Bicyclic 6-alkylidenepenems as β-lactamase inhibitors

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of formula (I) and their pharmaceutically acceptable salts as β-lactamase inhibitors, method of their production, pharmaceutical composition based on them, and methods of treatment involving the claimed compounds. In the general formula (I) one of A and B is hydrogen, while the other is optionally substituted condensed bicyclic heteroaryl group; if aromatic ring part of bicyclic heteroaryl group is imidazole, non-aromatic ring part does not include S atom adjacent to head carbon atom of bridge group; X is S; R5 is H, C1-C6-alkyl or C5-C6-cycloalkyl; or its pharmaceutically acceptable salt where bicyclic heteroaryl group is (1-A) , where one of Z1, Z2 and Z3 is independently S, while the others are CR2 or S, if one of Z1-Z3 is carbon and is linked to the rest of molecule; W1, W2 and W3 are independently CR4R4, S, O or N-R1, if it does not form S-S, O-O, or S-O link with saturated ring system; t=1-4; R1 is H, C1-C6-alkyl, C5-C7-cycloalkyl, -C=O-aryl, -C=O(C1-C6)-alkyl, -C=O(C5-C6)-cycloalkyl, aryl-C1-C6-alkyl, optionally substituted C1-C6-alkoxy; heteroalkyl- C1-C6-alkyl or C=O(heteroaryl), where heteroaryl is 6-member ring containing 1 nitrogen atom, R2 is hydrogen, C1-C6-alkyl, R4 ir H, C1-C6-alkyl.

EFFECT: efficient application in bacterial infection treatment.

29 cl, 3 tbl, 58 ex

 

This invention relates to certain bicyclic 6-alkylidene, which act as inhibitors β-lactamase wide range. β-Lactamase hydrolyzing β-lactam antibiotics and as such act as the primary cause of bacterial resistance. Compounds according to this invention, when combined with β-lactam antibiotics, will ensure effective treatment of life-threatening bacterial infections.

Penicillins and cephalosporins are the most frequently and widely used in clinical practice β-lactam antibiotics. However, the development of resistance to various pathogens to β-lactam antibiotics has a damaging effect on the effective treatment of bacterial infections (Coleman, K. Expert Opin. Invest. Drugs 1995, 4, 693; Sutherland, R. Infection 1995, 23 (4) 191; Bush, K, Cur. Pharm. Design 1999, 5, 839-845). The most significant known mechanism related to the development of bacterial resistance to β-lactam antibiotics is the production of serine β-lactamases of class A, class b and class C. These enzymes destroy β-lactam antibiotics, which leads to the loss of antibacterial activity. Enzymes of class-And most of hydrolyzing penicillins, whereas lactamase class To have a profile of the substrate, foster's is in store hydrolysis of a cephalosporin (Bush, K.; Jacoby, G.A.; Medeiros, A. A. Antimicrob. Agents Chemother. 1995, 39, 1211). At the moment there is information about about 250 different β-lactamase (Payne, D.J.: Du, W and Bateson, J.H. Exp. Opin. Invest. Drugs 2000, 247) and there is a need for a new generation of inhibitors β-lactamase wide range. Bacterial resistance to these antibiotics could be significantly reduced by the introduction of β-lactam antibiotic in combination with a compound that inhibits these enzymes.

Commercially available inhibitors β-lactamases, such as clavulanic acid, sulbactam and tazobactam, effective against all pathogens, producing lactamase class-A. clavulanic acid is used in clinical practice in combination with amoxicillin and tikarcillina, as well as sulbactam with ampicillin and tazobactam with piperacillin. However, these compounds are ineffective against organisms producing lactamase class C. the Mechanism of inactivation β-lactamase class A (such as PCI and 1) explained (Bush, K.; Antimicrob. Agents Chemother. 1993, 37, 851; Yang, Y.; Janota, K.; Tabei, K.; Huang, N.; Seigal, M.M.; Lin, Y.I.; Rasmussen, B.A. and Shlaes, D.M. J. Biol. Chem. 2000, 35, 26674-26682).

In 1981 the band Beecham opened 6-alkylidene General structure 1 as inhibitors β-lactamases. [N.F. Osborne, U.S. patent 4485110 (1984); N.F. Osborne, European patent application 81301683.9, 1981]

R1and R2independently researched the Simo mean hydrogen, or C1-10is a hydrocarbon group, or managerialism group, and R3means hydrogen or an organic group. After that, the same group discovered compounds of General formula1where R1contains a group of 1,2,3-triazole [N.F. Osborne, European patent application 84301255.0]. The following year, the same group applied for 3 patents on the structure 1, where R1means optionally substituted six-membered or five-membered aromatic system mongolica [N.F. Osborne, European patent application 85100520.7; European patent application 85100521.5; European patent application 85300456-2]. European patent application No. 86305585.1 discloses the synthesis and suitability (Z)-6-(1-methyl-1,2,3-triazole-4-ylmethylene)stump-3-carboxylate 2 as an inhibitor β-lactamases of class-a and class-C.

European patent application 86305584,4 reveals the formation of compounds of General formula1where R1= non-aromatic heterocyclic group, and published PCT application [N.J. Broom; P.D. Edwards, N.F. Osborne and S. Coulton PCT WO 87/00525], revealing R1= condensed bicyclic heteroaromatic group. Similarly the patent application [N.J. Broom; G. Brooks; S. Coulton, European patent application 88311786.3; N.J. Broom; G. Brooks; B.P. Clarke, European patent application 88311787.1) describe the preparation and use of compounds of General structure 1, g is e R 1means substituted five-membered heteroaromatic ring. The method of obtaining compounds of General formula1described Coulton and others [S. Coulton; J.B. Harbridge; N.F. Osborne and G. Walker, European patent application No 87300193.7].

In 1993, a group of Beecham [A.V. Stachulski and R. Walker, PCT WO 93/03042] disclosed the preparation and use of compounds of General formula1where R1= (C1-6)-alkyl, and R2= CH2X or COY, where X = halogen or CONR2.

In the last decade, the Beecham group received three patents describing compounds of General formula 3. [N.J. Broom; F.P. Harrington, PCT WO 94/10178; K. Coleman; J.E. Neale PCT WO 95/28935; K. Coleman; J.E. Neale, PCT WO 95/17184], where R1= hydrogen or an organic group, and R4and R5both can denote hydrogen or one or more substituents replacing hydrogen atoms in the ring system shown below.

This invention relates to a new low molecular weight compounds β-lactam wide spectrum and in particular to a class of bicyclic heteroaryl-substituted 6-alkylidene that are inhibiting β-lactamase and antibacterial properties. The connection, therefore, applicable in the treatment of bacterial infections in humans and animals, either by itself or in combination with other antibiotics.

In accordance with this invention proposed compounds of General form is s I or their pharmaceutically acceptable salts or hydrolyzable in vivo esters R 5:

and the preferred compounds of formula

where:

one of A and b denotes hydrogen and the other is optionally substituted condensed-bicyclic heteroaryl. The expression "condensed bicyclic heteroaryl"used in the description and the claims, means the following:

group containing two condensed rings, one of which has aromatic character [i.e. meets the Huckel rule (4n+2)], and the other ring is non-aromatic;

condensed bicyclic heteroaryl contains from one to six heteroatoms selected from the group consisting of O, S, N and N-R1;

Condensed bicyclic heteroaryl connected with the rest of the molecule through a carbon atom in the aromatic ring as shown in formula I;

Aromatic ring condensed bicyclic of heteroaryl contains from five to six atoms in the ring (including the head atoms of the bridging group)selected from CR2, N, O, S or N-R1. Aromatic ring condensed bicyclic of heteroaryl contains from 0 to 3 heteroatoms selected from the group consisting of O, S, N and N-R1.

Non-aromatic ring condensed bicyclic of heteroaryl contains about the five to eight ring atoms (including the head atoms of the bridging group), selected from CR4R4N, N-R1, O, S(O)nwhere n = 0-2. Non-aromatic ring condensed bicyclic of heteroaryl contains from 0 to 4 ring heteroatoms selected from N, N-R1, O or S(O)nwhere n = 0-2.

X represents O or S, preferably S;

R5means N, hydrolyzable in vivo ester, such as C1-6-alkyl, C5-6-cycloalkyl, CHR3OCOC1-C6or salts such as Na, K, Ca; preferably R5means H or a salt;

R1means H, optionally substituted C1-C6-alkyl, optionally substituted aryl, optionally substituted-heteroaryl or mono or bicyclic saturated heterocycles, optionally substituted C3-C7-cycloalkyl, optionally substituted C3-C6alkenyl, optionally substituted C3-C6-quinil provided that the double bond, and triple bond should be present at the carbon atom that is directly linked to N; optionally substituted C1-C6-perfluoroalkyl, optionally substituted by a group-S(O)Palkyl or aryl where p is 2, optionally substituted-C=O-heteroaryl, optionally substituted-C=O-aryl, optionally substituted-C=O(C1-C6)-alkyl, optionally substituted-C=O(C3-C6-cycloalkyl, optionally substituted-C=O mo is about or bicyclic saturated heterocycles, optionally substituted C1-C6-alkylaryl, optionally substituted C1-C6-alkylglycerol, optionally substituted aryl-C1-C6-alkyl, optionally substituted heteroaryl-C1-C6-alkyl, optionally substituted C1-C6-alkyl-mono - or bicyclic saturated heterocycles, optionally substituted arylalkyl from 8-16 carbon atoms, -CONR6R7, -SO2NR6R7, optionally substituted arylalkylamines, optionally substituted-alkyl-O-alkylaryl, optionally substituted-alkyl-O-alkylglycerol, optionally substituted aryloxyalkyl, optionally substituted heteroepitaxial, optionally substituted aryloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted C1-C6-alkylresorcinol, optionally substituted C1-C6-alkylaminocarbonyl, optionally substituted alkilaminokarbeny, optionally substituted alkoxycarbonyl, optionally substituted aryloxyalkyl, optionally substituted heteroarylboronic. Preferred R1groups are H, optionally substituted alkyl, optionally substituted aryl, -C=O(C1-C6)-alkyl, C3-C6alkenyl, C3-C6-quinil, optionally substituted cyclol the sludge, SO2-alkyl, SO2aryl, optionally substituted heterocycle, -CONR6R7and optionally substituted heteroaryl.

R2means hydrogen, optionally substituted C1-C6-alkyl, optionally substituted C2-C6alkenyl having 1-2 double bonds, optionally substituted C2-C6-quinil with 1-2 triple bond, halogen, cyano, N-R6R7, optionally substituted C1-C6-alkoxy, hydroxy; optionally substituted aryl, optionally substituted heteroaryl, COOR6, optionally substituted alkilaminokarbeny, optionally substituted, aryloxy, optionally substituted, heteroaromatic, optionally substituted C3-C6-alkenylamine, optionally substituted C3-C6-alkyloxy, C1-C6-alkylamino-C1-C6-alkoxy, alkylenedioxy, optionally substituted, aryloxy-C1-C6-alkylamino, C1-C6-perfluoroalkyl, optionally S(O)q-substituted C1-C6-alkyl, optionally S(O)q-substituted aryl, where q denotes 0, 1 or 2, CONR6R7, guanidino or cyclic guanidino, optionally substituted C1-C6-alkylaryl, optionally substituted arylalkyl, optionally substituted C1-C6-alkylglycerol, optional substituted the initial heteroaryl-C 1-C6-alkyl, optionally substituted C1-C6-alkyl-mono - or bicyclic saturated heterocycles, optionally substituted arylalkyl from 8 to 16 carbon atoms, SO2NR6R7, optionally substituted arylalkylamines, optionally substituted aryloxyalkyl, optionally substituted heteroepitaxial, optionally substituted aryloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroepitaxial, optionally substituted C1-C6-alkylresorcinol, optionally substituted C1-C6-alkylaminocarbonyl, optionally substituted aryloxyalkyl, optionally substituted heteroepitaxial, optionally substituted alkilaminokarbeny. Preferred groups R2are H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroaryl, halogen, CN, hydroxy, optionally substituted heterocycle, -CONR6R7, COOR6, optionally substituted aryl, S(O)q-alkyl and S(O)q-aryl.

R3means hydrogen, C1-C6-alkyl, C5-C6-cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl; preferred groups R3are H or C1-C6-alkyl;

R4OZNA the AET N, optionally substituted C1-C6-alkyl; one of R4means OH, C1-C6-alkoxy, -S-C1-C6-alkyl, COOR6, -NR6R7, -CONR6R7; or R4R4together can be =O or R4R4together with the carbon atom to which they are attached, may form a Spiro system of five to eight members with or without heteroatoms selected from N, O, S=(O)n (where n = 0 to 2), N-R1; preferred groups R4are H, C1-C6-alkyl, NR6R7or R4R4together with the carbon atom to which they are attached, may form a Spiro system of five to eight members with or without heteroatoms, for example, one or two atoms of oxygen, nitrogen and sulfur;

R6and R7independently denote H, optionally substituted C1-C6-alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6-alkylaryl, optionally substituted arylalkyl, optionally substituted heteroaromatic, optionally substituted C1-C6-alkylglycerol, R6and R7together may form a 3-7-membered saturated ring system optionally having one or two heteroatoms, such as N-R1, O, S=(O)nn = 0-2. Preferred groups R6andR 7are H, C1-C6-alkyl, arylalkyl, heteroaromatic or R6and R7together form a 3-7-membered saturated ring system optionally having one or two heteroatoms.

The term alkyl means altergroup straight and branched chain, containing from 1 to 12 carbon atoms, preferably from 1 to 6 chain carbon atoms.

The term of alkenyl means altergroup straight and branched chain, containing from 2 to 8 carbon atoms in the chain containing at least one double bond and no triple bond, preferably altergroup has one or two double bonds. Such altergroup can exist in the E or Z conformations; the compounds according to this invention include both conformations. In the case of alkenyl heteroatoms such as O, S or N-R1must not be present on the carbon atom which is linked by a double bond;

The term quinil includes altenergy and straight and branched chain of 2 to 6 carbon atoms containing at least one triple bond, preferably Alchemilla has one or two triple bond. In the case of quinil heteroatoms such as O, S or N-R1should not be present at the carbon atom that is bound to double or triple bond;

The term cycloalkyl refers to a alicyclic hydrocarbon group having 3-7 the volume of carbon. Used herein, the term " perfluoroalkyl refers to a saturated aliphatic hydrocarbon groups and straight and branched chain, having at least one carbon atom and two or more fluorine atoms. Examples include CF3CH2CF3, CF2CF3and CH(CF3)2. The term halogen means Cl, Br, F and I.

If alkyl, alkenyl, quinil or cycloalkyl is "optionally substituted", are possible one or two of the following substituent: nitro, -aryl, -heteroaryl, alkoxycarbonyl-, -alkoxy, -alkoxyalkyl, alkyl-O-C2-C4-alkyl-O-, -cyano, -halogen, -hydroxy, -N-R6R7, -COOH, -COO-alkyl, -trifluoromethyl, -triptoreline, arylalkyl, alkylaryl, R6R7N-alkyl-, HO-C1-C6-alkyl-, alkoxyalkyl-, alkyl-S-, -SO2N-R6R7, -SO2Other6, -CO2H, CONR6R7, aryl-O-, heteroaryl-O-, -S(O)saryl (where s = 0-2), -alkyl-O-alkyl-NR6R7-alkylaryl-O-alkyl-N-R6R7C1-C6-alkyl, alkenyl, quinil, cycloalkyl, alkoxyalkyl-O-, R6R7N-alkyl and-S(O)s-heteroaryl (where s = 0-2); Preferred substituents for alkyl, alkenyl, quinil and cycloalkyl include halogen, nitro, aryl, heteroaryl, -COOH, -COO-alkyl, alkoxycarbonyl-, alkoxy-alkoxyalkyl, -cyano, hydroxy, and-N-R6R7.

Aryl means the fragrance is ical hydrocarbon portion of the molecule, selected from the group consisting of the following groups: phenyl, α-naphthyl, β-naphthyl, biphenyl, antril, tetrahydronaphthyl, fluorenyl, indanyl, biphenylyl, acenaphthene. The preferred origrami are phenyl and biphenyl.

Heteroaryl means an aromatic heterocyclic ring system (monocyclic or bicyclic), where heterogroup selected from the following: (1) furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazol, isothiazol, imidazole, N-Mei, pyridine, pyrimidine, pyrazin, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazol, benzimidazole, N-methylbenzimidazole, azobenzenes indazol, hinzelin, quinoline and isoquinoline; (2) a bicyclic aromatic heterocycle, where the phenyl ring, a pyridine, pyrimidine or pyridazine is (a) a condensed 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) condensed with a 5 - or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atom; (c) fused with 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together or one oxygen atom or one sulfur atom; or (d) of kondensirovannye the 5-membered aromatic (unsaturated) heterocyclic ring, having one heteroatom selected from O, N or S. Preferred heteroarylboronic are furan, oxazole, thiazole, isoxazol, isothiazol, imidazole, N-Mei, pyridine, pyrimidine, pyrazin, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, quinoline, isoquinoline and naphthiridine.

If aryl or heteroaryl is "optionally substituted", the possible substituents are one or two of the following: nitro, -aryl, -heteroaryl, alkoxycarbonyl-, -alkoxy, -alkoxyalkyl, alkyl-O-C2-C4-alkyl-O-, -cyano, -halogen, -hydroxy, -N-R6R7, -trifluoromethyl, -triptoreline, arylalkyl, alkylaryl, R6R7N-alkyl-, HO-C1-C6-alkyl-, alkoxyalkyl-, alkyl-S-, -SO2N-R6R7, -SO2Other6, -CO2H, CONR6R7, aryl-O-, heteroaryl-O-, -S(O)Saryl (where s = 0-2), -alkyl-O-alkyl-NR6R7-alkylaryl-O-alkyl-N-R6R7C1-C6-alkyl, alkenyl, quinil, cycloalkyl, alkoxyalkyl-O-, R6R7N-alkyl and-S(O)s-heteroaryl (where s = 0-2); Preferred substituents for aryl and heteroaryl include alkyl, halogen, -N-R6R7, trifluoromethyl, -triptoreline, arylalkyl and alkylaryl.

Arylalkyl means aryl-C1-C6-alkyl-; arylalkyl include benzyl, 1-is teletel, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like. The term "optionally substituted" refers to neumestnomu or substituted by 1 or 2 substituents on the alkyl group or aryl, which have the values specified above.

Alkylaryl means C1-C6-alkylaryl. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents on the aryl or the alkyl portion of the molecule, the definitions of which are given above.

Heteroaryl-C1-C6-alkyl means substituted by heteroaryl accelgroup, where the chain of the alkyl has 1-6 carbon atoms (straight or branched). Alkylheteroatom include heteroaryl-(CH2)1-6- and the like. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents on the alkyl - or heteroaryl, definitions of which are given above.

C1-C6-alkylglycerol means chain alkyl of 1-6 carbon atoms (straight or branched), attached to heteroaryl, which is connected with the rest of the molecule. For example, C1-C6-alkylglycerol-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents on the alkyl - or heteroaryl, definitions of which are given above.

Saturated or partially saturated heterocyclic group defined the AK heterocyclic ring, selected from groups: aziridinyl, azetidine, 1,4-dioxane, hexahydroazepin, piperazinil, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholine, dehydrobenzperidol, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydroisoxazole, dihydrofurane, dihydroimidazole, dihydroindole, dihydroisoxazole, dihydroisoxazole, dihydroimidazole, dihydrooxazolo, dihydropyrazine, dihydropyrazolo, dihydropyridines, dihydropyrimidines, dihydropyrrole, dihydroquinoline, dihydrotetrazolo, dihydrothiazolo, dihydrothiazolo, dehydration, dihydrotriazine, dihydroisocodeine, dihydro-1,4-dioxane, tetrahydrofuranyl, tetrahydrothieno, tetrahydroquinolines and tetrahydroisoquinolines. Preferred saturated or partially saturated heterocycles are aziridinyl, azetidine, 1,4-dioxane, hexahydroazepin, piperazinil, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholine, tetrahydroquinoline, tetrahydroisoquinoline, dihydroimidazole and dihydroisoxazole.

C1-C6-alkyl-mono - or bicyclic saturated or partially saturated heterocycles defined as C1-C6-altergroup with a straight or branched chain)attached to the heterocycles (defined earlier) through a carbon atom or a nitrogen atom, and the other end of the alkyl chain PR is connected to the rest of the molecule. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at the alkyl or heterocyclic portion of the molecule, the definitions of which are given above.

Arylalkylamines defined as aryl-C1-C6-alkyl-O-C1-C6-alkyl-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at the alkyl and/or aryl parts, definitions of which are given above.

Alkyloxyalkyl defined as C1-C6-alkyl-O-C1-C6-alkyl-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at the alkyl part is as defined above.

Aryloxyalkyl defined as aryl-O-C1-C6-alkyl-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present on the alkyl or aryl portion as defined above.

Heteroepitaxial defined as heteroaryl-C1-C6-alkyl-O-C1-C6-alkyl-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at the alkyl or heteroaryl part, the definitions of which are given above.

Aryloxyalkyl defined as aryl-O-aryl-. The term optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents, present on the aryl part is as defined above.

Aryloxyalkyl defined as aryl-O-heteroaryl - or-aryl-O-heteroaryl. With this definition or aryl part, or heteroaryl portion may be attached to the rest of the molecule. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present on the aryl part or on the heteroaryl part, the definitions of which are given above.

Alkylresorcinol defined as aryl-O-aryl-C1-C6-alkyl-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present on the aryl part is as defined above.

Alkylaminocarbonyl defined as heteroaryl-O-aryl-C1-C6-alkyl-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present on the aryl part or on the heteroaryl part, the definitions of which are given above.

Alkylarylsulfonates defined as R6R7N-C1-C6alkyl-O-aryl-C1-C6-alkyl-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present on the alkyl or aryl portion whose definitions given above; R6and R7have the values specified above.

Alkoxycarbonyl defined as C1-C6-alkyl-O-C=O-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at the alkyl part of alkoxygroup as defined above.

Aryloxyalkyl defined as aryl-O-C=O-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present on the aryl part is as defined above.

Heteroarylboronic defined as heteroaryl-O-C=O-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at the heteroaryl part, the definition of which is given above.

Alkoxy is defined as C1-C6-alkyl-O-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at the alkyl part is as defined above.

Aryloxy defined as aryl-O-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present on the aryl part is as defined above.

Heteroaromatic defined as heteroaryl-O-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at the heteroaryl part, the definition of which is given above.

Alkenylacyl defined as C3-C6-alkene-O-. Example allyl-O-, a group of similar but-2-EN-O. the Term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at the alkene group, as defined above, provided that no heteroatoms, such as O, S or N-R1no on the carbon atom that is attached to the double bond.

Alkyloxy defined as C3-C6-alkyne-O-. Example CH triple bond C-CH2-O-, a similar group. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at the alkyne group, as defined above, provided that no heteroatoms, such as O, S or N-R1not on the carbon atom that is attached to a double or triple bond.

Acylaminoalkyl defined as R6R7N-C1-C6-alkyl-O-C1-C6-alkyl-, where the end altergroup attached to the oxygen atom is connected with the rest of the molecule. Values of R6and R7above. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at the alkyl part is as defined above.

Alkylenedioxy defined as-O-CH2-O - or-O-(CH2)2-O-;

Aryloxyalkyl determine Elen as R 6R7N-C1-C6-alkyl-O-aryl where aryl is attached to the rest of the molecule; the Term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present on the alkyl or aryl group, the definitions of which are given above.

Arylalkenes defined as aryl-C2-C8-alkene-, provided that any heteroatom such as O, S or N-R1no on the carbon atom that is attached to the double bond. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present on alkinoos or aryl group, the definitions of which are given above.

Heteroepitaxial defined as heteroaryl-O-C1-C6-alkyl-. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at the heteroaryl part, the definition of which is given above.

Heteroepitaxial defined as heteroaryl-O-aryl-, where allgraph attached to the rest of the molecule. The term ' optionally substituted ' refers to unsubstituted or substituted by 1 or 2 substituents present at heteroaryl or arrgroups, definitions of which are given above.

Alkoxy, alkoxyalkyl, alkoxyalkyl, alkylthiols are groups, where the alkyl chain (straight or once atlanna) consists of 1-6 carbon atoms. Aryloxy, heteroaromatic, aaltio, heteroaromatic are groups where the aryl and heteroaryl are as described above. Arylalkylamine, heteroarylboronic, arylalkyl, heteroskedacity are groups where the aryl and heteroaryl are such as defined above, and where the alkyl chain (straight or branched) consists of 1-6 carbon atoms. Aryloxyalkyl, heteroepitaxial, aryloxyalkyl, heteroaromatics are substituents, where the alkyl radical has 1 to 6 carbon atoms. The terms monoalkylamines, dialkylamino belong to groups with one or two accelgroup, where the alkyl chain has 1-6 carbon atoms and groups may be the same or different. The terms monoalkylamines and dialkylaminoalkyl belong to monoalkylamines and dialkylamines with one or two accelgroup (same or different), associated with the nitrogen atom which is attached to altergroup from 1-3 carbon atoms.

Examples of condensed bicyclic heteroaryl are optionally substituted ring systems, such as one of the following:

4,5,6,7-tetrahydrothieno[3,2-c]pyridine, optionally substituted, for example, arylalkyl, such as benzyl; alkoxyalkyl, such as 4-methoxybenzyl; C1-C6-alkyl, such as methyl; heteroallyl, so ka is pyridine-3-ylmethyl; group arylalkyl-CO-, such as phenylacetyl; or a group heteroaryl-CO-, such as pyridine-3-ylcarbonyl; for example, the group alkyl-CO-, such as acetyl;

5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin, optionally substituted, for example, C1-C6-alkyl, such as methyl;

5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin;

6,7-dihydro-5H-pyrrolo[1,2-a]imidazole;

5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin;

5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;

4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine;

6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin, optionally substituted, for example, C1-C6-alkyl, such as methyl;

6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin;

4H-5-thia-1,6a-diazapentane;

7H-imidazo[1,2-c]thiazole;

4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin;

6,7-dihydro-4H-thieno[3,2-c]Piran;

6,7-dihydro-4H-thieno[3,2-c]thiopyran;

6,7-dihydro-4H-thieno[3,2-C]pyridine, optionally substituted C2-C7-alkoxycarbonyl;

6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin;

5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin, optionally substituted arylalkyl, such as benzyl;

5,5-dioxo-4,5,6,7-tetrahydro-5λ6-pyrazolo[5,1-C][1,4]thiazin;

4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin;

5,6-dihydro-4H-cyclopent[b]furan;

4,5-dihydro-6-thia-1,7a-dietingen;

5,6-dihydro-8-H-imidazo[2,1-c][1,4]thiazin;

4H-5-thia-1,6a-diazapentane;

2,3-dihydropyrazolo[5,1-b]thiazole;

2,3-dihydropyrazolo[5,1-b]oxazol;

6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin;

6,7-5H-dihydropyrazolo[5,1-b]oxazin and

4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin, optionally substituted, for example, a group alkoxyalkyl-CO-, such as 2-methoxyacetyl, or group alkyloxyalkyl-CO-, such as methoxyacetyl.

Additional examples of bicyclic heteroaryl are the following:

In the formula1-AZ1, Z2and Z3independently mean CR2, N, O, S or N-R1and one of Z1-Z3mean carbon and connected to the rest of the molecule as shown in formula1. When one of Z means CR2two other Z can mean either two atoms of N or one atom of N, O, S, N-R1in any combination without disturbing the aromatic structure; when two Z = CR2another Z may be optionally selected from N, O, S or N-R1in any combination without disturbing the aromatic structure;

W1, W2and W3independently mean CR4R4, S, SO, SO2, O, N-R1, C=O, provided that it can be no S-S or O-O or S-O due to formation of the saturated ring system; t = 1-4.

In formula 1-B Z1, Z2and Z3independently mean CR2, N, O, S or N-R1and one of Z1-Z3mean carbon and connected to the rest of the molecule as shown in formula1 . When one of Z = CR2then the other two Z independently can be CR2, N, O, S or N-R1in any combination without disturbing the aromatic structure;

when two Z = N, then a different carbon atom in the ring is associated with a group Panama molecules, as shown in the formula1.

W1, W2and W3independently mean CR4R4, S, SO, SO2, O, N-R1t = 1-4;

Y1and Y2= N or C, provided that when the aromatic heterocycle is imidazole, saturated ring may not contain a S adjacent to the carbon atom in the head of the bridge.

In formula 1-C Z1, Z2, Z3and Z4independently mean CR2or N and one of Z1-Z4mean carbon and connected to the rest of the molecule.

W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1provided that there was no S-S or O-O or S-O bond with the formation of the saturated ring system; t = 1-4.

Y1and Y2independently mean C or N.

The most preferred version of the formula 1-A:

1. t = 1-3.

2. In formula 1-A Z1means N, S, N-R1or O and one of Z2or Z3mean CR2and another Z2or Z3mean carbon and connected to the rest of the molecule as shown in formula1.

3. In formula 1-A Z3means N, S, N-R1what if O and one of Z 2or Z1mean CR2and another Z2or Z1mean carbon and connected to the rest of the molecule as shown in formula1.

4. In formula 1-A Z2means N, S, N-R1or O and one of Z1or Z3mean CR2and another Z1or Z3means the carbon associated with the rest of the molecule as shown in formula1.

5. In formula 1-A Z1means N, N-R1, O or S and Z2means N, O or S and Z3means the carbon associated with the group Panama molecules, as shown in the formula1.

6. In formula 1-A Z3means N, N-R1, O or S and Z2means N, O or S and Z1means the carbon associated with the group Panama molecule as shown in formula I.

7. In formula 1-A Z1means N, N-R1, O or S and Z3means N, O or S and Z2means the carbon associated with the group Panama molecule as shown in formula I.

8. In formula 1-A Z1means N, S, N-R1or O and Z2or Z3mean CR2and another Z2or Z3mean carbon and connected to the rest of the molecule; W1, W2and W3independently mean CR4R4.

9. In formula 1-A Z3means N, S, N-R1or O and one of Z2or Z1mean CR2and another Z2or Z1mean carbon and is connected with the rest of the cha is part of a molecule; W1, W2and W3independently mean CR4R4.

10. In formula 1-A Z2means N, S, N-R1or O and one of Z1or Z3mean CR2and another Z1or Z3mean carbon and connected to the rest of the molecule; W1, W2and W3independently mean CR4R4.

11. In formula 1-A Z1means N, N-R1, O or S and Z2means N, O or S; Z3means the carbon associated with the group Panama molecule; W1, W2, W3independently mean CR4R4.

12. In formula 1-A Z3means N, N-R1, O or S; Z2means N, O or S; Z1means the carbon associated with the group Panama molecule; W1, W2, W3independently mean CR4R4.

13. In formula 1-A Z1means N, N-R1, O or S; Z3means N, O or S; Z2means the carbon associated with the group Panama molecule; W1, W2, W3independently mean CR4R4.

14. In formula 1-A Z3means N, N-R1, O or S; Z1means N, O or S; Z2means the carbon associated with the group Panama molecule; W1, W2, W3independently mean CR4R4.

15. In formula 1-A Z1means N, S, N-R1or O; one of Z2or Z3mean CR2and another Z2or Z3oznachaet the carbon and connected to the rest of the molecule, t = 1-3; one W2means N-R1, O or S(O)nn = 0-2, and the other W2mean CR4R4.

16. In formula 1-A Z3means N, S, N-R1or O; one of Z2or Z1mean CR2and another Z2or Z1mean carbon and connected to the rest of the molecule, t = 1-3; one W2means N-R1, O or S(O)nn = 0-2, and the other W2= CR4R4.

17. In formula 1-A Z2means N, S, N-R1or O; one of Z1or Z3mean CR2and another Z1or Z3mean carbon and connected to the rest of the molecule; t = 1-3; one W2means N-R1, O or S(O)nn = 0-2 and another W2mean CR4R4.

18. In formula 1-A, when Z1= N, N-R1, O or S and Z2= N, O or S and Z3= carbon associated with the group Panama molecules, where t = 1-3, then one W2= N-R1, O or S(O)nn = 0-2 and another W2= CR4R4.

19. In formula 1-A Z3= N, N-R1, O or S and Z2= N, O or S and Z1= carbon associated with the group Panama molecules, where t = 1-3, then one W2= N-R1, O or S(O)nn = 0-2 and another W2= CR4R4.

20. In formula 1-A when Z1= N, N-R1, O or S and Z3= N, O or S and Z2= carbon associated with the group Panama molecules, where t = 1-3, then one W2= N-R1, O or S(O)nn = -2 and the other W 2= CR4R4.

21. In formula 1-A Z1= N, S, N-R1or O and Z2or Z3= CR2and another Z2or Z3mean carbon and connected to the rest of the molecule; then W1and W3= CH2or both of the hydrogen atoms on the methylene linkages can be replaced with the formation of the Spiro system with or without heteroatoms selected from O, S=(O)n(n = 0-2), N-R1with the formation of five - to eight-membered cyclic system; t = 1-3; one W2= N-R1, O or S(O)nn = 0-2 and another W2= CR4R4.

22. In formula 1-A Z3= N, S, N-R1or O and Z2or Z1= CR2and another Z2or Z1mean carbon and connected to the rest of the molecule; then W1and W3= CR4R4; where t = 1-3, then one W2= N-R1, O or S(O)nn = 0-2 and another W2= CR4R4.

23. In formula 1-A Z2= N, S, N-R1or O and Z1or Z3= CR2and another Z1or Z3mean carbon and connected to the rest of the molecule; then W1and W3= CR4R4where t = 1-3, then one W2= N-R1, O or S(O)nn = 0-2, and the other W2= CR4R4.

24. In formula 1-A, when Z1= N, N-R1, O or S and Z2= N, O or S, then Z3= carbon associated with the group Panama molecules; then W1and W3 = CR4R4where t = 1-3, then one W2= N-R1, O or S(O)nn = 0-2 and another W2= CR4R4.

25. In formula 1-A Z3= N, N-R1, O or S and Z2= N, O or S, then Z1= carbon associated with the group Panama molecules; then W1and W3= CR4R4where t = 1-3, then one W2= N-R1, O or S(O)nn = 0-2, and the other W2= CR4R4.

26. In formula 1-A when Z1= N, N-R1, O or S and Z3= N, O or S, then Z2= carbon associated with the group Panama molecules; then W1and W3= CR4R4; t = 1-3; one W2means N-R1, O or S(O)nn = 0-2, and the other W2mean CR4R4.

27. In formula 1-A Z3means N, N-R1, O or S; Z1means N, O or S; Z2means the carbon associated with the rest of the molecule; W1and W3independently mean CR4R4; t = 1-3; one W2means N-R1, O or S(O)nn = 0-2, and the other W2mean CR4R4.

The most preferred options of the formula 1-B:

28. In formula 1-B t=3.

29. In formula 1-B Z1and Z3mean N; Y1means N; Y2means C and Z2mean carbon and connected to the rest of the molecule as shown in formula I.

30. In formula 1-B Z2and Z3mean N; Y1means N; Y2oznacza the t C and Z 1mean carbon and connected to the rest of the molecule as shown in formula I.

31. In formula 1-B Z1means N, Y1means N, Y2means C, one of Z2or Z3mean CR2and another Z2or Z3mean carbon and connected to the rest of the molecule as shown in formula I.

32. In formula 1-B Z1means N, Y1means C, Y2means N, one of Z2or Z3mean CR2and another Z2or Z3mean carbon and connected to the rest of the molecule as shown in formula I.

33. In formula 1-B Z1means N, Y1means N, Y2means C, one of Z2or Z3mean CR2and another Z2or Z3mean carbon and connected to the rest of the molecule as shown in formula1, W1and W3independently mean CR4R4; t = 1-3; one W2means N-R1, O, S=(O)n(n = 0-2) and the other W2mean CR4R4.

34. In formula 1-B Z1means N, Y1means C, Y2means N, one of Z2or Z3mean CR2and another Z2or Z3mean carbon and connected to the rest of the molecule as shown in formula I; W1and W3independently mean CR4R4; t = 1-3; one W2means N-R1, O, S=(O)n(n = 0-2) and other Wsub> 2mean CR4R4.

35. In formula 1-B Z3means N; Y1means N; Y2means C; one of Z1or Z2mean CR2and another Z1or Z2mean carbon and connected to the rest of the molecule as shown in formula I.

36. In formula 1-B Z2means N; Y1means N; Y2means C; one of Z1or Z3mean CR2and another Z1or Z3mean carbon and connected to the rest of the molecule as shown in formula I.

37. In formula 1-B Z1and Z2mean N; Y1means N; Y2means C and Z3mean carbon and connected to the rest of the molecule as shown in formula I.

38. In formula 1-B Z1, Z2and Z3independently mean CR2; Y1means C; Y2means N; except that one of Z1-Z3mean carbon and connected to the rest of the molecule as shown in formula I.

39. In formula 1-B Z1and Z3mean N; Y1means N; Y2means C; Z2mean carbon and connected to the rest of the molecule as shown in formula I; and t = 1-3.

40. In formula 1-B Z2and Z3mean N; Y1means N; Y2means C; and Z1mean carbon and connected to the rest of the molecule, and t = 1-3;

41. In formula 1-B Z2and Z3OZNA is up N, Y1means C and Y2=N and Z1mean carbon and connected to the rest of the molecule and t = 1-3;

42. In formula 1-B Z2and Z3mean N, Y1means N; Y2means C; Z1mean carbon and connected to the rest of the molecule; W1and W3independently mean CH2or both of the hydrogen atoms on the methylene linkages can be replaced with the formation of the Spiro system with or without heteroatoms selected from O, S(O)nn = 0-2, N-R1with the formation of five - to eight-membered cyclic system; t = 1-3 and W2means CH2N-R1, O, S(O)nwhere n = 0-2.

43. In formula 1-B Z3means N; Y1means N; Y2means C; Z1mean CR2and Z2indicates the carbon atom that is linked with the rest of the molecule.

44. In formula 1-B Z3means N; Y1means N; Y2means C; Z1mean CR2; Z2indicates the carbon atom that is linked with the rest of the molecule; W1, W2and W3independently mean CR4R4; t = 1-3.

45. In formula 1-B Z3means N; Y1means N; Y2means C; Z1mean CR2; Z2indicates the carbon atom that is linked with the rest of the molecule; W1and W3independently mean CR4R4; and one of W2means N-R1, O or S(O)n and another W2mean CR4R4; t = 1-3.

46. In formula 1-B Z3means N; Y1means N; Y2means C; Z1mean CR2; Z2indicates the carbon atom that is linked with the rest of the molecule; W1and W2independently mean CR4R4; W3means N-R1, O or S(O)n; and t = 2.

47. In formula 1-B Z3means N; Y1means N; Y2means C; Z1mean CR2; Z2indicates the carbon atom that is linked with the rest of the molecule; W1and W3independently mean CR4R4; W2means N-R1, O or S(O)n; and t = 1.

48. In formula 1-B Z2means N; Y1means N; Y2means C; Z3mean CR2; Z1means the carbon associated with the rest of the molecule; W1and W2mean CH2or both of the hydrogen atoms on the methylene linkages can be replaced with the formation of the Spiro system with or without heteroatoms selected from O, S(O)nn = 0-2, N-R1with the formation of five - to eight-membered cyclic system; W3means N-R1, O or S(O)n; and t = 3.

49. In formula 1-B Z2means N; Y1means N; Y2means C, Z3mean CR2; Z1means the carbon associated with the rest of the molecule; W1and W3regardless of who appoints CH 2or both of the hydrogen atoms on the methylene linkages can be replaced with the formation of the Spiro system with or without heteroatoms selected from O, S(O)nn= 0-2, N-R1with the formation of five - to eight-membered cyclic system; and one W2means N-R1, O or S(O)nand another W2mean CR4R4; and t = 2.

50. In formula 1-B Z2means N; Y1means N; Y2means C; Z3mean CR2; Z1means the carbon associated with the rest of the molecule; W1and W3independently mean CH2or both of the hydrogen atoms on the methylene linkages can be replaced with the formation of the Spiro system with or without heteroatoms selected from O, S(O)nn = 0-2, N-R1with the formation of five - to eight-membered cyclic system; W2means N-R1, O or S(O)n; and t = 1.

51. In formula 1-B Z2means N; Y1means N; Y2means C; Z1mean CR2; Z3indicates the carbon atom that is linked with the rest of the molecule; W1and W3independently mean CR4R4; one of W2means N-R1, O or S(O)nand another W2mean CR4R4and t = 3.

52. In formula 1-B Z2means N; Y1means N; Y2means C; Z1mean CR2; Z3means a carbon atom, is knitted with the rest of the molecule; W1and W3independently mean CR4R4; one W2means N-R1, O or S(O)nand another W2mean CR4R4; and t = 2.

53. In formula 1-B Z2means N; Y1means N; Y2means C; Z1mean CR2; Z3indicates the carbon atom that is linked with the rest of the molecule; W1and W3independently mean CR4R4; W2means N-R1, O or S(O)n; and t = 1.

54. In formula 1-B Z1and Z2mean N; Y1means N; Y2means C; Z3mean carbon and connected to the rest of the molecule; W1and W3independently mean CR4R4; one of W2means N-R1, O or S(O)nand another W2mean CR4R4; and t = 3.

55. In formula 1-B Z1and Z2mean N; Y1means N; Y2means C; Z3mean carbon and connected to the rest of the molecule; W1and W3independently mean CR4R4; one of W2means N-R1, O or S(O)nand another W2mean CR4R4; and t = 2.

56. In formula 1-B Z1and Z2mean N; Y1means N; Y2means C; Z3mean carbon and connected to the rest of the molecule; W1and W3independently mean CR4R4; W2means N-R1, O or S(O) n; and t = 1.

57. In formula 1-B Z1and Z2independently mean CR2; Y1means C; Y2means N; Z3mean carbon and connected to the rest of the molecule; W1and W3independently mean CR4R4; one of W2means N-R1, O or S(O)n; another W2mean CR4R4and t = 3.

58. In formula 1-B Z1and Z2independently mean CR2; Y1means C and Y2mean N and Z3mean carbon and connected to the rest of the molecule; W1and W3independently mean CR4R4; and one W2means N-R1, O or S(O)nand another W2mean CR4R4and t = 2.

59. In formula 1-B Z1and Z2independently mean CR2; Y1means C; Y2means N; Z3mean carbon and connected to the rest of the molecule; W1and W3independently mean CR4R4; W2means N-R1, O or S(O)n; and t = 1.

60. In formula 1-B Z1and Z3independently mean CR2; Y1means C; Y2means N; Z2mean carbon and connected to the rest of the molecule; W1and W3independently mean CR4R4; one W2means N-R1, O or S(O)n; another W2mean CR4R4and t = 3.

61. In formula 1-B Z1and Z3/sub> independently mean CR2; Y1means C; Y2means N; Z2mean carbon and connected to the rest of the molecule; W1and W3independently mean CR4R4; and one W2means N-R1, O or S(O)nand another W2mean CR4R4; and t = 2.

62. In formula 1-B Z1and Z3independently mean CR2; Y1means C; Y2means N; Z2mean carbon and connected to the rest of the molecule; W1and W3independently mean CR4R4; W2means N-R1, O or S(O)n; and t = 1.

63. In formula 1-B Z3and Z2independently mean CR2; Y1means C; Y2means N; Z1mean carbon and connected to the rest of the molecule; W1and W2independently mean CR4R4; one W2means N-R1, O or S(O)n; another W2mean CR4R4; and t = 3.

64. In formula 1-B Z3and Z2independently mean CR2; Y1means C; Y2means N; Z1mean carbon and connected to the rest of the molecule; W1and W3independently mean CR4R4; one W2means N-R1, O or S(O)n; another W2mean CR4R4; and t = 2.

65. In formula 1-B Z3and Z2independently mean CR2; Y1oznachaet is C; Y2means N; Z1mean carbon and connected to the rest of the molecule; W1and W3independently mean CR4R4; W2means N-R1, O or S(O)n; and t = 1.

66. In formula 1-B Z3means N; Y1means N; Y2means C; one of Z1and Z2mean CR2and other means C; W1mean CR4R4; W2mean CR4R4; W3means CH2N-R1or O; and t = 1.

67. In formula 1-B Z3means N; Y1means N; Y2means C; one of Z1and Z2mean CR2and other means C; W1mean CR4R4; W2means C=O; W3means N-R1and t = 1.

68. In formula 1-B Z3means N; Y1means N; Y2means C; one of Z1and Z2mean CR2and other means C; W1means N-R1, W2means C=O; W3mean CR4R4; and t = 1.

69. In formula 1-B Z3means N; Y1means N; Y2means C; one of Z1and Z2mean CR2and other means C; W1means C=O; W2means N-R1; W3means CH2; and t = 1.

The most preferred options of the formula 1-C are:

70. In formula 1-C Z1, Z2, Z3and Z4independently mean CR2; one of Z1- 4mean carbon and connected to the rest of the molecule; Y1and Y2mean C; t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

71. In formula 1-C Z1, Z2, Z3and Z4independently mean CR2and one of Z1-Z4mean carbon and connected to the rest of the molecule; Y1and Y2= C or N; t = 1-3; W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

72. In formula 1-C Z1, Z2, Z3and Z4independently mean CR2; Y1and Y2mean N; t = 1-3; W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

73. In formula 1-C Z1mean N and Z2, Z3and Z4independently mean CR2; Y1and Y2mean C; t = 1-3; W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

74. In formula 1-C Z1mean N and Z2, Z3and Z4independently mean CR2; one of Z1-Z4mean carbon and connected to the rest of the molecule; Y1means C; Y2means N; t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

75. In formula 1-C Z2= N and Z1, Z3and Z4 independently mean CR2; one of Z1-Z4mean carbon and connected to the rest of the molecule; Y1and Y2mean C; t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

76. In formula 1-C Z2mean N and Z1, Z3and Z4independently mean CR2; one of Z1-Z4mean carbon and connected to the rest of the molecule; Y1means C; Y2means N; t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

77. In formula 1-C Z3means N; Z1, Z2and Z4independently mean CR2; one of Z1-Z4mean carbon and connected to the rest of the molecule; Y1and Y2mean C; t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

78. In formula 1-C Z3mean N and Z1, Z2and Z4independently mean CR2; one of Z1-Z4mean carbon and connected to the rest of the molecule; Y1means C and Y2means N; t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

79. In formula 1-C Z4mean N and Z1, Z2and Z3independently mean CR2; one of Z1Z 4mean carbon and connected to the rest of the molecule; Y1and Y2mean C; t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

80. In formula 1-C Z4mean N and Z1, Z2and Z3independently mean CR2; one of Z1-Z4mean carbon and connected to the rest of the molecule; Y1means N; Y2means C; t =1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

81. In formula 1-C Z1mean N and Z2, Z3and Z4independently mean CR2; one of Z1-Z4mean carbon and connected to the rest of the molecule; Y1and Y2mean C; t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

82. In formula 1-C Z1and Z2mean N and Z3or Z4independently mean CR2; one of Z1-Z4mean carbon and connected to the rest of the molecule; Y1means C; Y2means N; t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

83. In formula 1-C Z1and Z3mean N and Z2or Z4independently mean CR2; one of Z1-Z4mean carbon and is connected with the rest of the Oh molecules; Y1means C; Y2means N; t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

84. In formula 1-C Z1and Z4mean N and Z2or Z3independently mean CR2; one of Z1-Z4mean carbon and connected to the rest of the molecule; Y1means N; Y2means C; t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

85. In formula 1-C Z1, Z2, Z3mean N and Z4mean carbon and connected to the rest of the molecule; Y1means C; Y2means N; t =1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O, or H-R1.

86. In formula 1-C Z1, Z3and Z4mean N and Z2mean carbon and connected to the rest of the molecule; Y1and Y2mean C; t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

87. In formula 1-C Z1, Z2and Z4mean N and Z3mean carbon and connected to the rest of the molecule; Y1and Y2mean C and t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

88. In formula 1-C Z2, Z3, Z4mean N and Z1oz ACHAT carbon and connected to the rest of the molecule; Y1and Y2mean C and t = 1-3; and W1, W2and W3independently mean CR4R4, S, SO, SO2, O or N-R1.

The most preferred compounds of this invention are:

1. (5R,6Z)-6-[(5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

2. (5R),(6Z)-6-(7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

3. (5R),(6Z)-7-oxo-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

4. (5R,6Z)-6-{[5-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

5. (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

6. (5R),(6Z)-6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

7. (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

8. (5R),(6Z)-6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

9. (5R)(6Z)-7-oxo-6-(4,5,6,7-Tetra is droperidol[1,5-a]pyridine-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

10. (5R),(6Z)-6-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

11. (5R)(6Z)-6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

12. (5R)(6Z)-7-oxo-6-(4H-5-thia-1,6a-diazapentane-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

13. (5R)(6Z)-6-(7H-imidazo[1,2-c]thiazole-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt;

14. (5R,6Z)-7-oxo-6-[(4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methylene]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

15. 6-(6,7-dihydro-4H-thieno[3,2-c]Piran-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

16. 6-(6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

17. 6-(5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

18. 2-(2-carboxy-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-EN-6-ylidenemethyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid, ethyl ester;

19. 7-oxo-6-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

20. (5R),(6Z)-6-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)--oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

21. (5R,6Z)-7-oxo-6-{[5-(pyridine-3-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

22. (5R,6Z)-7-oxo-6-{[5-(pyridine-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

23. (5R,6Z)-7-oxo-6-{[5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

The compounds of this invention possess inhibitory property against β-lactamase and antibacterial properties and is applicable for the treatment of infectious diseases of humans and animals. It should be noted that the use of compounds according to this invention in combination with β-lactam antibiotics leads to increased antibacterial activity (synergistic effect) against organisms producing (lactamase) class-a and class-C. β-lactam antibiotics include penicillin antibiotics, such as piperacillin, amoxicillin, tikarcillin, benzylpenicillin, ampicillin, other penicillins, and cephalosporins, such as cefatrizine, tsefaloridin, cefalotin, Cefazolin, cephalexin, cefradine, other known cephalosporins, aztreonam and latamoxef (moxalactam). Most preferably, the compounds of this invention be used with piperacillin the om or amoxicillin, which has a broad spectrum of activity against gram-positive and gram-negative pathogens.

Compounds according to this invention can be used to simultaneously or sequentially with β-lactam antibiotic ("co-administration"). Using means introducing the compound directly or in vivo, for example, prodrugs. When the compounds according to this invention is administered in conjunction with β-lactam antibiotic, the ratio of the number of connections to the number β-lactam antibiotic may vary within a wide range. Attitude β-lactam antibiotic to the inhibitor β-lactamase may vary from 1:1 to 100:1. Preferably the ratio of β-lactam antibiotic to the inhibitor β-lactamase less than 10:1. The composition of this invention can be in a form suitable for oral (PO), intravenous (IV) or local injection. The compositions according to the invention can be in the form of tablets, capsules, creams, syrups, suspensions, sterile solutions suitable for injection or infusion. Preferably, the compounds according to this invention is administered in conjunction with piperacillin intravenously or with amoxicillin intravenous or oral.

The structural formula of compounds includes any tautomers, all stereoisomers (unless stereochemistry is clear Ref is on) and all crystalline forms.

The definition of IC50for inhibitor-based Panama

Inhibitory β-lactamase activity of inhibitors based on Panama determined spectrophotometrically as described Bush and others [Bush, K., Macalintan, C., Rasmussen, B.A., Lee, V., and Yang, Y. Antimicrobial Agents and Chemotherapy 1993, 37, 851]. The analysis used a homogeneous peeled β-lactamase class AND 1 from E. coli and Imi-1 from Enterobacter cloacae, CcrA enzyme class from Bacteroides fragilis and AmpC enzyme class from Enterobacter cloacae. The concentration of the enzyme for THE-1, Imi-1, CcrA and AmpC were 4,3, 7,1, of 1.2 and 2.1 nm, respectively. A wide range of concentrations of inhibitor were obtained in 50 mm RHO4, pH 7.0, to enable possible value IC50. The substrate used to initiate the reaction of the enzyme was nitrocefin at 50 µg/ml in the same buffer as for the inhibitor. First, the enzyme and the inhibitor (20 ál each) were subjected to pre-incubation for 10 minutes at 25°before adding a volume of 160 ál of nitrocefin. The initial degree of hydrolysis was monitored for 5 minutes using a molecular devices Spectra Max 250 c kinetic Protocol program SoftMax. Readings from Spectra Max 250 taken out and transferred to Microsoft Excel. The percentage of inhibition for each concentration of inhibitor was calculated on the basis of the control of enzyme activity. The concentration of inhibitor, which caused a 50% reduction of enzyme Akti the activity (IC 50), was determined graphically.

Table 1
IC50(nm)
ConnectionClass aClassClass
THE-1ImiCcRAmpC
Example 14,22,126012
Example 24,4221205,8
Example 3of 5.4283206,2
Example 70,47,8664,8
Example 81,250141,5
Example 92,290623,2
Example 1010651403,0
Example 111,018611,2
Example 121,4561101,5
Example 132,9161603,1
When is EP 14 2,56826the 3.8
Example 151,28,614the 3.8
Example 163,125124,2
Example 1712242826
Example 182,8501209,2
Example 194,827001704,6
Example 201,49,6183,1
Example 219,84028018
Example 226,14211011
Example 234,6401407,8
Example 241,15641,5
Example 251,11231622,7
Example 260,7354892,3
Example 2725,5732
Example 28NDND NDND
Example 29NDNDNDND
Example 302,923007,82,5
Example 311,4561101,5
Example 32NDNDNDND
Example 331,159410,85
Example 344,234996,5
Example 354,2230306,1
Example 366,34131404,5
ND = not determined

Testing of antimicrobial sensitivity. Activity in vitro of antibiotics was determined by the method of dilution of microbology, as recommended by the National Committee for clinical laboratory standards (NCCLS). (NCCLS. 2000. Test methods antimikrobnoe sensitivity dilution for bacteria that grow aerobically; approved standards M7-A5, vol 19, the national Committee for clinical laboratory standards, Vilanova, PA). For the test procedure used II broth Mueller-Hinton (MHBII) (BBL Cockeysville, MD). Mick is attrazione tablets, containing 50 μl per well twofold serial dilutions piperazillina, combined with a constant number (4 µg/ml) inhibitor β-lactamase, was inoculable 50 ál of the supernatant to obtain the corresponding density (105CFU/ml) in a final volume of 100 μl. The plates were incubated for 18-22 hours at 35°in the presence of air. Minimum inhibitory concentration (MIC) for all isolates were determined as the lowest concentration of antimicrobial agent that completely inhibits growth of the organism was detected with the naked eye. Data MIC, obtained by the above procedure are presented in table 2.

Table 2< / br>
These minimum inhibitory concentration (mcg/ml): Inc: 35°C for 18 hours
Example 1E.Coli GC2844E.Coli GC2847 (TEM-1)E.Coli GC2920 (IRT-2)E.Coli GC2894 (Ampc)E.Cloacae GC1477 (Ampc)P.aeruginos GC1764 (Ampc)S. Marcescens GC1781 Sme-1+AmpcE.Coli GC22033S.aureus GC2216
12221632320,510,12
221622 >648110,25
322126416120,5
428226432220,50
7224216111<0,06
8222280,2522<0,06
9121216412<0,06
10132116>64411<0,06
11242232211<0,06
12242232111 <0,06
130,5120,51610,52<0,06
141320,5064>64641621
152162832822<0,06
16216143216210,12
172824324120,25
18216232>6464220,50
192828>6464420,5
20232232>646422<0,06
1 232232>6464210,25
222>64264>6464420,5
23264232>6464420,5
24242464212ND
252422320,522ND
262821632824ND
2724216321622ND
28242416222ND
29282 832822ND
302812168820,06
3124223210,510,5
32222216212ND
332442160,5140,06
34432432>643222ND
352422641820,25
362422161140,06
ND=not determined

Antibacterial protection in vivo

Materials:

Animals:

Infection:

In the experiment using clinical isolates adapted to cause infection in mice, including infection by E. coli, K. pneumoniae, M. morganii, E. cloacae, S. marcescens, C. freundii, susceptible, streptococci, P. aeruginosa and N. gonorrhoeae.

Preparation:

Animal place five in a cage with free access to food and water in accordance with NIH guidelines.

Experimental Protocol:

Mice provoked by the injection of 0.5 ml administered intraperitoneally or 0.05 ml intranasal pre-defined bacterial inoculum suspended in the broth, saline or porcine gastric mucin (enriched dry bovine hemoglobin for N. gonorrhoeae). Bacterial inoculum equivalent to 10-100 LD50specific infectious strain and will result in the death of the untreated control animals within 7 days: "Bacterial virulence in mice". Antibacterial dose (concentration dose obtained twofold serial dilutions of the antibiotic) is dissolved or suspended in 0.2% aqueous agar or mucocele, phosphate buffered saline or adjuvant vocational, subcutaneously or intravenously as follows:

(a) Orally or subcutaneously: Dose volume of 0.5 ml is injected through 1/2 hours after infection. The second dose can be entered after 3 h after infection for the treatment of infections caused by more virulent organisms.

b) Intravenous: Dose volume of 0.2 ml is injected through 1/2 hours after infection. For the treatment of infections caused by more virulent organisms can be introduced more doses for up to 48 hours (Intravenous dosing should not exceed 3 doses/24 h period.)

C) Oral pre-treatment: specific conditions required regulation of the pH of the stomach in order to increase the stability of the antibiotic in the stomach. For this purpose, 0.5 ml of phosphate buffered saline solution (pH of 7.8, is 0.06 M) (or specific suitable adjuvant) is administered orally through 1/2 hours after infection, and then, after 5 minutes, inject 0.5 ml of antibiotic (oral)contained in phosphate buffered saline solution (pH of 7.8, is 0.06 M).

The types of animals

Next is a detailed explanation in relation to the number of animals needed to determine the efficacy in vivo:

New antibiotics was tested at 5 different dose levels of 5 mice at the dose level at each of the three routes of administration (oral, subcutaneous and intravenous). The first is touch three routes of administration should be investigated with the to determine absorbed whether oral medicine and/or which one of them is the most effective way. This requires 25 mice/path with 3 ways/antibiotic or 75 mice on a new test connection. One or two new antibiotic can be tested for the experiment (75-150 mice).

C) the effectiveness of the new compounds should be studied in comparison with a standard or an antibiotic known efficiency. Known or previously tested antibiotics was tested at 5 dose levels with 5 mice per dose level only by entering in the amount of 25 mice/antibiotic. Usually 3-6 antibiotics can be tested for the experiment (75-150 mice).

(C) Untreated controls in each of these trials untreated animals infect 3 different concentrations of bacterial inoculum of 10 mice at the concentration (as a whole 30 mice in each and every challenge). These untreated controls are used to determine and maintain the level of infection between 10-100 LD50, as required for comparison testing with the test for validity.

Determination of the protective effects of antibacterial agents

Protective effects of antibacterial agent (agents) measured by the surviving infected untreated animals compared to the treated animals. To make this determination, the animal is examined 7 days after treatment. A census of the survivors carried out twice a day and at this time, the dead and dying animals are removed. The relationship survived for 7 days from three separate tests combine to estimate the average effective dose (ED50) using a computerized program for probit analysis (Cleeland, R. and E. Squires. 1991. Evaluation of New Antimicrobials in Vitro and in Experimental Animal Infections. In Antibiotics in Laboratory Medicine, 3rd edition, published by Victor Lorian. Willams and Wilkins Baltimore, Maryland. page 752-783). The test is carried out three times on separate days, to ensure a statistically reasonable number of animals and to minimize variation in test results on the basis of the results from one day to another and from test to test.

19
Table 3
ExampleED50mg/kgThe attitude of piperacillin to the inhibitor
132-642:1
2>642:1
316-324:1
432-644:1
722,84:1
818,94:1
931,34:1
10
11 13,94:1
1220,04:1
1318,0
14
15
16
17of 37.94:1
18
1959,24:1
20
21
221284:1
231284:1
2464
2530
2630
2728
2831
2946
30ND
3120
3246
33>64
3432
35
3690

The method according to the invention

This invention relates to a method for obtaining compounds of formula I, which contains the exposure reductive elimination of the compounds of formula II:

where a' means a or b, the values of which are indicated above, X denotes O or S, R means ester leaving group, such as acetate, mesilate, triflate or tosylate, and R is a protective group, followed, if necessary, removing the protective group to obtain the compound of formula I, where R5means hydrogen and, if desired, converting in a pharmaceutically acceptable salt or ester, where R5means C1-C6-alkyl, C5-C6-cycloalkyl or CHR3OCOC1-C6-alkyl.

Compounds of General formula I can conveniently be obtained by the new soft and easy way, namely the condensation of suitably substituted aldehyde 4 with the derived 6-bromptom structure 1 (scheme 1) in the presence of anhydrous MgBr2or MgBr2:epirate and bases, such as triethylamine or DBU or DMAP, preferably at a temperature of from -20°-40°C. Intermediate alderny product 5 can be functionalized with acid chlorides or anhydrides of acids to acetate, Tr is the flat or tosilata 6. Compound 6 can be safely converted into the desired product in the recovery process of elimination using a metal, such as activated zinc, and phosphate buffer at 20° - 35°at pH from 6.5 to 8.0. If the protecting group on the oxygen of the carboxylate is Deputy p-nitrobenzyl, then reductive elimination and the removal of the protective group can be accomplished in one stage. However, if the protective group other than the Deputy p-nitrobenzyl, may follow the two-stage procedure depending on the nature of the protective group. The product can be isolated as the free acid or as a salt of an alkali metal. The above two-stage procedure can be carried out in one stage by carrying out the entire process in one stage without isolation of the intermediate compound 6. This is the most widespread relatively simple and effective procedure in terms of yield and economic feasibility. This procedure can be adapted to synthesize on an industrial scale and is negotiating with a variety of aldehydes. Alternatively, compound 6 can be galogenirovannami at a pressure of 40 pounds per square inch in the presence of Pd/C (10%) in THF and 6.5 phosphate buffer to obtain a final product.

The above-mentioned reaction of aldol condensation is one the camping is very flexible and can be applied to any derivative bromptom, where carboxypropyl protected by a different group than the 4-nitrobenzyl. Examples of other protective groups are benzyl, derived p-methoxybenzyl, benzhydrol derivatives of trityl, alkyl and allyl. However, when the protective group other than 4-nitrobenzanthrone, a separate stage of removal of the protective group must be carried out after the recovery procedure of elimination. Chemical mechanisms associated with the stage of removal of the protective group, is well known to specialists in this field.

Scheme 1

P = -OMs (mesilate), -OTf (triflate), -OTs (tosylate)

The required aldehydes 4 for the above transformations can be obtained from their corresponding alcohol derivatives by oxidation with MnO2or by Swern oxidation. In some cases, the required aldehyde functionality can be entered directly in the heterocyclic portion of the molecule by reaction Vilsmier Haack using DMF/POCl3. The aldehydes required for this study, can be obtained, as shown in schemes 2-5. N-(tert-butoxycarbonyl)- (ie) t-Boc-protected-4-piperidone treated with DMF/POCl3to obtain 4-chloro-3-formyl-derivative (scheme 2). This reaction can be conducted at tetrahydro-4H-Piran-4-Ohe and the corresponding derived tetrahydro-4H-Piran-4-it, to get the appropriate oxygen and sulfur derivatives. This reaction can also be carried out on the derivatives of five-to eight-membered cyclic ketones. Intermediate chloroformyl connection may be subjected to interaction with 2-mercapto-ethyl acetate to obtain thieno-derived. Ester can be converted into alcohol, which can be turned into the source of the aldehyde functionality. Scheme 3 illustrates the derivatization imidazole-tetrahydropyridine and derived imidazopyridine. 2-aminopyridine or 2-aminopyrazine can be subjected to interaction with ethyl-bromopyruvate in boiling ethanol to obtain cyklinowanie derivative (scheme 3). The restoration of one ring can be achieved.

Scheme 2

This sequence can be carried out on the basis of tetrahydro-4H-Piran-4-it and the corresponding tetrahydro-4H-thiopyran-4-it. The reaction Vilsmier can be implemented in a five-to eight-membered cyclic ketones.

Scheme 3

...by hydrogenation over Pd/C at a pressure of 40 pounds per square inch in a standard apparatus. After that, the ester group can be restored to alcohol and converted into the aldehyde. In the case of X = N intermediate complex aminoether can be derivatization with suitable R1Q (where Q means at Adamou group or condensable group). In the case of scheme 3, where R1= N, can be the synthesis procedure is shown in outline in figure 4.

Scheme 4

Additional aldehydes can be synthesized as shown in General terms in schemes 5-7.

Scheme 5

The aldehydes required for examples 24-32, 34 and 35 is obtained by, as shown in the diagrams 8-18.

Scheme 6

Scheme 7

Scheme 8

Scheme 9

Scheme 10

Scheme 11

Scheme 12

Scheme 13

Scheme 14

Scheme 15

Scheme 16

Scheme 17

Scheme 18

Experimental part

Example 1

Obtain (5R,6Z)-6-[(5-benzyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)methylene]-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1ethyl 5-benzoyl-4,5,6,7-Tetra is idrogeno[3,2-c]pyridine-2-carboxylate:

To mix the dry DMF (of 7.3 g, 100 mmol) is added slowly POCl3(12,25 g, 80 mmol) at a temperature between 0°C and 5°C. After adding utverzhdennuyu mass dissolved in CH2Cl2(20 ml) and stirred at room temperature for 2 hours Again lower the temperature to 0°C and slowly add 1-benzoyl-4-piperidone in CH2Cl2. After the addition the reaction mixture was stirred at room temperature for 2 h and poured on crushed ice and sodium acetate. All this is stirred for 30 minutes at room temperature. Extracted with CH2Cl2; well washed with water, dried over anhydrous MgSO4and concentrate. The crude product was dissolved in CH2Cl2and slowly add a mixture of ethylmercaptan (9.6 g, 80 mmol)/Et3N (10.1 g, 100 mmol) at room temperature. The reaction mixture is boiled with the return of phlegmy for 2 h and quenched with water. Layer CH2Cl2well washed with water, dried over anhydrous MgSO4filter and concentrate. The product was then purified column chromatography on SiO2, elwira a mixture of 50% ethyl acetate-hexane. A yellow oil. Yield: 6.4 g (25%); M+H 316.

Stage 2: (5-benzyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)methanol:

To a stirred suspension of LAH (2.0 g) is added slowly at 0°C a solution of ethyl 5-benzoyl-4,5,6,7-tetrahydrothieno,2-c]pyridine-2-carboxylate (6.0 g, 19 mmol) in THF. After the addition, the reaction mixture is stirred for 30 minutes and quenched with saturated NH4Cl. All of this is diluted with CHCl3and filtered. The filtrate is washed with saturated salt solution and dried over anhydrous MgSO4. It is filtered and taken to the next stage without cleaning. Yield: 4.5 g, 91%. Yellow liquid.

Stage 3: 2-formyl (5-benzyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine:

To a stirred solution of (5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methanol (4.0 g, to 15.4 mmol) in CH2Cl2(300 ml) is added activated MnO2(20 g, excess) and stirred at room temperature for 18 h In the end, the reaction mixture was filtered through celite and washed with CHCl3. The reaction mixture was well washed with water, dried and concentrated. Find the product clean and take it to the next stage without cleaning. Yield: 3.0 g (76%). (M+H: 257).

Stage 4: 4-nitrobenzyl-6-[(atomic charges)(5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

2-Formyl (5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (565 mg, 2.2 mmol) and a solution in dry THF (20 ml) of 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (772 mg, 2.0 mmol) are added sequentially to a solution in dry acetonitrile (15 ml), anhydrous MgBr2:O(Et)2 (390 mg, 1.5 mmol) in an argon atmosphere at room temperature. After cooling to -20°C add Et3N (2.0 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20°C and treated with acetic anhydride (1.04 million ml) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered through a pad of celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of ethyl acetate:hexane (1:1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers take to the next stage. Pale yellow amorphous solid. Yield: 550 mg, 40%. M+H 687.

Stage 5: (5R,6Z)-6-[(5-benzyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid:

4-Nitrobenzyl-6-[(atomic charges)(5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (450 mg, of 0.65 mmol) dissolved in THF (20 ml) and acetonitrile (10 ml Sizeaction Zn dust (5,2 g) add quickly with 0.5 M phosphate buffer (pH 6.5, 28 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 hours at room temperature. The reaction mixture was filtered, cooled to 3°C and add 0.1 M NaOH to bring the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated in high vacuum at 35°C, receiving a yellow precipitate. The product was then purified by chromatography with reversed-phase column with resin NR. First column elute with deionized water (2 l) and later a mixture of 10% CAN:water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone and filtered. Dried. Yield: 50 mg, 18% in the form of yellow crystals, TPL 198°C. (M+H) 411.

1H NMR (DMSO-d6) δ d of 2.7 (m, 2H), 2,8 (USM, 2H), 3,4 (m, 2H), and 3.8 (s, 2H), and 6.3 (s, 1H), 6,5 (s, 1H), and 7.1 (s, 1H), 7,28 (s, 1H), and 7.4 (c, 5H).

Example 2

Obtaining the sodium salt of (5R),(6Z)-6-(7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: ethyl ester of imidazo[1,2-a]pyrazin-2-carboxylic acid:

Ethyl-bromopyruvate (62,9 g) are added to a solution of DME (258 ml) 2-aminopyrazine (24.8 g) at room temperature and stirred is for 2.5 hours The reaction mixture was cooled to 0°C and stirred for 30 minutes, obtaining a pale brown precipitate. The precipitate is filtered and washed with Et2O getting pale brown crystals. The suspension of sediment (66,1 g) in EtOH (1,29 l) is heated at boiling point with the return of phlegmy before becoming a clear solution. After boiling with the return of phlegmy for 2 h, the reaction mixture was concentrated under reduced pressure, then mixed with CHCl3and saturated aqueous NaHCO3. The mixture is filtered through a pad of celite and the separated organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute CHCl3-MeOH (99/1˜97/3) and the collected fractions are concentrated under reduced pressure, followed by recrystallization from CHCl3-Et2O. Mentioned in the title compound obtained as bednarova crystals. Output: 10,9 g, 22%).

1H NMR (CDCl3) δ d of 1.46 (t, 3H, J=7.2 Hz), 4,49 (q, 2H, J=7,2 Hz), of 7.96 (d, 1H, J=4,7 Hz), 8,08 (DD, 1H, J=1,2, 4,7 Hz), compared to 8.26 (s, 1H), of 9.21 (d, 1H, J=1.2 Hz).

Stage 2: hydrochloride ethyl ester 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylic acid:

0,46 M HCl - EtOH (169 ml) and 10% Pd-C (50% moisture) (1,37 g) are added to a solution in EtOH (546 ml), ethyl ether complex, imidazo[1,2-a]pyrazin-2-carboxylic key is lots (of 13.7 g). The mixture hydrogenizing under pressure H240 psi at room temperature for 15 hours, the Reaction mixture was filtered and Pd-C was washed with EtOH. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute CHCl3-MeOH (9/1˜2/1). Specified in the title compound obtained as brown crystals, Yield: 10.4 g, 63%.

1H NMR (CDCl3) δ D. to 1.38 (t, 3H, J=7,1 Hz), 3,90 (t, 2H, J=5.7 Hz), and 4.40 (q, 2H, J=7,1 Hz), 4,59 (t, 2H, J=5.7 Hz), 4,80 (s, 2H), to 8.20 (s, 1H).

Stage 3: ethyl ester 7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylic acid:

Et3N (3,44 ml), 37% HCHO aqueous (2,02 ml) and NaBH3CN (1.78 g) are added successively to a solution in MeOH (75 ml) of the hydrochloride of ethyl ether complex 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylic acid (5.2 g) at room temperature and stirred for 3.5 h in nitrogen atmosphere. The mixture was diluted with CH2Cl2and washed with 50% aqueous K2CO3. The organic layer is dried (K2CO3) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of CHCl3-acetone (1/1˜1/2). Specified in the title compound obtained as an orange oil. Output: 2,68 g, 57%).

1H NMR (CDCl3) δ d of 1.37 (t, 3H, J=7,1 Hz), of 2.50 (s, 3H), 2,85 (t, 2H, J=5.5 Hz), of 3.69 (s, 2H), 4,06 (t, 2H, J=5.5 Hz), 4,36 (t, 2H, J=7,1 Hz), 7,52 (s, 1H).

Stage 4: 7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carbaldehyde:

a 1.01 M solution of DIBAL in toluene (13,6 ml) is added to the dry solution in CH2Cl2(86 ml) of ester ethyl 7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylic acid (1.8 g) in a nitrogen atmosphere at -78°C and stirred for 2 h the Mixture was quenched with 1 M HCl. The reaction mixture was filtered through a pad of celite. The filtrate is washed with 50% aqueous K2CO3and the aqueous layer was extracted with CH2Cl2three times. The combined organic layer is dried (K2CO3) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of CHCl3-MeOH (19/1˜9/1). Specified in the title compound 5 obtained as colorless crystals. Output: 591 mg, 42%).

1H NMR (CDCl3) δ d of 2.51 (s, 3H), 2,87 (t, 2H, J=5.5 Hz), 3,70 (s, 2H), 4,10 (t, 2H, J=5.5 Hz), 7,53 (s, 1H), 9,82 (d, 1H, J=1.4 Hz).

Stage 5: 4-nitrobenzyloxy ester (5R,6RS)-6-[(RS)-acetoxy(7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (mixture of diastereoisomers):

7-Methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carbaldehyde (1.19 g) are added to a solution in dry acetonitrile (97 ml) is espagnola MgBr 2(of 4.05 g) in a nitrogen atmosphere at room temperature. Solution in dry THF (97 ml) 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (3,32 g) is added to the mixture, cooled to -20°C and add Et3N (3.0 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture is stirred for 4.5 h at -20°C and treated with acetic anhydride (1,36 ml) in one portion. The reaction mixture is heated to 0°C and stirred for 17 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of CHCl3-acetone (9/1˜2/1). Specified in the header connection receive as a mixture of two diastereoisomers. Red oil. Yield: 1.13 g

1H NMR (CDCl3) δ d of 1.20 (s, 0,81×3H), 2,24 (s, 0,19×3H), 2,48 (s, 3H), 2,80˜2,84 (m, 2H), 3,57˜to 3.67 (m, 2H), 3,97˜was 4.02 (m, 2H), 5,27 (d, 1H, J=13,6 Hz), 5,42 (d, 0,19×1H, J=13,6 Hz), the 5.45 (d, 0,81×1H, J=13,6 Hz), 6,07 (s, 0,19×1H), 6.30-in (C, 0,81×2H), 6,79 (s, 0,19×1H), 6,80 (s, 0,19×1H), 7,02 (0,81×1H), 7,44 (s, 0,19×1H), 7,47 (0,81×1H), 7,60 (d, 0,19×2H, J=8,2 Hz), a 7.62 (d, 0,81#x000D7; 2H, J=8.6 Hz), by 8.22˜compared to 8.26 (m, 2H).

Stage 6: sodium salt of (5R),(6Z)-6-(7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid:

4-Nitrobenzyloxy ester (5R,6RS)-6-[(RS)-acetoxy(7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1,11 g) dissolved in THF (32 ml) and acetonitrile (32 ml). Sizeaction Zn dust (4,46 g) add quickly with 0.5 M phosphate buffer (pH 6.5, 48 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction mixture was filtered through a pad of celite, cooled to 3°C and add 1 M NaOH to bring the pH to 7.5. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated in high vacuum at 35°C. the Concentrate is subjected to column chromatography on resin Diaion HP-21 (20 ml, Mitsubishi Kasei Co. Ltd.) After the adsorption is carried column elute H2O-MeCN (1/0˜95/5). Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid. Output: 417 mg, 65%: TPL 200°C (decomposition).

1H NMR (D2O) δ d 2,32 (s, 3H), 2,79˜of 2.81 (m, 2H), 3,54 (s, 2H), 3,95 (t, 2H, J=5.6 Hz), to 6.39 (s, 1H), 6,85 (s, 1H), 6.87 in (s, 1H), 7,26 (who, 1H).

Example 3

Obtaining the sodium salt of (5R),(6Z)-7-oxo-6-[5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

2-Getapiversion

2-Getapiversion can be obtained according to the procedures in U.S. patent 5629322.

Stage 1: 4-p-nitrobenzenesulfonyl-2-getapiversion

48,7% solution of p-nitrobenzotrifluoride in 1,4-dioxane (10,7 ml) are added to a solution in dichloromethane (110 ml), 2-cefoperazone (2,21 g) and diisopropylethylamine (4.6 ml) at 0°C and stirred for 0.5 h at 0°C. To the reaction mixture are added water (300 ml) and extracted with dichloromethane (3 × 100 ml). The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, elute with a mixture of CHCl3-methanol (30:1) and is listed in the title compound obtained as white solids (7,1 g, quantitative yield).

1H NMR (d, CDCl3) δ 3,42 is-3.45 (m, 2H), 3,74 (t, 2H, J=5.4 Hz), 4,19 (s, 2H), 5,26 (s, 2H), 6,39 (USS, 1H), 7,52 (d, 2H, J=8.6 Hz), 8,24 (d, 2H, J=8.6 Hz).

Stage 2: 5-methoxy-4-p-nitrobenzenesulfonyl-1,2,3,6-tetrahydropyrazin:

Tetrafluoroborate trimethylhexane (97%, 3.7 g) are added to a solution in dry dichloromethane (120 ml) of 4-p-nitrobenzenesulfonyl-2-cefoperazone (6.7 g) at room temperature and displacement is more for 17 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate and the organic layer separated. The aqueous layer was extracted with ethyl acetate (3 × 100 ml)then the combined organic layer was washed with saturated aqueous sodium hydrogen carbonate and a saturated solution of salt. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and indicated in the title compound obtained as a pale brown solid. Exit; 5.7 g, 80.6%of.

1H NMR (d, CDCl3) δ of 3.48 (m, 2H), only 3.57 (m, 2H), 3,70 (s, 3H), of 3.97 (s, 2H), 5,26 (s, 2H), 7,52 (d, 2H, J=8.7 Hz), 8,23 (d, 2H, J=8.7 Hz).

Stage 3: 2-imino-4-p-nitrobenzenesulfonyl-piperazine:

A mixture of 5-methoxy-4-p-nitrobenzenesulfonyl-1,2,3,6-tetrahydropyridine (5.7 g) and ammonium chloride (1.6 g) in dry ethanol (100 ml) is heated to boiling with the return of phlegmy for 4 hours. The reaction mixture was then concentrated under reduced pressure. Dichloromethane (100 ml) is added to the residue and extracted with water (3 × 50 ml)then the combined organic layer was washed with dichloromethane. The aqueous layer was neutralized with 10% aqueous solution of potassium bicarbonate and then extracted with dichloromethane (8 × 50 ml). The combined organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and specified in the header of the connection is of get in the form of a white solid. Yield: 4.9 g, 91.2 per cent.

1H NMR (d, CDCl3) δ 3,49 (USS, 4H), 3,98 (USS, 2H), 5,26 (s, 2H), 7,52 (d, 2H, J=8.6 Hz), 8,23 (d, 2H, J=8.6 Hz).

Stage 4: 7-p-nitrobenzenesulfonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carbaldehyde (9) and 7-p-nitrobenzenesulfonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-carbaldehyde:

A mixture of 2-bromo-3-hydroxypropane (2.8 g), monohydrate p-toluensulfonate acid (33 mg) and 2-propanol (3.5 ml) in cyclohexane (28 ml) is subjected to azeotropic distillation until the temperature of the steam rises to 80°C. the Reaction mixture was concentrated under reduced pressure. The residue is dissolved in dry acetonitrile (30 ml). Solution in dry acetonitrile (310 ml) of 2-imino-4-p-nitrobenzenesulfonyl-piperazine (4.7 g) is added at room temperature. The reaction mixture was stirred at room temperature for 3 h and then the reaction solution is removed in vacuum. The residue is dissolved in ethyl acetate (170 ml) and add triethylamine (2.4 ml), then the reaction mixture is heated to boiling point with the return of phlegmy for 1.5 hours, the Reaction mixture was cooled to room temperature and then add water (170 ml) to the reaction mixture and separate the mixture. The aqueous layer was extracted with dichloromethane (2 × 100 ml). The combined organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The remainder of the paragraph will gorhaut column chromatography on silica gel, elute with a mixture of CHCl3-methanol (50:1) and is listed in the title compound obtained as brown solid (yield: 2.9 g, 51.6 per cent) and get his regioisomer (orange amorphous solid, yield: 0.8 g, 14.9 per cent.

1H NMR (d, CDCl3) δ 3,99 (t, 2H, J=5.4 Hz), 4,14 (t, 2H, J=5.4 Hz), is 4.85 (s, 2H), from 5.29 (s, 2H), 7,54 (d, 2H, J=8.6 Hz), EUR 7.57 (s, 1H), 8,24 (d, 2H, J=8.6 Hz), 9,85 (s, 1H).

Regioisomer1H NMR (d, CDCl3) δ of 3.95 (t, 2H, J=5.4 Hz), of 4.44 (t, 2H, J=5.4 Hz), to 4.87 (s, 2H), from 5.29 (s, 2H), 7,54 (d, 2H, J=8.7 Hz), 7,78 (s, 1H), 8,24 (d, 2H, J=8.7 Hz), 9,71 (s, 1H).

Stage 5: p-nitrobenzyloxy ester (5R)-6-[acetoxy(7-p-nitrobenzenesulfonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid:

Solution in dry acetonitrile (25 ml) 7-p-nitrobenzenesulfonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carbaldehyde (1.6 g) are added to a solution MgBr2(2.2 g) in dry acetonitrile (55 ml) under nitrogen atmosphere at room temperature, the mixture is then stirred for 10 minutes Add the solution in dry THF (80 ml), 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1.8 g), the mixture is cooled to -20°C, then add triethylamine (1.6 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 3 h at -20°C and treated with 4,4-di is ethylaminoethanol (58,3 mg) and acetic anhydride (0,89 ml) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. To the reaction mixture is added 10% aqueous citric acid solution (320 ml) and the aqueous layer was extracted with ethyl acetate (3 × 160 ml). The organic layer is washed with water, saturated sodium hydrogen carbonate solution and saturated salt solution, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, elute with a mixture of CH2Cl2-acetone (20:1) and specified in the header connection receive as a mixture of two diastereoisomers (81:19, brown foamy amorphous solid. Yield: 2.1 g, 59.9 per cent.

1H NMR (d, CDCl3) δ a 2.01 (s, 2,43H), 2,24 (s, 0,57H), 3,93-of 3.96 (m, 2H), was 4.02-of 4.05 (m, 2H), 4,74 was 4.76 (m, 2H), 5,28 (d, 1H, J=13.5 Hz), 5,28 (s, 2H), of 5.45 (d, 1H, J=13.5 Hz), 6,07 (s, 0,19H), of 6.29 (s, 0,81H), of 6.31 (s, 0,81H), to 6.80 (s, 0,19H), 6,83 (s, 0,19H), was 7.08 (s, 0,81H), the 7.43 (s, 0,19H), 7,46 (s, 0,81H), 7,54 (d, 2H, J=8.6 Hz), to 7.61 (d, 2H, J=8,8 Hz), 8,24 (d, 4H, J=8,3 Hz).

Stage 6: sodium salt of (5R),(6Z)-7-oxo-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid:

p-Nitrobenzyloxy ester (5R)-6-[acetoxy(7-p-nitrobenzenesulfonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (2.0 g) dissolved in THF (63 ml). Sizeaction Zn dust (7.9 g) just add 0.5 mol/l is ostatnim buffer (pH 6.5, 63 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction solution is filtered through a pad of celite and the pad washed with water (150 ml) and n-butanol (150 ml). The aqueous layer was separated and then the organic layer extracted with water (2 × 50 ml). The combined organic layer is concentrated to 61 g and subjected to column chromatography on resin Diaion HP-21 (80 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with water and then 5% aqueous solution of acetonitrile. Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid. Yield: 172 mg, 20.1%in: TPL 150°C (decomposition).

1H NMR (d, D2O) δ to 3.02 (t, 2H, J=5.6 Hz), 3,82 (s, 2H), with 3.89 (d, 2H, J=5.6 Hz), 6,38 (s, 1H), 6,84 (s, 1H), 6.87 in (s, 1H), 7,24 (s, 1H); IR (KBr).

Example 4

Obtain (5R,6Z)-6-{[5-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: 5-tert-butyl-2-ethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-in primary forms:

5-tert-butyl-2-ethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-in primary forms receive according to the procedure described in General terms in example 1 (stage 1) from tert-butyl 1-piperidinyloxy the ATA (9,9 g, 50 mmol), POCl3(6.3 g, 40 mmol) and DMF (3.8 g, 50 mmol). Intermediate chloroformyl connection is subjected to interaction with ethylmercaptan (6.0 g, 50 mmol) and Et3N. the Product was then purified column chromatography on SiO2, elwira mixture 3:1 hexane:ethyl acetate. Yield: 8.7 g, 56%. White liquid. (M+H) 312.

Stage 2: tert-butyl 2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-carboxylate:

tert-Butyl 2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate receive according to the procedure described in General terms in example 1 (stage 2). On the basis of 5-tert-butyl-2-ethyl-6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-in primary forms (1.0 g, is 3.21 mmol) and LiAlH4(500 mg, excess) isolate 807 mg (yield 92%) of the alcohol derivative in the form of a white liquid. (M+H) 270.

Stage 3: tert-butyl 2-(formyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate:

tert-Butyl 2-(formyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate receive according to the procedure described in General terms in example 1 (stage 3). On the basis of tert-butyl 2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (1.0 g, 3.7 mmol) in methylene chloride (100 ml) and activated MnO2(5 g, excess) isolate 800 g (yield 81%) of the aldehyde derivative as a brown solid. (M+H) 268.

Stage 4: 2-(formyl)-6,7-dihydrothieno[3,2-c]-5(4H)-pyridine:

2-(formyl)-6,7-dihydrothieno[3,2-c]5(4H)-pyridine get from tert-butyl 2-(formyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (1.0 g, 3.7 mmol)dissolved in CH2Cl2(20 ml), MeOH (90% of 20 ml) and 1 N. HCl in dioxane (10 ml). The reaction mixture was stirred at room temperature for 48 hours In the end the reaction mixture is concentrated to dryness and taken to the next stage without purification. Output: 750 mg (HCl salt, quantitative yield). M+H 168.

Stage 5: 2-formyl[5-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno][3,2-c]pyridine:

To a stirred solution of 2-(formyl)-6,7-dihydrothieno[3,2-c]-5(4H)-pyridine (1.4 g, 5.2 mmol) in DMF (20 ml) is added at room temperature 4-methoxybenzylamine (0,94 g, 6.2 mmol) and N,N-diisopropylethylamine (10 ml, excess). The reaction mixture was stirred for 24 h and quenched with water. The reaction mixture is extracted with chloroform, well washed with water and dried over anhydrous MgSO4. It is filtered and concentrated. The product was then purified column chromatography on SiO2, elwira with ethyl acetate. Pale yellow oil. Yield: 470 mg, 35%. M+H 288.

Stage 6: 4-nitrobenzyl-6-[(atomic charges)[5-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate:

2-Formyl[5-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno][3,2-c]pyridine (574 mg, 2.0 mmol) and a solution in dry THF (20 ml) of 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (772 mg, 2.0 mmol) are added sequentially to crestore in dry acetonitrile (15 ml), anhydrous MgBr 2:O(Et)2(390 mg, 1.5 mmol) in an argon atmosphere at room temperature. After cooling to -20°C add Et3N (2.0 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20°C and treated with acetic anhydride (1.04 million ml) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered through a pad of celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of ethyl acetate:hexane (1:1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers take to the next stage. Pale yellow amorphous solid. Yield: 550 mg, 40%. M+H 714 and 716.

Stage 7: (5R,6Z)-6-{[5-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid:

4-Nitrobenzyl-6-[(atomic charges)[5-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (300 mg, 0.42 mmol) p is straut in THF (20 ml) and acetonitrile (10 ml). Sizeaction Zn dust (5,2 g) add quickly with 0.5 M phosphate buffer (pH 6.5, 28 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction mixture was filtered, cooled to 3°C and add 0.1 M NaOH to bring the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated in high vacuum at 35°C, receiving a yellow precipitate. The product was then purified by chromatography with reversed-phase column with resin NR. First column elute with deionized water (2 l) and later a mixture of 10% CAN:water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone and filtered. Dried. Yield: 50 mg, 18%, as yellow crystals, TPL 127°C. (M+H) 441.

1H NMR (DMSO-d6) δ d of 2.7 (m, 2H), 2,8 (USM, 2H), 3,4 (m, 2H), 3,74 (s, 3H), and 3.8 (s, 2H), and 6.6 (s, 1H), to 6.88 (DD, 2H), 7,14 (s, 1H), 7,24 (DD, 2H), and 7.4 (s, 1H), to 7.59 (s, 1H).

Example 5

Obtaining the sodium salt of (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: hydroiodide 5-methylthio-3,6-dihydro-2H-[1,4]thiazine

Hydroiodide 5-methylthio-3,6-dihydro-2H-[1,4]thiazine get method, which is described in General terms in U.S. patent 5629322.

Stage 2: hydrochloride 3-aminothiophene

Hydroiodide 5-methylthio-3,6-dihydro-2H-[1,4]thiazine (7,1 g) dissolved in 10% aqueous restoe K2CO3(150 ml) and the aqueous layer was extracted with CH2Cl2(5 × 70 ml). The combined organic layer is dried (MgSO4), filtered and concentrated under reduced pressure. Ammonium chloride (1.7 g) is added to the obtained residue in dry ethanol (128 ml) and heated to boiling point with the return of phlegmy for 1 h, the Reaction mixture was cooled to room temperature. The reaction solution is removed in vacuum and receive hydrochloride aminothiazoline in the form of a brown solid (4.3 g, quantitative yield).

1H NMR (d, DMSO-d6) δ a 3.15 (t, 2H, J=5,9 Hz), 3,74 (t, 2H, J=5,9 Hz), 3,83 (s, 2H), 8,97 (USS, 1H), 9,38 (USS, 1H), 9,99 (USS, 1H).

Stage 3: 5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-2-carbaldehyde and 5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-3-carbaldehyde

A mixture of 2-bromo-3-hydroxypropane (7, 4.3 g), monohydrate p-toluensulfonate acid (52 mg) and 2-propanol (5,3 ml) in cyclohexane (43 ml) is subjected to azeotropic distillation until the temperature of the vapor reaches 80°C. the Reaction mixture was concentrated under reduced pressure. The residue is dissolved in dry ethanol (28 ml). The mixture solution in dry ethanol (143 ml) of the hydrochloride of 3-aminothiophene (4.3 g) and 28% solution in methanol methylate the sodium (5.0 ml) is added at room temperature. The reaction mixture was stirred at room temperature for 1 h and then the reaction solution is removed in vacuum. The residue is dissolved in chloroform (128 ml) and add triethylamine (3.6 ml), then the reaction mixture is heated to boiling point with the return of phlegmy for 2.5 hours, the Reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue is dissolved in dichloromethane (300 ml) and washed with 50% aqueous solution of K2CO3(2 × 100 ml). The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, elute with a mixture of CHCl3-acetone (10:1), and receive 5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-2-carbaldehyde (brown solid, 445 mg, 10.3 per cent) and 5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-3-carbaldehyde (brown solid, 872 mg, 20.2 per cent).

5,6-Dihydro-8H-imidazo[2,1-c][1,4]thiazin-2-carbaldehyde:1H NMR (d, CDCl3) δ of 3.07 (t, 2H, J=5.7 Hz), of 3.95 (s, 2H), 4,33 (t, 2H, J=5.7 Hz), 7,55 (s, 1H), 9,83 (s, 1H).

5,6-Dihydro-8H-imidazo[2,1-c][1,4]thiazin-3-carbaldehyde:1H NMR (d, CDCl3) δ 3,05 (t, 2H, J=5.7 Hz), 3,98 (s, 2H), br4.61 (t, 2H, J=5.7 Hz), 7,73 (s, 1H), RS 9.69 (s, 1H).

Stage 4: (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt:

The solution is to dry the m acetonitrile (20 ml) 5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-2-carbaldehyde (392 mg) are added to a solution MgBr 2(1.1 g) in dry acetonitrile (20 ml) under nitrogen atmosphere at room temperature, the mixture is then stirred for 10 minutes a Solution in dry THF (40 ml) of 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1.0 g) is added and the mixture is cooled to -20°C, then add triethylamine (0.8 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 3.5 h at -20°C and treated with 4-dimethylaminopyridine (30 mg) and acetic anhydride (of 0.44 ml) in one portion. The reaction mixture is heated to 0°C and stirred for 14 h at 0°C. To the reaction mixture is added 10% aqueous citric acid solution (240 ml) and the aqueous layer was extracted with ethyl acetate (3 × 100 ml). The combined organic layer washed with water, saturated sodium hydrogen carbonate solution and saturated salt solution, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The remainder of the roughly purified column chromatography on silica gel, elute with a mixture of CH2Cl2-acetone (50:1) and the crude p-nitrobenzyl ester (5R)-6-[acetoxy(5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid obtained as a solid substance.

Received the specified solid clear to lodochnoy chromatography on SiO 2, elwira a mixture of 50% ethyl acetate:hexane. The obtained pale yellow solid was dissolved in THF (17 ml). Sizeaction Zn dust (2.2 g) just add 0.5 mol/l phosphate buffer (pH 6.5, 17 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction solution is filtered through a pad of celite and the pad washed with water (40 ml) and n-butanol (30 ml). The aqueous layer was separated and then the organic layer is extracted with 0.5 mol/l phosphate buffer (pH 6.5, 2 × 10 ml). The combined organic layer is concentrated to 23 g, was added 1 mol/l NaOH to bring the pH to 7.25, and subjected to column chromatography on resin Diaion HP-21 (30 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with water and then with 10% aqueous solution of acetonitrile. The combined active fractions are concentrated in a high vacuum at 35°C and lyophilized, receiving sodium salt of (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid as a yellow amorphous solid (168 mg, 20.9 percent). TPL 135°C (decomposition).

1H NMR (d, D2O) δ 3,00 (t, 2H, J=5.7 Hz), 3,80 (AB, 2H, J=16,7, to 18.1 Hz), 4,19 (t, 2H, J=5.7 Hz), 6,44 (d, 1H, J=0.8 Hz), 6.89 in (s, 1H), 6,93 (s, 1H), 7,29 (s, 1H); M+H=322.

Example 6

Obtaining the sodium salt of (5R),(6Z)-6-(6,7-dihydr the-5H-pyrrolo{1,2-a]imidazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carbaldehyde

28% sodium Methoxide (5,26 g) are added to a solution in EtOH (250 ml) hydrochloride 4,5-dihydro-3H-pyrrol-2-ylamine (3,27 g) at room temperature. After stirring for 5 min at room temperature add to the mixture of 2-bromo-3-propoxyphenyl (5,79 g) at room temperature, then the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was brought to dryness in vacuum. The residue is dissolved in CHCl3(300 ml) and add triethylamine (3.8 ml). The mixture is heated to boiling with the return of phlegmy for 3 hours. The reaction mixture is cooled to room temperature, washed with 50% K2CO3, dried over anhydrous K2CO3, filtered and evaporated under reduced pressure. The residue is subjected to column chromatography on silica gel, elute with a mixture of CHCl3-acetone (2:1) and receive 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carbaldehyde (41%, 1.51 g) as a pale yellow solid.

1H NMR (d, CDCl3) δ 2,62 is 2.7 (m, 2H), 2,90-to 2.94 (m, 2H), 4,07 (t, 2H, J=7,2 Hz), to 7.59 (s,1H), 9,80 (s, 1H).

Stage 2: (5R),(6Z)-6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt

6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carbaldehyde (1,36 g) are added to a solution in dry acetonitrile (55 ml) anhydrous MgBr 2(5,64 g) in an argon atmosphere at room temperature. Solution in dry THF (155 ml) 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (3,86 g) is added to the mixture, cooled to -20°C and add Et3N (4,18 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 3 h at -20°C and treated with acetic anhydride (1.89 ml) and DMAP (370 mg) in one portion. The reaction mixture is heated to 0°C and stirred for a 14.5 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 1 M aqueous citric acid solution, saturated sodium hydrogen carbonate solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered. The filter is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is dissolved in THF (166 ml) and acetonitrile (77 ml). Sizeaction Zn dust (23,2 g) add quickly with 0.5 M phosphate buffer (pH 6.5, 243 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction mixture was filtered, cooled to 3°C and add 1 M NaOH to bring the pH to 8. The filtrate is washed with ethyl acetate and the aqueous layer was separated. Again add 1 M NaOH to the aqueous layer to bring the pH to 8. Received see what camping was concentrated in high vacuum at 35° C. the Concentrate is subjected to column chromatography on resin Diaion HP-21 (20 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with a mixture of H2O-MeCN (1/0˜9/1)to give purified active fractions of sodium salt of (5R),(6Z)-6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-ylmethylene)-7-oxo-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (681 mg, 24%, pH 7.8). TPL 190°C (decomposition).

1H NMR (d, D2O): δ 2,48-of 2.56 (m, 2H), 2,74-and 2.79 (m, 2H), 3,94-to 3.99 (m, 2H), 6,47 (d, 1H, J=0.7 Hz), 6,94 (s, 1H), 6,95 (s, 1H), was 7.36 (s, 1H); (M+H) 291.

Example 7

Obtaining the sodium salt of (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: morpholine-3-one

Morpholine-3-one is obtained by the method in U.S. patent 5349045.

Stage 2: morpholine-3-tion

A mixture of morpholine-3-one (4.7 g) and Lawesson reagent (10.3 g) in dry THF (94 ml) is heated to boiling with the return of phlegmy for 1.5 hours, the Reaction mixture was cooled to room temperature and the reaction solvent is removed in vacuum. The residue is subjected to column chromatography on silica gel and elute with a mixture of CHCl3-methanol (50:1)to give yellow solid. Recrystallization of the crude PR the product from hexane-ethyl acetate gives specified in the header (4.0 g, 72,2%) as a yellow powder.

1H NMR (CDCl3) δ of 3.45 (t, 2H, J=5,1 Hz), 3,91 (t, 2H, J=5,1 Hz), 4,55 (s, 2H).

Stage 3: 5-methylthio-3,6-dihydro-2H-[1,4]oxazin

A mixture of morpholine-3-thione (4.7 g) and under the conditions (13 ml) in dry CH2Cl2(140 ml) was stirred at room temperature for 15 hours, the Reaction mixture was filtered and the solid is washed with CH2Cl2. The obtained solid substance was dissolved in 50% aqueous solution of K2CO3(150 ml) and the aqueous layer was extracted with CH2Cl2(8 × 100 ml). The combined layer of CH2Cl2dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and specified in the header obtained as a pale yellow oil (3.6 g, 67,8%).

1H NMR (CDCl3) δ 2,32 (s, 3H), 3,71-3,74 (m, 4H), 4,14-to 4.15 (m, 2H).

Stage 4: hydrochloride 3-aminomorpholine

A mixture of 5-methylthio-3,6-dihydro-2H-[1,4]oxazine (3.6 g) and ammonium chloride (1.5 g) in dry ethanol (136 ml) is heated to boiling with the return of phlegmy for 1 h, the Reaction mixture was cooled to room temperature. The reaction solvent is removed in vacuum and is listed in the title compound obtained as a pale brown solid (3.6 g, 97.7 percent).

1H NMR (DMSO-d6) to 3.34 (m, 2H), 3,86 (t, 2H, J=5,2 Hz), 4,47 (s, 2H).

Stage 5: 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-carbaldehyde (9) and 5,6-dihydro-8H-imidazo[2,1-c]1,4]oxazin-3-carbaldehyde

A mixture of 2-bromo-3-hydroxypropane (4.1 g), monohydrate p-toluensulfonate acid (52 mg) and 2-propanol (5,2 ml) in cyclohexane (42 ml) is subjected to azeotropic distillation until the temperature of the vapor reaches 80°C. the Reaction mixture was concentrated under reduced pressure. The residue is dissolved in dry ethanol (50 ml). The mixture solution in dry ethanol (200 ml) of the hydrochloride of 3-aminomorpholine (3.4 g) and 28% solution of sodium methylate in methanol (4.8 g) is added at room temperature. The reaction mixture was stirred at room temperature for 2 h and then the reaction solvent is removed in vacuum. The residue is dissolved in chloroform (125 ml) and add triethylamine (3.5 ml), then the reaction mixture is heated to boiling point with the return of phlegmy within 2 hours the Reaction mixture is cooled to room temperature and then concentrated under reduced pressure. The residue is dissolved in dichloromethane (300 ml) and washed with 50% aqueous solution of K2CO3(2 × 100 ml). The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel and elute with a mixture of CHCl3-acetone (4:1), obtaining specified in the header (pale orange solid, 1.4 g, 36.3 per cent) and other regioisomer (pale orange solid, 609 mg, 16.1 per cent).

Desirable is not already installed: 1H NMR (CDCl3) δ 4,08-to 4.15 (m, 4H), 4,88 (s, 2H), 7,58 (s, 1H), 9,85 (s, 1H).

Unwanted regioisomer:1H NMR (CDCl3) δ 4,06 (t, 2H, J=5,2 Hz), and 4.40 (t, 2H, J=5,2 Hz), the 4.90 (s, 2H), of 7.75 (s, 1H), 9,72 (s, 1H).

Stage 6: (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt

Solution in dry acetonitrile (66 ml) 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-carbaldehyde (1.2 g) are added to a solution MgBr2(3.6 g) in dry acetonitrile (66 ml) in nitrogen atmosphere at room temperature, the mixture is then stirred for 10 minutes a Solution in dry THF (132 ml) p-nitrobenzyl-(5R, 6S)-6-bromine-3-carboxylate (3.4 g) is added and the mixture is cooled to -20°C, then add triethylamine (2.8 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 4 h at -20°C and treated with 4-dimethylaminopyridine (100 mg) and acetic anhydride (1.5 ml) in one portion. The reaction mixture is heated to 0°C and stirred for 18 h at 0°C. To the reaction mixture is added 10% aqueous citric acid solution (1 l) and the aqueous layer was extracted with ethyl acetate (3 × 500 ml). The combined organic layer washed with water, saturated sodium hydrogen carbonate solution and saturated salt solution, dried (MgSO4) and filtered. The filtrate kontsentriruitesi reduced pressure and the crude p-nitrobenzyl ester (5R)-6-[acetoxy(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid obtained as a brown amorphous solid.

Sizeaction Zn dust (14 g) just add 0.5 mol/l phosphate buffer (pH 6.5, 72 ml) to a solution in THF (72 ml) p-nitrobenzylamine of ester (5R)-6-[acetoxy(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2.5 h at room temperature. The reaction solution is filtered through a pad of celite and the pad washed with water (170 ml) and n-butanol (170 ml). The aqueous layer was separated and then the organic layer is extracted with 0.5 mol/l phosphate buffer (pH 6.5, 2 × 50 ml). The combined organic layer is concentrated to 90 g, was added 1 mol/l NaOH to bring the pH to 7.5, and subjected to column chromatography on resin Diaion HP-21 (120 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with water and then 5% aqueous solution of acetonitrile. The combined active fractions are concentrated in a high vacuum at 35°C and lyophilized, getting listed in the title as a yellow amorphous solid (756 mg, 29.1 percent). TPL 130°C (decomposition).

1H NMR (DMSO-d6) δ 3,98-4,01 (m, 2H), 4.04 the-4,07 (m, 2H), 4,74 (AB, 2H, J=15,3, 22.9 Hz), 6,40 (d, 1H, J=0.8 Hz), 6,55 (s, 1H), 6,95 (d, 1H, J=0.6 Hz), 7,54 (s, 1H); IR (KBr) 3412, 1741, 1672, 1592, 1549 cm-1; λmax(H2O) 304 nm.

Primer

Obtaining the sodium salt of (5R),(6Z)-6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: ethyl ester of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid

Specified in the header of the connection receives the same way as Ranganathan and employees (Indian J. Chem. 1991, 30, 169-175).

Stage 2: (5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-ylmethanol

MeOH (2,73 ml) are added to a solution in THF (180 ml) LiBH4(1.63 g) in a nitrogen atmosphere at room temperature and then to suspension add ethyl ester of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid (8,11 g) and stirred for 2 h at 40°C. the Mixture is quenched with a 1 mol/l HCl at pH 1 and stirred for 1 h at room temperature. Solid K2CO3add to the solution to bring the pH to 8 and the mixture is extracted with AcOEt. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure, obtaining mentioned in the title compound as brown crystals (4,87 g, 78%).

1H NMR (CDCl3) δ 2,44 (t, 1H, J=5.8 Hz), 2,54-2,62 (m, 2H), 2,87 (t, 2H, J=7.4 Hz), 4,10 (t, 2H, J=7,2 Hz), 4,63 (d, 2H, J=5.8 Hz), 5,96 (s, 1H).

Stage 3: 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbaldehyde

MnO2(activated) (24.4 g) are added to a solution in CHCl3(350 ml) of (5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-yl)methane is La (4,87 g) and boil with the return of phlegmy for 1 h in nitrogen atmosphere. The reaction mixture was filtered through a pad of celite. The volume of the filtrate reduced under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of n-hexane-AcOEt (1/1-1/2). Specified in the title compound obtained as a yellow oil (4.35 g, 91%).

1H NMR (CDCl3) δ 2,63-a 2.71 (m, 2H), 2.95 and (t, 2H, J=7.4 Hz), 4,22 (t, 2H, J=7.4 Hz), of 6.52 (s, 1H), of 9.89 (s, 1H).

Stage 4: (5R),(6Z)-6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt

5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbaldehyde (1,36 g) are added to a solution in dry acetonitrile (148 ml) of anhydrous MgBr2(5,52 g) in a nitrogen atmosphere at room temperature. Solution in dry THF (148 ml) of 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (content of 97%) (3,97 g) is added to the mixture, cooled to -20°C and add Et3N (4,18 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 4 h at -20°C and treated with acetic anhydride (1.89 ml) and DMAP (123 mg) in one portion. The reaction mixture is heated to 0°C and stirred for 14 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, the ode and saturated salt solution. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure.

The residue is dissolved in THF (106 ml) and acetonitrile (49 ml). Sizeaction Zn dust (22,5 g) add quickly with 0.5 M phosphate buffer (pH 6.5, 155 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room temperature. The reaction mixture was filtered through a pad of celite. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was cooled to 3°C and add 1 M NaOH to bring the pH to 8.0. The mixture was concentrated in high vacuum at 35°C. the Concentrate is subjected to column chromatography on resin Diaion HP-21 (79 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with a mixture of H2O-MeCN (1/0-9/1). Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (848 mg, 29%, a pH of 7.1). TPL 190°C (decomposition).

1H NMR (D2O) δ 2,49 (m, 2H), 2,78 (t, 2H, J=7.4 Hz), was 4.02 (t, 2H, J=7.4 Hz), 6,01 (s, 1H), 6,29 (s, 1H), 6.90 to (s, 2H).

Example 9

Obtaining the sodium salt of (5R),(6Z)-7-oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: tetrahydropyrazino[1,2-c][1,2,3]oxadiazole

Kontsentrirovano the Yu HCl (1,96 ml) and NaNO 2(2.2 g) are added to a solution of H2O (21 ml) DL-pipecolinic acid (3.04 from g) in a nitrogen atmosphere at 0°C and stirred for 1 h, the Solution extracted with CH2Cl2and the organic layer was washed with a saturated solution of salt. The mixture is dried over Na2SO4and concentrate under reduced pressure to give crude (2RS)-1-nitrosopiperidine-2-carboxylic acid as pale yellow crystals.

Triperoxonane anhydride (1,93 g) are added to a solution in THF (92 ml) of the crude (2RS)-1-nitrosopiperidine-2-carboxylic acid in a nitrogen atmosphere at 0°C and stirred for 5 h at 0°C and for 2 h at room temperature. The solution is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of n-hexane-AcOEt (1/1-0/1). Specified in the title compound obtained as colorless crystals (1.10 g, 33%).

1H NMR (CDCl3) δ 1,93 of 1.99 (m, 2H), 2,08-of 2.15 (m, 2H), 2,65 (t, 2H, J=6.5 Hz), 4.26 deaths (t, 2H, J=6,1 Hz).

Stage 2: ethyl ester 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid

Ethylpropyl (804 mg) are added to a solution in o-xylene (15 ml) tetrahydropyrazino[1,2-c][1,2,3]oxadiazole (1.04 g) in a nitrogen atmosphere and boil with the return of phlegmy for 16 hours the Solution is concentrated under reduced pressure. The residue is subjected to column chromatography is as silica gel, then the column elute with a mixture of n-hexane-AcOEt (2/1-1/1). Specified in the title compound obtained as a yellow oil (871 mg, 65%) and ethyl ester 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid obtained as a yellow oil (345 mg, 26%).

1H NMR (CDCl3) δ of 1.39 (t, 3H, J=7,1 Hz), 1,84 is 1.91 (m, 2H), 2,02-of 2.09 (m, 2H), 2,82 (t, 2H, J=6.4 Hz), 4,22 (t, 2H, J=6.2 Hz), 4,39 (q, 2H, J=7,1 Hz), 6,53 (s, 1H).

Stage 3: (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-yl)methanol

MeOH (0,29 ml) are added to a solution in THF (19 ml) LiBH4(content 90%) (174 mg) in a nitrogen atmosphere at room temperature, then to suspension add ethyl ester 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid (862 mg) and stirred for 1 h at room temperature and 1.5 h at 40°C. the Mixture is quenched with a 1 mol/l HCl at pH 1 and stirred for 1 h at room temperature. Solid K2CO3add to the solution to bring the pH to 8 and the mixture is extracted with AcOEt. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure, obtaining mentioned in the title compound as a pale yellow oil (691 mg, 95%).

1H NMR (CDCl3) δ 1,80-to 1.87 (m, 2H), 1,98-2,05 (m, 2H), 2,77 (t, 2H, J=6.4 Hz), 2,81-2,84 (ush., 1H), 4.09 to (t, 2H, J=6,1 Hz), to 4.62 (d, 2H, J=5.3 Hz), 5,96 (s, 1H).

Stage 4: 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-carbaldehyde

MnO2(activities is) (3,36 g) are added to a solution in CHCl 3(44 ml) (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-yl)methanol (673 mg) and boil with the return of phlegmy for 1 h in nitrogen atmosphere. The reaction mixture was filtered through a pad of celite. The volume of the filtrate reduced under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of n-hexane-AcOEt (2/1-1/2). Specified in the title compound obtained as a pale yellow oil (510 mg, 77%).

1H NMR (CDCl3) δ 1,90 (m, 2H), 2,10 (m, 2H), 2,84 (t, 2H, J=6.4 Hz), to 4.23 (t, 2H, J=6.2 Hz), of 6.52 (s, 1H), 9,92 (s, 1H).

Stage 5: (5R)(6Z)-7-oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt

4,5,6,7-Tetrahydropyrazolo[1,5-a]pyridine-2-carbaldehyde (483 mg) are added to a solution in dry acetonitrile (48 ml) anhydrous MgBr2(1,81 g) in a nitrogen atmosphere at room temperature. Solution in dry THF (48 ml) 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (content of 97%) (1.28 g) is added to the mixture, cooled to -20°C and add Et3N (1.35 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20°C and treated with acetic anhydride (0,61 ml) and DMAP (40 mg) in one portion. The reaction mixture is heated to 0°C and stirred is for 16 h at 0° C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, water and saturated salt solution. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure.

The residue is dissolved in THF (35 ml) and acetonitrile (16 ml). Sizeaction Zn dust (7,43 g) add quickly with 0.5 M phosphate buffer (pH 6.5, 51 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room temperature. The reaction mixture was filtered through a pad of celite. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was cooled to 3°C and add 1 M NaOH to bring the pH to 8.0. The mixture was concentrated in high vacuum at 35°C. the Concentrate is subjected to column chromatography on resin Diaion HP-21 (105 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with a mixture of H2O-MeCN (1/0-85/15). Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (427 mg, 41%, a pH of 7.7). TPL 190°C (decomposition).

1H NMR (D2O) δ 1,67-1,71 (m, 2H), 1.85 to 1,89 (m, 2H), 2,64 (t, 2H, J=6.3 Hz), of 3.97 (t, 2H, J=6,1 Hz), 5,97 (s, 1H), and 6.25 (s, 1H), 6,85 (s, 1H), to 6.88 (s, 1H).

Example 10

Obtaining the sodium salt of (5R),(6Z)-6-(7-m is Teal-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: 5-methoxy-1-methyl-3,6-dihydro-1H-pyrazin-2-he

Specified in the header of the connection receives the same way as S.Rajappa and B.G.Advani (Tetrahedron. 1973, 29, 1299-1302).

Stage 2: 5-amino-1-methyl-3,6-dihydro-1H-pyrazin-2-he

A mixture of 5-methoxy-1-methyl-3,6-dihydro-1H-pyrazin-2-she (2.3 g) and ammonium chloride (936 mg) in dry ethanol (32 ml) was stirred at room temperature for 1 h and then boiled with the return of phlegmy within 2 hours the Reaction mixture is cooled to room temperature and evaporated under reduced pressure. The residue is triturated with chloroform at room temperature for 30 minutes the Precipitate is filtered off and dried in vacuum. Hydrochloride 5-amino-1-methyl-3,6-dihydro-1H-pyrazin-2-get it in the form of a pale brown powder (1.7 g, 66%).

A solution of the hydrochloride 5-amino-1-methyl-3,6-dihydro-1H-pyrazin-2-it (662 mg) in methanol (10 ml) supplemented with 10% aqueous solution of potassium bicarbonate at 0°and then stirred for 40 min at 0°C. the Mixture is concentrated under reduced pressure. The residue is triturated with chloroform (18 ml) and methanol (2 ml) at room temperature for 30 minutes the Precipitate is filtered off and dried in vacuum. The compound obtained as pale brown powder (515 mg, quantitative yield).

1H NMR (DMSO-d6) δ is 2.88 (s, 3H), of 3.94 (s, 2H), 4,42 (s, 2H).

Stage 3: 7-methyl-6-oxo-5,6,7,8-tetrahydro is imidazo[1,2-a]pyrazin-2-carbaldehyde and 7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-carbaldehyde

A solution of 2-bromo-3-isopropoxypyridine (1.3 g) in dry acetonitrile (60 ml) are added to a solution of 5-amino-1-methyl-3,6-dihydro-1H-pyrazin-2-it (782 mg) in dry acetonitrile (60 ml) at room temperature. The reaction mixture was stirred at room temperature for 20 h, add triethylamine (0.95 ml) and then boiled with the return of phlegmy within 2 hours the Reaction mixture is cooled to room temperature and then evaporated under reduced pressure. The residue is dissolved in chloroform (10 ml) and washed with 50% aqueous solution of K2CO3(10 ml). The aqueous layer was extracted with chloroform. The organic layer is dried (MgSO4) and filtered. The filtrate is evaporated under reduced pressure. The residue is subjected to column chromatography on silica gel and elute with a mixture of CHCl3-MeOH (95:5), receiving specified in the title compound 7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carbaldehyde as a pale yellow solid (541 mg, 49.1 per cent) and regioisomer 7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-carbaldehyde as a pale yellow solid (128 mg, 11.6 percent).

7-Methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carbaldehyde:1H NMR (CDCl3) δ 3,17 (s, 3H), and 4.68 (s, 2H), 4,78 (s, 2H), 7,66 (s, 1H), 9,83 (s, 1H).

7-Methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-carbaldehyde:1H NMR (CDCl3) δ and 3.16 (s, 3H), 4,70 (s, 2H), to 5.03 (s, 2), of 7.82 (s, 1H), 9,73 (s, 1H).

Stage 4: (5R,6RS)-6-[acetoxy(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 4-nitrobenzyloxy ester

7-Methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carbaldehyde (319 mg) are added to a solution in dry acetonitrile (32 ml) anhydrous MgBr2(786 mg) in a nitrogen atmosphere at room temperature. Solution in dry THF (32 ml) of 4-nitro-benzyl ether complex (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (687 mg) are added to a mixture, cooled to -20°C and add triethylamine (of 0.60 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 3 h at -20°C and treated with 4-dimethylaminopyridine (44 mg) and acetic anhydride (0.35 ml) in one portion. The reaction mixture is heated to 0°C and stirred for 20 h at 0°C. the Mixture is diluted with ethyl acetate and H2O. After separation of the organic layer the aqueous layer was extracted with ethyl acetate. The organic layers are combined and washed with 5% aqueous citric acid solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then elute with chloroform. The criminal code is mentioned in the title compound obtained as a mixture of diastereoisomers (yellow amorphous solid; 410 mg, 38%).

1H NMR (CDCl3) δ 2,03 (s, 0,7×3H), of 2.09 (s, 0,3×3H)and 3.15 (s, 3H), 4,59-to 4.62 (m, 2H), 4,66 (s, 0,3×2H), 4,67 (s, 0,7×2H), 5,28 (d, 1H, J=13.5 Hz), 5,43 (d, 0,3×1H, J=13.5 Hz), the 5.45 (d, 0,7×1H, J=13.5 Hz), 6,07 (s, 0,3×1H), 6,28 (s, 0,7×1H), 6,32 (s, 0,7×1H), 6,83 (s, 0,3×1H), 6,86 (s, 0,3×1H), 7,10 (s, 0,7×1H), 7,44 (s, 0,3×1H), 7,47 (s, 0,7×1H), 7,60 (l, 0,7×2H, J=8.6 Hz), to 7.61 (d, 0,3×2H, J=8.6 Hz), 8,24 (d, 2H, J=8.6 Hz).

Stage 5: sodium salt of (5R),(6Z)-6-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid and the sodium salt of (5R),(6E)-6-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

4-Nitrobenzyloxy ester (5R,6RS)-6-[acetoxy(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (481 mg) dissolved in THF (6,7 ml) and acetonitrile (3.1 ml). Sizeaction Zn dust (1.92 g) and 0.5 M phosphate buffer (pH 6.5, to 9.9 ml) is added to the mixture. The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction solution is mixed with ethyl acetate and filtered through a pad of celite. The pad is washed with water and the aqueous layer was separated. The aqueous layer was cooled to 3°C and add 1 M NaOH to bring the pH d is an 8.0. The mixture was concentrated in high vacuum at 35°C and lyophilized. The residue is separated by preparative HPLC (Inertsil ODS-2, GL Science Inc., 10 × 250 mm, 0.05 mol/l phosphate buffer (pH 7,1):CH3CN = 93:7, 4,0 ml/min). The separated fractions of sodium salt of (5R),(6Z)-6-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid and sodium salt of (5R),(6E)-6-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid is cooled to 3°C and add 1 M NaOH to bring the pH to 8.0, respectively. Each solution was concentrated in high vacuum at 35°C. Each concentrate is subjected to column chromatography on resin Diaion HP-21 (60 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with water and then with a mixture of 5% acetonitrile-water. Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, receiving specified in the header connection - sodium salt of (5R),(6Z)-6-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid as a yellow amorphous solid (125 mg, 44.4 per cent TPL 115-117°C (decomposition)and connection - sodium salt of (5R),(6E)-6-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid as a yellow am hego solid (19 mg, 6,7%), respectively.

The compound (5R),(6Z)-6-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt1H NMR (δ, D2O) to 2.99 (s, 3H), of 4.54 (s, 2H), of 4.66 (s, 2H), 6,38 (s, 1H), 6,85 (s, 1H), 6.90 to (s, 1H), 7,30 (s, 1H).

The compound (5R),(6E)-6-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt1H NMR (δ, D2O) to 2.94 (s, 3H), of 4.45 (s, 2H), 4,56 (s, 2H), from 6.22 (s, 1H), 6.48 in (s, 1H), 6,94 (s, 1H), 7,69 (s, 1H).

Example 11

Obtaining the sodium salt of (5R)(6Z)-6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: (3R)-thiomorpholine-3-carboxylic acid

Specified in the header of the connection receives the same way as Shiraiwa and employees (Biosci. Biotechnol. Biochem. 1998, 62, 2382-2387).

Stage 2: 3-oxo-3a,4,6,7 there-tetrahydro-3H-2-oxa-5-thia-1-Aza-7a-ateneonline

NaNO2(3,14 g) are added to a solution of 1 mol/l HCl (33,7 ml) of (3R)-thiomorpholine-3-carboxylic acid (4,96 g) in a nitrogen atmosphere at 0°C and stirred for 0.5 hours, the Solution is extracted with CHCl3(5 times) and the organic layer was washed with a saturated solution of salt. The mixture is dried over MgSO4and concentrate under reduced pressure to give crude (3R)-4-nitrosomorpholine-3-carboxylic acid in the form of pale yellow to the of itallow.

Triperoxonane anhydride (7,07 g) are added to a solution in THF (169 ml) of the crude (3R)-4-nitrosomorpholine-3-carboxylic acid in a nitrogen atmosphere at 0°C and stirred for 3 h at 0°C for 17 h at room temperature. The solution is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of n-hexane-AcOEt (1/1-0/1). Specified in the title compound obtained as pale brown crystals (3,41 g, 64%).

1H NMR (CDCl3) δ a 3.15 (t, 2H, J=5.5 Hz), 3,71 (s, 2H), 4,54 (t, 2H, J=5,5 Hz).

Stage 3: ethyl ester of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-carboxylic acid

Ethylpropyl (2,33 g) are added to a solution in o-xylene (72 ml) of 3-oxo-3a,4,6,7 there-tetrahydro-3H-2-oxa-5-thia-1-Aza-7a-ananiindeua (3,41 g) in a nitrogen atmosphere and boil with the return of phlegmy for 15 hours the Solution is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of n-hexane-AcOEt (2/1-1/1). Specified in the title compound obtained as a yellow oil (3.13 g, 68%) and other unwanted regioisomer ethyl ester of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-3-carboxylic acid obtained as a yellow oil (556 mg, 12%).

1H NMR (CDCl3) δ to 1.31 (t, 3H, J=7,1 Hz), 3.04 from (t, 2H, J=5.7 Hz), 3,81 (s, 2H), 4,32 (q, 2H, J=7,1 Hz), and 4.40 (t, 2H, J=5.7 Hz),is 6.54 (s, 1H).

Stage 4: (6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-yl)methanol

LiBH4(content 90%) (536 mg) and MeOH (0.9 ml) are added to a solution in THF (59 ml) of ester ethyl 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-carboxylic acid (3.13 g) in a nitrogen atmosphere at room temperature and stirred for 3 h at 40°C. the Mixture is quenched with a 1 mol/l HCl at pH 1 and stirred for 1 h at room temperature. Solid K2CO3add to the solution to bring the pH to 8 and the mixture is extracted with AcOEt. The organic layer is dried (K2CO3) and filtered. The filtrate is concentrated under reduced pressure, obtaining mentioned in the title compound as a pale yellow oil (of 2.51 g, quantitative yield).

1H NMR (CDCl3) δ 2,58 (ush., 1H), of 3.07 (t, 2H, J=5.7 Hz), of 3.84 (s, 2H), 4,33 (t, 2H, J=5.7 Hz), 4,63 (d, 2H, J=3,9 Hz), equal to 6.05 (s, 1H).

Stage 5: 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-carbaldehyde

MnO2(activated) (11,46 g) are added to a solution in CHCl3(135 ml) (6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-yl)methanol (2,31 g) and boil with the return of phlegmy for 1 h in nitrogen atmosphere. The reaction mixture was filtered through a pad of celite. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of n-hexane-AcOEt (1/1). Specified in the header connection receive is in the form of pale yellow crystals (1.78 g, 78%).

1H NMR (CDCl3) δ a 3.15 (t, 2H, J=5.8 Hz), 3,90 (s, 2H), 4,48 (t, 2H, J=5.8 Hz), to 6.58 (s,1H), 9,92 (s, 1H).

Stage 6: sodium salt of (5R)(6Z)-6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-carbaldehyde (841 mg) are added to a solution in dry acetonitrile (39 ml) anhydrous MgBr2(1.88 g) in a nitrogen atmosphere at room temperature. Solution in dry THF (39 ml) 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (content of 99.7%) (1,93 g) is added to the mixture, cooled to -20°C and add Et3N (2,79 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 3 h at -20°C and treated with acetic anhydride (0,94 ml) and DMAP (61 mg) in one portion. The reaction mixture is heated to 0°C and stirred for 17 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, water and saturated salt solution. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure.

The residue is dissolved in THF (83 ml) and acetonitrile (39 ml). Sizeaction Zn dust (7,72 g) add quickly with 0.5 M phosphate buffer (pH 6.5, 122 ml). Reaction the first vessel cover with foil, to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room temperature. The reaction mixture was filtered through a pad of celite. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was cooled to 3°C and add 1 M NaOH to bring the pH to 8.0. The mixture was concentrated in high vacuum at 35°C. the Concentrate is subjected to column chromatography on resin Diaion HP-21 (150 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with a mixture of H2O-MeCN (1/0-85/15). Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (371 mg, 22%, pH 8.0). TPL 190°C (decomposition).

1H NMR (D2O) δ 3,03 (t, 2H, J=5.7 Hz in), 3.75 (s, 2H), 4,22 (t, 2H, J=5.7 Hz), 6,07 (s, 1H), 6,27 (s, 1H), 6,86 (s, 1H), 6.89 in (s, 1H).

Example 12

Obtaining the sodium salt of (5R)(6Z)-7-oxo-6-(4H-5-thia-1,6a-diazapentane-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: 3-oxo-3a,4-dihydro-3H,6H-2-oxa-5-thia-1-Aza-6a-azonia-3a-pentalene

Concentrated HCl (15 ml) and NaNO2(16.6 g) are added to a solution of H2O (166 ml) L-thioproline (24.3 g) in a nitrogen atmosphere at 0°C and stirred for 2 hours, the Solution is extracted with CH2Cl2, the organic layer is dried over MgSO4and concentrate under reduced pressure, olucha crude N-nitroso-derivative as a yellow solid.

Triperoxonane anhydride (5.0 ml) are added to a solution in THF (350 ml) of crude N-nitrosation in nitrogen atmosphere at 0°C and stirred for 5 h at 0°C. the Solution is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of n-hexane-AcOEt (1:1). Specified in the title compound obtained as a pale brown solid (4.0 g, 15.1 per cent).

1H NMR (CDCl3) δ Android 4.04 (t, 2H, J=1.7 Hz), of 5.40 (t, 2H, J=1.7 Hz).

Stage 2: ethyl ester 4H-5-thia-1,6a-diazapentane-2-carboxylic acid

Ethylpropyl (3.1 ml) are added to a solution in o-xylene (130 ml) of 3-oxo-3a,4-dihydro-3H,6H-2-oxa-5-thia-1-Aza-6a-azonia-3a-pentalene (4.0 g) under nitrogen atmosphere and boil with the return of phlegmy for 19 hours the Solution is cooled to room temperature and concentrate under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of n-hexane-AcOEt (4:1). Specified in the title compound obtained as yellow solid (2.7 g, 49,3%) and ethyl ester 4H-5-thia-1,6a-diazapentane-3-carboxylic acid obtained as pale yellow crystals (1.2 g, 21.7 per cent).

1H NMR (CDCl3) δ of 1.40 (t, 3H, J=7,1 Hz), 4,11 (d, 2H, J=2.1 Hz), and 4.40 (q, 2H, J=7,1 Hz), 5,24 (t, 2H, J=1.6 Hz), is 6.61 (s, 1H)

Stage 3: (4H-5-thia-1,6a-diazapentane-2-yl)methanol

iBH 4(content 90%) (459 mg) are added to a solution in a simple ether (126 ml) of ester ethyl 4H-5-thia-1,6a-diazapentane-2-carboxylic acid (2.5 g) and MeOH (of 0.77 ml) in nitrogen atmosphere at room temperature, then boiled with the return of phlegmy for 1.5 hours the Mixture was quenched with a 1 mol/l HCl (25 ml) and stirred for 1 h at room temperature. The mixture is neutralized with a saturated solution of sodium bicarbonate and share. The aqueous layer was extracted with dichloromethane (10 × 25 ml). The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute AcOEt. Specified in the title compound obtained as a pale yellow solid (1.7 g, 87.9 per cent).

1H NMR (CDCl3) δ 2,95 (t, 1H, J=5.6 Hz), 4,07 (s, 2H), to 4.62 (d, 2H, J=5,1 Hz), 5,13 (t, 1H, J=1.6 Hz), 6,04 (s, 1H).

Stage 4: 4H-5-thia-1,6a-diazapentane-2-carbaldehyde

Solution in dry dichloromethane (8 ml) DMSO (2.2 ml) is added dropwise to a solution in dry dichloromethane (110 ml) oxalicacid (2.0 ml) at -78°C. the Reaction mixture was stirred for 15 min at the same temperature. Solution in dry dichloromethane (40 ml) (4H-5-thia-1,6a-diazapentane-2-yl)methanol (1.7 g) is added dropwise to the reaction mixture at -78°C and stirring is continued for an additional 15 Minregion mixture was allowed to warm to -45° C and stirred for 1 hour Triethylamine (11.3 ml) is added dropwise and the reaction mixture was allowed to warm to 0°C. After 20 min, add a saturated solution of ammonium chloride (50 ml) and water (100 ml) and carry out the separation. The aqueous layer was extracted with AcOEt (3 × 150 ml). The combined organic layers washed with water (200 ml) and saturated salt solution (200 ml), dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with hexane - AcOEt (1:1). Specified in the title compound obtained as yellow solid (1.7 g, quantitative yield).

1H NMR (CDCl3) δ of 4.13 (s, 2H), 5,26 (d, 2H, J=1.4 Hz), 6,59 (s, 1H), 9,90 (s, 1H).

Stage 5: (5R)(6Z)-7-oxo-6-(4H-5-thia-1,6a-diazapentane-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid, sodium salt

Solution in dry acetonitrile (92 ml) 4H-5-thia-1,6a-diazapentane-2-carbaldehyde (1.7 g) are added to a solution in dry acetonitrile (92 ml) MgBr2(5.0 g) in a nitrogen atmosphere at room temperature, the mixture is then stirred for 10 minutes a Solution in dry THF (184 ml) p-nitrobenzyl-(5R,6S)-6-bromine-3-carboxylate (4.3 g) is added and the mixture is cooled to -20°C, then add triethylamine (7.4 ml) in one portion. The reaction vessel is covered with foil to exclude light. Rea is operating, the mixture is stirred for 3 h at -20° C and treated with 4-dimethylaminopyridine (138 mg) and acetic anhydride (2.1 ml) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. an Aqueous solution of 1 mol/l citric acid (1000 ml) is added to the reaction mixture and the aqueous layer was extracted with ethyl acetate (3 × 400 ml). The combined organic layers washed with water, saturated sodium hydrogen carbonate solution and saturated salt solution, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the crude p-nitrobenzyl ester (5R)-6-[acetoxy(4H-5-thia-1,6a-diazapentane-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid obtained as a brown amorphous solid.

Sizeaction Zn dust (19.3 g) just add 0.5 mol/l phosphate buffer (pH 6.5, 100 ml) to a solution in THF (100 ml) of crude p-nitrobenzyl of ester (5R)-6-[acetoxy(4H-5-thia-1,6a-diazapentane-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2.5 h at room temperature. The reaction solution is filtered through a pad of celite and the pad washed with water (200 ml) and n-butanol (200 ml). The aqueous layer was separated and then the organic layer is extracted with 0.5 mol/l phosphate b is from (pH 6.5, 2 × 50 ml). The combined organic layers are concentrated to 90 g, was added 1 mol/l NaOH to bring the pH to 8.0, and subjected to column chromatography on resin Diaion HP-21 resin (180 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with water and then 15% aqueous solution of acetonitrile. The combined active fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (634 mg, 17.4%and a pH of 7.25). TPL 150°C (decomposition).

1H NMR (D2O) δ 4,00 (s, 2H), 5,09 (s, 2H), 6,14 (s, 1H), 6,36 (s, 1H), 6,91 (s, 1H), 6,92 (s, 1H); IR (KBr) 3381, 1752, 1683, 1600, 1558 cm-1; λmax(H2O) 292, 196 nm.

Example 13

Obtaining the sodium salt of (5R)(6Z)-6-(7H-imidazo{1,2-c]thiazole-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: thiazolidin-4-one

Specified in the header of the connection receives the same way as Marvin M. and Allen R. Harkness. (Tetrahedron Letters. 1994, 35, 6971-6974).

Stage 2: thiazolidin-4-tion

The Lawesson reagent (33,5 g) are added to a solution of thiazolidin-4-it (14.2 g) in dry THF (690 ml) and the reaction mixture is boiled with the return of phlegmy within 2 hours the Mixture is cooled to room temperature and evaporated under reduced pressure. The residue is triturated with a solution of CHCl3:MeOH = 7:3 (65 ml) at room temperature for 30 minutes the Precipitate of otherthrow who live, wash solution CHCl3:n-hexane = 7:3 (15 ml) and dried in vacuum. Thiazolidin-4-tion obtained as pale yellow powder (10.7 g, 65%).

1H NMR (CDCl3) δ 4,08 (s, 2H), 4,70 (s, 2H).

Stage 3: 4-methylthio-2,5-dihydrothiazolo

Methyliodide (28.4 g) are added to the boiling solution of thiazolidin-4-thione (9.5 g) in chloroform (400 ml) and the reaction mixture is boiled with the return of phlegmy for 1.5 hours To the reaction mixture add additional methyliodide (56,8 g) 5 portions at intervals of 30-60 minutes After boiling with the return of phlegmy for 1 h, the reaction mixture was cooled to room temperature. Then add a 10% aqueous solution of potassium bicarbonate (200 ml) and stirred for 15 min at room temperature. After separation of the organic layer the aqueous layer was extracted with CHCl3(100 ml × 3). The organic layers are combined, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and dried in vacuum. After drying specified in the title compound obtained as a brown oil (11,0 g, quantitative yield).

1H NMR (CDCl3) δ of 2.51 (s, 3H), 3,91 (t, 2H, J=3.5 Hz), to 5.21 (t, 2H, J=3.5 Hz).

Stage 4: thiazolidin-4-ylideneamino

A mixture of 4-methylthio-2,5-dihydrothiazolo (10.7 g) and ammonium chloride (6.4 g) in dry ethanol (400 ml) is boiled with the return of phlegmy within 27,5 hours the Reaction with the ect cooled to room temperature and evaporated under reduced pressure. The residue is dissolved in chloroform (300 ml) and 10% aqueous solution of potassium bicarbonate (200 ml), then stirred for 20 min at room temperature. After separation of the organic layer the aqueous layer was extracted with chloroform (100 ml × 5). The organic layers are combined, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and dried in vacuum, obtaining the raw thiazolidin-4-ylideneamino (5.5 g) as a brown solid substance, which is contained in the product, which is ethoxy-derived and 4-methylthio-2,5-dihydrothiazolo, which is the starting material. The relation of these three compounds identified1H-NMR as 61:34:5, respectively.

1H NMR (CDCl3) δ of 3.75 (t, 2H, J=2,8 Hz), equal to 4.97 (t, 2H, J=2,9 Hz).

Stage 5: 7H-imidazo[1,2-c]thiazole-2-carbaldehyde

A solution of 2-bromo-3-isopropoxypyridine (6,9 g) in dry acetonitrile (326 ml) are added to a solution of crude, thiazolidin-4-ylideneamino (3.3 grams) in dry acetonitrile (326 ml) at room temperature. The reaction mixture was stirred at room temperature for a period of 19.5 hours, add triethylamine (4.9 ml) and then boiled with the return of phlegmy within 2 hours the Reaction mixture is cooled to room temperature and then evaporated under reduced pressure. The residue is dissolved in dichloromethane (300 ml) and washed with 50% aqueous solution of hydrocarbo the ATA potassium (20 g). After filtration and separation of the aqueous layer was extracted with dichloromethane (50 ml × 4). The organic layers are combined, dried (MgSO4) and filtered. The filtrate is evaporated under reduced pressure. The residue is subjected to column chromatography on silica gel and elute with a mixture of CHCl3-MeOH (100:3)to give crude 7H-imidazo[1,2-c]thiazole-2-carbaldehyde as a brown solid. The crude product was subjected to recrystallization twice from a mixture of CHCl3-n-hexane (1-th time: 30:5, 2: 30:60) at 0°C, receiving the desired aldehyde as a pale-brown crystals (Yield: 1.84 g, 15%).

1H NMR (CDCl3) δ 4.09 to (t, 2H, J=1.3 Hz), 5,08 (t, 2H, J=1.2 Hz), 7,63 (s, 1H), 9,81 (s, 1H).

Stage 6: (5R)(6Z)-6-(7H-imidazo[1,2-c]thiazole-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt

7H-imidazo[1,2-c]thiazole-2-carbaldehyde (841 mg) are added to a solution in dry acetonitrile (116 ml) anhydrous MgBr2(of 2.93 g) in a nitrogen atmosphere at room temperature. Solution in dry THF (116 ml) 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (content of 99.7%) (of 2.51 g) is added to the mixture, cooled to -20°C and add Et3N (2,20 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 4 h at -20°C and treated with acetic and what hydride (1,26 ml) and DMAP (160 mg) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, water and saturated salt solution. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure.

The residue is dissolved in THF (53 ml) and acetonitrile (25 ml). Sizeaction Zn dust (15.1 g) and 0.5 M phosphate buffer (pH 6.5, 78 ml) is added to the mixture. The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room temperature. The reaction mixture was filtered through a pad of celite. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was cooled to 3°C and add 1 M NaOH to bring the pH to 8.0. The mixture was concentrated in high vacuum at 35°C. the Concentrate is subjected to column chromatography on resin Diaion HP-21 (321 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with a mixture of H2O-MeCN (1/0-9/1). Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (1.1 g, 51%, pH 7.5). TPL 145°C (decomposition).

1H NMR (D2O) δ 3,85 (s, 2H), 4,88 (s, 2H), 6,32 (s, 1H), 6,78 (s, 1H), 6,85 (s, 1H), 7,27 (s, 1H).

Example 14

u> Obtain (5R,6Z)-7-oxo-6-[(4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methylene]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: diethyl 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazole-3,5-in primary forms

To a solution of diethyl-3,5-pyrazolecarboxylate (2.17 g, 10 mmol) in acetonitrile (10 ml) in an atmosphere of nitrogen was added potassium carbonate (2,07 g, 15 mmol) and 2-bromoethoxy-tert-butyldimethylsilyl (2,90 g, 12 mmol). The mixture is stirred while boiling with the return of phlegmy for 18 hours Then cooled to room temperature, diluted with ethyl acetate (20 ml) and filtered through Magnesol. Filter pad elute 2 × 10 ml ethyl acetate and the combined filtrate is evaporated. The residue is dissolved in hexano and passed through a column of silica gel (70 g). After elution of hexane (100 ml) column elute with ethyl acetate. An ethyl acetate eluent is evaporated, getting 3,71 g of colorless oil. MS m/e 371 (MH+).

Stage 2: 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazole-3,5-dimethanol

To a solution of diethyl-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazole-3,5-in primary forms (0.74 g, 2 mmol) in methylene chloride (8 ml) under nitrogen atmosphere add 12 ml of 1.0 M solution of hydride diisobutylaluminum in methylene chloride at 0°C. After stirring at 0°C for 0.5 h the mixture is heated to room temperature for 0.5 hours Then it is ASAT 15 ml of saturated solution of ammonium chloride and extracted with ethyl acetate. The organic extract was washed with saturated salt solution, dried over anhydrous sodium sulfate and evaporated, receiving of 0.44 g of a white solid. TPL 82-83°C; MS m/e 287 (MH+).

Stage 3: 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazole-3,5-dicarbollide

To a stirred solution of 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazole-3,5-dimethanol (1.18 g, 4 mmol) in methylene chloride (20 ml) is added 4-methylmorpholine-N-oxide (2,89 g, 24 mmol) and molecular sieve 4A (4 g). The reaction mixture was stirred at room temperature for 10 min and then treated with perruthenate of tetrapropylammonium (0.15 g, 0.4 mmol). Stirring is continued for 2 hours a Solution of methylene chloride concentrate and diluted with simple ether (40 ml). The mixture is filtered through a pad of silica gel (40 g) and the filter pad elute 2 × 20 ml simple ether. The combined eluent was washed with 1 N. hydrochloric acid and saturated salt solution, dried over anhydrous sodium sulfate and evaporated, getting 0,79 g of a white solid. TPL 63-64°C, MS m/e 283 (MH*).

Stage 4: 4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-carbaldehyde

To a solution of 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazole-3,5-dicarbollide (1,02 g, 6,07 mmol) in THF (30 ml) type of 6.68 ml of 1.0 M solution of tetrabutylammonium fluoride in THF at 0°C. After stirring for 1 h the mixture processing is to see 10 ml of saturated solution of ammonium chloride and extracted with ethyl acetate. The organic solution was washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered through Magnesol and evaporated. Wet sticky substance washed with hexane, dried in vacuum and then dissolved in methylene chloride (20 ml). To this solution was added 4-methylmorpholine-N-oxide (2,89 g, 24 mmol) and molecular sieve 4A (6 g). The mixture is stirred at room temperature for 10 min and then treated with erotemata of tetrapropylammonium (0.11 g, 0.3 mmol). Stirring is continued for 2 hours a Solution of methylene chloride concentrate and diluted with ethyl acetate (40 ml). The mixture is filtered through a pad of silica gel (40 g) and the filter pad elute 2 × 20 ml ethyl acetate. The combined eluent was washed with 1 N. hydrochloric acid and saturated salt solution, dried over anhydrous sodium sulfate and evaporated, receiving of 0.30 g of a white solid. TPL 135-136°C, MS m/e 167 (MH+).

Stage 5: 4-nitrobenzyl-(5R)-6-[(atomic charges)(4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

To a solution of MgBr2(0,46 g, 2,52 mmol) in acetonitrile (13 ml) under nitrogen atmosphere add 4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-carbaldehyde (0.14 g, 0.84 mmol) at room temperature under stirring. Then add a solution of 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo the[3.2.0]hept-2-ene-2-carboxylic acid (0.32 g, 0.84 mmol) in THF (13 ml) and the mixture is cooled to -20°C. Add triethylamine (0.35 ml, 2,52 mmol) and the mixture was stirred at -20°C in the dark for 4 h Then treated with acetic anhydride (0.2 ml, 2.0 mmol) and 4-N,N-dimethylaminopyridine (12 mg, 0.1 mmol) and maintained at 0°C for 18 hours the Mixture is concentrated and the residue is dissolved in ethyl acetate. An ethyl acetate solution is washed with 5% citric acid, saturated sodium bicarbonate solution and saturated salt solution, dried over anhydrous sodium sulfate and evaporated. The crude material is subjected to chromatography on silica gel (EtOAc-CH2Cl2/1:5)to give 0.27 g not quite white solid. TPL 107-110°C, MS m/e 595 (MH+).

Stage 6: (5R,6Z)-7-oxo-6-[(4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

To a solution of 4-nitrobenzyl-(5R)-6-[(atomic charges)(4-oxo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0,22 g, and 0.37 mmol) in THF (15 ml) under nitrogen atmosphere is added 15 ml of phosphate buffer (0.5 M, pH 6.5) and 80 mg of 10% Pd/C. the Mixture hydrogenizing at 40-50 psi for 3 h and then filtered through celite. Filter pad washed with THF and the filtrate is extracted with ethyl acetate. The organic extract is dried over anhydrous magnesium sulfate and evaporated. The rest of the industry is with simple ether, getting 0.07 g yellow solid. MS m/e 320 (MH+).

1H NMR (DMSO-d6) δ 4,55-of 4.57 (m, 2H), 4,76-4,80 (m, 2H), 6,50 (s, 1H), 6,63 (s, 1H), 7,58 (s, 1H), 7,76 (s, 1H).

Example 15

Getting 6-(6,7-dihydro-4H-thieno[3,2-c]Piran-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: Obtain 6,7-dihydro-4H-thieno[3,2-c]Piran-2-carbaldehyde

POCl3(a 3.83 ml, 50 mmol) is added dropwise to a cooled on an ice bath DMF (of 3.85 ml, 50 mmol) for 3 minutes. Add DCM (20 ml) and the bath is lowered when the reaction medium becomes viscous. Reaction support at 23°C for 2 h Then cooled to 0°C. Then 4H-Piran-4-one (5 g, 50 mmol) in 10 ml of DCM is added dropwise within 3 minutes. Reaction support at 0°C for 2 hours the Mixture was poured on a solution of sodium acetate with ice and extracted with DCM (2 × 200). The combined organic layers are dried over magnesium sulfate. Filter the drying agent and concentrate, receiving 5.0 g of product. The compound was dissolved in DCM (200 ml) and added to 6.0 g of ethyl 2-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carbaldehyde and 10 ml of TEA. The mixture is boiled with the return of phlegmy for 18 hours Then washed with water and dried over magnesium sulfate. Then it is filtered, concentrated and subjected to flash chromatogaphy with 20% ethyl acetate in hexane. The collected material was dissolved in 100 ml THF and the EAP is skiwelt LAH (150 ml, 0.5 M in THF) and leave at 23°With 10 minutes. Then it is boiled with the return of phlegmy for 18 hours Extinguish at 23°With the addition of water and at the end of 1 N. HCl, to lighten the mixture. Extracted with ethyl acetate (2 × 200 ml) and the combined organic layers are dried over magnesium sulfate. Filtration and concentration to give 2.3 g of product. The crude material was dissolved in DCM (300 ml) and add manganese dioxide (15 g). The reaction is carried out at 23°C for 0.5 hours Then add 2 × 15 g of oxidant through every half hour. The material is then filtered through a pad of celite and concentrate. Column flash chromatography gives 1,206 g (14% yield) of oily product.

H-NMR: δ 9,84 (s, 1H), 7,41 (s, 1H), 4,74 (s, 2H), 4.00 points (t, 2H, J=5.6 Hz), 2,96 (t, 2H, J=5.6 Hz); MS: 169,1 (M+H).

Stage 2: Obtain 6-(6,7-dihydro-4H-thieno[3,2-c]Piran-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

6,7-dihydro-4H-thieno[3,2-c]Piran-2-carbaldehyde (336 mg, 2 mmol) was dissolved in 20 ml of acetonitrile and then add the magnesium bromide (516 mg, 2 mmol) in an atmosphere of N2. The mixture was stirred at 23°within half an hour. Then 4-nitrobenzyloxy ester of 6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (770 mg, 2 mmol) in 20 ml of THF are injected all at once and the mixture is immediately cooled to -20°C. Then injected triethylamine (1 ml) and the mixture was stirred at -20°for the of three hours. Then inject acetic anhydride (0.4 ml) and the mixture was stirred at 0°C for 18 hours, the Reaction medium is then diluted with 400 ml ethyl acetate and washed with 100 ml of 5% citric acid, 100 ml saturated sodium bicarbonate solution and 100 ml of saturated salt solution. The organic layer is then dried over magnesium sulfate, filtered and concentrated. Column flash chromatography using 20% ethyl acetate in hexane gives 491 mg (41%) of product. This product is then dissolved in 15 ml THF and 15 ml of aqueous phosphate buffer (pH 6.5). The mixture was then exposed to hydrogen at 45 psi for one hour with 0.5 g 10% palladium on carbon. Then it is filtered through a pad of celite and concentrated in vacuo to remove most of THF. The solution is then cooled to zero degrees and alkalinized to pH 8 1 N. sodium hydroxide. Then purify by HPLC with reversed phase using 2 liters of water and then 5% acetonitrile in water. Water is then removed by concentration in vacuum and collect 100 mg (38%) of product. TPL: >250°C.

H-NMR: δ of 7.36 (s, 1H), 7,15 (s, 1H), 6,55 (s, 1H), 6,44 (s, 1H), br4.61 (s, 2H), 3,88 (m, 2H), 2,86 (m, 2H), and 2.27 (m, 2H), USD 1.43 (t, 3H); MS: 320,3 (M-H).

Example 16

Getting 6-(6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: Obtain 6,7-dihydro-4H-thieno[3,2-c]t is operan-2-carbaldehyde

POCl3(as 4.02 ml, 43 mmol) is added dropwise to a cooled on an ice bath DMF (3,34 ml, 43 mmol) for 3 minutes. Add DCM (20 ml) and the bath is lowered when the reaction medium becomes viscous. The reaction medium is supported at 23°C for 2 h Then cooled to 0°With again. Tetrahydrothiopyran-4-one (5 g, 43 mmol) in 10 ml of DCM is then added dropwise over 3 minutes. The reaction medium is supported at 0°C for 2 hours was Diluted with DCM (250 ml) and then washed with 200 ml ice saturated aqueous solution of sodium acetate. The organic layer is dried over sodium sulfate. Filter the drying agent, concentration and column flash chromatography using 10% ethyl acetate in hexane to give 1.3 g (8 mmol) of the product. The compound was dissolved in DCM (100 ml) and add 1.2 ml (11 mmol) of ethyl-2-mercaptoacetate and 1 ml of TEA. The mixture is boiled with the return of phlegmy for 18 hours Then washed with water and dried over magnesium sulfate. Filtration, concentration and flash chromatography with 20% ethyl acetate in hexane to give 1.1 g (11% yield) of product.

H-NMR: δ of 6.68 (s, 1H), to 4.73 (s, 2H), 3,68 (s, 2H), 3.04 from (t, 2H, J=7,6 Hz), 2.91 in (t, 2H, J=7,6 Hz); MS (EI): 185,99 (M+).

1.1 g of ethyl ether complex (4.8 mmol) of 6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylic acid are dissolved in 100 ml of THF and injected LAH (40 ml, 0,5M DMG) and the reaction mixture is left at 23°With 1 minute. Then it is boiled with the return of phlegmy for 18 hours Extinguish at 23°With water (10 ml). The organic layer is decanted and the rest is washed with 20 ml DCM. The combined organic layers dried over sodium sulfate. Filtration, concentration and flash column-chromatography with 10-20% ethyl acetate to give 940 mg of crude product. This crude material was dissolved in DCM (40 ml) and add manganese dioxide (2 grams). The reaction is carried out at 23°within half an hour. The material is then filtered through a pad of celite and concentrate. Column flash chromatography give 320 mg (36%) of product.

H-NMR: δ 9,82 (s, 1H), 7,46 (s, 1H), of 3.56 (s, 2H), 3.15 in (t, 2H, J=7.2 Hz), 2.95 and (t, 2H, J=7,2 Hz); MS (EI): 228,02 (M+).

Stage 2: Obtain 6-(6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carbaldehyde (320 mg, 1,72 mmol) dissolved in 17 ml of acetonitrile and then add apirat magnesium bromide (450 mg, of 1.74 mmol) in an atmosphere of N2. The mixture was stirred at 23°within half an hour. Then inject 4-nitrobenzyloxy ester of 6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (660 mg, 1,72 mmol) in 17 ml of THF all at once and the mixture is immediately cooled to -20°C. then injected triethylamine (1 ml) and the mixture was stirred at -20°C for three hours. Then inject oxycyanide (0.4 ml) and the mixture was stirred at 0° C for 18 hours, the Reaction medium is then diluted with 400 ml ethyl acetate and washed with 100 ml of 5% citric acid, 100 ml saturated sodium bicarbonate solution and 100 ml of saturated salt solution. The organic layer is then dried over magnesium sulfate, filtered and concentrated. Column flash chromatography using 20% ethyl acetate in hexane gives 461 mg (44%) of product. This product is then dissolved in 20 ml THF and 20 ml of aqueous phosphate buffer (pH 6.5). The mixture was then exposed to hydrogen under a pressure of 40 psi for one and a half hours with 0.5 g 10% palladium on carbon. Then filtered through a pad of celite and concentrated in vacuo to remove most of THF. The solution is then cooled to zero degrees and alkalinized to pH 8 1 N. sodium hydroxide. It is then purified by HPLC with reversed phase using 2 liters of water and then 5% acetonitrile in water. Water is then removed by concentration in vacuo and collected 21 mg (8,6%) of product. TPL:>250°C

H-NMR: 7,34 (s, 1H), 7,18 (s, 1H), 6,59 (s, 1H), 6,44 (s, 1H), 3,71 (s, 2H), 2,93 (s, 2H), 2,50 (s, 2H); MS: 338,0 (M+H).

Example 17

Obtain 6-(5-Methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: Receive (5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methanol

Diethyl ester of 6,7-dihydro-4H-ment is about[3,2-c]pyridine-2,5-dicarboxylic acid (46 g, 163 mmol) was dissolved in 200 ml of THF. In the solution injected LAH (1M, THF) 300 ml at 23°C. the whole is stirred at 23°C for 18 hours, the Reaction mixture was quenched with 10 ml of water and dried directly over sodium sulfate. Filtration and concentration to give 29.3 g (160 mmol, 98%) of crude product.

H-NMR: 6,55 (s, 1H), 4,70 (s, 2H), 3,41 (s, 2H), 2,86 (t, 2H, J=5.6 Hz), 2,73 (t, 2H, J=5.6 Hz), of 2.38 (s, 3H); MS: 184,0 (M+H).

Stage 2: Obtain 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carbaldehyde

DMSO (1.7 ml, 24 mmol) in 5 ml of CH2Cl2cooled to -50 - -60°s Oxalicacid (1 ml, 11 mmol) in 20 ml of DCM is then added dropwise within 5 minutes at 50°C. the Mixture was kept at -50°C for 5 minutes and then add 1,67 g (9 mmol) (5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methanol in 20 ml of DCM at 50°and the mixture is stirred for another 15 minutes at 50°C. Then add triethylamine (7 ml) at -50°and after 5 minutes the bath is removed and the mixture was naturally warmed up to 23°C. It was washed with 100 ml of water and extracted with 100 ml of ethyl acetate. The combined organic layers are dried over magnesium sulfate. Filtration, concentration and flash column-chromatography using 0-15% methanol in ethyl acetate to give 736 mg (45% yield) of product.

H-NMR: 9,81 (s, 1H), 7,42 (s, 1H), of 3.56 (s, 2H), 3.00 for (t, 2H, J=5.6 Hz), 2.91 in (t, 2H, J=5.6 Hz), of 2.51 (s, 3H); MS: 182,1 (M+H).

Stage 3: The floor is giving 6-(5-methyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Ethyl ester of 2-formyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid (724 mg, 4 mmol) dissolved in 40 ml of acetonitrile and then add apirat magnesium bromide (1.2 g and 4.65 mmol) in an atmosphere of N2. The mixture was stirred at 23°within half an hour. Then inject 4-nitrobenzyloxy ester of 6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1.54 g, 4 mmol) in 40 ml THF all at once and the mixture is immediately cooled to -20°C. Then injected triethylamine (2 ml) and the mixture was stirred at -20°C for 3 hours Then inject acetic anhydride (0,66 ml) and the mixture was stirred at 0°C for 48 hours Reaction medium is then diluted with 500 ml ethyl acetate and washed with 50 ml of 5% citric acid, 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated salt solution. Other 300 ml of ethyl acetate used for washing each aqueous solution. The combined organic layers dried over sodium sulfate. Filtration, concentration and flash chromatography using 20% ethyl acetate in hexane to give 1.56 g (64% yield) of product. This product is then dissolved in 20 ml THF and 20 ml of aqueous phosphate buffer (pH 6.5). The mixture was then exposed to hydrogen under a pressure of 40 psi for two hours with 0.5 g 10% palladium on carbon. Then it is filtered through a pad of celite and conc who are in vacuum, to remove most of THF. The solution is then cooled to zero degrees and alkalinized to pH 8 1 N. sodium hydroxide. It is then purified by HPLC with reversed phase, using 2 liters of water and then 5% acetonitrile in water. Water is then removed by concentration in vacuum and collect 112 mg (13%) of product. TPL: >250°C.

H-NMR: δ of 7.48 (s, 1H), 7,37 (s, 1H), 7,21 (s, 1H), 7,10 (s, 1H), 3,41 (s, 2H), 2,88 (s, 2H), 2,68 (s, 2H), is 2.37 (s, 3H); MS: 335,0 (M+H).

Example 18

Receipt of ester ethyl 2-(2-carboxy-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-EN-6-ylidenemethyl)-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid

Ethyl ester of 2-formyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid (480 mg, 2 mmol) was dissolved in 20 ml of acetonitrile and then add apirat magnesium bromide (516 mg, 2 mmol) in an atmosphere of N2. The mixture was stirred at 23°within half an hour. Then inject 4-nitrobenzyloxy ester of 6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (770 mg, 2 mmol) in 20 ml of THF all at once and the mixture is immediately cooled to -20°C. Then injected triethylamine (1 ml) and the mixture was stirred at -20°C for 3 hours Then inject acetic anhydride (0.4 ml) and the mixture was stirred at 0°C for 48 hours Reaction medium is then diluted with 200 ml ethyl acetate and washed successively with 50 ml of 5% citric acid, 50 ml of n is casinogo solution of sodium bicarbonate and 50 ml of saturated salt solution. The organic layer is then dried over sodium sulfate. Filtration, concentration and flash chromatography using 20% ethyl acetate in hexane gives 690 mg (50% yield) of product. The fraction of this product (456 mg, 0.69 mmol) is then dissolved in 15 ml THF and 15 ml of aqueous phosphate buffer (pH 6.5). The mixture was then exposed to hydrogen under a pressure of 40 psi for two hours with 0.5 g 10% palladium on carbon. Then it is filtered through a pad of celite and concentrated in vacuo to remove most of THF. The solution is then cooled to zero degrees and alkalinized to pH 8 1 N. sodium hydroxide. It is then purified by HPLC with reversed phase, using 2 liters of water and then 5% acetonitrile in water. Water is then removed by concentration in vacuo and collected 18 mg (5%) of the product. TPL: >250°C.

H-NMR: to 7.35 (s, 1H), 7,24 (s, 1H), is 6.61 (s, 1H), 6,45 (s, 1H), 4,48 (s, 2H), 4,08 (q, 2H, J=7,2 Hz), 3,68 (m, 2H), 2,87 (m, 2H), 1,20 (t, 3H, J=7.2 Hz); MS: 393,0 (M+H).

Example 19

Getting 7-oxo-6-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: Getting 6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-2-carbaldehyde

Cicaplast (6,45 g, 50 mmol) is dissolved in 400 ml of CH2Cl2and then add methyliodide (16 ml, 5 EQ.). The mixture is stirred under nitrogen atmosphere for 18 hours Then treated with 100 the l potassium carbonate (50%, water). The organic layer is then dried over magnesium sulfate. After filtration and concentration gain of 7.3 g of material. This material is dissolved in 300 ml of ethanol and added 2.83 g of ammonium chloride. The mixture is boiled with the return of phlegmy for 1 h Then the solvent is removed in vacuum. Half of the material add 200 ml of ethanol followed by the addition of 1.35 g (25 mmol) of sodium methoxide and 4.8 g (25 mmol) of 2-bromo-3-isopropoxyphenyl and the mixture was stirred at 23°C for 2 h Then the solvent is removed and 200 ml of chloroform added along with 10 ml of triethylamine. The mixture is boiled with the return of phlegmy for 2 h and then cooled to 23°C. the Reaction medium was partitioned between 300 ml of DCM and 2×150 potassium carbonate (50%). The organic layer is dried over magnesium sulfate. After filtration and concentration obtain 2.1 g of oily product.

H-NMR: 9,62 (s, 1H), 7,60 (s, 1H), is 6.61 (s, 1H), 6,45 (s, 1H), 4,58 (s, 2H), 2,96 (2m, H), 1,90 (m, 2H), 1,72 (m, 2H); MS: 164,9 (M+H).

Stage 2: Obtain 7-oxo-6-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

6,7,8,9-Tetrahydro-5H-imidazo[1,2-a]azepin-2-carbaldehyde (1,312 g, 8 mmol) is dissolved in 80 ml of acetonitrile and then add apirat magnesium bromide (2,94 g, 8 mmol) in an atmosphere of N2. The mixture was stirred at 23°within half an hour. Then inject 4-nitroben the silt ester of 6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1,155 g, 3 mmol) in 60 ml THF all at once and the mixture is immediately cooled to -20°C. Then injected triethylamine (4 ml) and the mixture was stirred at -20°C for 4 h and Then acetic anhydride (1 ml) was injected and the mixture was stirred at 0°C for 20 hours, the Reaction medium is then diluted with 500 ml ethyl acetate and washed with 100 ml of 5% citric acid, 100 ml saturated sodium bicarbonate solution and 100 ml of saturated salt solution. The organic layer is then dried over sodium sulfate. Filtration, concentration and flash chromatography using 20% ethyl acetate in hexane gives 800 mg of product. This product is then dissolved in 20 ml THF and 20 ml of aqueous phosphate buffer (pH 6.5). The mixture was then exposed to hydrogen under a pressure of 40 psi for 1 h with 0.5 g 10% palladium on carbon. Then it is filtered through a pad of celite and concentrated in vacuo to remove most of THF. The solution is then cooled to zero degrees and alkalinized to pH 8 1 N. sodium hydroxide. It is then purified by HPLC with reversed phase, using 2 liters of water and then 5% acetonitrile in water. Water is then removed by concentration in vacuum and collect 131 mg (31%) of product. TPL: >250°C.

H-NMR: δ for 7.78 (s, 1H), 7,02 (s, 1H), 6,94 (s, 1H), 6,36 (s, 1H), 3,92 (m, 2H), 2,80 (m, 2H), 1,78 (m, 2H), 1.61 of (m, 2H), and 1.54 (m, 2H); MS: 318,2 (M+H).

Example 20

Getting Natrii the th salt of (5R),(6Z)-6-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: ethyl ester of 7-benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylic acid

Et3N (6,27 ml), PhCHO (4,92 ml) are added successively to a solution in EtOH (81 ml) of the hydrochloride of ethyl ether complex 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylic acid (for 9.47 g) at room temperature and stirred for 3 h under nitrogen atmosphere. Then NaBH3CN (2,97 g) are added to the reaction mixture and stirred for 19 hours the Mixture is filtered through a pad of celite and diluted with CH2Cl2and washed with 50% aqueous solution of K2CO3. The organic layer is dried (K2CO3) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of CHCl3-acetone (1/0˜9/1) and CHCl3-MeOH (19/1˜9/1). Specified in the title compound obtained as pale yellow crystals (4,16 g, 36%).

1H NMR (CDCl3) δ of 1.36 (t, 3H, J=7,1 Hz), 2,87 (t, 2H, J=5,2 Hz), 3,71 (s, 2H, in), 3.75 (s, 2H), 4,01 (m, 2H), 4,34 (q, 2H, J=7,1 Hz), 7,25-7,34 (m, 5H), 7,51 (s, 1H).

Stage 2: 7-benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carbaldehyde

a 1.01 M solution of DIBAL in toluene (1 ml + 0.2 ml + 0.3 ml) are added to a solution in dry CH2Cl2(5 ml) of ester ethyl 7-benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylic acid (283 mg) in a nitrogen atmosphere at -78&x000B0; C and stirred for 1.5 hours the Mixture was quenched with 1 M HCl (5 ml). The reaction mixture was filtered through a pad of celite. The filtrate is washed with 50% aqueous solution of K2CO3and the aqueous layer was extracted with CH2Cl2. The combined organic layer is dried (K2CO3) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of CHCl3-acetone (9/1˜4/1) and CHCl3-MeOH (19/1). Specified in the title compound obtained as colorless crystals (148 mg, 61%).

1H NMR (CDCl3) δ 2,90 (t, 2H, J=5.5 Hz), 3,74 (s, 2H), 3,76 (s, 2H), 4,06 (t, 2H, J=5.5 Hz), 7,28-to 7.35 (m, 5H), 7,53 (s, 1H), 9,80 (s, 1H).

Stage 3: 4-nitrobenzyloxy ester (5R,6RS)-6-[(RS)-acetoxy(7-benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (mixture of diastereoisomers)

7-Benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carbaldehyde (139 mg) are added to a solution in dry acetonitrile (8.7 ml) anhydrous MgBr2(325 mg) in a nitrogen atmosphere at room temperature. Solution in dry THF (8,7 ml) 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (223 mg) are added to a mixture, cooled to -20°C and add Et3N (of 0.24 ml) in one portion. The reaction vessel cover with foil to which SkyCity light. The reaction mixture was stirred for 5 h at -20°C and treated with acetic anhydride (0,11 ml) and DMAP (7 mg) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, water and saturated salt solution. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of n-hexane-AcOEt (3/1-1/1). Specified in the title compound obtained as a mixture of two diastereoisomers (80/20, purple amorphous solid, 233 mg, 61%).

1H NMR (CDCl3) δ 1,99 (s, 0,8×3H), of 2.23 (s, 0,2×3H), 2,83˜2,89 (m, 2H), 3,68 (d, 2H, J=4,9 Hz), 3,71 (s, 2H), 3,94˜4,13 (m, 2H), 5,27 (d, 1H, J=13,6 Hz), 5,41 (d, 0,2×1H, J=13,6 Hz), the 5.45 (d, 0,8×1H, J=13,6 Hz), equal to 6.05 (s, 0,2×1H), 6,28 (s, 0,8×1H), of 6.31 (s, 0,8×1H), 6,790 (C, 0,2×1H), 6,793 (s, 0,2x1H), 7,01 (s, 0,8×1H), 7,27˜of 7.36 (m, 5H), 7,42 (C, 0,2×1H), 7,46 (s, 0,8×1H), to 7.61 (d, 2H, J=8.6 Hz), by 8.22 (d, 2H, J=8.6 Hz).

Stage 4: sodium salt of (5R),(6Z)-6-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

4-Nitrobenzyloxy ester (5R,6RS)-6-[(RS)-acetoxy(7-benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1.27 g) was dissolved in THF (55 ml) and acetonitrile (25 ml). Sizeaction Zn dust (5,08 g) add quickly with 0.5 M phosphate buffer (pH 6.5, 80 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction mixture was filtered through a pad of celite. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was cooled to 3°C and add 1 M NaOH to bring the pH to 8.0. The mixture was concentrated in high vacuum at 35°C. the Concentrate is subjected to column chromatography on resin Diaion HP-21 (79 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with a mixture of H2O-MeCN (1/0-4/1). Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (390 mg, 49%, a pH of 7.7). TPL 180°C (decomposition).

1H NMR (D2O) δ 2,84˜2,95 (m, 2H), 3,61 (d, 2H, J=7,2 Hz), to 3.67 (s, 2H), 3.96 points (t, 2H, J=5.7 Hz), to 6.43 (s, 1H), 6.89 in (s, 1H), 6,93 (s, 1H), 7,28˜7,37 (m, 6H).

Example 21

Obtain (5R,6Z)-7-oxo-6-{[5-(pyridine-3-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-ylmethylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: 2-formyl[5-(pyridine-3-ylmethyl)-4,5,6,7-tetrahydrothieno][3,2-C]pyridine

To a stirred solution of 2-(formyl)-6,7-dihydrothieno[3,2-c]-5(4H)pyridine (1,05 g, 5.2 mmol) in DMF (20 ml), add hydrochlo the ID 3-picolylamine (0,852 g, 5.2 mmol) and N,N-diisopropylethylamine (10 ml, excess) at room temperature. The reaction mixture was stirred for 24 h and quenched with water. The reaction mixture is extracted with chloroform, well washed with water and dried over anhydrous MgSO4. It is filtered and concentrated. The product was then purified column chromatography on SiO2, elwira with ethyl acetate. Pale yellow semi-solid substance. Yield: 800 mg, 59%. M+H 259.

Stage 2: 4-nitrobenzyl-6-[(atomic charges)[5-(pyridine-3-ylmethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

2-Formyl[5-(pyridine-3-ylmethyl)-4,5,6,7-tetrahydrothieno][3,2-c]pyridine (516 mg, 2.0 mmol) and a solution in dry THF (20 ml) of 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (772 mg, 2.0 mmol) are added sequentially to a solution in dry acetonitrile (15 ml), anhydrous MgBr2:O(Et)2(390 mg, 1.5 mmol) in an argon atmosphere at room temperature. After cooling to -20°C add Et3N (2.0 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20°C and treated with acetic anhydride (1.04 million ml) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% is one solution of citric acid, a saturated solution of sodium bicarbonate and a saturated solution of salt. The organic layer is dried (MgSO4) and filtered through a pad of celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of ethyl acetate:hexane (1:1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers take to the next stage. Pale yellow amorphous solid. Yield: 700 mg, 51%. M+H 685 and 687.

Stage 3: (5R,6Z)-6-{[5-(pyridine-3-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

4-Nitrobenzyl-6-[(atomic charges)[5-(pyridine-3-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (686 mg, 1.0 mmol) dissolved in THF (20 ml) and acetonitrile (10 ml). Sizeaction Zn dust (5,2 g) add quickly with 0.5 M phosphate buffer (pH 6.5, 28 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction mixture was filtered, cooled to 3°C and add 0.1 M NaOH to bring the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated in high vacuum at 35°C, the floor is th yellow precipitate. The product was then purified by chromatography with reversed-phase column with resin HP-21. First column elute with deionized water (2 liters) and later a mixture of 10% CAN:water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone and filtered. Dried. Yield: 50 mg, 12%, in the form of yellow crystals. TPL 134-136°C. (M+H)412.

1H NMR (DMSO-d6) δ d of 2.8 (m, 2H), 2,92 (USM, 2H), 3,6 (m, 2H), 3,86 (s, 2H), and 6.3 (s, 1H), 6,41 (s, 1H), 7,17 (s, 1H), 7,29 (s, 1H), 7,35 (m, 1H), and 7.7 (m, 1H), 8,48 (d, 1H), 8,54 (s, 1H).

Example 22

Obtain (5R,6Z)-7-oxo-6-{[5-(pyridine-3-carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid:

Stage 1: 2-formyl[5-(pyridine-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno][3,2-C]pyridine

To a stirred solution of 2-(formyl)-6,7-dihydrothieno[3,2-c]-5(4H)pyridine (606 mg, 3.0 mmol) in DMF (20 ml), add hydrochloride nicotinanilide (531 mg, 3.0 mmol) and N,N-diisopropylethylamine (10 ml, excess) at room temperature. The reaction mixture was stirred for 24 h and quenched with water. The reaction mixture is extracted with chloroform, well washed with water and dried over anhydrous MgSO4. It is filtered and concentrated. The product was then purified column chromatography on SiO2, elwira with ethyl acetate. Pale yellow semi-solid, vases is in. Yield: 600 mg, 73%. M+H 273.

Stage 2: 4-nitrobenzyl-6-[(atomic charges)[5-[pyridine-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)carbonyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

2-Formyl[5-(pyridine-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno][3,2-c]pyridine (400 mg, 1.4 mmol) and a solution in dry THF (20 ml) of 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (772 mg, 2.0 mmol) are added sequentially to a solution in dry acetonitrile (15 ml), anhydrous MgBr2:O(Et)2(619 mg, 2.4 mmol) in an argon atmosphere at room temperature. After cooling to -20°C add Et3N (2.0 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20°C and treated with acetic anhydride (1.04 million ml) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered through a pad of celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of ethyl acetate:Gex is n (1:1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers take to the next stage. Pale yellow amorphous solid. Yield: 300 mg, 30%. TPL 71°C. M+H 701.

Stage 3: sodium salt of (5R,6Z)-6-{[5-(pyridine-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

4-Nitrobenzyl-6-[(atomic charges)[5-(pyridine-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (800 mg, to 1.14 mmol) dissolved in THF (20 ml) and acetonitrile (10 ml). Sizeaction Zn dust (5,2 g) add quickly with 0.5 M phosphate buffer (pH 6.5, 28 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction mixture was filtered, cooled to 3°C and add 0.1 M NaOH to bring the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated in high vacuum at 35°C, receiving a yellow precipitate. The product was then purified by chromatography with reversed-phase column with resin HP-21. First column elute with deionized water (2 liters) and later a mixture of 10% CAN:water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. Yellow solid substance p is washed with acetone and filtered. Dried. Yield: 50 mg, 12%, in the form of yellow crystals. TPL 195°C. (M+H)426.

Example 23

Obtain (5R,6Z)-7-oxo-6-{[5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: 2-formyl[5-(phenylacetyl)-4,5,6,7-tetrahydrothieno][3,2-c]pyridine

To a stirred solution of 2-(formyl)-6,7-dihydrothieno[3,2-c]-5(4H)-pyridine (0,41 mg, 2 mmol) in DMF (20 ml) add phenylacetylene (0.35 mg, 2.2 mmol) and N,N-diisopropylethylamine (10 ml, excess) at room temperature. The reaction mixture was stirred for 24 h and quenched with water. The reaction mixture is extracted with chloroform, well washed with water and dried over anhydrous MgSO4. It is filtered and concentrated. The product was then purified column chromatography on SiO2, elwira with ethyl acetate. White solid. Yield: 510 mg, 89%. M+H 286.

Stage 2: 4-nitrobenzyl-6-[(atomic charges)[5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

2-Formyl[5-(phenylacetyl)-4,5,6,7-tetrahydrothieno][3,2-c]pyridine (340 mg, 1.2 mmol) and a solution in dry THF (20 ml) of 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (390 mg, 1.0 mmol) are added sequentially to a solution in dry acetonitrile (15 ml), anhydrous MgBr2:O(Et)2(310 mg, 1,mmol) in an argon atmosphere at room temperature. After cooling to -20°C add Et3N (2.0 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20°C and treated with acetic anhydride (1.04 million ml) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered through a pad of celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of ethyl acetate:hexane (1:1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers take to the next stage. Pale yellow amorphous solid. Yield: 360 mg, 50%. M+H 713.

Stage 3: (5R,6Z)-6-{[5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

4-Nitrobenzyl-6-[(atomic charges)[5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (300 mg, 0.4 mmol) dissolved in THF (50 ml) and 0.5 M phosphate buffer (pH 6.5, 28 ml). Carry out the hydrogenation under pressure is m 40 psi in the presence of 10% Pd/C (80 mg) for 2 h, in the end, the reaction mixture was filtered through a pad of celite and concentrate. Separated yellow solid was dissolved in ethyl acetate and well washed with water. The organic layer is dried and concentrated. Separated yellow solid triturated with diethyl simple ether and filtered. The yellow solid is washed thoroughly diethyl simple broadcast and receive connection 95% purity. Yield: 160 mg, 91%. Yellow solid, TPL 166-169°C. (M+H) 439.

Example 24

Obtaining the sodium salt of (5R),(6Z)-6-(5,5-dioxo-4,5,6,7-tetrahydro-5λ6-pyrazolo[5,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: 5,5-dioxo-4,5,6,7-tetrahydro-5λ6-pyrazolo[5,1-c][1,4]thiazin-2-carbaldehyde

m-Chloroperbenzoic acid (the content of 69%) (6,36 g) are added to a solution of CH2Cl2(111 ml) of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazin-2-carbaldehyde (1.86 g) at 0°C. the Reaction mixture was stirred for 0.5 h at the same temperature and stirred for 18 h at room temperature. The reaction mixture was concentrated under reduced pressure. The residue is triturated with 10 ml THF and filtered, obtaining crystals. The filtrate is concentrated under reduced pressure. The residue is triturated with 5 ml of THF and filtered, obtaining crystals. The combined crystals are dried under reduced Yes the tion, getting listed in the title compound as colorless crystals (1,96 g, 89%).

1H NMR (CDCl3) δ of 3.60 (t, 2H, J=6,1 Hz), 4,47 (s, 2H), 4,87 (t, 2H, J=6,1 Hz), of 6.71 (s, 1H), 9,94 (s, 1H).

Stage 2: 4-nitrobenzyloxy ester (5R,6RS)-6-[(RS)-acetoxy(5,5-dioxo-4,5,6,7-tetrahydro-5λ6-pyrazolo[5,1-c][1,4]thiazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

5,5-Dioxo-4,5,6,7-tetrahydro-5λ6-pyrazolo[5,1-c][1,4]thiazin-2-carbaldehyde (1,95 g) are added to a solution in dry acetonitrile (112 ml) anhydrous MgBr2(the content of 98%) (5,48 g) in a nitrogen atmosphere at room temperature. Solution in dry THF (112 ml) 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (content of 96.5%) (3.88 g) is added to the mixture, cooled to -20°C and add Et3N (content 99%) (3,79 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 3 h at -20°C and treated with acetic anhydride (content 97%) (3,79 ml) and DMAP (content 99%) (120 mg) in one portion. The reaction mixture is heated to 0°C and stirred for 16 h at 0°C. To the reaction mixture are added acetic anhydride (content 97%) of (0.95 ml) and DMAP (content 99%) (120 mg) in one portion. The mixture is diluted with ethyl acetate and washed with 5% aqueous solution of citric KIS is the notes, a saturated solution of sodium bicarbonate and a saturated solution of salt. The organic layer is dried (MgSO4), and then concentrated under reduced pressure. The residue is purified column chromatography on silica gel (CHCl3: acetone = 19:1 to 4:1), obtaining mentioned in the title compound as a pale brown amorphous solid (diastereomers (8:2), 1.35 g, 22%).

1H NMR (CDCl3) δ 2,07 (s, 3H×0,2 in), 2.25 (s, 3H×0,8), 3,45-of 3.60 (m, 2H), 4,39 (d, 1H, J=17,0 Hz), of 4.44 (d, 1H, J=17,0 Hz), 4,65-4,78 (m, 2H), 5,28 (d, 1H, J=13.5 Hz), 5,43 (d, 1H×0,8, J=13.5 Hz), 5,44 (d, 1H×0,2, J=13.5 Hz), equal to 6.05 (s, 1H×0,8), of 6.20 (s, 1H×0,8), to 6.22 (s, 1H×0,2H), 6,38 (s, 1H×0,2), to 6.39 (s, 1H×0,2), 6,79 (s, 1H×0,8), 7,42 (s, 1H×0,8), 7,44 (s, 1H×0,2), 7,60 (d, 2H, J=8.7 Hz), 8,24 (d, 2H, J=8.7 Hz).

Stage 3: sodium salt of (5R),(6Z)-6-(5,5-dioxo-4,5,6,7-tetrahydro-5λ6-pyrazolo[5,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

4-Nitrobenzyloxy ester (5R,6RS)-6-[(RS)-acetoxy(5,5-dioxo-4,5,6,7-tetrahydro-5λ6-pyrazolo[5,1-c][1,4]thiazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1,33 g) dissolved in THF (19 ml) and acetonitrile (9 ml). Sizeaction Zn dust (5.32 g) add quickly with 0.5 M phosphate buffer (pH 6.5, 27 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room t is mperature. Insoluble material is filtered off and washed with H2O (27 ml). To the filtrate add H2O (27 ml) and washed with ethyl acetate (27 ml) and the aqueous layer was cooled to 3°C and add 1 M HCl to bring the pH to 2.5. The mixture is stirred for 1 d at the same temperature and add H2O (55 ml), then stirred for 4 d at the same temperature. The mixture is stirred for 10 h at room temperature. The resulting mixture is cooled to 3°C and add 1 M NaOH to bring the pH to 8. The mixture was concentrated in high vacuum at 35°C. the Concentrate is treated with column chromatography on resin Diaion HP-21 (80 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with a mixture of H2O-MeCN (1/0-9/1). Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (306 mg, 38%, a pH of 7.4). TPL 180°C (decomposition).

1H NMR (D2O) δ a 3.83 (t, 2H, J=6,1 Hz), and 4.68 (s, 2H), 4.72 in (t, 2H, J=6,1 Hz), 6,37 (s, 1H), 6,40 (s, 1H), 6,95 (s, 1H), 6,98 (s, 1H).

Example 25

Obtaining the sodium salt of (5R),(6Z)-7-oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Piperazine-2-carboxylic acid, dihydrochloride:

Specified in the header of the connection receives the same way as M. T. Wu and employees (Bioorg. Med Chem. Lett. 1993, 3, 2023-2028).

Stage 1: 1-(4-nitrobenzyloxy) ester piperazine-1,3-dicarboxylic acid

CuCO3·Cu(OH)2·H2O (15,8 g) are added to a solution of H2O (275 ml) dihydrochloride piperazine-2-carboxylic acid (22,3 g), the mixture is then boiled with the return of phlegmy and stirred for 10 minutes, the Insoluble material is filtered and washed with hot H2O (165 ml). The filtrate is cooled to room temperature and NaHCO3(9.2 grams) and 1,4-dioxane (220 ml) is added to a blue solution. The mixture is cooled to 0°C and NaHCO3(18.5 g) and a 50% solution of 4-nitrobenzyl-chloroformiate in 1,4-dioxane (61,7 g) is added to the mixture for 0.5 hours After stirring for an additional 1.5 h at 0°C the precipitate is filtered off and washed with cold H2O (140 ml), EtOH (100 ml), acetone (200 ml) and Et2O (100 ml), then he is allowed to dry under reduced pressure to obtain pale blue crystals. The crystals are added to a solution of 1 mol/l HCl (330 ml) EDTA-2Na (20,5 g) for 30 min and stirred for 2 h at room temperature. The suspension is filtered and the filtered material was diluted with EtOH-H2O (7:3, 550 ml) and boil with the return of phlegmy within 10 minutes the Reaction mixture is filtered, receiving colorless crystals. The recrystallization of the filtrate spend 3 times, getting extra crystals. Question what these crystals are dried under reduced pressure, getting listed in the title compound (26,25 g, 77%) as colorless crystals.

1H NMR (D2O) δ 2,54-2,61 (m, 1H), 2,89 (dt, 2H, J=12,7, 3,4 Hz), 2,97 (ush., 1H), 3,13 (ush., 1H), 3,62-Android 4.04 (m, 2H), 5,16 (s, 2H), 7,49 (d, 2H, J=8.6 Hz), 8,14 (d, 2H, J=8.6 Hz).

Stage 2: 5-(4-nitrobenzenesulfonyl)-3-oxo-3a,4,6,7 there-tetrahydro-3H-2-oxa-1,5-diaza-7a-isoniazide-3a-ID

Solution in H2O (300 ml) NaNO2(the content of 98.5%) (6,66 g) are added to a solution of acetic acid (864 ml) of 1-(4-nitrobenzyl) of ester piperazine-1,3-dicarboxylic acid (26,72 g) in a nitrogen atmosphere at 0°C for 0.5 h and stirred for Additional 1 h the solution in H2O (132 ml) NaNO2(the content of 98.5%) (2,41 g) are added to the solution at 0°C for 0.5 h and stirred for 1 h the Solution is concentrated under reduced pressure and to the residue add H2O (500 ml). The solution is extracted with AcOEt (5 times) and the organic layer was washed with a saturated solution of salt. The mixture is dried over MgSO4filter and concentrate under reduced pressure to give crude 1-(4-nitrobenzyloxy) ester 4-nitrosopiperidine-1,3-dicarboxylic acid as a pale brown amorphous substance (27,83 g (gross)25,77 g (net), 88,2%).

Solution in THF (10 ml) triperoxonane anhydride (24,0 g) are added to a solution in THF (371 ml) of crude 1-(4-nitrobenzyl) of ester 4-nitrosopiperidine-1,3-dicarboxylic acid the nitrogen atmosphere at 0° C for 15 minutes the Solution is stirred for 1.5 h at 0°C and for 1 h at room temperature. Solution in THF (5 ml) triperoxonane anhydride (8.0 g) is added to the solution over 5 min and stirred for 20 h at room temperature. To the solution add triperoxonane anhydride (8.0 g) for 5 min and the solution stirred for 4 hours the Precipitate is filtered and washed with THF and Et2O. the Filtrate is concentrated under reduced pressure. The residue is triturated with THF, filtered and washed with Et2O. These materials are combined and dried under reduced pressure, obtaining mentioned in the title compound as colorless crystals (22,3 g, 91%).

1H NMR (CDCl3) δ 4,06 (t, 2H, J=5.4 Hz), 4,37 (t, 2H, J=5.4 Hz), 4,63 (s, 2H), and 5.30 (s, 2H), 7,54 (d, 2H, J=8.7 Hz), of 8.25 (d, 2H, J=8.7 Hz).

Stage 3: 5-(4-nitrobenzyloxy) ester 2-ethyl ether complex 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2,5-dicarboxylic acid

Ethylpropyl (content 99%) (8,28 g) are added to a solution in o-xylene (348 ml) of 5-(4-nitrobenzenesulfonyl)-3-oxo-3a,4,6,7 there-tetrahydro-3H-2-oxa-1,5-diaza-7a-isoniazide-3a-IDA (22,3 g) in a nitrogen atmosphere and boil with the return of phlegmy for 16 hours the Solution is concentrated under reduced pressure, then subjected to column chromatography on silica gel 3 times (n-hexane/AcOEt = 2/1-1/3). Specified in the title compound obtained as a pale-yellow is kristallov (16.78 in g, 64%). In addition, receive 5-(4-nitrobenzyloxy) ester 3-ethyl ether complex 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-3,5-dicarboxylic acid in the form of pale yellow crystals (6,18 g, 24%).

1H NMR (CDCl3) δ of 1.39 (t, 3H, J=7,1 Hz)to 4.01 (t, 2H, J=5.5 Hz), or 4.31 (t, 2H, J=5.5 Hz), and 4.40 (q, 2H, J=7,1 Hz), 4,79 (s, 2H), from 5.29 (s, 2H), only 6.64 (s, 1H), 7,54 (d, 2H, J=8.6 Hz), 8,24 (d, 2H, J=8.6 Hz).

Stage 4: 4-nitrobenzyloxy ester of 2-hydroxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylic acid

LiBH4(640 mg) and MeOH (1.2 ml) are added to a solution in THF (267 ml) of 5-(4-nitrobenzyl) of ester 2-ethyl ether complex 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-2,5-dicarboxylic acid (10 g) in a nitrogen atmosphere at room temperature and stirred for 3 h at 40°C. Additional LiBH4(523 mg) and MeOH (1.0 ml) are added to the solution and stirred for 1 h at 40°C and 1 h at 50°C. the Mixture is acidified with 3 mol/l HCl to pH 2 and stirred for 1 h at room temperature, then the solid K2CO3add to the solution to bring the pH to 8. Insoluble material is filtered off and the filtrate is extracted with AcOEt. The organic layer is dried (K2CO3) and concentrate under reduced pressure. The residue is purified column chromatography on silica gel (CHCl3/MeOH =49/1-19/1), getting mentioned in the title compound as pale yellow crystals (8,4 g, 95%).

1H NMR (CDCl3) δ 1,69 (ush., 1H), 3,98 (t, 2H, J=5.5 Hz), 4,19 (t, 2H, J=5,5 Hz)and 4.65 (s, 2H), and 4.75 (s, 2H), 5,28 (s, 2H), between 6.08 (s, 1H), 7,53 (d, 2H, J=8.7 Hz), 8,24 (d, 2H, J=8.7 Hz).

Stage 5: 4-nitrobenzyloxy ester of 2-formyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylic acid

MnO2(activated) (84,2 g) are added to a solution in CHCl3-MeOH (95:5, 253 ml) 4-nitrobenzylamine of ester 2-hydroxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylic acid (8,42 g) and the mixture is boiled with the return of phlegmy for 1 h in nitrogen atmosphere. The reaction mixture was filtered through a pad of celite. To the filtrate add silica gel (20 g) and the solvent is removed under reduced pressure, obtaining silica gel, covered with a wet reagent. The specified subjected to silica gel adsorption process column chromatography on silica gel and the column elute CHCl3-MeOH (49/1 to 19/1). Specified in the title compound obtained as yellow crystals (2,82 g, 34%).

1H NMR (CDCl3) δ of 4.05 (t, 2H, J=5.5 Hz), 4,32 (t, 2H, J=5.5 Hz), to 4.81 (s, 2H), from 5.29 (s, 2H), 6,62 (s, 1H), 7,54 (d, 2H, J=8.7 Hz), 8,24 (d, 2H, J=8.7 Hz), to 9.93 (s, 1H).

Stage 6: 4-nitrobenzyloxy ester 2-{(RS)-acetoxy[(5R,6RS)-6-bromo-2-(4-nitrobenzylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-EN-6-yl]methyl}-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylic acid

4-Nitrobenzyloxy ester of 2-formyl-6,7-dihydro-4H-pyrazolo[1,5-a]feast of the in-5-carboxylic acid (2,71 g) are added to a solution in dry acetonitrile (164 ml) anhydrous MgBr 2(the content of 98%) (6,17 g) in a nitrogen atmosphere at room temperature. Solution in dry THF (164 ml) 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (content of 96.5%) (3,27 g) is added to the mixture, cooled to -20°C and add Et3N (content 99%) (9,24 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 1.5 h at -20°C and treated with acetic anhydride (content 97%) (3,19 ml) and DMAP (content 99%) (203 mg) in one portion. The reaction mixture is heated to 0°C and stirred for 1 h at 0°C. Acetic anhydride (3,19 ml) was added to the solution and stirred for 15 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, water and saturated salt solution. The organic layer is dried (MgSO4), followed by concentration under reduced pressure. The residue is purified column chromatography on silica gel three times (n-hexane - AcOEt (1/1 to 2/3), CHCl3-acetone (29/1 to 19/1) and CHCl3-acetone (29/1)). Specified in the title compound obtained as a yellow amorphous substance (GeoStereo-mix (64:36), 3,30 g, 53%).

1H NMR (CDCl3) δ to 2.06 (s, 3H×0,36), and 2.26 (s, 3H×0,64), 3.95 to Android 4.04 (m, 2H), 4,18 (s, 2H), 4,73 (d, 1H, J=18.2 Hz), 4,78 (d, 1H, J=18.2 Hz), 5,28 (who, 1H, J=13.5 Hz), 5,28 (s, 2H), 5,43 (d, 1H×0,64, J=13.5 Hz), 5,44 (d, 1H×0,36), the 6.06 (s, 1H×0,64), between 6.08 (s, 1H×0,64), 6,24 (s, 1H×0,36), 6,27 (s, 1H×0,36), 6,41 (s, 1H×0,36), 6,79 (s, 1H×0,64), 7,42 (s, 1H×0,64), 7,44 (s, 1H×0,36), 7,53 (d, 2H, J=8.6 Hz), 7,60 (d, 2H, J=8,8 Hz), 8,24 (d, 2H, J=8,8 Hz), 8,24 (d, 2H, J=8.6 Hz).

Stage 7: sodium salt of (5R),(6Z)-7-oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

To a solution in THF (43 ml) and acetonitrile (20 ml) of 4-nitrobenzylamine of ester 2-{(RS)-acetoxy[(5R,6RS)-6-bromo-2-(4-nitrobenzylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-EN-6-yl]methyl}-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-carboxylic acid quickly added Zn dust (12,36 g) 0.5 M phosphate buffer (pH 6.5, 63 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room temperature. Insoluble material is filtered off and washed with H2O (63 ml). The filtrate is washed with ethyl acetate (63 ml) and the aqueous layer was cooled to 3°C and add 1 M HCl to bring the pH to 2.5. The mixture is stirred for 4 h at the same temperature and add H2O (63 ml) and 1 M HCl to bring the pH to 2.5, and then stirred for 17 h at the same temperature. To the mixture was added 1 M NaOH to bring the pH to 8. The mixture was concentrated in high vacuum at 35°C. the Concentrate is treated with a column of chromatogra what s on the resin Diaion HP-21 (124 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with a mixture of H2O-MeCN (1/0-95/5). Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (288 mg, 22%, a pH of 8.8). TPL 160°C (decomposition).

1H NMR (D2O) δ to 2.94 (t, 2H, J=5.6 Hz), to 3.67 (d, 1H, J=and 17.2 Hz), 3,70 (d, 1H, J=and 17.2 Hz), 3,82 (t, 2H, J=5.6 Hz), of 5.84 (s, 1H), 6,03 (s, 1 H), of 6.65 (s, 1H), to 6.67 (s, 1H).

Example 26

Derivatization 5,5-dimethyl-2-piperidone sodium salt of (5R,6Z)-6-(5,5-dimethyl-4H-1,6a-diazapentane-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

5-5-Dimethyl-2-piperazinone receive according to the method of Nagasawa (J. Med. Chem., 20, 1176 (1977)).

Stage 1: 3,3-dichloro-5,5-dimethyl-2-piperidone

To a cold (0°C) stirred solution of 5,5-dimethyl-2-piperidone (30,2 g, 0.24 mol) in 475 ml of CHCl3add PCl5(57,1 g, 0.26 mol) at such a speed that the temperature never exceeds 7°C. After complete addition, stirring is continued for 10 min Sulfurylchloride (96,6 g to 0.72 mol) is added slowly and the mixture is heated with the return of phlegmy within 1 h the Solution is concentrated under reduced pressure. The residue is cooled in an ice bath and diluted with 250 ml of ice water. The product is then extracted with CHCl3(6 × 250 ml) and the organic layer is dried (MgSO4and f is trout. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel column and then elute with a mixture of CHCl3-MeOH (50:1). Specified in the title compound obtained as white solids (41,3 g, and 88.8%). (J. Med. Chem., 20, 1176 (1977)).

1H NMR (CDCl3) δ of 1.17 (s, 6H), was 2.76 (s, 2H), 3,19 (d, 2H, J=3.0 Hz), 6,82 (USS, 1H).

Stage 2: 3-chloro-5,5-dimethyl-2-piperidone

To 40,8 g (0.21 mol) of 3,3-dichloro-5,5-dimethyl-2-piperidone dissolved in 410 ml of AcOH, add 10% Pd/C (humidity 50%, 6.2 g) and NaOAc·3H2O (62,4 g, 0.46 mol) and the mixture hydrogenizing under a pressure of 300 kPa for 20 minutes, the hydrogen Pressure was adjusted to 300 kPa every 5 minutes, the Catalyst was removed by filtration and the filtrate concentrated under reduced pressure. To the residue add CHCl3(400 ml) and water (300 ml) and the aqueous layer was neutralized with 4 mol/l NaOH. The mixture is separated and the aqueous layer was extracted with CHCl3(5 × 300 ml) and the organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel column and then elute with a mixture of hexane-AcOEt (1:1). Specified in the title compound obtained as a white solid (20.4 g, 59.9 per cent). (J. Med. Chem., 20, 1176 (1977)).

1H NMR (CDCl3) δ 1,10 (s, 3H), of 1.12 (s, 3H), 2,02 (DD, 1H, J=10,8, to 13.6 Hz), measuring 2.20 (DDD, 1H, J=2,2, 6,7, to 13.6 Hz), 2,97 (DDD, 1H, J=2,3, 3,9, 12.1 Hz), up 3.22 (d, 1H, J=12 Hz), of 4.44 (DD, 1H, J=6,8 and 10.7 Hz), 6,66 (USS, 1H).

Stage 3: 4,4-dimethylpiperidin-2-carboxylic acid

A suspension of 20.4 g (0.13 mol) of 3-chloro-5,5-dimethyl-2-piperidone and of 45.2 g (0.14 mol) of Ba(OH)3-8H2O in 252 ml of water is heated in a Parr apparatus at 150°C for 6 hours Then add to 18.6 g (0.14 mol) of ammonium sulfate. The precipitate is filtered off and the solution concentrated under reduced pressure to dryness. Crude 4,4-dimethylpiperidin-2-carboxylic acid is obtained as a white solid (37.5 g). (J. Med. Chem., 20, 1176 (1977), EP 0447704 A1, page 17).

1H NMR (D2O) δ 1,10 (s, 3H), 1,11 (s, 3H), of 1.88 (DD, 1H, J=7,8, 13,2 Hz), of 2.21 (DD, 1H, J=9,2, 13,2 Hz), 3,12 (DD, 2H, J=11,5, with 23.5 Hz), 4,22 (DD, 1H, J=8,1, 8,9 Hz).

Stage 4: 5,5-dimethyl-3-oxo-3a,4-dihydro-3H,6H-2-oxa-5-1-Aza-6a-azonia-3a-pentalene

To a suspension of 37.5 g of crude 4,4-dimethylpiperidin-2-carboxylic acid in 420 ml of AcOH add a solution of 13.3 g (to 0.19 mol) NaNO2in 210 ml of water for 15 min at room temperature and stirred for 3 hours the Solution is concentrated under reduced pressure. To the residue add acetone (250 ml) and the precipitate is filtered off and the solution concentrated under reduced pressure to dryness and receive crude 4,4-dimethyl-1-nitrosopyrrolidine-2-carboxylic acid as a brown oil.

To a solution of crude 4,4-dimethyl-1-nitrosopyrrolidine-2-carboxylic acid in 252 ml of dry THF add triperoxonane anhydride (81.3 g, 0,39 m is l) under nitrogen atmosphere at 0° C and stirred for 6 h at 0°C. the Solution is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel column and then elute with a mixture of n-hexane - AcOEt (2:1). Specified in the title compound obtained as brown solid (12.0 g, 61.7 per cent).

1H NMR (CDCl3) δ to 1.38 (s, 6H), 2,71 (s, 2H), 4,12 (s, 2H).

Stage 5: ethyl ester of 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid

A solution of 5,5-dimethyl-3-oxo-3a,4-dihydro-3H,6H-2-oxa-5-1-Aza-6a-azonia-3a-pentalene (10.8 g, 0.07 mol) and ethylpropyl (10,8 ml, 0.11 mol) in o-xylene (350 ml) is boiled with the return of phlegmy in nitrogen atmosphere for 16 hours the Solution is cooled to room temperature and concentrate under reduced pressure. The residue is subjected to column chromatography on silica gel column and then elute with a mixture of n-hexane - AcOEt (3:1). Specified in the title compound obtained as a pale brown solid (4,63 g, 31.7 percent) and ethyl ester of 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid obtained as yellow solid (4,73 g, 32.4 percent).

Ethyl ester of 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid:1H NMR (CDCl3) δ of 1.29 (s, 6H), of 1.40 (t, 3H, J=7,1 Hz), 2,71 (s, 2H), 3,93 (s, 2H), 4,39 (q, 2H, J=7,1 Hz), is 6.54 (s, 1H).

Ethyl ester of 5,5-dimethyl-5,6-Digi the ro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid: 1H NMR (CDCl3) δ to 1.32 (s, 6H), of 1.33 (t, 3H, J=7,1 Hz), 2,89 (s, 2H), 3,90 (s, 2H), 4.26 deaths (q, 2H, J=7,1 Hz), of 7.90 (s, 1H).

Stage 6: 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbaldehyde

To 4,63 g (of 22.2 mmol) of ester ethyl 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylic acid in 222 ml of dry THF added LiAlH4(0.85 grams, of 22.3 mmol) under nitrogen atmosphere at 0°C and then stirred for 1 h the Mixture was quenched with water (5.0 ml) and the precipitate is filtered through a pad of celite and the pad washed with water (50 ml) and THF (150 ml). The filtrate is concentrated under reduced pressure and then water is added (50 ml). The aqueous layer was extracted with CHCl3(5 × 100 ml). The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the crude 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-yl)methanol obtained as yellow solid (3,19 g).

To 3,19 g crude (5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-yl)methanol in 222 ml of CHCl3add activated MnO2(18.5 g) in a nitrogen atmosphere at room temperature and then boiled with the return of phlegmy for 1 h the Mixture was filtered through a pad of celite and the filtrate concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel column and then elute with a mixture of hexane-AcOEt (3:1). Specified in the title compound obtained as cor is cinefogo solids (2,48 g, 68,0% of ester).

1H NMR (CDCl3) δ to 1.32 (s, 6H), 2,73 (s, 2H), 3,95 (s, 2H), of 6.52 (s, 1H), 9,90 (s, 1H).

Stage 7: sodium salt of (5R)(6Z)-6-(5,5-dimethyl-4H-1,6a-diazapentane-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Solution in dry acetonitrile (16 ml) of 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-6]pyrazole-2-carbaldehyde (2,48 g, 15.1 mmol) are added to a solution in dry acetonitrile (90 ml) MgBr2(of 3.07 g, 16.4 mmol) under nitrogen atmosphere at room temperature and then the mixture is stirred for 15 minutes a Solution in dry THF (106 ml) p-nitrobenzyl-(5R,6S)-6-bromine-3-carboxylate (5.30 g, of 13.8 mmol) is added and the mixture is cooled to -20°C and then add triethylamine (4.6 ml, 33.0 mmol) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 3 h at -20°C and treated with 4-dimethylaminopyridine (172 mg, 1.4 mmol) and acetic anhydride (2.6 ml, 27.6 mmol) in one portion. The reaction mixture is heated to 0°C and stirred for 16 h at 0°C. ethyl Acetate (420 ml) and an aqueous solution of 1 mol/l citric acid (210 ml) is added to the reaction mixture and divide it. The organic layer was washed with a saturated solution of sodium bicarbonate and a saturated solution of salt, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the crude p-nitrobenzyloxy is false ether (5R)-6-[acetoxy(5,5-dimethyl-4H-1,6a-diazapentane-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid obtained as a brown amorphous substance.

Sizeaction Zn dust (32,0 g) just add 0.5 mol/l phosphate buffer (pH 6.5, 167 ml) to a solution in THF (114 ml) and acetonitrile (53 ml) of crude p-nitrobenzyl of ester (5R)-6-[acetoxy(5,5-dimethyl-4H-1,6a-diazapentane-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room temperature. The reaction solution is cooled at 0°C and then the pH was adjusted to 8.0. Ethyl acetate (85 ml) is added to the mixture and filtered through a pad of celite. The pad is washed with water (120 ml). The aqueous layer was separated and then the organic layer is extracted with 0.5 mol/l phosphate buffer (pH 6.5, 2 × 50 ml). The combined organic layers are cooled at 0°C and then the pH was adjusted to 8.5. The mixture is concentrated to 325 g and then subjected to column chromatography on resin Diaion HP-21 (240 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with water (480 ml) and then aqueous solution of acetonitrile (10%, 480 ml, 20%, 720 ml). The combined active fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (2.00 g, 42.8 per cent, pH 7,16). TPL 150°C (decomposition).

1H NMR (D2O) δ to 1.19 (s, 6H), to 2.67 (s, 2H), 3,85 (s, 2H), x 6.15 (s, 1H), 6,45 (s, 1H), of 6.96 (s, 1H), 7,03 (s, 1H; IR (KBr) 3422, 1752, 1683, 1598, 1557 cm-1; λmax(H2O) 296,198 nm.

Example 27

Obtaining the sodium salt of (5R),(6Z)-6-(5,6-dihydro-4H-cyclopent[b]furan-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: methyl ester of 5,6-dihydro-4H-cyclopent[b]furan-2-carboxylic acid

Specified in the header connection receive according to the procedure Tim Johnson and employees (Synlett 2001, 5, 646-648).

Stage 2: (5,6-dihydro-4H-cyclopent[b]furan-2-yl)methanol

Methyl ester of 5,6-dihydro-4H-cyclopent[b]furan-2-carboxylic acid (2.24 g) are added to a solution in THF (59 ml) LiAlH4(511 mg) in a nitrogen atmosphere at 0°C and stirred for 1 h at 0°C. the Mixture is quenched with 10 ml of water and filtered. The filtrate is concentrated under reduced pressure and the resulting aqueous solution is extracted with CHCl3. The organic layer was washed with saturated salt solution and dried over MgSO4and filtered. The filtrate is concentrated, getting mentioned in the title compound as a yellow oil (1.86 g, quantitative yield).

1H NMR (CDCl3) δ of 1.66 (t, 1H, J=5,9 Hz), 2,38 is 2.46 (m, 2H), 2,50 is 2.55 (m, 2H), 2,65-2,70 (m, 2H), 4,54 (d, 2H, J=5,9 Hz), x 6.15 (s, 1H).

Stage 3: 5,6-dihydro-4H-cyclopent[b]furan-2-carbaldehyde

Activated MnO2(9.3 g) are added to a solution in CHCl3(135 ml) of (5,6-dihydro-4H-cyclopent[b]furan-2-yl)methane is a (1.86 g) and boil with the return of phlegmy for 1 h in nitrogen atmosphere. The reaction mixture was filtered through a pad of celite. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of n-hexane-AcOEt (9/1-7/1). Specified in the title compound obtained as yellow crystals (1.51 g, 77%).

1H NMR (CDCl3) δ 2,47-to 2.57 (m, 2H), 2.63 in (t, 2H, J=6.8 Hz), 2,78 (t, 2H, J=7,3 Hz), 7,06 (s, 1H), 9,44 (s, 1H).

Stage 4: 4-nitrobenzyloxy ester (5R,6RS)-6-[(RS)-acetoxy(5,6-dihydro-4H-cyclopent[b]furan-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Solution in acetonitrile (50 ml) 5,6-dihydro-4H-cyclopent[b]furan-2-carbaldehyde (1,33 g) are added to a solution in dry acetonitrile (101 ml) anhydrous MgBr2(the content of 98%) (5,52 g) in a nitrogen atmosphere at room temperature. Solution in dry THF (151 ml) 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (content of 96.5%) (3,91 g) is added to the mixture, cooled to -20°C and add Et3N (content 99%) (8,28 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20°C and treated with acetic anhydride (content 97%) (4,13 ml) and DMAP (content 99%) (121 mg) in one portion. The reaction mixture is heated to 0°C and stirred for 16 h at 0°C. Speciesbased with ethyl acetate and washed with 5% aqueous citric acid solution, a saturated solution of sodium bicarbonate and a saturated solution of salt. The organic layer is dried (MgSO4), then filtered. The filtrate is concentrated under reduced pressure. The residue is purified column chromatography on silica gel (n-hexane:AcOEt= 4:1 - 3:1), getting listed in the title compound as a brown amorphous solid (3,34 g, 61%).

1H NMR (CDCl3) δ of 2.21 (s, 3H), 2.40 a-2,48 (m, 2H), 2,53 (t, 2H, J=7.0 Hz), 2,69 (t, 2H, J=7.0 Hz), 5,28 (d, 1H, J=13.5 Hz), 5,43 (d, 1H, J=13.5 Hz), 6,00 (s, 1H), 6,37 (s, 1H), of 6.71 (s, 1H), 7,41 (s, 1H), 7,60 (d, 2H, J=8.1 Hz), 8,24 (d, 2H, J=8.1 Hz).

Stage 5: sodium salt of (5R),(6Z)-6-(5,6-dihydro-4H-cyclopent[b]furan-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

4-Nitrobenzyloxy ester (5R,6RS)-6-[(RS)-acetoxy(5,6-dihydro-4H-cyclopent[b]furan-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (3.28 g) was dissolved in THF (46 ml) and acetonitrile (21 ml). Sizeaction Zn dust (13,12 g) add quickly with 0.5 M phosphate buffer (pH 6.5, 67 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.25 hours at room temperature. The reaction mixture was filtered through a pad of celite. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was cooled to 3°C and add 1 M NaOH to bring the pH to 8.0. The mixture was concentrated in high the m vacuum at 35° C. the Concentrate is subjected to column chromatography on resin Diaion HP-21 (181 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with a mixture of H2O-MeCN (1/0-85/15). Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, receiving specified in the header of the crude product (288 mg). Its clear column chromatography on resin Diaion HP-21 (100 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with a mixture of H2O-MeCN (1/0-85/15). Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (185 mg, 10%, pH of 7.2). TPL 170°C (decomposition).

1H NMR (D2O) δ 2,24-of 2.30 (m, 2H), is 2.37 (t, 2H, J=6.5 Hz), 2,52-to 2.57 (t, 2H, J=7,1 Hz), 6,32 (s, 1H), 6,55 (s, 1H), 6.73 x (s, 1H), 6,86 (s, 1H).

Example 28

Obtaining the sodium salt of (5R)(6Z}-6-(4,5-dihydro-6-thia-1,7a-dietingen-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: hydrochloride DL-tetrahydro-1,3-thiazin-4-carboxylic acid

Hydrochloride DL-tetrahydro-1,3-thiazin-4-carboxylic acid get according to the method of Lewis (J. Med. Chem., 21, 1070 (1978)).

Stage 2: 4,5-dihydro-3aH,7H-2-oxa-3-oxo-6-thia-1-Aza-7a-asanyone

To a suspension of the hydrochloride DL-tetrahydro-1,3-thiazin-4-carboxylic acid (48.6 g, 0.26 mol) in 666 ml of AcOH add a solution of 27.4 g (0.40 mol) NaNO2in 333 ml of water for 6 min at room temperature and stirred for 3 hours The solution is concentrated under reduced pressure. Acetone (300 ml) is added to the residue and the precipitate is filtered off. The filtrate is concentrated under reduced pressure to dryness and the crude 3-nitroso[1,3]diazinon-4-carboxylic acid is obtained as a brown amorphous solid.

To a solution of crude 3-nitroso[1,3]diazinon-4-carboxylic acid in 530 ml of dry THF add triperoxonane anhydride (168,4 g, 0.80 mol) for 60 min in a nitrogen atmosphere at 0°C and stirred for 5 h at 0°C. the Solution is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel column and then elute with a mixture of n-hexane - AcOEt (1:2). Specified in the title compound obtained as a brown powder (28,0 g, 67.0 per cent).

1H NMR (CDCl3) δ 3,00 (t, 2H, J=5.7 Hz), of 3.07 (t, 2H, J=5.7 Hz), 5,16 (s, 2H).

Stage 3: ethyl ester of 4,5-dihydro-6-thia-1,7a-dietingen-2-carboxylic acid

A solution of 4,5-dihydro-3aH,7H-2-oxa-3-oxo-6-thia-1-Aza-7a-azonyanyisa (28,0 g, 0.18 mol) and ethylpropyl (27,0 ml, 0.27 mol) in o-xylene(590 ml) is boiled with the return of phlegmy in nitrogen atmosphere for 16 hours the Solution is cooled to room temperature and concentrate under reduced pressure. The residue is subjected to column chromatography on silica gel column and then elute with a mixture of n-hexane-AcOEt (3:1). Specified in the header connection receive is in the form of a pale brown needle-shaped crystals (22.1 g, 58,7%) and ethyl ester of 4,5-dihydro-6-thia-1,7a-dietingen-3-carboxylic acid obtained as pale brown crystals (12.7 g, 33,9%).

Ethyl ester of 4,5-dihydro-6-thia-1,7a-dietingen-2-carboxylic acid:1H NMR (CDCl3) δ of 1.39 (t, 3H, J=7,1 Hz), 2,98 (t, 2H, J=6,1 Hz), 3,21 (t, 2H, J=6,1 Hz), and 4.40 (q, 2H, J=7,1 Hz)to 5.17 (s, 2H), 6,60 (s, 1H).

Ethyl ester of 4,5-dihydro-6-thia-1,7a-dietingen-3-carboxylic acid:1H NMR (CDCl3) δ of 1.34 (t, 3H, J=7,1 Hz)to 2.99 (t, 2H, J=6,1 Hz), of 3.45 (t, 2H, J=6,1 Hz), 4,28 (q, 2H, J=7,1 Hz), 5,11 (s, 2H), a 7.85 (s, 1H).

Stage 4: 4,5-dihydro-6-thia-1,7a-dietingen-2-carbaldehyde

To 22.1 grams (0.10 mol) of ester ethyl 4,5-dihydro-6-thia-1,7a-dietingen-2-carboxylic acid in 520 ml of dry THF added LiAlH4(3,95 g, 0.10 mol) in nitrogen atmosphere at 0°C and then stirred for 45 minutes the Mixture was quenched with water (20 ml) and the precipitate is filtered through a pad of celite and the pad washed with water (100 ml) and THF (250 ml). The filtrate is concentrated under reduced pressure and then add water (300 ml). The aqueous layer was extracted with CH2Cl2(6 × 500 ml). The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the crude product is obtained as pale yellow crystals (17,2 g).

To 17,2 g crude (4,5-dihydro-6-thia-1,7a-dietingen-2-yl)methanol (520 ml CHCl3add activated MnO2(88.0 g) in the atmosphere is ore of nitrogen at room temperature and then boiled with the return of phlegmy within 2 hours The mixture is filtered through a pad of celite and the filtrate concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel column and then elute with a mixture of hexane-AcOEt (2:1). Specified in the title compound obtained as yellow crystals (13,0 g, 74,5%).

1H NMR (CDCl3) δ 3,00 (t, 2H, J=6.0 Hz), 3,23 (t, 2H, J=6.0 Hz), is 5.18 (s, 2H), return of 6.58 (s, 1H), 9,92 (s, 1H).

Stage 5: sodium salt of (5R)(6Z)-6-(4,5-dihydro-6-thia-1,7a-dietingen-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Solution in dry acetonitrile (11 ml) 4,5-dihydro-6-thia-1,7a-dietingen-2-carbaldehyde (1.70 g, 10.1 mmol) are added to a solution in dry acetonitrile (60 ml) MgBr2(2,03 g, 11.0 mmol) under nitrogen atmosphere at room temperature and then the mixture is stirred for 10 minutes a Solution in dry THF (71 ml) p-nitrobenzyl-(5R,6S)-6-bromine-3-carboxylate (3.55 g, 9.2 mmol) is added and the mixture is cooled to -20°C and then add triethylamine (3.1 ml, of 22.2 mmol) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 3 h at -20°C and treated with 4-dimethylaminopyridine (0.11 g, 0.9 mmol) and acetic anhydride (1.8 ml, of 18.6 mmol) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. ethyl Acetate (280 ml) and an aqueous solution of 1 mol/l citric acid (140 ml) to ablaut to the reaction mixture and divide it. The organic layer was washed with a saturated solution of sodium bicarbonate and a saturated solution of salt, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the crude p-nitrobenzyl ester (5R)-6-[acetoxy(4,5-dihydro-6-thia-1,7a-dietingen-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid obtained as a brown amorphous solid.

Sizeaction Zn dust (21,4 g) just add 0.5 mol/l phosphate buffer (pH 6.5, 112 ml) to a solution in THF (76 ml) and acetonitrile (36 ml) of crude p-nitrobenzyl of ester (5R)-6-[acetoxy(4,5-dihydro-6-thia-1,7a-dietingen-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic the acid. The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room temperature. The reaction solution is cooled at 0°C and then the pH was adjusted to 8.0. Ethyl acetate (56 ml) is added to the mixture and filtered through a pad of celite. The pad is washed with water (150 ml). The aqueous layer was separated and then the organic layer is extracted with 0.5 mol/l phosphate buffer (pH 6.5, 2 × 30 ml). The combined organic layers are cooled at 0°C and then the pH was adjusted to 8.0. The mixture is concentrated to 236 g and then subjected to column chromatography on resin Diaion HP-21 (480 ml, Mitsubishi Kasei Co. Ltd.). Once adsorbed the I column elute with water (960 ml) and then aqueous solution of acetonitrile (5%, 960 ml, 10%, 960 ml, 20%, 960 ml). The combined active fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (1.28 g, 40.5 percent, the pH was 7.45). TPL 200°C (decomposition).

1H NMR (D2O) δ 2,95 (t, 2H, J=6,1 Hz), of 3.12 (t, 2H, J=6,1 Hz), to 5.08 (s, 2H), 6,23 (s, 1H), 6,46 (s, 1H), 6,97 (s, 1H), 7,01 (s, 1H); IR (KBr) 3382, 1752, 1684, 1597, 1554 cm-1; λmax(H2O) 366, 292, 197 nm.

Example 29

Obtaining the sodium salt of (5R),(6Z)-6-(6,6-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]piridin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: Obtain 5,5-dimethyl-2-piperidone

5,5-Dimethyl-2-piperazinone (1) are obtained according to the method of Nagasawa (J. Med. Chem., 23, 1176 (1977)).

Stage 2: Obtaining 3,3-dimethyl-6-methoxy-2,3,4,5-tetrahydropyridine

Tetrafluoroborate trimethylhexane (97%, 11.9 g, 78 mmol) are added to a solution in dry dichloromethane (156 ml) 5,5-dimethyl-2-piperidone Ltd (9.93 g, 78 mmol) at room temperature and stirred for 14 h, the Reaction mixture is neutralized with 10% aqueous solution of sodium bicarbonate and the organic layer separated. The aqueous layer was extracted with ethyl acetate (3 × 120 ml)then the combined organic layer washed with 10% aqueous sodium hydrogen carbonate solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered. Phil is spending concentrated under reduced pressure and indicated in the title compound obtained as a pale yellow oil (9.0 g, 82,0%).

1H NMR (CDCl3) δ to 0.92 (s, 6H), 1,49 (t, 2H, J=7,0 Hz)to 2.18 (t, 2H, J=7.0 Hz), 3,19 (s, 2H), 3,63 (s, 3H).

Stage 3: monohydrochloride 5,5-dimethylpiperidin-2-ylideneamino

A mixture of 3,3-dimethyl-6-methoxy-2,3,4,5-tetrahydropyridine (9.0 g, 64 mmol) and ammonium chloride (3.4 g, 64 mmol) in dry ethanol (160 ml) is heated to boiling with the return of phlegmy within 2 hours the Reaction mixture was then concentrated under reduced pressure and indicated in the title compound obtained as white solids (9,9 g, a 94.6%).

1H NMR (DMSO-d6) δ of 0.95 (s, 6H), of 1.52 (t, 2H, J=6.9 Hz), to 2.55 (t, 2H, J=6.9 Hz), 2,99 (d, 2H, J=2.1 Hz).

Stage 4: 6,6-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbaldehyde and 6,6-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-carbaldehyde

A mixture of 2-bromo-3-hydroxypropane (10.1 g, 67 mmol), monohydrate p-toluensulfonate acid (of 0.13 g, 0.6 mmol) and 2-propanol (of 12.6 ml, 165 mmol) in cyclohexane (100 ml) is subjected to azeotropic distillation until the temperature of the vapor will not exceed 80°C. the Reaction mixture was concentrated under reduced pressure. The residue is dissolved in dry EtOH (200 ml). Solution in dry EtOH (350 ml) monohydrochloride 5,5-dimethylpiperidin-2-ylideneamino (9,9 g, 61 mmol) and a solution in dry EtOH (50 ml), NaOMe (28%, 11,7 g, 61 mmol) is added at room temperature. The reaction mixture was stirred at room temperature for 2 h and then the reaction is Astor removed in vacuum. The residue is dissolved in CHCl3(300 ml) and add triethylamine (8.5 ml, 61 mmol) and then the reaction mixture is heated to boiling point with the return of phlegmy within 2 hours the Reaction mixture is cooled to room temperature and then the reaction solution is removed in vacuum. The residue is dissolved in CH2Cl2(600 ml) and washed with 50% aqueous rastvorov K2CO3(2 × 200 ml). The combined aqueous solution is extracted with CH2Cl2(2 × 200 ml). The combined organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, elute with a mixture of CHCl3-methanol (50:1) and get listed in the title compound 6,6-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbaldehyde (brown solid, 4.4 g, 40.7 per cent) and 6,6-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-carbaldehyde (orange solid, 1.7 g, 15.8 per cent).

6,6-Dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbaldehyde:1H NMR (CDCl3) δ 1,10 (s, 6H), 1,78 (t, 2H, J=6.9 Hz), 2.95 and (t, 2H, J=6.9 Hz), 3,71 (s, 2H), 7,46 (s, 1H), 9,83 (s, 1H).

6,6-Dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-carbaldehyde:1H NMR (CDCl3) δ of 1.09 (s, 6H), 1,74 (t, 2H, J=6.8 Hz), of 2.97 (t, 2H, J=6.8 Hz), of 4.05 (s, 2H), 7,74 (s, 1H), for 9.64 (s, 1H).

Stage 5:sodium salt of (5R),(6Z)-6-(6,6-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]piridin-2-ILM is tilen)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Solution in dry acetonitrile (28 ml) 6,6-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbaldehyde (4,55 g, 26 mmol) are added to a solution in dry acetonitrile (152 ml) MgBr2(5,22 g, 28 mmol) under nitrogen atmosphere at room temperature and then the mixture is stirred for 10 minutes a Solution in dry THF (180 ml) p-nitrobenzyl-(5R,6S)-6-bromine-3-carboxylate (8,94 g, 23 mmol) is added and the mixture is cooled to -20°C and then add triethylamine (7.8 ml, 56 mmol) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 3 h at -20°C and treated with 4-dimethylaminopyridine (to 0.29 g, 2.4 mmol) and acetic anhydride (4.4 ml, 47 mmol) in one portion. The reaction mixture is heated to 0°C and stirred for 16 h at 0°C. ethyl Acetate (715 ml) are added to the reaction mixture and then the organic layer was washed with 1 mol/l aqueous solution of citric acid, saturated sodium hydrogen carbonate solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the crude p-nitrobenzyl ester (5R)-6-[acetoxy(6,6-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid obtained as a brown amorphous solid.

Sizeaction Zn dust is (53,6 g) just add 0.5 mol/l phosphate buffer (pH 6.5, 282 ml) to a solution in THF (192 ml) and acetonitrile (90 ml) p-nitrobenzylamine of ester (5R)-6-[acetoxy(6,6-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 h at room temperature. The reaction mixture is cooled at 0°C and then the pH was adjusted to 7.6. Ethyl acetate (140 ml) is added to the reaction mixture and the mixture is then filtered through a pad of celite and the pad washed with water (200 ml). The aqueous layer was separated and then the organic layer is extracted with 0.5 mol/l phosphate buffer (pH 6.5, 2 × 50 ml). the pH of the combined organic layer was adjusted to 8.1 and the mixture is concentrated to 584, 1 mol/l NaOH is added to bring the pH to 8.2 and subjected to column chromatography on resin Diaion HP-21 (420 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute 2,5% (2 volume layer), 5% (2 volume layer), 10% (volume 1 layer) and 20% aqueous solution of acetonitrile. The combined active fractions are concentrated in a high vacuum at 35°C and lyophilized give crude sodium salt of (5R),(6Z)-6-(6,6-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]piridin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid as a yellow amorphous solid (1.19 g).

The crude sodium salt of (5R),(6Z)-6-(6,6-dimethyl-56,7,8-tetrahydroimidazo[1,2-a]piridin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid purified preparative HPLC (Mightysil RP-18 GP (5 ), Kanto Chemical Co. Inc., 35 × 250 mm, 0.05 mol/l phosphate buffer (pH 7,2):CH3CN = 70:30, 20 ml/min). The purified product absoluut column chromatography on resin Diaion HP-21 (50 ml) and specified in the header of the connection get in the amount of 230 mg (2,8%) as a yellow amorphous solid. TPL 210°C (decomposition).

1H NMR (D2O) δ of 0.91 (s, 3H), of 0.93 (s, 3H), and 1.63 (t, 2H, J=6.8 Hz), of 2.72 (t, 2H, J=6.8 Hz), 3,60 (s, 2H), 6,44 (s, 1H), 6.90 to (s, 1H), 6,91 (s, 1H), 7,19 (s, 1H).

Example 30

Obtain (5R),(6Z)-6-(5,6-dihydro-8-H-imidazo[2,1-c][1,4]thiazin-3-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Solution in dry acetonitrile (40 ml) 5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-3-carbaldehyde (813 mg) are added to a solution in dry acetonitrile (40 ml) MgBr2(2.2 g) under nitrogen atmosphere at room temperature, the mixture is then stirred for 10 minutes Add the solution in dry THF (80 ml) p-nitrobenzyl-(5R, 6S)-6-bromine-3-carboxylate (2.1 g), the mixture is cooled to -20°C, then add triethylamine (1.7 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 3.5 h at -20°C and treated with 4,4-dimethylaminopyridine (64 mg) and acetic anhydride (0.9 ml) in one portion. The reaction mixture is heated to 0°C and stirred for 14 h at 0°C. To the reaction mixture is added 10% aqueous solution lim is authorized acid (500 ml) and the aqueous layer was extracted with ethyl acetate (3 × 200 ml). The organic layer is washed with water, saturated sodium hydrogen carbonate solution and saturated salt solution, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel and elute with a mixture of CH2Cl2-acetone (20:1)to give crude n-nitrobenzyloxy ester (5R)-6-[acetoxy(5,6-dihydro-8H-imidazo[2,1-c][1,4]thiazin-3-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid as a brown solid.

The solid obtained the specified chromatography, dissolved in THF (11 ml). Sizeaction Zn dust (1.4 g) just add 0.5 mol/l phosphate buffer (pH 6.5, 11 ml). The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction solution is filtered through a pad of celite and the pad washed with water (26 ml) and n-butanol (26 ml). The aqueous layer was separated and then the organic layer is extracted with 0.5 mol/l phosphate buffer (pH 6.5, 2 × 5 ml). The combined organic layer is concentrated to 18 g, was added 1 mol/l NaOH to bring the pH to 7.3, and subjected to column chromatography on resin Diaion HP-21 (20 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with water and then 5% aqueous solution of acetonitrile. United Akti the basic fraction was concentrated in a high vacuum at 35° C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (81 mg). TPL 145°C (decomposition).

1H NMR (D2O) δ 3,05-is 3.08 (m, 1H), 3,83 (s, 1H), 4,13-4,16 (m, 1H), 6,37 (s, 1H), 6,91 (s, 1H), 7,01 (s, 1H),? 7.04 baby mortality (s, 1H); IR (KBr) 3371, 1770, 1672, 1613 cm-1; λmax(H2O) 314 nm.

Example 31

Obtaining the sodium salt of (5R)(6Z)-7-oxo-6-(4H-5-thia-1,6a-diazapentane-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: Obtaining 3-oxo-3a,4-dihydro-3H,6H-2-oxa-5-thia-1-Aza-6a-azonia-3a-pentalene

Concentrated HCl (15 ml) and NaNO2(16.6 g) are added to a solution of H2O (166 ml) L-thioproline (24.3 g) in a nitrogen atmosphere at 0°C and stirred for 2 hours, the Solution is extracted with CH2Cl2, the organic layer is dried over MgSO4and concentrate under reduced pressure to give crude N-nitroso compound as a yellow solid.

Triperoxonane anhydride (5.0 ml) are added to a solution in THF (350 ml) of crude N-nitroso-thioproline in nitrogen atmosphere at 0°C and stirred for 5 h at 0°C. the Solution is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of n-hexane-AcOEt (1:1). Specified in the title compound obtained as a pale brown solid (4.0 g, 15.1 per cent).

1 3) δ Android 4.04 (t, 2H, J=1.7 Hz), of 5.40 (t, 2H, J=1.7 Hz).

Stage 2: Getting ethyl ether complex 4H-5-thia-1,6a-diazapentane-2-carboxylic acid

Ethylpropyl (3.1 ml) are added to a solution in o-xylene (130 ml) of 3-oxo-3a,4-dihydro-3H,6H-2-oxa-5-thia-1-Aza-6a-azonia-3a-pentalene (4.0 g) under nitrogen atmosphere and boil with the return of phlegmy for 19 hours the Solution is cooled to room temperature and concentrate under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of n-hexane-AcOEt (4:1). Specified in the title compound obtained as yellow solid (2.7 g, 49,3%) and ethyl ester 4H-5-thia-1,6a-diazapentane-3-carboxylic acid obtained as pale yellow crystals (1.2 g, 21.7 per cent).

1H NMR (CDCl3) δ of 1.40 (t, 3H, J=7,1 Hz), 4,11 (d, 2H, J=2.1 Hz), and 4.40 (q, 2H, J=7,1 Hz), 5,24 (t, 2H, J=1.6 Hz), is 6.61 (s, 1H).

Stage 3: Receive (4H-5-thia-1,6a-diazapentane-2-yl)methanol

LiBH4(content 90%) (459 mg) are added to a solution in a simple ether (126 ml) of ester ethyl 4H-5-thia-1,6a-diazapentane-2-carboxylic acid (2.5 g) and MeOH (of 0.77 ml) in nitrogen atmosphere at room temperature, then boiled with the return of phlegmy for 1.5 hours the Mixture was quenched with a 1 mol/l HCl (25 ml) and stirred for 1 h at room temperature. The mixture is neutralized with a saturated solution of sodium bicarbonate and sec is given. The aqueous layer was extracted with dichloromethane (10 × 25 ml). The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute AcOEt. Specified in the title compound obtained as a pale yellow solid (1.7 g, 87.9 per cent).

1H NMR (CDCl3) δ 2,95 (t, 1H, J=5.6 Hz), 4,07 (s, 2H), to 4.62 (d, 2H, J=5,1 Hz), 5,13 (t, 1H, J=1.6 Hz), 6,04 (s, 1H).

Stage 4: Getting 4H-5-thia-1,6a-diazapentane-2-carbaldehyde

Solution in dry dichloromethane (8 ml) dimethylsulfoxide (2.2 ml) is added dropwise to a solution in dry dichloromethane (110 ml) oxalicacid (2.0 ml) at -78°C. the Reaction mixture was stirred for 15 min at the same temperature. Solution in dry dichloromethane (40 ml) (4H-5-thia-1,6a-diazapentane-2-yl)methanol (1.7 g) is added dropwise to the reaction mixture at -78°C and stirring is continued for an additional 15 min the Reaction mixture was allowed to warm to -45°C and stirred for 1 hour Triethylamine (11.3 ml) is added dropwise and the reaction mixture was allowed to warm to 0°C. After 20 min, add a saturated solution of ammonium chloride (50 ml) and water (100 ml) and separate the mixture. The aqueous layer was extracted with AcOEt (3 × 150 ml). The combined organic layers washed with water (200 ml) and saturated salt solution (200 ml), drying the (MgSO 4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with hexane-AcOEt (1:1). Specified in the title compound obtained as yellow solid (1.7 g, quantitative yield).

1H NMR (CDCl3) δ of 4.13 (s, 2H), 5,26 (d, 2H, J=1.4 Hz), 6,59 (s, 1H), 9,90 (s, 1H).

Stage 5: Obtain the sodium salt of (5R)(6Z)-7-oxo-6-(4H-5-thia-1,6a-diazapentane-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Solution in dry acetonitrile (92 ml) 4H-5-thia-1,6a-diazapentane-2-carbaldehyde (1.7 g) are added to a solution in dry acetonitrile (92 ml) MgBr2(5.0 g) in a nitrogen atmosphere at room temperature, the mixture is then stirred for 10 minutes a Solution in dry THF (184 ml) p-nitrobenzyl-(5R,6S)-6-bromine-3-carboxylate (4.3 g) is added and the mixture is cooled to -20°C, then add triethylamine (7.4 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 3 h at -20°C and treated with 4-dimethylaminopyridine (138 mg) and acetic anhydride (2.1 ml) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. an Aqueous solution of 1 mol/l citric acid (1000 ml) is added to the reaction mixture and the aqueous layer was extracted with ethyl acetate (3 × 400 ml). Unite the military organic layers washed with water, a saturated solution of sodium bicarbonate and a saturated solution of salt, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the crude p-nitrobenzyl ester (5R)-6-[acetoxy(4H-5-thia-1,6a-diazapentane-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid obtained as a brown amorphous substance.

Sizeaction Zn dust (19.3 g) just add 0.5 mol/l phosphate buffer (pH 6.5, 100 ml) to a solution in THF (100 ml) of crude p-nitrobenzyl of ester (5R)-6-[acetoxy(4H-5-thia-1,6a-diazapentane-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2.5 h at room temperature. The reaction solution is filtered through a pad of celite and the pad washed with water (200 ml) and n-butanol (200 ml). The aqueous layer was separated and then the organic layer is extracted with 0.5 mol/l phosphate buffer (pH 6.5, 2 × 50 ml). The combined organic layers are concentrated to 90 g, was added 1 mol/l NaOH to bring the pH to 8.0, and subjected to column chromatography on resin Diaion HP-21 (180 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with water and then 15% aqueous solution of acetonitrile. The combined active fractions are concentrated in a high vacuum at 35° and lyophilised, getting listed in the title compound as a yellow amorphous solid (634 mg, 17.4%and a pH of 7.25). TPL 150°C (decomposition).

1H NMR (D2O) δ 4,00 (s, 2H), 5,09 (s, 2H), 6,14 (s, 1H), 6,36 (s, 1H), 6,91 (s, 1H), 6,92 (s, 1H); IR (KBr) 3381, 1752, 1683, 1600, 1558 cm-1; λmax(H2O) 292, 196 nm.

Example 32

Obtaining the sodium salt of (5R)(6Z)-6-(2,3-dihydropyrazolo[5,1-b]thiazole-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: Obtaining 3-oxo-3a,4-dihydro-3H,6H-2-oxa-4-thia-1-Aza-6a-azonia-3a-pentalene

To a suspension of thiazolidin-2-carboxylic acid (39.9 g, 0.30 mol) in 1000 ml of acetic acid is added a solution of 31.0 g (0.45 mol) of sodium nitrite in 500 ml of water for 13 minutes at room temperature and stirred for 5 hours. The reaction solution is concentrated under reduced pressure. To the residue add acetone (500 ml) and the precipitate is filtered through a pad of celite. The pad was washed with acetone (500 ml). The filtrate is concentrated under reduced pressure to dryness and the crude 3-nitrothiazole-2-carboxylic acid is obtained as a yellow solid.

To a solution of crude 3-nitrothiazole-2-carboxylic acid in 600 ml of dry tetrahydrofuran add triperoxonane anhydride (189,6 g, 0.90 mol) for 20 minutes in a nitrogen atmosphere at 0°C and stirred for 19 hours at 0°C. Races is the thief concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel column and then elute with a mixture of n-hexane-ethyl acetate (1:1). Specified in the title compound obtained as pale brown crystals (19.2 g, 44.5 percent).

1H NMR (CDCl3) δ 3,98 (t, 2H, J=7,7 Hz)and 4.65 (t, 2H, J=7,7 Hz).

Stage 2: Getting ethyl ether complex of 2,3-dihydropyrazolo[5,1-b]thiazole-6-carboxylic acid and ethyl ether complex of 2,3-dihydropyrazolo[5,1-b]thiazole-7-carboxylic acid

Ethylpropyl (20,3 ml, 0.20 mol) are added to a solution in o-xylene (600 ml) of 3-oxo-3a,4-dihydro-3H,6H-2-oxa-4-thia-1-Aza-6a-azonia-3a-pentalene (19.2 g, 0.13 mol) in nitrogen atmosphere and boil with the return of phlegmy for 21 hours. The solution is cooled to room temperature and concentrate under reduced pressure. The residue is subjected to column chromatography on silica gel column and then elute with a mixture of n-hexane-ethyl acetate (2:21 to 1:1). A mixture of ethyl ether complex of 2,3-dihydropyrazolo[5,1-b]thiazole-6-carboxylic acid and ethyl ether complex of 2,3-dihydropyrazolo[5,1-b]thiazole-7-carboxylic acid obtained as brown oil in the ratio 1:1.5, respectively. (21.2 g, Output: 80,0%).

Ethyl ester of 2,3-dihydropyrazolo[5,1-b]thiazole-6-carboxylic acid:1H NMR (CDCl3) δ of 1.39 (t, 3H, J=7,1 Hz), 3,82 (t, 2H, J=7.5 Hz), 4,39 (q, 2H, J=7,1 Hz), 4,42 (t, 2H, J=7.5 Hz), of 6.52 (s, 1H).

Ethyl Konyagin 2,3-dihydropyrazolo[5,1-b]thiazole-7-carboxylic acid: 1H NMR (CDCl3) δ of 1.34 (t, 3H, J=7,1 Hz), 3,85 (t, 2H, J=7.8 Hz), 4,28 (q, 2H, J=7,1 Hz), 4,39 (t, 2H, J=7.8 Hz), 7,87 (s, 1H).

Stage 3: 2,3-dihydropyrazolo[5,1-b]thiazole-6-carbaldehyde and 2,3-dihydropyrazolo[5,1-b]thiazole-7-carbaldehyde

To the mixture [of 21.2 g (0.11 mol)] ethyl ether complex of 2,3-dihydropyrazolo[5,1-b]thiazole-6-carboxylic acid and ethyl ether complex of 2,3-dihydropyrazolo[5,1-b]thiazole-7-carboxylic acid in 540 ml of dry tetrahydrofuran added LiAlH4(of 4.05 g, 0.11 mol) in nitrogen atmosphere at 0°C and then stirred for 2.5 hours at room temperature. The mixture was quenched with water (15 ml) and the precipitate is filtered through a pad of celite. The pad is washed with water (100 ml) and tetrahydrofuran (500 ml). The filtrate is concentrated under reduced pressure and then add water (150 ml). The aqueous layer was extracted with dichloromethane (15 × 250 ml). The combined organic layers are dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the mixture of (2,3-dihydropyrazolo[5,1-b]thiazol-6-yl)methanol and (2,3-dihydropyrazolo[5,1-b]thiazol-7-yl)methanol obtained as a pale brown oil (15.5 g).

To a mixture of [15.5 g (0.10 mol)] (2,3-dihydropyrazolo[5,1-b]thiazol-6-yl)methanol and (2,3-dihydropyrazolo[5,1-b]thiazol-7-yl)methanol in 500 ml of chloroform, add activated MnO2(77,7 g) in a nitrogen atmosphere at room temperature and then boiled with the return FLEG is s for 3 hours. The mixture is filtered through a pad of celite and the filtrate concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel column and then elute with a mixture of hexane-ethyl acetate (2:1 to 1:1). Specified in the title compound 2,3-dihydropyrazolo[5,1-b]thiazole-6-carbaldehyde obtained as yellow crystals (2.50 g, 15.2%) and 2,3-dihydropyrazolo[5,1-b]thiazole-7-carbaldehyde obtained as a pale brown solid (5,57 g, 33.8 percent).

2,3-Dihydropyrazolo[5,1-b]thiazole-6-carbaldehyde:1H NMR (CDCl3) δ 3,86 (t, 2H, J=7.5 Hz), of 4.45 (t, 2H, J=7.5 Hz), 6,50 (s, 1H), 9,83 (s, 1H).

2,3-Dihydropyrazolo[5,1-b]thiazole-7-carbaldehyde:1H NMR (CDCl3) δ to 3.92 (t, 2H, J=7.9 Hz), and 4.40 (t, 2H, J=7.9 Hz), to $ 7.91 (s, 1H), 9,76 (s, 1H).

Stage 4: Obtain the sodium salt of (5R)(6Z)-6-(2,3-dihydropyrazolo[5,1-b]thiazole-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Solution in dry acetonitrile (19 ml) of 2,3-dihydropyrazolo[5,1-b]thiazole-6-carbaldehyde (2.50 g, 16.2 mmol) are added to a solution in dry acetonitrile (106 ml) MgBr2(3,67 g to 19.9 mmol) under nitrogen atmosphere at room temperature, the mixture is then stirred for 10 minutes. Solution in dry tetrahydrofuran (125 ml) p-nitrobenzyl-(5R, 6S)-6-bromine-3-carboxylate (6,23 g, 16.2 mmol) is added and the mixture is cooled to -20°C, then add triethylamine (5.4 ml, of 38.7 mmol) in one portion. The reaction is Oud cover with foil, to exclude light. The reaction mixture is stirred for 3 hours at -20°C and treated with 4-dimethylaminopyridine (198 mg, of 1.62 mmol) and acetic anhydride (3.1 ml, from 32.9 mmol) in one portion. The reaction mixture is heated to 0°C and stirred for 16 hours at 0°C. ethyl Acetate (500 ml) is added to the reaction mixture and then the organic layer was washed with aqueous solution of 1 mol/l citric acid, saturated sodium hydrogen carbonate solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the crude p-nitrobenzyl ester (5R)-6-[acetoxy(2,3-dihydropyrazolo[5,1-b]thiazol-6-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid obtained as a brown amorphous solid.

Sizeaction Zn dust (or 37.4 g) just add 0.5 mol/l phosphate buffer (pH 6.5, 196 ml) to the solution in tetrahydrofuran (134 ml) and acetonitrile (62 ml) p-nitrobenzylamine of ester (5R)-6-[acetoxy(2,3-dihydropyrazolo[5,1-b]thiazol-6-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 1.5 hours at room temperature. The reaction mixture is cooled at 0°C and then the pH was adjusted to 8.0. Ethyl acetate (100 is l) are added to the reaction mixture. The mixture is filtered through a pad of celite and the pad washed with water (300 ml). The aqueous layer was separated and then the organic layer is extracted with 0.5 mol/l phosphate buffer (pH 6.5, 2 × 50 ml). the pH of the combined organic layer was adjusted to 8.0 and the mixture is concentrated to 426, the Concentrate was adjusted to pH 8.0 and subjected to column chromatography on resin Diaion HP-21 (540 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with water (1 volume of the layer) and then 5% (2 volume layer), 10% (2 volume layer) and 20% aqueous solution of acetonitrile. The combined active fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as an orange amorphous solid (2,09 g, 39.2 per cent, pH 7,10). TPL 150°C (decomposition).

1H NMR (D2O) δ of 3.75 (t, 2H, J=7.5 Hz), 4,27 (t, 2H, J=7.5 Hz), 6,00 (s, 1H), 6,34 (s, 1H), 6,85 (s, 1H), 6,94 (s, 1H); IR (KBr) 3392, 1755, 1596, 1554 cm-1; λmax(H2O) 290, 223 nm.

Example 33

Obtaining the sodium salt of (5R)(6Z)-6-(2,3-dihydropyrazolo[5,1-b]oxazol-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: Getting ethyl-2,3-dihydropyrazolo[5,1-b][1,3]oxazol-6-carboxylate

To a stirred suspension of ethyl-5-hydroxy-1H-pyrazole-3-carboxylate (10,34 g, 0.66 mol) and 36,62 g of potassium carbonate in 500 ml of acetonitrile add 13,68 g of 1,2-dibromoethane and boil with the return of phlegmy is for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid washed with acetonitrile. The filtrate is concentrated to oil. The residue is dissolved in ethyl acetate and extracted with water. The organic phase is dried over MgSO4and evaporated to dryness. Get 5,80 g of the desired product (48%).

Stage 2: Obtain 2,3-dihydropyrazolo[5,1-b][1,3]oxazol-6-methanol

To a stirred solution of ethyl-2,3-dihydropyrazolo[5,1-b][1,3]oxazol-6-carboxylate (vs. 5.47 g, 35 mmol) in 100 ml THF added to 1.05 g of lithium borohydride and 1.54 g of methanol. The solution is heated at 40°C for 2.5 hours. The reaction mixture was quenched with 1 N. HCl and adjusted to pH 1.3 and stirred at room temperature for 1 hour. The reaction mixture was adjusted K2CO3to pH 8. The reaction mixture was extracted with ethyl acetate. The organic layer is dried over MgSO4and concentrated to oil and subjected to column chromatography, obtaining of 2.68 g of the desired product (65%).

Stage 3: Obtain 2,3-dihydropyrazolo[5,1-b][1,3]oxazol-6-carbaldehyde

To a stirred solution of 2,3-dihydropyrazolo[5,1-b][1,3]oxazol-6-methanol (2,60 g, 18.5 mmol) in 60 ml of CH3Cl add 12,9 g MnO2. The suspension is boiled with the return of phlegmy for 1.5 hours under nitrogen atmosphere. The reaction mixture was filtered through a pad of celite. The filtrate is concentrated and receiving VC is the OE oil. The product was then purified by chromatography. Obtain 2.15 g of product (84.3 percent).

Stage 4: 4-nitrobenzyl-(5R)-6-[(atomic charges)(2,3-dihydropyrazolo [5,1-b][1,3]oxazol-6-yl)-)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

2,3-dihydropyrazolo[5,1-b][1,3]oxazol-6-carbaldehyde (607 mg, 4.3 mmol) and a solution in dry THF (20 ml) of 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (1.54 g, 4.6 mmol) are added sequentially to a solution in dry acetonitrile (15 ml), anhydrous MgBr2:O(Et)2(of 2.21 g, 8.5 mmol) in an argon atmosphere at room temperature. After cooling to -20°C add Et3N (2.0 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20°C and treated with acetic anhydride (1.04 million ml) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered through a pad of celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of ethyl acetate:GE is San (1:1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers take to the next stage. Pale yellow amorphous solid. Yield: 1.9 g, 81%. M+H 566.

H NMR (CDCl3) 8,24 (2H, d, J=6.6 Hz), 7,60 (2H, d, J=6.6 Hz), 7,44 (1H, s)6,34 (1H, s), 6,23 (1H, s)to 5.56 (1H, s), 5,44 (1H, d, J=10,2 Hz), 5,27 (1H, d, J=10,2 Hz), 5,04 (2H, m), 4,30 (2H, m), 2,10 (3H, s).

Analysis. Calculated for C21H17BrN4O8S: C 44,61, H 3,03, N to 9.91

Found: C 45,00, H 3,14, At 9.53 N.

Stage 5: sodium salt of (5R,6Z)-6-(2,3-dihydropyrazolo[5,1-b][1,3]oxazol-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

4-Nitrobenzyl-6-[(atomic charges)(2,3-dihydropyrazolo[5,1-b][1,3]oxazol-6-yl)-)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (700 mg, 1.2 mmol) dissolved in THF (20 ml), acetonitrile (10 ml) and 0.5 M phosphate buffer (pH 6.5, 28 ml) and hydrogenizing over 10% Pd/C under pressure of 40 pounds per square inch. After 4 h the reaction mixture was filtered, cooled to 3°C and add 0.1 M NaOH to bring the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated in high vacuum at 35°C, receiving a yellow precipitate. The product was then purified by chromatography with reversed-phase column with resin NR. First column elute with deionized water (2 liters) and later a mixture of 10% acetonitrile:water. The fractions containing the product are collected and concentrated under reduced is th pressure at room temperature. The yellow solid is washed with acetone and filtered. Dried. Output: 276 mg, 73%, as a yellow amorphous solid. (M+H+Na) 314.

1H NMR (D2O) δ 6,97 (1H, s), to 6.95 (1H, s), 6,46 (1H, s)to 5.56 (1H, s), 5,07 (2H, d, J=6.3 Hz), 4,30 (2H, t, J=6.3 Hz).

Example 34

Obtain (5R,6Z)-6-[(5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methylene]oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (mixture of E+Z isomers, sodium salt)

Stage 1: 5-acetyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-carbaldehyde

To a cold (0° (C) suspension of 1.5 g (7.4 mmol) of the hydrochloride 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carbaldehyde in 50 ml of methylene chloride in an atmosphere of N2in dry conditions is added dropwise with stirring to 2.6 ml (2.5 EQ.) of triethylamine. RS stirred for 30 min at 0°C and a solution of 0.7 g (8.1 mmol, 1.1 EQ.) acetylchloride in 15 ml of methylene chloride is added dropwise, the RS can achieve CT and stirred for 3 hours. Filtered through a pad of celite, the filtrate is washed with 3 × 50 ml of water, dried, evaporated, obtaining 1.1 g (71,4%) specified in the title compound, a viscous oil, (M+H)+210,3.

Stage 2: Obtain 4-nitrobenzyl-(5R)-6-[(atomic charges)(5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-EN-carboxylate

5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carbaldehyde (540 mg, 2.57 m is mol) and a solution in dry THF (20 ml) of 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (950 mg, 2.5 mmol) are added sequentially to a solution in dry acetonitrile (15 ml), anhydrous MgBr2:O(Et)2(of 2.21 g, 8.5 mmol) in an argon atmosphere at room temperature. After cooling to -20°C add Et3N (2.0 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20°C and treated with acetic anhydride (1.04 million ml) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered through a pad of celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with a mixture of ethyl acetate:hexane (1:1).

The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers take to the next stage. Pale yellow amorphous solid. Output: 870 mg, 53%. TPL 46-48°C. (M+H)+637,6.

1H NMR (CDCl3) δ 2,15 (t, 6H), 2.8 to 3.0 (m, 2H), of 3.7-3.9 (m, 2H), 4,58-and 4.68 (m, 2H), and 5.30-of 5.45 (DD, 2H), to 5.85 (d, 1H), of 6.71 (s, 1H), 6,95 (s, 1H), 7,35-7,45 (d, 1H), 7,60 (DD, 2H), 8,25 (DD, 2H).

Stage 3: (5R,6Z)-6-[(5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]is iridin-2-yl)methylene]oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (Mixture of E+Z isomers. Sodium salt)

A solution of 0.77 g (1,21 mmol) 4-nitrobenzyl-(5R)-6-[(atomic charges)(5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in 40 ml of THF and 40 ml of phosphate buffer (pH 6,36) hydrogenizing under pressure of 40 psi for 3 hours in the presence of 0.4 g of catalyst 10% palladium on carbon. The reaction mixture was filtered through a pad of celite, the filtrate is brought to pH 8.0, concentrated in vacuo, the residue is purified on a column of reversed phase (amberlite)using a mixture of 5%-10% ACM/water as solvent, getting 0,107 g (23%) specified in the connection header, reddish crystals, TPL 362,4°C, (M+H)+409,5.

1H NMR: δ of 2.08 (s, 3H), 2,80-2,95 (m, 1H), 3,74 (m, 2H), 3,9-4,06 (d, 2H), 6,32-6.42 per (s, 1H), 6,50-6,60 (s, 1H), 6,98-7,20 (s, 1H), 7,30-7,40 (s, 1H).

Example 35

Obtain (5R,6Z)-6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: 4-nitrosomorpholine-3-carboxylic acid

To a solution of morpholine-3-carboxylic acid (of 6.96 g, 52 mmol) in water (20 ml) at 0°C in nitrogen atmosphere add concentrated hydrochloric acid (4 ml)and then sodium nitrite (5.0 g, 72 mmol) in small portions. The mixture was stirred at 0°C for 1 h and then concentrated in vacuo at 30-35°C. the Residue is stirred with 200 ml of AC the tone and filtered. The filtrate is evaporated and the residue treated with 50 ml of THF and concentrated. The process is repeated with 2 × 50 ml of THF, getting 11.87 per g of light yellow foam. MC (ESI) m/z 159,2 (M-H).

Stage 2: 6,7-dihydro-4H-[1,2,3]oxadiazole[4,3-c][1,4]oxazin-8-s-3-Olathe

Crude 4-nitrosomorpholine-3-carboxylic acid (11,0 g) from step 1 was dissolved in THF (250 ml) and cooled to 0°C. the Solution triperoxonane anhydride (7.4 ml, 52 mmol) in THF (20 ml) is added with stirring for 10 minutes the resulting mixture was stirred at 0°C for 5 h and warmed to room temperature for 16 hours the Solvent is evaporated and the residue is diluted with 250 ml ethyl acetate and stirred with 30 g of anhydrous potassium carbonate. The mixture is filtered through a pad of silica gel and the filtrate is evaporated. The residue is washed with a mixture of ethyl acetate-simple broadcast receiving 3.80 g of a white solid. TPL 132-133°C, MC (ESI) m/z 143,1 (M+H).

Stage 3ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-carboxylate

To a partial solution of 6,7-dihydro-4H-[1,2,3]oxadiazole[4,3-c][1,4]oxazin-8-s-3-olate (3,41 g, 24 mmol) in o-xylene (80 ml) is added ethylpropyl (2.7 ml, 26 mmol). The mixture is stirred at 140°C for 3 hours Then add an additional 2.0 ml (19 mmol) ethylpropyl and the mixture is stirred while boiling with the return of phlegmy within 18 hours of the Final solution is evaporated in vacuum and the residue dissolved in a mixture of methyl is of chloride and hexanol (1:5). The solution passed through a pad of silica gel and the filter pad elute with a mixture of methylene chloride-hexane, and then ethyl acetate. An ethyl acetate eluent is evaporated and the residue is washed with hexane getting 4,10 g of a white solid. TPL 63°C; MS (ESI) m/z 197,1 (M+H).

Stage 4: 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylmethanol

To a solution of ethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-carboxylate (1.57 in g, 8.0 mmol) in methylene chloride (30 ml) is added 24 ml of 1.0 M solution of hydride diisobutylaluminum in methylene chloride at 0°C in nitrogen atmosphere. After stirring for 0.5 h at 0°C the mixture is heated to room temperature for 2 hours Then treated with 30 ml of saturated solution of ammonium chloride and extracted with ethyl acetate. The organic solution was washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered and evaporated, getting 1.27 g of colorless oil. MS (ESI) m/z was 155.3 (M+H).

Stage 5: 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-carbaldehyde

To a solution of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylmethanol (1.08 g, 7.0 mmol) in 1,2-dichloroethane (30 ml) is added to 5.4 g of activated manganese dioxide at room temperature under stirring. The mixture is heated to 60°C for 1 h and then stirred at room temperature for 16 hours the Final mixture is filtered through a column of forces is of Kagel with those at the very top of telicom. Filter pad elute with methylene chloride and then with ethyl acetate. An ethyl acetate eluent is evaporated and the residue triturated getting 0,81 g of a white solid. TPL 91°C. MS (ESI) m/z 153,2 (M+H).

Stage 6: 4-nitrobenzyl-(5R)-6-[(atomic charges)(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

To a solution of MgBr2(0,94 g, 5.1 mmol) in acetonitrile (25 ml) under nitrogen atmosphere add 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-carbaldehyde (0.26 g, 1.7 mmol) at room temperature under stirring. Then add a solution of 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (of 0.58 g, 1.5 mmol) in THF (25 ml) and the mixture is cooled to -20°C. Enter triethylamine (of 0.71 ml, 5.1 mmol) and the mixture was stirred at -20°C in the dark for 5 hours Then treated with acetic anhydride (0.6 ml, 6,0 mmol) and 4-N,N-dimethylaminopyridine (24 mg, 0.2 mmol) and maintained at 0°C for 18 hours the Mixture is concentrated and the residue is dissolved in ethyl acetate. An ethyl acetate solution is washed with 5% citric acid, saturated sodium bicarbonate solution and saturated salt solution, dried over anhydrous sodium sulfate and evaporated. The crude material is subjected to chromatography on silica gel (EtOAc-CH2Cl2/1:5), receiving of 0.77 g of white foam. MS (ESI) m/z 578,9 (M+H).

Article is Diya 7 : (5R,6Z)-6-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

To a solution of 4-nitrobenzyl-(5R)-6-[(atomic charges)(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.35 g, 0.6 mmol) in THF (20 ml) under nitrogen atmosphere add 20 ml of phosphate buffer (0.5 M, pH 6.5) and 120 mg 10% Pd/C. the Mixture hydrogenizing under pressure 40-50 psi for 3 h and then filtered through celite. Filter pad washed with THF and the filtrate is extracted with ethyl acetate. The organic extract is dried over anhydrous magnesium sulfate and evaporated. The residue is washed by a simple broadcast receiving 0.09 g yellow solid. HRMS: calculated for C13H11N3O4S 305,0470; found (ESI+), 306,05434.

1H NMR (DMSO-d6) δ 4,07-4.09 to (t, 2H), 4,13-4,17 (t, 2H), 4,82 (s, 2H), 6,36 (s, 1H), 6,55 (s, 1H), 7,17 (s, 1H), 7,55 (s, 1H), 12,80 (USS, 1H).

Example 36

Obtaining the sodium salt of (5R)(6Z)-6-(6,7-5H-dihydropyrazolo[5,1-b]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Stage 1: Getting ethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-carboxylate

To a stirred suspension of ethyl-5-hydroxy-1H-pyrazole-3-carboxylate (10,34 g, 0.66 mol) and 36,62 g of potassium carbonate in 500 ml of acetonitrile add to 14.7 g of 1,3-dibromopropane and boil with the return of phlegm is for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid washed with acetonitrile. The filtrate is concentrated to oil. The residue is dissolved in ethyl acetate and extracted with water. The organic phase is dried over MgSO4and evaporated to dryness. Get 8,80 g of the desired product (68%). TPL 44-46°C. (M+H)+197,1.

Stage 2: Obtain 2,3-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-ylmethanol

To a stirred solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-carboxylate (4.0 g, 20 mmol) in 100 ml THF added 0.71 g of lithium borohydride and 1.03 g of methanol. The solution is heated at 40°C for 2.5 hours. The reaction mixture was quenched with 1 N. HCl and adjusted to pH 1.3 and stirred at room temperature for 1 hour. The reaction mixture is brought to pH 8 with K2CO3. The reaction mixture was extracted with ethyl acetate. The organic layer is dried over MgSO4and concentrated to oil and subjected to column chromatography, obtaining of 2.08 g of the desired product (67%). (M+H) 155.

Stage 3: Obtain 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-carbaldehyde

To a stirred solution of 2,3-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-ylmethanol (2,08 g, 13.5 mmol) in 60 ml of CH3Cl add 9,38 g MnO2. The suspension is boiled with the return of phlegmy for 2 hours in nitrogen atmosphere. The reaction mixture is filtered through what okladka of celite. The filtrate is concentrated, receiving a yellow oil. The product was then purified by chromatography. Obtain 2.15 g of product (78%).

Stage 4: 4-nitrobenzyl-(5R)-6-[(atomic charges)(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-carbaldehyde (330 mg, 2 mmol) solution in dry THF (20 ml) of 4-nitrobenzylamine of ester (5R,6S)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0,794 g, 2.2 mmol) are added sequentially to a solution in dry acetonitrile (15 ml), anhydrous MgBr2:O(Et)2(1.2 g) in an argon atmosphere at room temperature. After cooling to -20°C add Et3N (2.0 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 2 h at -20°C and treated with acetic anhydride (1.04 million ml) in one portion. The reaction mixture is heated to 0°C and stirred for 15 h at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution and saturated salt solution. The organic layer is dried (MgSO4) and filtered through a pad of celite. The pad is washed with ethyl acetate. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then is Alonso elute with a mixture of ethyl acetate:hexane (1:1). The collected fractions are concentrated under reduced pressure and the mixture of diastereoisomers take to the next stage. Pale yellow amorphous solid. Output: 0,76 g, 65%. M+H 579.

Stage 5: sodium salt of (5R)(6Z)-6-(6,7-5H-dihydropyrazolo[5,1-b]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylic acid

4-Nitrobenzyl-(5R)-6-[(atomic charges)(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (350 mg, 0.6 mmol) dissolved in THF (20 ml), acetonitrile (10 ml) and 0.5 M phosphate buffer (pH 6.5, 28 ml) and hydrogenizing over 10% Pd/C under a pressure of 40 psi. After 4 h the reaction mixture was filtered, cooled to 3°C and add 0.1 M NaOH to bring the pH to 8.5. The filtrate is washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated in high vacuum at 35°C, receiving a yellow precipitate. The product was then purified by chromatography with reversed-phase column with resin NR. First column elute with deionized water (2 liters) and later a mixture of 10% acetonitrile:water. The fractions containing the product are collected and concentrated under reduced pressure at room temperature. The yellow solid is washed with acetone and filtered. Dried. Yield: 103 mg, 52%, as a yellow amorphous solid. (M+H+Na) 327.

1H NMR (D2O) δ 6,97 (1H, s), 6,93 (1H, 8), 6,47 (1H, s), the 5.65 (1H, s) to 4.28 (2H, is), 4,10 (2H, m), of 2.21 (2H, m).

Example 37

Getting disodium salt of (5R),(6Z)-6-[5-(3-carboxypropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid

The specified connection is obtained by procedures described in General terms in the above examples. On the basis of the sodium salt of (5R),(6Z)-6-{5-[3-(4-nitrobenzenesulfonyl)propionyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (467 mg) and hydrogenative it over Pd/C (10%), isolated 276 mg (74%) of disodium salt of (5R),(6Z)-6-[5-(3-carboxypropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid as a yellow amorphous solid. TPL 180°C (decomposition).

1H NMR (D2O) δ to 2.41 (t, 2H), 2,42 (t, 2H), to 2.67 (t, 2H), rating of 2.72 (t, 2H), 3.95 to 4.09 to (m, 2H), 4,18 (t, 2H), 4,28 (t, 2H), and 4.75 (s, 2H), to 4.87 (s, 2H), 6,33 (s, 1H), 6,34 (s, 1H), 6,53 (s, 1H), 7,00 (s, 1H), 7,09 (s, 1H).

Example 38

Obtaining the sodium salt of (5R),(6Z)-6-[5-(2-methoxyacetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid

Sodium salt of (5R),(6Z)-7-oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (Example 25)

To a solution in THF (64 ml) and H2O (64 ml) sodium salt of (5R),(6Z)-7-oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (Example 25) (638 mg) slowly add 0.1 M aqueous NaOH, to bring the pH to 12.5, 0°C. To the mixture add methoxyacetanilide (0,28 ml) for 5 minutes the Mixture is stirred for 0.5 h at 0°C and methoxyacetanilide (0,09 ml) is added to the mixture. After stirring the mixture for 0.5 h at the same temperature, add 0.1 M aq. NaOH to bring the pH to 8.05. The mixture was concentrated in high vacuum at 35°C. the Concentrate is subjected to column chromatography on resin Diaion HP-21 (78 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute H2O-MeCN (1:0 to 9:1). Combined fractions are concentrated in a high vacuum at 35°C and lyophilized, getting mentioned in the title compound as a yellow amorphous solid (509 mg, 65%, pH 7,58). TPL 170°C (decomposition).

1H NMR (D2O) δ or 3.28 (s, 3H×1/2), 3,29 (s, 3H×1/2), of 3.78 (t, 2H×1/2, J=5.4 Hz), 3,89-3,93 (m, 2H×1/2), 4.09 to (t, 2H×1/2, J=5.4 Hz), 4,14 (t, 2H×1/2, J=5.4 Hz), 4,20 (s, 2H,×1/2), 4,25 (s, 2H×1/2), br4.61 (s, 2H×1/2), of 4.66 (s, 2H×1/2), to 6.19 (s, 1H×1/2), from 6.22 (s, 1H×1/2), 6,37 (s, 1H×1/2), 6,372 (s, 1H×1/2), 6.87 in (s, 1H), 6,93 (s, 1H).

Example 39

Obtaining the sodium salt of (5R),(6Z)-6-[5-(2-methoxyacetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid

(4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol

Methanol (150 ml) is added to a mixture of 4-nitrobenzylamine of ester 2-hydroxymethyl-6,7-dig the DRO-4H-pyrazolo[1,5-a]pyrazin-5-carboxylic acid (Example 25) (2.38 g) and 10% Pd-C (50% relative humidity, 1.19 g). The reaction mixture is stirred for 2 hours in hydrogen atmosphere. The mixture is filtered and concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute 50% methanol in chloroform. Specified in the title compound obtained as a white solid (1.08 g, 98%).

1H NMR (400 MHz, CD3OD) δ 3,22-of 3.25 (m, 2H), 3,99 (s, 2H), 4,03-4,06 (m, 2H), to 4.52 (s, 2H), the 6.06 (s, 1H).

[5-(4,5-Dihydrothiazolo-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethanol

A solution of hydrogen chloride (2 mol/l) in a simple diethyl ether (0.7 ml) are added to a solution in methanol (20 ml) (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (1.08 g) and 2-methylsulfanyl-4,5-dihydrothiazolo (1,03 g). The reaction mixture is boiled with the return of phlegmy within 4 days. The mixture was quenched with a small amount of saturated potassium carbonate solution, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then the column elute with 10% methanol in chloroform. Specified in the title compound obtained as white solids (1,49 g, 89%).

1H NMR (400 MHz, CDCl3) δ 2,04 (USS, 1H), 3,39 (t, 2H, J=7.5 Hz), 3,90 (t, 2H, J=5.3 Hz), 4,06 (t, 2H, J=7.5 Hz), is 4.21 (t, 2H, J=5.3 Hz), of 4.66 (s, 2H), 4,69 (s, 2H), 6,07 (s, 1H).

Sodium salt of (5R),(6Z)-6-[5-(4,5-dihydrothiazolo-2-yl)-4,5,6,7-tet is aeropuertola[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Activated manganese oxide (IV) (x 16.75 g) is added to the mixture solution in chloroform (180 ml) of [5-(4,5-dihydrothiazolo-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]methanol (3,35 g) at room temperature. The reaction mixture is boiled with the return of phlegmy within 1 h After boiling with the return of phlegmy the mixture is filtered through a pad of celite and the filtrate concentrated under reduced pressure. The residue is dried in vacuum and the crude 5-(4,5-dihydrothiazolo-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-carbaldehyde obtained as colorless solid. Thus obtained crude aldehyde (2,56 g) are added to a solution in dry acetonitrile (200 ml) MgBr2(of 7.36 g) in a nitrogen atmosphere at room temperature, the mixture is then stirred for 10 minutes. Solution in dry THF (200 ml) WLJ 20,014 (4,16 g) added and the mixture is cooled to -20°C. Then add triethylamine (11.3 ml) in one portion. The reaction vessel is covered with foil to exclude light. The reaction mixture was stirred for 1.5 hours at -20°C and treated with 4-dimethylaminopyridine (132 mg) and acetic anhydride (4,2 ml) in one portion. The reaction mixture is heated to 0°C and stirred for 20 hours at 0°C. the Mixture is diluted with ethyl acetate and washed with 5% aqueous citric acid solution, saturated sodium hydrogen carbonate solution and a saturated solution Sol is. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, then elute with a mixture of n-hexane-AcOEt (1:2) and a mixture of chloroform-methanol (9:1). Receive a 4-nitrobenzyloxy ester (5R,6RS)-6-{(RS)-acetoxy[5-(4,5-dihydrothiazolo-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]methyl}-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (5,41 g, 75.4 per cent).

4-Nitrobenzyloxy ester (5R,6RS)-6-{(RS)-acetoxy[5-(4,5-dihydrothiazolo-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl]methyl}-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (5,41 g) dissolved in THF (76 ml) and acetonitrile (35 ml). Sizeaction Zn dust (21,6 g) and 0.5 mol/l phosphate buffer (pH 6.5, 111 ml) is added to the mixture. The reaction vessel is covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 hours at 30-35°C. the Reaction mixture is cooled at 0°C and then the pH was adjusted to 7.6. Ethyl acetate is added to the reaction mixture and filtered through a pad of celite. The pad is washed with water and the aqueous layer was separated. The aqueous layer was concentrated in high vacuum at 35°C. the Concentrate is subjected to column chromatography on resin Diaion HP-21 (170 ml, Mitsubishi Kasei Co. Ltd.). After the adsorption is carried column elute with water and then 5%-15% aqueous solution of acetonitrile. Unite the military active fraction was concentrated in a high vacuum at 35° C and lyophilized, getting mentioned in the title compound as a crude yellow amorphous solid (1.60 g).

The crude compound purified preparative HPLC (Mightysil RP-18GP, KANTO CHEMICAL CO., INC., 35 × 250 mm, 0.05 mol/l phosphate buffer (pH 7,1):acetonitrile = 80:20, 25 ml/min) followed by desalting resin Diaion HP-21 (150 ml, Mitsubishi Kasei Co. Ltd.), getting listed in the title compound as a yellow amorphous solid (1.06 g, 31.5 per cent, pH 8,33). TPL 100°C (decomposition).

1H NMR (D2O) δ 3,18 (t, 2H, J=7,6 Hz), of 3.60 (t, 2H, J=5.3 Hz), to 3.73 (t, 2H, J=7,6 Hz), of 3.94 (t, 2H, J=5.3 Hz), 4,37 (s, 2H), 6,01 (s, 1H), 6,21 (s, 1H), 6,77 (s, 1H), 6,78 (s, 1H); IR (KBr) 3381, 1752, 1606 cm-1; λmax(H2O) 369, 291, 208 nm.

Example 40

Obtaining the sodium salt of (5R),(6Z)-6-[5-(2-methoxyacetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid

Getting ethyl-2-[(atomic charges)((5R)-6-bromo-2-{[(4-nitrobenzyl)oxy]carbonyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-EN-6-yl)methyl]-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate

Specified in the title compound is obtained from 0,669 g of methyl 2-formyl-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate and 1,155 g of 4-nitrobenzyl-(5R)-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate to yield 1.65 g of product (84%), which is used directly in the next stage. MS: 652,2 (M+H)

Receive (R,6Z)-6-{[6-(etoxycarbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

Specified in the title compound is obtained from of 1.65 g of ethyl-2-[(atomic charges)((5R)-6-bromo-2-{[(4-nitrobenzyl)oxy]carbonyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-EN-6-yl)methyl]-4,7-dihydrofuro[2,3-c]pyridine-6(5H)carboxylate with access 0,386 g of the product (41%). TPL: decomposes at 175°C. MS: 375,0 (M-H).

1H NMR (D2O) δ 6,91 (s, 1H), 6,84 (s, 1H), 6,62 (s, 1H), to 6.39 (s, 1H), to 4.41 (ush., 2H), Android 4.04 (q, 2H, J=5 Hz), 3,52 (ush., 2H), 2,42 (ush., 2H), 1.14 in (t, 3H, J=5 Hz).

1. The compound of the formula I

where one of a and b denotes hydrogen and the other denotes optionally substituted condensed-bicyclic heteroaryl; provided that if the aromatic ring is part of the bicyclic heteroaryl is imidazole, non-aromatic ring part may not contain an S atom adjacent to the head carbon atom bridging group;

X is S;

R5means H, C1-C6-alkyl or C5-C6-cycloalkyl;

or its pharmaceutically acceptable salt,

where the bicyclic heteroarylboronic is

where one of Z1, Z2and Z3independently mean S and other CR2or S, provided that one of Z1-Z3mean carbon and connected to the rest of the molecule;

W1, W2and W3 independently mean CR4R4, S, O or N-R1provided that no formation no S-S or O-O or S-O due to formation of the saturated ring system;

t=1-4;

R1means H, C1-C6-alkyl, C5-C7-cycloalkyl, -C=O-aryl, -C=O(C1-C6)-alkyl, -C=O(C5-C6-cycloalkyl, aryl-C1-C6-alkyl, optionally substituted C1-C6-alkoxy; heteroalkyl-C1-C6-alkyl or C=O(heteroaryl), where heteroaryl represents a 6-membered ring containing 1 nitrogen atom,

R2means hydrogen, C1-C6-alkyl,

R4means H, C1-C6-alkyl.

2. The compound of the formula I

where one of a and b denotes hydrogen and the other denotes optionally substituted condensed-bicyclic heteroaryl; provided that if the aromatic ring is part of the bicyclic heteroaryl is imidazole, non-aromatic ring part may not contain an S atom adjacent to the head carbon atom bridging group;

X is S;

R5means H, C1-C6-alkyl or C5-C6-cycloalkyl;

or its pharmaceutically acceptable salt,

where the bicyclic heteroarylboronic one is camping

where Z1, Z2and Z3independently mean CR2, N, O, S or NH, provided that one of Z1-Z3mean carbon and connected to the rest of the molecule;

W1, W2and W3independently mean CR4R4, S, O or N-R1provided that no formation no S-S or O-O or S-O due to formation of the saturated ring system;

t=1-4;

Y1and Y2independently denote N or C, provided that if the aromatic ring is part of the bicyclic heteroaryl is imidazole, non-aromatic ring part may not contain an S atom adjacent to the head carbon atom bridging group, and

R1means H, C1-C6-alkyl, C5-C7-cycloalkyl, -C=O(C1-C6)-alkyl, -C=O(C5-C6-cycloalkyl, -C(O)C1-C2-alkylcarboxylic, -C(=O)1-C6-alkoxy; or heteroaryl, which represents a 5-membered ring containing the N atom and/or S;

R2means hydrogen,

R4means N or C1-C6-alkyl.

3. The compound according to claim 1, where one of Z1-Z3means CR2.

4. The compound according to claim 2, where one of Z2or Z3means N, O or S.

5. The compound according to any one of claims 1, 3 and 4, where at least one of W1 , W2and W3mean CR4R4.

6. The compound according to claim 5, where W1, W2and W3independently mean CR4R4.

7. The compound according to any one of claims 1, 3-5, where t=1-3.

8. The compound according to claim 2, where t=3.

9. The compound according to claim 2 or 8, wherein at least two of Z1, Z2, Z3, Y1and Y2mean n

10. The connection according to claim 9, where three of Z1, Z2Z3, Y1and Y2mean n

11. The connection according to one of claim 2, 8-10, where two of W1, W2and W3independently mean CR4R4.

12. Connection to item 11, where R4means N.

13. The compound according to any one of claim 2 and 8-12, where one of Y1and Y2means and other means n

14. The compound according to any one of claim 2 and 8-13, where two of Z1, Z2and Z3independently mean CR2.

15. The compound that has the structure

where a, b and R5have the meanings defined in claim 1 or 2.

16. A compound selected from the group consisting of

(5R,6Z)-6-[(5-benzyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)methylene]-7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid;

sodium salt of (5R),(6Z)-6-(7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt (5),(6Z)-7-oxo-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R,6Z)-6-{[5-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-C][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R),(6Z)-6-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R),(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-C][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R),(6Z)-6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R)(6Z)-7-oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R),(6Z)-6-(7-methyl-6-oxo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R)(6Z)-6-(6,7-dihydro-4H-pyrazolo[5,1-C][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R)(6Z)-7-oxo-6-(4H-5-thia-1,6A-diazapentane-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R)(6Z)-6-(7H-imidazo[1,2-C]thiazole-2-ylmethylene)-7-OK, what about the-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

(5R,6Z)-7-oxo-6-[(4-oxo-6,7-dihydro-4H-pyrazolo[5,1-C][1,4]oxazin-2-yl)methylene]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

6-(6,7-dihydro-4H-thieno[3,2-C]Piran-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

6-(6,7-dihydro-4H-thieno[3,2-C]thiopyran-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

6-(5-methyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

ethyl ether complex of 2-(2-carboxy-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-EN-6-ylidenemethyl)-6,7-dihydro-4H-thieno[3,2-C]pyridine-5-carboxylic acid;

7-oxo-6-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R),(6Z)-6-(7-benzyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

(5R,6Z)-7-oxo-6-{[5-(pyridine-3-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

(5R,6Z)-7-oxo-6-{[5-(pyridine-3-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, and

(5R,6Z)-7-oxo-6-{[5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic key is lots;

sodium salt of (5R),(6Z)-6-(5,5-dioxo-4,5,6,7-tetrahydro-5λ6-pyrazolo[5,1-c][1,4]thiazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R),(6Z)-7-oxo-6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

(5R)(6Z)-6-(5,5-dimethyl-4H-1,6A-diazapentane-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, sodium salt of 5,5-dimethyl-2-piperidone;

sodium salt of (5R),(6Z)-6-(5,6-dihydro-4H-cyclopent[b]furan-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R)(6Z)-6-(4,5-dihydro-6-thia-1,7a-dietingen-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R),(6Z)-6-(6,6-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]piridin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

(5R),(6Z)-6-(5,6-dihydro-8-N-imidazo[2,1-C][1,4]thiazin-3-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R)(6Z)-7-oxo-6-(4H-5-thia-1,6A-diazapentane-2-ylmethylene)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R)(6Z)-6-(2,3-dihydropyrazolo[5,1-b]thiazole-6-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R)(6Z)-6-(2,3-dihydropyrazolo[5,1-b]oxazol-6-ileti the Yong)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

(5R,6Z)-6-[(5-acetyl-4,5,6,7-tetrahydrothieno[3,2-C]pyridine-2-yl)methylene]oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (mixture of E+Z isomers, sodium salt);

(5R,6Z)-6-(6,7-dihydro-4H-pyrazolo[5,1-C][1,4]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

sodium salt of (5R)(6Z)-6-(6,7-5H-dihydropyrazolo[5,1-b]oxazin-2-ylmethylene)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;

disodium salt of (5R),(6Z)-6-[5-(3-carboxypropyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid;

sodium salt of (5R),(6Z)-6-[5-(2-methoxyacetyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid;

sodium salt of (5R),(6Z)-6-[5-(4,dihydrothiazolo-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylmethylene]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid;

sodium salt of (5R),(6Z)-6-{[6-(etoxycarbonyl)-4,5,6,7-tetrahydrofuro[2,3-C]pyridine-2-yl]methylene}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-carboxylic acid.

17. A method of treating a bacterial infection or a disease of a patient in need of such treatment, which includes an introduction to the specified patient an effective amount of the compounds of formula I according to any one of claims 1 to 16 or its pharmaceutically acceptable salt.

18. Ways is by 17, where the compound is administered in conjunction with β-lactam antibiotic.

19. The method according to p, where the ratio of β-lactam antibiotic to the compound is in the range from about 1:1 to about 100:1.

20. The method according to claim 19, where the ratio of β-lactam antibiotic to the compound is less than 10:1.

21. The method according to 18, where beta-lactam antibiotic selected from the group consisting of a penicillin antibiotic and a cephalosporin antibiotic.

22. The method according to any one of p-21, where beta-lactam antibiotic selected from the group consisting of piperazillina, amoxicillin, tikarcillina, benzilpenitsillinom, ampicillin, sulbenicillin, cefatrizine, tsefaloridina, tsefalotina, Cefazolin, cephalexin, cephradine, aztreonam and latamoxef.

23. The method according to any one of p, 21 and 22, where beta-lactam antibiotic is piperacillin or amoxicillin.

24. The method according to any one of p and 21-23, where beta-lactam antibiotic is piperacillin, and it is administered to the patient intravenously.

25. The method according to any one of p and 21-23, where beta-lactam antibiotic is amoxicillin, and it is administered to the patient orally.

26. Pharmaceutical composition having inhibitory activity against β-lactamases, which contains a pharmaceutically acceptable carrier and an effective amount of a compound of formu the uly I

defined in any one of claims 1 to 16 or its pharmaceutically acceptable salt.

27. The composition p, optionally containing beta-lactam antibiotic.

28. The method of obtaining the compounds of formula I or its pharmaceutically acceptable salts, including the state rehabilitation elimination of compounds of formula II

where a' denotes a or b have the meanings given in claims 1, 2, X is O or S, R means ester leaving group, R means remove the protective group, to obtain a compound of the formula I

where a, b and X have the meanings defined in claim 1 or 2,

R5means hydrogen; for a time sufficient for the formation of these compounds under conditions effective to education or its pharmaceutically acceptable salt.

29. The method of obtaining the compounds of formula I, including the state rehabilitation elimination of compounds of formula II

where a' denotes a or b have the meanings defined in claim 1 or 2, X is O or S, R means ester leaving group, R means remove the protective group, to obtain a compound of the formula I

where a, b and X have the meanings defined in claim 1 or 2,

R5means C1-C6-alkyl or C5-C6-cycloalkyl; for a time sufficient for formation of compounds of the formula I, under conditions effective for his education.



 

Same patents:

FIELD: organic chemistry, antibiotics, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of carbapenem possessing high antibiotic activity with respect to methicillin-resistant microorganism Staphylococcus aureus, penicillin-resistant microorganism Streptococcus pneumoniae, influenza virus and microorganisms producing β-lactamase, and showing stability with respect to renal dehydropeptidase. Proposed derivatives of carbapenem represent compounds of the formulae (I) and (II) or their pharmaceutically acceptable salts wherein R1 represents hydrogen atom or methyl; each R2 and R3 represents independently hydrogen, halogen atom, carbamoyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylthio-group or formyl; n = 0-4; Hy represents 4-7-membered monocyclic or 9-10-bicyclic saturated or unsaturated heterocyclic group comprising 1-4 heteroatoms chosen from the group consisting of nitrogen and sulfur atoms wherein Hy group can be optionally substituted with halogen atom; substituted or unsubstituted lower alkyl, (lower alkyl)-thio-group, (lower alkyl)-sulfonyl, carboxyl, amino-group, aryl; or 6-membered monocyclic heterocyclic group comprising one or some nitrogen atoms. Also, invention describes the methods for treatment and/or prophylaxis of infectious diseases caused by gram-positive and gram-negative microorganisms that involve administration of indicated derivative of carbapenem in therapeutically and/or prophylactically effective doses to mammals including humans.

EFFECT: improved method for treatment and prophylaxis, valuable medicinal properties of derivatives.

22 cl, 2 tbl, 73 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to chemeric equivalent of somatostatin, chosen from DPhe- cyclo(Cys- 3ITyr-DTrp-Lys-Val-Cys)-Thr-NH2, DPhe-cyclo(Cys-3ITyr-DTrp-Lys-Thr-Cys)-Thr-NH2, DPhe-cyclo(Cys-Tyr-DTrp-Lys-Abu-Cys)-Thr-NH2, cyclo(Cys-Tyr-DTrp-Lys-Abu-Cys)-Thr-NH2, DTyr-DTyr-cyclo(Cys-Tyr-DTrp-Lys-Abu-Cys)Thr-NH2 and DTyr-DTyr-cyclo(Cys-3ITyr-DTrp-Lys-Thr-Cys)Thr-NH2 and a fragment, joined to a dopermine receptor, chosen from Dop2 , Dop3 , Dop4 and Dop5 . Methods are proposed of obtaining agonistic effect (1) to dopermine receptors; (2) to somatostatin receptors and (3) to dopermine and/or somatostatin receptors, which include introduction of an effective quantity of a chimeric equivalent of a subject in need. A pharmaceutical composition is proposed, which has agonistic effect to dopermine and/or somatostatin receptors, including an effective quantity of a chimeric equivalent.

EFFECT: chimeric equivalent, with agonistic effect to a dopermine and/or somatostatin receptor.

31 cl, 13 ex, 1 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (I): wherein R1 represents para-nitrobenzyl or allyl; X represents halogen atom. Method involves: (1) interaction of compound of the formula (IVa): wherein R1 represents para-nitrobenzyl or allyl, and R2 represents benzyl or substituted benzyl with P(OR3)3 in a solvent medium to yield compound of the formula (III): wherein R1 represents para-nitrobenzyl or allyl; R2 represents benzyl or substituted benzyl; R3 represents (C1-C6)-alkyl and (2) the following heating compound of the formula (III) in a solvent in the presence of LiCl and organic soluble base to form compound of the formula (II): wherein R1 represents para-nitrobenzyl or allyl; R2 represents benzyl or substituted benzyl, and (3) interaction of compound of the formula (II) with R4-OH and PX5 to form compounds of the formula (I) that is an intermediate compound in synthesis of cephalosporin.

EFFECT: improved method of synthesis.

14 cl, 5 ex

FIELD: chemical-pharmaceutical industry, chemical technology.

SUBSTANCE: invention relates to a method for preparing neurohormonal agent - abergin (α- and β-bromoergocryptines). Bromination of mixture of α- and β-ergocryptines is carried out with 50% excess of N-bromosuccinimide in chloroform medium with addition of dioxane (10:1). Method involves using dioxane with peroxide content in the amount 0.011-0.0145 mole part with respect to amount of alkaloids in the reaction medium wherein the parent concentration of ergotoxine alkaloids is 0.125-0.150 mole/l. Method provides enhancing yield of the end substance at the key stage of the bromination reaction.

EFFECT: improved preparing method.

1 tbl, 2 dwg, 1 ex

FIELD: genetic engineering, proteins, medicine, pharmacy.

SUBSTANCE: invention relates to a method for preparing a fused protein representing immunoglobulin Fc-fragment and interferon-alpha and can be used in treatment of hepatitis. Method involves construction of a fused protein comprising immunoglobulin Fc-fragment prepared from Ig G1 or Ig G3 in direction from N-end to C-end and the end protein comprising at least one interferon-alpha. Fc-fragment and the end protein are joined directly or by a polypeptide bridge. The fused protein is used for preparing a pharmaceutical composition used in treatment of liver diseases and in a method for targeting interferon-alpha into liver tissues. Invention provides preparing the fused protein eliciting with biological activity of interferon-alpha providing its concentrating in liver and showing enhanced solubility, prolonged half-time life in serum blood and enhanced binding with specific receptors.

EFFECT: improved targeting method, valuable biological properties of fused protein.

10 cl, 5 dwg, 9 ex

The invention relates to new derivatives of fatty acids, which drugs or agrochemicals, with improved performance as it relates to lipophilic derivative of biologically active compounds of the General formula CH3-(CH2)7-CH=CH-(CH2)n-X -, where n is an integer of 7 or 9; X is selected from the group comprising-COO-, -CONH-, -CH2O-, -CH2S-, -CH2O-CO-, -CH2NHCO-, -COS-; lipophilic group SN3-(CH2)7-CH=CH-(CH2)n-X - is CIS - or transconfiguration; And is a fragment of a molecule of biologically active compounds (BAC), non-nucleoside and nucleoside derivative and containing in its structure at least one of functional groups selected from a) alcohol, b) simple broadcast) phenol, (d) amino, (e) thiol, (f) carboxylic acids and (g) of ester carboxylic acid, provided that no connection specified in paragraph 1 of the claims

The invention relates to biotechnology and relates to a new and improved method of allocation of clavulanic acid from the aqueous culture broth producer clavulanic acid

The invention relates to a method for producing pharmaceutically acceptable salt of clavulanic acid of formula I by reacting clavulanic acid or its salts, in particular amine salt, with the source of cations capable of forming pharmaceutically acceptable salts of clavulanic acid, in particular potassium salt, isobutyl alcohol (2-methyl-1-propanol) as a solvent in the presence of water
The invention relates to a method for producing and/or purification of clavulanic acid or its pharmaceutically acceptable salt or a complex ester comprising removing solids from the containing clavulanic acid fermentation broth by microfiltration with the formation of the first filtrate having a pH of 5.8 to 6.2, further removal of solids from the first filtrate by ultrafiltration using membranes from polysulfone, having a cutoff molecular weight of from 10 to 30 kDa and transmission capacity from 10 to 30 lm-2h-1with the formation of the second filtrate, further concentration by removal of water and the treatment of the concentrated second filtrate with allocation of clavulanic acid or its pharmaceutically acceptable salt or a complex ester, reduce the amount of impurities having the absorption at 420 nm

The invention relates to a method for producing and/or purification of clavulanic acid or its pharmaceutically acceptable salt or ester, comprising the following stages: adding additional solvent selected from alcohols WITH1-C6and mixtures thereof, to a solution of clavulanic acid is not miscible with water, the solvent; contacting the solution with an amine of the formula I

< / BR>
where R1, R2, R3and R4independently represent hydrogen, a straight or branched alkyl WITH1-C8hydroxyalkyl2-C4or the group NR1R2and NR3R4together denote a heterocyclic group containing 3 to 6 methylene groups, possibly substituted by oxygen, sulfur or aminogroups, R5denotes hydrogen or methyl, n is an integer 1 to 3; the allocation of the resulting amine salt of clavulanic acid; and converting the amine salt in the clavulanic acid or its pharmaceutically acceptable salt or ester

The invention relates to diclofenaco salt formed by clavulanic acid and Daminova ether having the formula (I) described in the description, in which R1is C1-C4-alkylene, and each of the radicals R2and R3is a hydrogen or C1-C8the alkyl

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for synthesis of compounds of the formula (I): wherein one of substitutes A or B means hydrogen atom (H) and another one means aryl substituted optionally with one or two R2, heteroaryl substituted optionally with one or two R2, and so on; R represents H, (C1-C6)-alkyl, (C5-C6)-cycloalkyl or -CHR3-OCO-(C1-C6)-alkyl or salt; R2 represents hydrogen atom, optionally substituted (C1-C6)-alkyl, optionally substituted (C2-C6)-alkenyl, and so on; R3 represents hydrogen atom, (C1-C6)-alkyl, (C5-C6)-cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl. Method for synthesis of these compounds involves the following steps: (a) condensation of substituted aldehyde of the formula: (A'-CHO) (17) wherein A' represents A, such as given above when B represents hydrogen atom; or B, such as given above when A represents hydrogen with derivative of 6-bromopenem of the formula (16): wherein R represents p-nitrobenzyl in the presence of Lewis acid and a weak base at low temperature that results to formation of intermediate aldol product of the formula (18): ; (b) interaction of intermediate compound of the formula (18) with chloroanhydride or acid anhydride of the formula: (R8)Cl or (R8)2O or with tetrahalogen methane of the formula: C(X1)4 and triphenylphosphine wherein R8 represents alkyl-SO2, aryl-SO2, alkyl-CO or aryl-CO; X1 represents Br, J or Cl atoms to form intermediate compound of the formula (19): wherein R9 represents X1 or -OR8, and conversion of intermediate compound of the formula (19) to the end compound of the formula (I). Also, invention relates to 4-nitrobenzyl-(5R,6S)-6-bromopenem-3-carboxylate of the formula (16) and to a method for its synthesis. Method involves the following steps: (A) (i) interaction of 6-aminopenicillanic acid with hydrobromic acid in organic solvent and water to form 6-bromopenicillanic acid of the formula (21): and its conversion to p-nitrobenzyl-6-bromopenicillanate of the formula (22): wherein R represents p-nitrobenzyl by interaction with 4-nitrobenzyl bromide in the presence of a base in organic solvent; (B) oxidation of compound of the formula (22) to form p-nitrobenzyl-6-bromopenicillanate-1-oxide of the formula (23) given in the invention description; (C) boiling compound of the formula (23) with 2-mercaptobenzothiazole in aromatic solvent to form 4-nirobenzyl-(2R)-2-[(3S,4R)-4-(benzothiazol-2-yldithio)-3-bromo-2-oxoazethidin-1-yl]-3-methylbut-3-enoate of the formula (24) given in the invention description; (D) dissolving compound of the formula (24) in organic solvent and interaction with an organic tertiary base to form 4-nitrobenzyl-2-[(3S,4R)-4-(benzothiazol-2-yldithio)-3-bromo-2-oxoazethidin-1-yl]-3-methylbut-2-enoate of the formula (25) given in the invention description; (E) conversion of compound of the formula (25) to 4-nitrobenzyl-2-[(3S,4R)-3-bromo-4-formylthio-2-oxoazethidin-1-yl]-3-methylbut-2-enoate of the formula (26) given in the invention description as result of interaction of with organic acid in aromatic organic medium in the presence of a mixture acetic anhydride/organic tertiary base and trialkyl- or triarylphosphine in the range of temperature from about -10°C to about -30°C, and (F) passing ozonized oxygen through solution of compound of the formula (26) in organic solvent for 3-4 h at temperature from -70°C to -90°C and the following the intramolecular cyclization reaction using a phosphite reagent. Invention provides the increased yield and economy method for synthesis of derivatives of 6-alkylidenepenem.

EFFECT: improved method of synthesis.

41 cl, 2 tbl, 42 ex

The invention relates to a method for producing 2-halogenosilanes formula I, where R1represents a protective group for the alcoholic hydroxyl, R2represents a protective group for carboxyl and X represents a halogen, including interaction of the compounds of formula III with 2-halogenoalkanes acid in an organic solvent in the presence of organic base and a Lewis acid at a temperature of from -10 to +40oWith obtaining the compounds of formula V, which communicates with the air oxalicacid in an organic solvent in the presence of an organic base at a temperature of from -60 to +20oC, preferably from -20 to +10oWith obtaining the compounds of formula VII, which cyclist in a suitable solvent with an organic phosphite or phosphonite at a temperature of 20-140oWith

The invention relates to a new method of obtaining new hyalinella formula I

where In represents the structure of the General formula II

Q represents the structure of General formula III,

where R1- lower alkyl or a saturated or unsaturated WITH3- C6carbocycle, optionally substituted with halogen;

R2is hydrogen or amino group;

And - nitrogen or the group CR4where R4represents halogen, hydrogen;

R - piperazinil, unsubstituted or substituted lower alkyl or a group of formula IV

Наl - fluorine, chlorine, bromine or iodine,

or their salts, characterized in that conduct the reaction interaction lactam compounds IN IT, where has the above significance, in which optional pre-protected hydroxy and carboxyl functional group, with phosgene at a temperature of from -80oC to about 0oC with formation of an intermediate product of the formula V

where have the above values,

and the resulting intermediate product is subjected to interaction with the compound of General formula HQ, where Q have the above meanings, in which optional pre-protected carboxyl functional group, to follow the

The invention relates to new derivatives Panama General formula (I) in which R1means (C1-C6)hydroxyalkyl; R2means carboxyl group or an esterified carboxyl group, easily activated in vivo, or carboxylate anion; R3means a hydrogen atom, (C1-C4)alkyl, optionally substituted carboxamide group; R4means a hydrogen atom, (C1-C6)alkyl, optionally substituted phenyl, (C1-C6)aminoalkyl; or R3and R4connected together, form a pyrolidine, piperidine or aziridine ring, optionally substituted hydroxyl group, alkanoyloxy and carbamoyloximes; R5and R6independently from each other mean a hydrogen atom, (C2-C6)alkyl, (C1-C6)alkyl carboxamide or linked together to form a 4-methylpiperazin; n is selected from 1,2,3, and their pharmaceutically acceptable salts have antibacterial properties

The invention relates to new derivatives Panama General formula (I) in which R1means (C1-C6)hydroxyalkyl; R2means carboxyl group or an esterified carboxyl group, easily activated in vivo, or carboxylate anion; R3means a hydrogen atom, (C1-C4)alkyl, optionally substituted carboxamide group; R4means a hydrogen atom, (C1-C6)alkyl, optionally substituted phenyl, (C1-C6)aminoalkyl; or R3and R4connected together, form a pyrolidine, piperidine or aziridine ring, optionally substituted hydroxyl group, alkanoyloxy and carbamoyloximes; R5and R6independently from each other mean a hydrogen atom, (C2-C6)alkyl, (C1-C6)alkyl carboxamide or linked together to form a 4-methylpiperazin; n is selected from 1,2,3, and their pharmaceutically acceptable salts have antibacterial properties

The invention relates to a new method of obtaining premovic esters in accordance with acceptable derivative slit acid and the corresponding azetidinone
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