N-ampicillino (Na-salt), R 0, R1and R2have the values listed above)

a) Obtain 3,5-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl chloride

Connection received similar substance 10A) of the substance 21 and pentachloride phosphorus tetrachloride. It was a colorless foamy substance (yield: 90% of theory).

b) Obtain N-[3,5-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl]ampicillin

Connection received similar substance 10B) of 3,5-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl chloride and sodium salt of ampicillin. It was a white powder, which was obtained with the yield of 80% of theory.

C) Sodium salt: Connection received similar substance 18 from N-[3,5-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl] ampicillin and 2-ethylhexanoate sodium ethyl ester of acetic acid. Thus obtained white powder with a yield of 40% of theory.

Example 23

Obtaining 3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propionic acid (formula I, where R1means of SOON3, R2means N, R3means (CH2oWith the release of 55% of theory.

Example 24

Obtaining the sodium salt of N-[3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propionyl] ampicillin (formula I, where R1means of SOON3, R2means N, R3represents (CH2)2CO-N-ampicillino (Na-salt))

a) Obtaining 3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propionitrile

The compound was obtained analogously to substance 10A) of the substance 23 and pentachloride phosphorus tetrachloride. In this way received a yellowish oil with a yield of 100% of theory.

b) Obtaining N-[3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propionyl]ampicillin

Connection received similar substance 10B) of 2-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)Propionaldehyde and sodium salt of ampicillin. Thus obtained white powder with a yield of 88% of theory.

C) Sodium salt: Salt received similar substance 18 from N-[3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propionyl] ampicillin and 2-ethylhexanoate sodium in ethyl ether uksu,5-bis[3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propionamido]benzoic acid (formula I, where R1means of SOON3, R2means N, R3identical to R18where R10, R11mean N, R12identical to R19in position 3, COR9in position 5, and R9IT means, R15, R14mean N, n is 2, R1, R2have the values listed above)

The compound was obtained analogously to substance 5 of the 3.5-diaminobenzoic acid and 2 mol. equivalents of 3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl) propionitrile (substance 24A)) in an aqueous solution of sodium bicarbonate. Thus obtained colorless crystals with a melting point of 160-165oWith the release of 50% of theory.

Example 26

Obtaining the sodium salt of N-{3,5-bis[3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propionamido] benzoyl} ampicillin (formula I, where R1means of SOON3, R2means N, R3identical to R18where R10, R11mean N, R12identical to R19in position 3, COR in position 5, and R9is a N-ampicillino (Na-salt), R15, R14mean N, n is 2, R1, R2have the values listed above)

a) Obtaining N-{ 3,5-bis[3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propionyl ampicillin. Thus obtained white powder with a yield of 80% of theory.

b) Sodium salt: Connection received similar substance 18 from N-{ 3,5-bis[3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propionamido] benzoyl} ampicillin and 2-ethylhexanoate sodium ethyl ester of acetic acid. Thus obtained white powder with a yield of 18% of theory.

Example 27

Obtain 3,5-bis[(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)acetylamino] benzoic acid (formula I, where R1means of SOON3, R2means N, R3identical to R18where R10, R11mean N, R12identical to R19in position 3, COR9in position 5, and R9IT means, R15, R14mean H, n is 1, R1, R2have the values listed above)

The compound was obtained analogously to substance 5 of the 3.5-diaminobenzoic acid and 2 mol. equivalents (8 methoxycarbonylamino-2,4-dioxo-1,3-benzoxazin-3-yl)acetylchloride (substance 10A) in an aqueous solution of sodium bicarbonate. After recrystallization from ethyl ether-acetic acid obtained colorless crystals with a melting temperature of 190-195oWith the release of 53% of theory.

Example 28

Receipt(formula I, where R1means of SOON3, R2means N, R3identical to R18where R10, R11mean N, R12identical to R19in position 3, COR9in position 5, and R9is a N-ampicillino (Na-salt), R15, R14mean H, n is 1, R1, R2have the values listed above)

a) Obtaining N-{ 3,5-bis[(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)acetylamino]benzoyl}ampicillin

Connection received similar substance 12 of substance 27 and sodium salt of ampicillin. Thus obtained white powder with a yield of 90% of theory.

b) Sodium salt: Salt received similar substance 18 from N-{3,5-bis[(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)acetylamino]benzoyl}ampicillin and 2-ethylhexanoate sodium ethyl ester of acetic acid. Thus obtained white powder with a yield of 17% of theory.

Example 29

Getting 4-chloro-3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoic acid (formula I, where R1means of SOON3, R2means N, R3identical to R20where R13mean CL in position 2, COR9in position 5, and R9IT means, p is 0)

Connection get the nom solution of sodium bicarbonate. After recrystallization from ethyl ether-acetic acid obtained colorless crystals with a melting point 234-236oWith the release of 41% of theory.

Example 30

Obtaining the sodium salt of N-[4-chloro-3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl] ampicillin (formula I, where R1means of SOON3, R2means N, R3identical to R20where R13means S1 in position 2, COR9in position 5, and R9is a N-ampicillino (Na-salt), R is 0)

a) Obtaining 4-chloro-3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl chloride.

Connection received similar substance 10A) of the substance 29 and pentachloride phosphorus tetrachloride. In this way received a yellow powder with a yield of 94% of theory and with a melting point of 76-78oC.

b) Obtaining N-[4-chloro-3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl] ampicillin

Connection received similar substance 10B) of 4-chloro-3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl chloride and sodium salt of ampicillin. Thus obtained white powder with a yield of 87% of theory.

C) Sodium salt: Salt received analogues is of Kanata sodium ethyl ester of acetic acid. Thus obtained white powder with a yield of 55% of theory.

Example 31

Obtaining 2-hydroxy-4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoic acid (formula I, where R1means of SOON3, R2means N, R3identical to R20where R13means HE is in position 3, COR in position 4, and R9IT means, p is 0)

The compound was obtained analogously to substance 5 of 4-aminosalicylic acid and 2,3-di-(methoxycarbonylamino)of benzoyl chloride in an aqueous solution of sodium bicarbonate. After recrystallization from ethyl ether-acetic acid obtained colorless crystals with a melting point 261-262oWith the yield 68% of theory.

Example 32

Obtaining the sodium salt of N-[2-hydroxy-4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl] ampicillin (formula I, where R1means of SOON3, R2means N, R3identical to R20where R13means HE is in position 3, COR9in position 4, and R9is a N-ampicillino (Na-salt), R is 0)

a) Obtaining succinimido-2-hydroxy-4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoate: To a solution of 0,224 g substance 31 and 0,069 g of N-hydroxysuccinimide in which closeclicked in 5 ml of anhydrous dioxane. The mixture was stirred for 8 h at 20oC, the precipitate was filtered and the solvent is kept under vacuum. The remaining oil otverdel in the trituration with a small amount of isopropanol. After recrystallization from ethyl ether-acetic acid obtained white powder with a yield of 0.23 g (81% of theory) and with a melting point 145-150oC.

b) Obtaining N-[2-hydroxy-4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl] ampicillin: 0,191 g three-hydrate ampicillin in atmosphere argon suspended in a mixture of 5 ml of tetrahydrofuran and 5 ml of water and adding 138 μl of triethylamine to prepare a solution. Then under stirring was added a solution of 0,233 g succinimido-2-hydroxy-4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoate in 5 ml of tetrahydrofuran and the mixture was stirred for 10 h at 20oC. Then the reaction mixture was evaporated at 20oWith and the residue was mixed with water and ethyl ester of acetic acid. After acidification of the organic phase was separated, washed with saturated sodium chloride solution and water, dried over sodium sulfate and finally almost completely evaporated. The addition of petroleum ether derived ampicilln received similar substance 18 from N-[2-hydroxy-4-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl] ampicillin and 2-ethylhexanoate sodium ethyl ester of acetic acid. Thus obtained white powder with a yield of 19% of theory.

Example 33

Obtaining 3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoic acid (formula I, where R1means of SOON3, R2means N, R3identical to R20where R13IT means, COR9in position 3, and R9IT means, p is 0)

The compound was obtained analogously to substance 5 from 3-aminobenzoic acid and 2,3-di-(methoxycarbonylamino)of benzoyl chloride in an aqueous solution of sodium bicarbonate. After recrystallization from ethyl ether-acetic acid obtained colorless crystals with a yield of 71% of theory and with a melting point 250-253oC.

Example 34

Obtaining the sodium salt of N-[3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl] ampicillin (formula I, where R1means of SOON3, R2means N, R3identical to R20where R13means H, COR9in position 3, and R9is a N-ampicillino (Na-salt), R is 0)

a) Obtaining 3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl chloride

Connection received similar substance 10A) of the substance 33 and pentachloride phosphorus tetrachloride. This PU is co-1,3-benzoxazin-3-yl)benzoyl]ampicillin

Connection received similar substance 10B) of 3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl chloride and sodium salt of ampicillin. Thus obtained white powder with a yield of 87% of theory.

C) Sodium salt: Salt received similar substance 18 from N-[3-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)benzoyl] ampicillin and 2-ethylhexanoate sodium ethyl ester of acetic acid. Thus obtained white powder with a yield of 59% of theory.

Example 35

Obtain 1-benzyl ester 2L-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)pentadecanoic acid (formula I, where R1means of SOON3, R2means N, R3means CHR4-COR5where R4means (CH2)2COOH and R5represents O-benzyl)

1 g of 1-benzyl ester of L-glutamic acid was dissolved in an atmosphere of argon in 40 ml of anhydrous tetrahydrofuran. While cooling with ice and stirring was added first to 1.24 ml of triethylamine and then a solution of 1.22 g of 2,3-di-(methoxycarbonylamino) of benzoyl chloride in 10 ml of anhydrous tetrahydrofuran. After stirring for 20 h at 20oWith the tetrahydrofuran was removed under vacuum and the residue sexualbehavior phase acetic acid was separated. Then repeatedly washed with water and saturated sodium chloride solution and finally concentrated. Purification was performed by preparative GHUR. In this way received a foamy substance yellowish color output is 0.260 g, which was 13% of theory.

Example 36

Obtaining the sodium salt of benzyl ester 4-ampicillinbuy-2L-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)butyric acid (formula I, where R1means of SOON3, R2means N, R3means CHR4-COR5where R4means (CH2)2CO-N-ampicillino (Na-salt) and R5represents O-benzyl)

a) Obtaining benzyl ester 4-chlorocarbonyl-2L-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)butyric acid

Connection received similar substance 10A) of the substance 35 and pentachloride phosphorus tetrachloride. In this way received a yellow oil with a yield of 97% of theory.

b) Obtaining benzyl ester 4-ampicillinbuy-2L-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)butyric acid

Connection received similar substance 10B) of the benzyl ester 4-chlorocarbonyl-2L-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxa the AI.

C) Sodium salt: Salt received similar substance 18 from 4-ampicillinbuy-2L-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)butanoyl] ampicillin and 2-ethylhexanoate sodium ethyl ester of acetic acid. Thus obtained white powder with a yield of 46% of theory.

Example 37

Obtaining 2L-[2L, 6-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanamide] -6-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanoic acid (formula I, where R1means of SOON3, R2means N, R3means CHR4-COR5where R4means (CH2)4-Y, and R5identical to R17where X means HE, n = 4)

a) Obtaining benzyl ether 2L-[2L,6-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanamide] -6-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanoic acid: 1.55 g of Tris-p-toluensulfonate benzyl ester 6-amino-2-(2,6-diaminohexanoic)hexanoic acid was dissolved in argon atmosphere in 20 ml of anhydrous dimethylformamide and the solution under cooling with ice and stirring was mixed first with 1,48 ml of triethylamine, and then with a solution of 1.53 g of 2,3-di-(methoxycarbonylamino)of benzoyl chloride in 10 ml of anhydrous demeti the Yali under vacuum and the residue was mixed with water and ethyl ester of acetic acid. While cooling with ice and stirring, acidified, and then atrovaginata phase acetic acid was separated. Then repeatedly washed with water and saturated sodium chloride solution and finally evaporated. Purification was performed by preparative GHUR (eluent: acetonitrile/water = 1/1 0.5% triperoxonane acid, resulting in 0.25 g of a yellowish oil (14% of theory).

b) of 0.250 g of benzyl ether 2L- [2L,6-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanamide] -6-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanoic acid was subjected to catalytic hydrogenation in 30 ml of ethanol using 0.06 g of palladium on charcoal (10% Pd) at 20oC and normal pressure. After filtration through brownmillerite was evaporated and was isolated from the ethyl ester of acetic acid solid foamy yellowish substance with access 0,220 g (98% of theory).

Example 38

Obtaining the sodium salt of N-{2L- [2 the remotest peaks,6'-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanamide] -6- (8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanoyl} ampicillin (formula I, where R1means of SOON3, R2means N, R3means CHR4-COR5, (Na-salt), n = 4)

a) Obtaining N-{2L-[2L,6-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanamide]-6-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanoyl}ampicillin

Connection received similar substance 12 from substance 37 and sodium salt of ampicillin. Thus obtained white powder with a yield of 90% of theory.

b) Sodium salt: Salt received similar substance 18 from N-{2L-[2L, 6-bis(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanamide] -6-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexanoyl} ampicillin and 2-ethylhexanoate sodium ethyl ester of acetic acid. Thus obtained white powder with a yield of 15% of theory.

Example 39

Obtain 3-hydroxy-2L-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propanoic acid (formula I, where R1means of SOON3, R2means N, R3means CHR4-COR5where R4means of CH2HE and R5means IT)

a) Obtaining benzyl ether 2L-N-(2,3-dimethoxybenzoyl)serine

Connection received similar substance 35 of the hydrochloride benzyl ester of L-serine and 2,3-di-(methoxycarbonylamino)of benzoyl chloride in tetrahydrofuran. Dimethoxybenzoyl)serine suspended in 50 ml of ethanol and was added 300 mg of catalyst palladium on coal (10%). After placing it in an atmosphere of hydrogen and the mixture was shaken for 2 h at 20oC and normal pressure. After filtration through brownmillerite was evaporated. After purification by preparative GHUR got a white foamy substance with exit 599 mg (48% of theory).

Example 40

Obtaining the sodium salt of N-[3-hydroxy-2L-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propionyl]ampicillin (formula I, where R1means of SOON3, R2means N, R3means CHR4-COR5where R4means of CH2HE and R5is a N-ampicillino (Na-salt))

a) Obtaining N-[3-hydroxy-2L-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propionyl] ampicillin

Connection received similar substance 12 from substance 39 and sodium salt of ampicillin. Thus obtained white powder with a yield of 90% of theory.

b) Sodium salt: Salt received similar substance 18 from N-[3-hydroxy-2L-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)propionyl] ampicillin and 2-ethylhexanoate sodium ethyl ester of acetic acid. Thus obtained white powder with a yield of 10% of theory.

Example 41

Obtaining (8 ethoxycarbonyl-2,4-diox N, R3means of CH2COOH)

Connection received similar substance 1 of glycine and 2,3-di-(ethoxycarbonyl)of benzoyl chloride in an aqueous solution of sodium bicarbonate. After recrystallization from ethyl ether-acetic acid obtained colorless crystals with a melting point of 162-163oWith the release of 69% of theory.

Example 42

Obtain N-{ N'-[6-(8-methoxycarbonyl-2,4-dioxo-1,3-benzoxazin-3-yl)hexyl] -N'-[2,3-di-(methoxycarbonylamino)benzoyl] -6-aminohexyl} -N-[2,3-di-(methoxycarbonylamino)benzoyl] glycine (formula I, where R3mean Z-CHR4-COR5; R1, R7mean of SOON3; R2, R4, R6mean N, R5IT means, n = 6, m = 2)

a) Obtaining benzyl ester (R5means och2C6H5): To a solution of 880 mg tosilata benzyl ester N-[N'-(6-aminohexyl)-6-aminohexyl]glycine and 1.04 ml of triethylamine in 20 ml dichloromethane at -30oC was added a solution of 864 mg of 2,3-di-(methoxycarbonylamino)of benzoyl chloride in 5 ml of dichloromethane. The mixture was stirred for 1 h at -10oC and for 1 h at room temperature and then filtered. The solution was concentrated and the residue was dissolved in 20 ml ethyl ester wislocki, a saturated solution of sodium bicarbonate and water. After drying and removal of the solvent under vacuum obtained colorless solid with a yield 650 mg, which accounted for 60% of theory.

b) Receiving acid: (R5means IT):

The above benzyl ether was first made in methanol in the presence of 100 mg of Pd/C (10%) for 3 h in the apparatus for shaking at room temperature. After filtering off the catalyst through brownmillerite the solvent is kept under vacuum. In this way received a colourless solid with a yield 70% of theory.

1. Derivatives of benzoxazinone formula I

< / BR>
in which R1represents H or Coolkill;

R2represents H, alkyl, halogen;

R3represents the following placeholders:

a) R3means-Z-CHR4-COR5where Z represents a group

< / BR>
R4means H, alkyl, phenyl, or R4means (CH2)nSOKH, where X denotes OA, where a represents H, alkali metal ion, or where X represents the residue of a series of penicillin, for example, ampicillin, amoxicillin, or O-allamatriciana, which is connected through NH-group, and where n = 1-10, or R4OS and R2have the above values, and both benzoxazinones radicals can be identical or different;

n may mean 1-10;

R5means OA, where a has the above meanings, or benzyl, or R5means NH-CHR8-COR9where R8represents H or alkyl, and R9means OA, where a has the above values, or R9represents the balance of a number of penicillin, such as ampicillin or amoxicillin, or O-allamatriciana, which is connected through NH-group, or R5represents the balance of a number of penicillin, such as ampicillin, or amoxiillin, or O-allamatriciana, which is connected through NH-group, or R5represents a group

< / BR>
(this group is an R17)

where X and Y have the above meanings;

n = 1-3;

R6means N;

R7means H, acyl;

n = 1-10;

m = 1-2, or

b) R3means CHR4-COR5where R4and R5have the above values, or R4means of CH2HE or

in R3represents a group

< / BR>
(this group is an R18)

where R10and/or R11mean H, alkyl;

znaczenia, and R12represents H, or R12represents a group

< / BR>
(this group is an R19)

where R1, R2have the above values;

R14, R15have the same meaning as R1, R2;

n may mean 1-10, or

g) R3represents a group

< / BR>
(this group is an R20)

where R13and COR9can be in all possible positions;

R13represents H, alkyl, halogen, hydroxy or benzoxazinones the radical Y;

R9has the above meanings;

p = 0-2, or

d) R3represents a group

< / BR>
(this group is an R21)

or R3represents a group

< / BR>
(this group is an R22)

where R9has the above meanings;

R16represents H,

and split under physiological conditions esters of such compounds of formula I having a free carboxy group in the residue R3.

2. The compounds of formula I on p. 1, where R1means carboxyethyl, R2means N, R3means CHR4-COR5>means carboxyethyl, R2means N, R3means CH2CONHCHR8-COOH, where R8means H or alkyl.

4. (8 Methoxycarbonylamino-2,4-dioxopentanoate-3-yl)acetic acid under item 1.

5. (8 Methoxycarbonylamino-2,4-dioxopentanoate-3-yl)acetylglycine under item 1.

6. The compounds of formula I on p. 1, where X or R5or R9represents the balance of a number of penicillin, such as ampicillin or amoxicillin, or O-allamatriciana, which is connected through NH-group.

7. The compounds of formula I under item 1 or 6, where X or R5or R9represents the balance of ampicillin.

8. The compounds of formula I under item 1 or 6, where X or R5or R9represents the balance of amoxicillin or O-allamatriciana.

9. N-(8-methoxycarbonyl-2,4-dioxopentanoate-3-ylacetic)ampicillin on PP. 1, 6, or 7.

10. N-(8-methoxycarbonyl-2,4-dioxopentanoate-3-ylacetic)amoxicillin PP. 1, 6, or 8.

11. Drug, possess siderophore activity, including active compound of formula I under item 1 and conventional media.

12. Drug on p. 11, characterized in that active compound sod is R, ampicillin, amoxicillin, or O-allometrically, which is connected through NH-group optionally having antibacterial activity.

13. The compounds of formula I according to any one of paragraphs. 1-10, with siderophore activity.

14. The compounds of formula I on p. 13, where X or R5or R9means the residue from a number of penicillin, for example, ampicillin, amoxicillin, or O-allometrically, which is connected through NH-group optionally having antibacterial activity.

 

Same patents:

The invention relates to compounds: N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino] sulfonyl] -4-(2-oxazolyl)[1,1'-biphenyl] -2-yl] methyl]-N,3,3-trimethylbutyramide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl] -4'-(2-oxazolyl)[1,1'-biphenyl] -2-sulfonamide and their pharmaceutically acceptable salts, such as lithium, sodium or potassium salt or a salt with a base, which is an organic amine

The invention relates to new derivatives of oxadiazole General formula I, in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen; Z denotes a radical of the formula II, R1means phenyl radical, which is optionally substituted directly or through alkylene bridges with the number of carbon atoms from 1 to 4 once, twice or three times by one or more substituents from the series halogen, C1-C4-alkyl, CF3, -NR5R6, NO2, -OR7

The invention relates to compounds of formula (I) R4-A-CH(R3)N(R2)B-R1where a is optionally substituted phenyl group, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring, and provided that the atom of the ring, in anthopology towards OR4- joined the group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted; In - pyridyl or pyridazinyl; R1located on the ring In the 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula СОNRaRa1where Rais hydrogen or C1-6alkyl, and Ra1- C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rb- C1-6alkyl, trifluoromethyl, or a 5-membered heteroaryl selected from isooxazolyl and thiadiazolyl, optionally substituted C1-6the alkyl or C1-4alkanolamines; R2- C1-6alkyl; R3is hydrogen; R4- C1-4alkyl, C3-7cycloalkyl,1-3alkyl or their pharmaceutically acceptable salt or in vivo hydrolyzable esters

The invention relates to a new method of obtaining isoxazolidinone the compounds of formula (II) in which R represents an optionally substituted aromatic hydrocarbon group or its salt, by reacting the compounds of formula (1) or its salt with the compound of the formula (2) in the presence of an inorganic base in an aqueous solvent with getting aspartates the compounds of formula (3), which interacts with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of base followed by heating for decarboxylation to obtain the compounds of formula (4), to which is added p-toluensulfonate acid to obtain oxazolidinedione derivative of the formula (5)which then restores the tetrahydrofuran in the presence of NaBH4and methanol to obtain oxazolidinones the compounds of formula (6) and its further interaction with methylchloride in the presence of triethylamine to obtain methanesulfonate derivative of the formula (7), which interacts with the compound of the formula (8) in the presence of potassium carbonate to obtain benzylidene derivative of the formula (9), which is further restored in an atmosphere of hydrogen for the floor is warping with obtaining the compounds of formula (11)

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to derivatives of N-sulfanilimide formula I, where R1and R2denote hydrogen, halogen, C1-4alkyl, C1-4alkoxycarbonyl or phenyl which can be substituted one to three times, equal or different residues from the group comprising halogen, C1-4alkyl, trifluoromethyl; R3- halogen, cyano, trifluoromethyl; R4- 4-isoxazolyl, pyrazolyl, which may be substituted with halogen, C1-4the alkyl, amino group, cycloalkyl, as well as their acid-salt additive

The invention relates to new derivatives of 4.1-benzoxazepin-2-she is of the formula (I), where R1lower alkyl, substituted by at least one optionally substituted hydroxyl group, R2and R3independently of one another is hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C1-C4alkoxygroup; X is a bond, methylene group or a linking group with a chain length of 1-7 atoms, selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n = 1 or 2 independently from each other: E-bond or an oxygen atom, -NR5-, -CONR7-, where R5-methylsulphonyl, R6and R7independently of one another(i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxypropyl, (iii) benzyl, Y is optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted, or tetrazolyl, or piperidine, and the ring And is substituted by 1-3 substituents selected from the group consisting of atoms of Halogens or their salts

The invention relates to new imidazole derivative of General formula (1), where n1is an integer from 1 to 3, a represents hydrogen, linear or branched C1-C10-alkyl, which may be optionally substituted C3-C7-cycloalkyl or lower alkoxy, or a radical selected from the group shown in the formula of the invention, Y represents a radical selected from the group described in the claims, or to his new pharmaceutically acceptable salts

The invention relates to new derivatives of piperidineacetate-2-it General formula I, where R1and R2each independently from each other represents an unsubstituted or once substituted phenyl residues, substituents which may be OA, Hal, NH2, OTHER3; R3denotes-CO-alkyl, where alkyl has 1 to 7 carbon atoms; And indicates WITH1-C6alkyl; Hal denotes F, CL, Br or J

The invention relates to new compounds of the formula (I), where R1is (C3-C7)cycloalkyl group or a 3-7-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur, which may be optionally substituted by oxopropoxy; R2- aryl group, which optionally can be substituted by 1-3 halogen atoms; And a is methylene or carbonyl group; a simple bond; D is oxygen atom or sulfur; G is - (C1-C4)alkylenes group; L is a group of the formula-C(R4)(R5)-, where R4and R5defined in the claims, Z is two hydrogen atoms or an oxygen atom, n = 0 or 1, or its pharmaceutically acceptable salts, esters, Quaternary amines or hydrates

The invention relates to new halogensubstituted the benzimidazole of the formula I, in which R1, R2, R3and R4mean hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, a group of the formula Z - R5where R5means unsubstituted phenyl, pyridinyl which can be substituted by trifluoromethyl, and Z denotes oxygen, sulfur; R2and R3together signify unsubstituted or substituted alkylenes chain with 3 or 4 links, in which two (non-adjacent) carbon atoms may be replaced by oxygen atom; A denotes a group of the formula: - SO2- R6or

,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt

The invention relates to new derivatives of 4.1-benzoxazepin-2-she is of the formula (I), where R1lower alkyl, substituted by at least one optionally substituted hydroxyl group, R2and R3independently of one another is hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C1-C4alkoxygroup; X is a bond, methylene group or a linking group with a chain length of 1-7 atoms, selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n = 1 or 2 independently from each other: E-bond or an oxygen atom, -NR5-, -CONR7-, where R5-methylsulphonyl, R6and R7independently of one another(i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxypropyl, (iii) benzyl, Y is optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted, or tetrazolyl, or piperidine, and the ring And is substituted by 1-3 substituents selected from the group consisting of atoms of Halogens or their salts

The invention relates to an improved process for the preparation of substituted indole derivatives useful in the treatment and prevention of migraine

The invention relates to a derivative of oxazolidin-2-it General formula (I):

< / BR>
where X is O,

Y denotesor

< / BR>
R1indicatesor< / BR>
R2and R3each, independently of one another, denotes H, A or benzyl;

A denotes alkyl with 1-6 C-atoms;

D denotes amidinopropane, aminomethyl, aminohydrocinnamic, 5-methyl-1,2,4-oxadiazolidine-3-yl or guanidinate;

r and s independently of one another denote 0, 1, 2, 3 or 4;

however, if necessary, free amino - or amidinopropane can be protected partially or fully protective for the amino function groups, as well as their enantiomers, diastereomers and physiologically acceptable salts
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