6-(substituted methylene)panama, method of their production, intermediate products and pharmaceutical composition

 

(57) Abstract:

Describes a new 6-(substituted methylene )stump of General formula (I) in which R2represents a condensed bicyclic heterocyclic system of rings General formula (II), where m is 2 or 3; p is 0, 1 or 2; and R3means hydrogen, salt-forming cation or farmacevtichesky acceptable hydrolyzable in vivo ester, the symbol indicates that the double bond may be either E or Z configuration. Describes a pharmaceutical composition based on compounds of the formula (II), exhibiting inhibitory-lactamase activity, and a method of inhibiting-lactamase in the treatment of bacterial infacy in humans and animals. 10 S. and 6 C.p. f-crystals, 1 table.

This invention relates to new chemical compounds, in particular 6-(substituted methylene)pepmov and their derivatives with-lactamase-inhibiting action and antibacterial properties. The invention also concerns methods for producing such compounds, pharmaceutical compositions containing them and their use.

A compound of the basic type disclosed in WO087/00525 and have the structure (A):

< / BR>
where Ra, Rb, Rcand Rdare times c and Rdis hydrogen and the other, respectively, a 5-membered heteroaromatic ring or non-aromatic heterocyclic group.

According to the present invention new enemy formula (I) is represented

< / BR>
in which R1is hydrogen or an organic Deputy;

R2is a system of condensed bicyclic heterocyclic ring of General formula:

< / BR>
where R4and R5independently of one another are hydrogen or one or more substituents replacing hydrogen atoms in the shown ring system; a is 2 or 3;

p is 0, 1 or 2;

R3represents hydrogen, salt-forming cation or afrobrazil group; and

the symbol indicates that the double bond may be either E or Z configuration.

The compound of formula (I), its salts and esters can exist in isomeric forms, all of which, including the racemates and diastereoisomers, are included in the scope of the present invention.

In addition, the compounds of formula (I) can exist in two isomeric forms with a methylene group at the 8-position, i.e. in the E-and Z-isomeric forms. For the most part preferred Z-isomer, as more AK is out structure (IA):

< / BR>
In the main formula (I) R1denotes hydrogen

For example, R1may represent hydrogen or a group of the formula-R5or-SR5where R5denotes unsubstituted or substituted (C1-10) hydrocarbon or heterocyclic group.

Preferably R1represents hydrogen, (C1-10)alkyl or (C1-10)alkylthio or substituted (C1-10)alkyl or substituted (C1-10)alkylthio, where a Deputy may be hydroxy, (C1-10)alkoxy, (C1-6)alkanoyloxy, halogen, mercapto, (C1-6)alkylthio, heterocyclic, amino, (mono or di)-(C1-6)alkylamino, (C1-6)alkanolamine, carboxy or (C1-6)alkoxycarbonyl.

Examples of suitable organic groups R1are methyl, ethyl, propyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, hydroxymethyl, methoxymethyl, ethoxymethyl, acetoxymethyl, (1 or 2),-acetoxyethyl, aminomethyl, 2-amino-ethyl, atsetamidometil, 2-acetamidate, carboxymethyl, 2-hydroxyethylthio, methoxymethyl, 2-methoxyacetyl, acetoxymethyl, 2-aminoacylation, acetamidomethyl, 2-acetamidoacrylate, carboxymethylthio, 2-carboxymethylthio, aryl(especially phenyl), arieti (especially phenylthio). p is P>1can be hydrogen.

Suitable groups R2include: 2,3-dihydroimidazo 2.1 - thiazol-6-yl, 2,3-dihydro-1-(R, S)-accomidate[2,1-b] thiazol-6-yl, 2,3-dihydro-1,1-dioximes[2,1-b] thiazol-6-yl, 6,7-dihydro-5H-imidazo[2,1-b] thiazin-2-yl and 6,7-dihydro-8,8-dioxo-5H-imidazo-[2,1-b] [1,3]thiazin-2-yl.

Examples of suitable substituents R4and R5include (C1-6)alkanoyloxy, heterocyclyl, amino, (C1-6)alkanolamine, (mono or di)-(C1-6)alkylamino, hydroxy, (C1-6)alkoxy, sulfo, mercapto, (C1-6)alkylthio, (C1-6)alkylsulfonyl, (C1-6)alkylsulfonyl, heterocyclic, aaltio, sulfamoyl, carbarnoyl, amidino, guanidino, nitro, halogen, carboxy, carboxy salts, carboxy esters, arylcarbamoyl and heterocalixarenes groups, and unsubstituted or substituted (C1-6)alkyl, (C2-6)alkenyl, (C2-6)quinil, aryl and aryl (C1-6)alkyl group.

Examples of suitable optional substituents for the above-mentioned (C1-6)alkyl, (C2-6)alkenyl, (C2-6)quinil, aryl and aryl-(C1-6)alkyl substituents are (C1-6)alkanoyl, (C1-6)alkanoyloxy, heterocyclyl, amino, (C1-6)alkanolamine, (mono or di)- (C1-6)alkylamino, hydroxy, (C

Suitable R4and R5both can be hydrogen.

Suitable pharmaceutically acceptable salts of 3-carboxyl-group of compounds of formula (I) or other carboxyl groups which may be present as optional substituents are those in which R3represents a metal ion, such as aluminum salts, alkali metal salts (e.g. sodium, lithium or potassium), salts of alkaline earth metals (e.g. calcium salts or magnesium), ammonium salts and salts of substituted ammonium, for example salts with lower alkylamines followed (e.g., triethylamine), hydroxy-lower alkylamines followed (for example, 2-hydroxyethylamine), di(2-hydroxyethyl)amine, three(2-hydroxyethyl) - amine, bis-(2-hydroxyethyl)amine, Tris(2-hydroxyethyl)amine, lower-alkylamines followed (for example, dicyclohexylamine) or with procaine, dibenzylamine, N N-dibenzyl-Ethylenediamine, 1-ethenamine, N-methylmorpholine, N-ethylpiperidine, N-benzyl - phenethylamine, dehydroabietylamine, Ethylenediamine, N, N'-bishydroxyethyl, with the bases of the pyridine type such as pyridine, collidine and hinali the salts with penicillins.

Pharmaceutically acceptable salts can be salts with acids of any amino or substituted amino groups (groups) which may be present as optional substituents in the compounds of formula (I), or any nitrogen atom of the heterocyclic ring. Suitable salts include, for example, hydrochloride, sulfates, acid sulfates, acetates, phosphates, etc., and other pharmaceutically acceptable salts are known from previous works. Suitable salts are hydrochloride and acid sulfates.

Preferred salts are salts of sodium.

If R3represents afrobrazil group, it may be a carboxylate-protecting group or a pharmaceutically acceptable hydrolyzable in vivo ether.

Suitable afrobrazil carboxyl-protecting groups are those which can be removed under normal conditions. Such groups for R3include benzyl, p-methoxybenzyl, benzoyl-methyl, p-nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, tert-butyl, tert-amyl, allyl, diphenylmethyl, triphenylmethyl, substituted, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, p-toluensulfonyl means aryl or heterocyclyl, or hydrolyzable in vivo ether radical such as described below.

The carboxyl group may be regenerated from any of the above ester using conventional methods, appropriate for the individual R3group, for example using catalyzed by acid and alkali hydrolysis, or by using enzyme catalysed hydrolysis, or by hydrogenolysis under conditions in which the remainder of the molecule is basically not affected.

Examples of suitable pharmaceutically acceptable hydrolyzable in vivo ester groups, which are eligible can contain R3are those which are rapidly decomposed in the human body with the formation of the original acid or its salts. Suitable ester group of this type include groups of formula (i), (ii), (iii), (iv) and (v):

< / BR>
< / BR>
-CO2CH2- OR' (iii)

< / BR>
< / BR>
where Rameans hydrogen, (C1-6) alkyl, (C3-7)cycloalkyl, methyl or phenyl;

is a (C1-6)alkyl, (C1-6)alkoxy, phenyl, benzyl, (C3-7)cycloalkyl, (C3-7)cycloalkane, (C1-6)-alkyl(C3-7)cycloalkyl, 1-amino(C1-6)alkyl or 1-(C1-6) alkylamino(C1-6)alkyl; or Raand Rbwill mastronet (C1-6alkylene, optionally substituted stands or ethyl; and

Rdand Reindependently of one another are (C1-6) alkyl;

Rfis a ((C1-6)alkyl;

Rgmeans hydrogen or phenyl, optionally substituted by three groups selected from halogen, (C1-6) alkyl or (C1-6) alkoxy;

Q is oxygen or NH;

Rhrepresents hydrogen or (C1-6) alkyl;

Rimeans hydrogen, (C1-6)alkyl, optionally substituted with halogen, (C2-6) alkenyl, (C1-6)) alkoxycarbonyl, aryl or heteroaryl; or

Rhand Ritogether form a (C1-6) alkylen;

Rjmeans hydrogen, (C1-6) alkyl or (C1-6) alkoxycarbonyl; and

Rkis a (C1-8) alkyl, (C1-8)alkoxy, (C1-6)-alkoxy(C1-6) alkoxy or aryl.

Examples of suitable hydrolyzable in vivo ester groups include, for example, aryloxyalkyl groups, such as acetoxymethyl, pivaloyloxymethyl-acetoxyethyl-pivaloyloxymethyl, I-(cyclohexyloxycarbonyloxy)prop-1-yl and (I-amino-ethyl)carbonylmethyl; alkoxycarbonylmethyl groups, such as ethoxycarbonylmethyl, taxicab is how dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-(alkoxycarbonyl)-2-alkenyl groups such as 2-(isobutoxide)Penta-2-enyl and 2-(etoxycarbonyl)but-2-enyl; lactonase groups, such as palidin and dimethoxypyridine; and ethers attached to the second-lactam antibiotic or / -lactamase-inhibitor.

Additional suitable pharmaceutically acceptable hydrolyzable in vivo ether group is a group of the formula:

< / BR>
where Rkis hydrogen, (C1-6)alkyl or phenyl.

Used herein, the term "aryl" includes phenyl and naphthyl, each optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, (C1-6) alkyl, phenyl, (C1-6) alkoxy, hydroxy(C1-6)alkyl, mercapto(C1-6)alkyl, halogen(C1-6)alkyl, hydroxy, amino, nitro, carboxy, (C1-6)alkylcarboxylic, alkoxycarbonyl, formyl or (C1-6)alkylcarboxylic. Used herein, the term "heterocyclyl" and "heterocyclic" includes aromatic and non-aromatic, single and fused rings, generally containing up to four heteroatoms in each ring, such as oxygen, nitrogen, and CE is p: halogen, (C1-6)alkyl, (C1-6)-alkoxy, halogen(C1-6)alkyl, hydroxy, carboxy, carboxy salts, carboxy esters, such as (C1-6)alkoxycarbonyl, (C1-6)alkoxycarbonyl(C1-6)alkyl, aryl and oxo. Each heterocyclic ring usually has 4 to 7, preferably 5 or 6 atoms in the ring. The term "heteroaryl reflects heteroaromatic or heterocyclic ring, or rings, suitably having 5 or 6 ring atoms in each ring. System condensed heterocyclic rings may include carbocyclic rings and need only include one heterocyclic ring. Compounds of the invention containing heterocyclic group can be in two or more tautomeric forms depending on the nature of the heterocyclic group; all such tautomeric forms are included within the scope of the invention.

Used herein, the terms "alkyl", "alkenyl", "quinil" and "alkoxy" includes straight and branched chain, containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl or butyl. Particular alkyl group is methyl.

Used herein, the term "halogen" represents fluorine, chlorine, bromine and iodine.

It is obvious that the scope of the invention target be present as optional substituents in the compounds of formula I.

Some compounds of formula (I) may include an amino group which may be protected. Suitable protective for amino groups are known from previous works, which can be removed under normal conditions, if necessary, without destroying the remainder of the molecule.

Examples of protective groups for the amino group include a (C1-6) alkanoyl; benzoyl; benzyl, optionally substituted in the phenyl ring by one or two substituents selected from (C1-4) alkyl, (C1-4)alkoxy, trifloromethyl, halogen or nitro; (C1-4)alkoxycarbonyl; benzyloxycarbonyl or trityl, substituted as indicated above for benzyl; allyloxycarbonyl, trichlorocyanuric or chloroacetyl.

Some compounds of formula (I) and (IA) can crystallize or precrystallization of solvents such as organic solvents. In these cases, may form a solvate. This invention includes a stoichiometric solvate, including hydrates as well as compounds containing variable amounts of solvents such as water, which can be obtained by a method such as lyophilization. The compounds of formula (I) and (IA) can be obtained from Krista who, the subsequent mixing this aqueous solution with a water-soluble organic solvent such as a lower aliphatic ketone, such as di(C1-6-alkylation, or (C1-6)alcohol, such as acetone or ethanol.

The compounds of formula (I) and (IA) are inhibitors-lactamase and/or antibiotics and are intended for use in pharmaceutical compositions. It is easy to assume that they are preferably each in significant pure form, for example at least 60% pure, more suitable for at least 75% pure and preferably at least 85% pure, especially at least 95% purity, in particular at least 98% pure (% are weight for weight basis).

The compounds of formula (I), and in particular of formula (IA), are assumed to be active inhibitors-lactamase and have the added advantage of improved pharmacokinetics.

Thus, specific compounds of formula (I) include the following pharmaceutical acceptable salt:

(5R)-6-[(Z)-(2,3-dihydroimidazo[2,1-b]thiazol-6-yl)methylene]- stump-3-carboxylate sodium (5R)-6-[(Z)-(2,3-dihydro-I(R,S)-accomidate[2,1-b]thiazol-6-yl)methylene] - stump-3-carboxylate sodium (5R)-6-[(Z)-(2,3-dihydro-1,1-dioxo the len] - the stump-3-carboxylate sodium (5R)-6-[(Z)-(6,7-dihydro-8,8-dioxo-5H-imidazo[2,1-b][1,3]thiazin-2-yl)methylene]- stump-3-carboxylate sodium.

The present invention relates to a method for obtaining compounds of formula (I) defined above, which comprises treating compound of formula (II):

< / BR>
where R1and R2are defined above in formula (I) values; Rxare protective group for carboxypropyl;

X represents a halogen atom; and

Z describes a halogen atom, hydroxy group, -S(O)qR7group or -- Se(O)qR7group, where q denotes 0, 1 or 2, r is 0 or 1 and R7describes a hydrogen atom or a heterocyclic group.

the reaction of reductive elimination to remove elements of the group X and Z, and then, if needed or required:

(i) conversion of the group Rxin another group, Rxsuch as Deputy R3,

(ii) conversion of the group R2in another group, R2,

(iii) the conversion of compounds in pharmaceutically acceptable salt.

The reaction of the reductive elimination can be performed in principle known essentially a way for such elimination reactions, for example, as opinium or iron, in the presence of acid (such as acetic acid or mineral acid or by reaction with an organic compound of trivalent phosphorus, such as triphenylphosphine, usually at a temperature in the range -20oto +40oC, preferably from 0o3 to 20oC. the Reaction may be conducted in the presence of polar or nonpolar, proton or aprotic organic solvent, for example dioxane, dimethoxyethane or tetrahydrofuran.

The product of this reaction is usually a mixture of isomers E and Z isomers of the formula (I). The desired isomer of General formula (I) can be isolated and purified in the usual way, for example by crystallization or chromatography. In addition, carboxypropyl-COORxcan be removed protective group and converted into free carboxy, salt-carboxy or ester carboxypropyl-COOR3in the usual way, for example described in EP 0232966A.

If you want to get a free acid or salt of the preferred isomer Panama formula (I) of this isomeric mixture, it may be carried out by chromatographic separation and subsequent removal of the protective groups the desired isomer to obtain the corresponding free acid AI and to obtain an isomeric mixture of the free acid or salt of formula (I) with subsequent fractional recrystallization to obtain the desired isomer of the acid or salt.

The compounds of formula (II) in which Z is a hydroxy group, can be obtained by the reaction of known (see EP 0232966) compounds of the formula (III):

< / BR>
where X, R1and Rxhave defined in the formula (II), with the aldehyde of formula (IV):

R2-CHO

where R2has the meaning as defined in formula (II), forming the corresponding halohydrin formula (II).

The reaction between the compound (III) and an aldehyde (IV) may conveniently be carried out in the presence of a base, preferably dinucleophiles base, preferably a strong base. Suitable bases are, for example, the Foundation of lithium amide, for example bestremembered lithium, dicyclohexylamine lithium, diisopropylamide lithium 2,2,6,6-tetramethylpiperidine lithium, diphenylamide lithium and utility.

Suitable solvents for the reaction are aprotic organic solvents (which may be polar or non-polar), such as tetrahydrofuran, toluene, dimethoxyethane, dimethylformamide and mixtures of two or more such solvents.

The reaction may conveniently be performed at a temperature in the range from -100oto room temperature, preferably from -85o0OK halogenides (III) in a different order. If you want to allocate gelegenheden Panama General formula (II), where Z describes the hydroxy-group, then the reaction mixture may conveniently be extinguished by adding a proton reagent such as acid, such as acetic acid or citric acid or water.

Aldehydes of formula (IV) can be obtained from known (for example, Reufen G. Jones, CA: (45) 7153e, Pat. USA 2541924) compounds of the formula (V):

< / BR>
where R is alkyl, for example (C1-6)alkyl, and R5has the above value,

the reaction with the known compounds of the formula (VI):

X-(CH2)m-Y (VI)

where m is as defined above values, X and Y represent halogen, preferably chlorine or bromine. Preferably, one of X or Y is chlorine and the other is bromine.

The compound of formula (VII) is:

< / BR>
The reaction between the compounds (V) and (VI) can be carried out in an organic solvent, such as DMF, in the presence of a base such as triethylamine.

The compound (VII) can cilitates, for example when processing an alkali metal hydride such as sodium hydride, in a solvent such as THF, with the formation of compound (VIII):

< / BR>
The compounds of formula (VIII) may then, Programatic is recovered when using, for example, diisobutylaluminium, with the formation of the corresponding aldehyde (IV) with p equal to 0. The corresponding aldehyde (IV) with p equal to 1 or 2, can then be obtained by oxidation of the sulfur atom using peroxy acids, such as chlormadinone acid.

Or, for example, the compound (VIII) can be processed with a peroxy acid such as defined previously, to oxidation of the sulfur atom and the formation of sulfoxide or sulfone compound (VIII) with subsequent recovery of CO2R groups to aldehyde groups, for example as indicated above, prior to the formation of aldehyde (IV) with p equal to 1 or 2.

Or, for example, CO2R group of the compound (VIII) can be partially restored to the formation of the corresponding hydroxymethylene compounds (IX):

< / BR>
for example, using lithium aluminum hydride. Then hydroxymethylene compound (IX) can be, for example, then oxidized, for example, using Mn (IV), for example MnO2before formation of the corresponding aldehyde (IV) with p equal to 0, and which is then further oxidized using peroxyacids before the formation of the aldehyde (IV) with p equal to 1 or 2.

Or hydroxymethylene the corresponding sulfoxide or sulfone (IX), and this sulfoxide or sulfon can then be oxidized, for example using Mn (IV), as described above, before turning hydroxymethylene group (IX) to the aldehyde group with the formation of the aldehyde (IV) with p equal to 1 or 2.

Or, for example, hydroxymethylene compound (IX) can allievate with the formation of compound (X):

< / BR>
where A is an acyl group, for example (C1-6)allgroups, such as acetyl. The acylation can be carried out using Alliluyeva agent A, for example gelegenheid or acid anhydride. The compound (X) can then be oxidized using peroxyacids before the formation of the corresponding sulfoxide or sulfone. Hydroxymethylene group can then be regenerated, for example, when processing methanolic ammonia with subsequent oxidation hydroxymethylene group, for example when using Mn (IV), as described above, before the formation of the corresponding aldehyde groups in the aldehyde (IV).

The compounds of formula (II) in which Z is a substituted hydroxy group or a group of formula-S(O)qR7or-Se(O)rR7can be obtained from compounds of formula (II) in which Z represents hydroxypropoxy, such as 4-methoxybenzyl, these protective groups can be removed with the formation of the original acid known methods, for example in the case of treatment 2-methoxybenzyl group Lewis acid, such as ethylaminoethanol or aluminised. Pharmaceutically acceptable salts can be derived from such acids during processing the substrate to conventional methods, if necessary. Suitable bases include sodium bicarbonate, forming a sodium salt.

Crystalline forms of the compounds of formula (I) can, for example, be obtained by dissolving the compound (I) in a minimum amount of water is usually at room temperature, then followed by the addition of an organic solvent, miscible with water, such as (C1-6)alcohol or ketone, such as ethanol or acetone, resulting in the crystallization, which may contribute to cooling or mashing.

Compounds of formula (II), (IV), (VII), (VIII), (IX) and (X) and their corresponding sulfoxidov or sulfones mentioned above, rely on new and constitute additional aspects of this invention.

The present invention also provides a pharmaceutical composition that includes a compound of formula (I), Chaly (I) are - lactamase-inhibitory activity and antibacterial properties and is useful in the treatment of infections in animals, especially mammals, including humans, in particular humans and animals (including farm animals. Connections may be used, for example, for the treatment of infections inter issues, respiratory tract, urinary tract, soft tissues, especially in humans.

Connections may be used to treat infections caused by, for example, Staphylococcus ausens, Klebsiella aerogenes, Escherichia coli, Proteus sp. and Bacteroides fragilis. Usually predominantly the compound of the invention is used in mixture or combination with a penicillin, cephalosporin or other lactamase antibiotic, which often results in Energeticheskiy effect due to lactamase-inhibiting properties of the compounds of the invention. In such cases, the compound of formula (I) or (IA) and others laktamovogo antibiotics can be administered separately or in the form of a single composition containing both active ingredient, as described in more detail below. Compositions of the invention include compositions in the form adapted for oral, topical or parenterale introduction and can be used for treatment of bacterial infections in animals-mammals and is soedineniya formula (I) or (IA) can receptionists for the introduction of conventional methods, used in medicine and veterinary medicine, by analogy with other antibiotics.

The composition may receptorrelated for administration by any route, such as oral, topical or parenteral. The composition can be in the form of tablets, capsules, powders, granules, pellets, creams or preparative liquid forms such as solutions or suspensions for oral administration or in sterile solutions or suspensions for parenteral administration.

Preparative forms for local application of the present invention may constitute, for example, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives additives, solvents to facilitate the permeability of the drug and softening additives for ointments and creams.

Formulation may also contain compatible conventional carriers, such as Foundation creams and ointments, and ethanol or oleography alcohol for lotions. Such media may be present as from about 1% to about 98% of the preparative form. Most usually they will make up about 80% of the preparative form.

Tablets and ka is AK linking agents, such as syrup, Arabian gum, gelatin, sorbitol, tragakant or polyvinylpyrrolidone; fillers, such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletiruemye lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; loosening agents, for example potato starch; or acceptable wetting agents such as sodium lauryl sulfate. Tablets can be coated, which cause known in normal pharmaceutical practice methods. Liquid formulation for oral administration may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be a dry product to connect it before use with water or other suitable basis. Such a liquid formulation may contain the usual additives, such as suspendresume agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, gel, aluminum stearate or hydrogenated edible fats, emulsifying agents, for example lecithin, monooleate sorbitol or Arabian gum; non-aqueous binder (which may include shegot; protecting additives, for example methyl - or propyl-p-hydroxybenzoate or sorbic acid, and, if required, the conventional perfumes or coloring additives.

Suppositories will contain the usual bases for suppositories, for example cocoa butter or other glycerides.

For injecting liquid unit dosage forms obtained using the compound and a sterile environment, preferably water. The connection depending on the environment and the concentration may or suspendibility or to dissolve in the environment. Upon receipt of the solutions the compound can be dissolved in water for injection and sterilized by filtration before filling into a suitable vessel or ampoule and sealed.

Favorably, when agents such as local anesthetics, preservatives agents and buffering agents can be dissolved in the environment. To improve the stability of the composition can be frozen after filling into the vessel and the water is removed in vacuum. The dry lyophilized powder is then sealed in a vessel and it is applied vial with water for injection to obtain a liquid form prior to use. Suspensions for parenteral administration get in about the implementation may not be accompanied by filtration. The connection may be sterilized by treatment with ethylene oxide before suspendirovanie in a sterile environment. Mainly surfactant and wetting agent included in the composition to facilitate uniform distribution of the connection.

The compositions may contain from 0.1 wt.%, preferably 10-60 wt.%, the active material, depending on the method of administration. If the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dose used for the treatment of an adult, will preferably be from 100 to 300 mg per day, for example, 1500 mg per day depending on the route and frequency of administration. These doses correspond to 1.5 to 50 mg/kg / day. Preferably the dosage is from 5 to 20 mg/kg / day.

Toxicological actions do not see, when the compound of formula (IA) or its pharmaceutically acceptable salt or ester, hydrolyzable in vivo entered in the above range of doses.

The composition of the invention may include a compound of formula (I) or (IA) as an active ingredient or therapeutic agent or it may also include one or more additional active ing is whether their proprietarty. A composition comprising a compound of the invention and another active ingredient or therapeutic agent, especially penicillin, cephalosporin or other-lactam antibiotic, or proprietarty, may show an increased efficiency, in particular, can show Energeticheskiy effect.

Penicillins, cephalosporins and other-lactam antibiotics that are suitable for co-injection with the compound of the formula (I) or (IA) or a separate introduction or inclusion in compositions of the invention include known compounds exhibiting instability, or, in other words, sensitive-lactamase, and compounds with a degree of resistance to - lactamase.

Examples of penicillins, suitable for co-injection with the compounds of the invention include benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxicillin, ampicillin, tikarcillin, ciclacillin, pirinelli, azlotillin, mezlocillin, piperacillin and other well known penicillins. Penicillins can be used in the form of their prepreparation, for example in the form of hydrolyzable in vivo esters, for example acetaminophe, pivaloyloxymethyl, ethoxycarbonylmethyl adducts of penicillins, containing 6- -aminoacetate side chain (for example, hetacillin, metampicillin and similar derivative of amoxicillin); and-esters of carbenicillin and tikarcillina, for example phenyl and Indology-ethers.

Examples of cephalosporins that may be administered with the compounds of the invention are cefatrizine, tsefaloridin, cefalotin, Cefazolin, cephalexin, cefacetrile, cephapirin, cefamandole, NAPAT, cefadin, 4-hydroxyethoxy, cephaloglycin, cefoperazon, cefsulodin, ceftazidime, cefuroxime, cefmetazole, Cefotaxime, Ceftriaxone, and other known cephalosporins, all of which can be used in the form of their prepreparation.

Examples-lactam antibiotics other than penicillins and cephalosporins, which may be administered together with the compounds of the invention are aztreonam, latamoxef (Moxalactam - trade mark) and other known-lactam antibiotics, all of which can be used in the form of their prepreparation.

Particularly suitable penicillins for co-injection with the compounds of the invention are ampicillin, amoxicillin, carbenicillin, piperacillin, azlotillin, mezlocillin, tikarcillin. These penicillins can use xicillin can be used in the form of ground particles zwitterionic form (usually as the trihydrate ampicillin or amoxicillin trihydrate) for use in input or pour suspension, for example, the method here described previously for compounds of the invention. Amoxicillin, for example in the form of sodium salt or the three-hydrate, especially preferred for use in sinergeticheskih compositions of the invention.

Particularly suitable cephalosporins for co-injection with the compounds of the invention include Cefotaxime and ceftazidime, which can be used in the form of their pharmaceutically acceptable salts, for example their sodium salts.

The compound of formula (I) or (IA) may be administered to a patient in an antibacterial effective amount, or, when the compound of the invention are used in combination with a penicillin, cephalosporin or other-lactam antibiotic, it can be used in Energetichesky effective amount.

The compounds of formula (I) or (IA)) can suitable be administered to a patient in a daily dose of from 0.7 to 50 mg/kg body weight. For an adult human (of approximately 70 kg body weight) may be given daily from 50 to 3000 mg, preferably from 100 to 1000 mg of the compounds of the invention, predominantly from 1 to 6, preferably from 2 to 4 individual doses. However, there may be used higher or lower doses according to clinical practice.

If the compounds of formula (I) or (IA) are administered together with a penicillin, cephalosporin or other-lactam antibiotic, the ratio of the number of compounds of the invention to the amount of other-lactam antibiotic may vary in a wide range. The above-mentioned ratio may, for example, be from 100:1 to 1:100, more particularly it may be from 2:1 to 1:30.

The number of penicillin or a cephalosporin or other-lactam antibiotic in sinergeticheskoj compositions of the invention will typically about like a number, in which the connection is typically used per se, for example from about 50 mg, mainly from about 62.5 mg to about 3000 mg per unit dose, more typically about 125, 250, 500, or 1000 mg per unit dose.

The present invention concerns the compounds of formula (I) or its pharmaceutically acceptable salts, its use as a therapeutic drug or a single, or in combination with-lactam antibiotic.

The present invention additionally relates to compounds of formula (I) or farm the AI with a-lactam antibiotic.

The present invention includes a method of treating bacterial infections in humans and animals, which includes the introduction of therapeutically effective amounts of compounds of formula (I) or its pharmaceutically acceptable salt or one, or in combination with-lactam antibiotic.

The present invention also includes the use of compounds of formula (I) or its pharmaceutically acceptable salt to obtain drugs for the treatment of bacterial infections, or one, or in combination with-lactam antibiotic.

The present invention also includes the use of compounds of formula (I) or its pharmaceutically acceptable salt as an inhibitor-lactamase.

Compounds of the present invention are active against lactamase-enzyme produced by a wide range of organisms, including gram-negative organisms and gram-positive organisms.

The following examples illustrate the compounds of the present invention and of the intermediates for their preparation.

Method 1. 2,3-Dihydroimidazo[2,1-b]thiazole-6-carboxaldehyde

Method 1

a) Ethyl-2,3-dihydroimidazo[2,1-b]thiazole-6-carboxylate.

Ethyl-2-mercaptoethyl by triethylamine (1.11 g, 11 mmol). This solution is added dropwise to the rapidly stirred solution of 1,2-dibromethane (9.4 g, 50 mmol) in DMF (5 ml), incubated 0.5 hours, poured into a mixture of ethyl acetate (100 ml) and water (50 ml). The organic phase is washed with water (I ml), dried over anhydrous magnesium sulfate, evaporated to dryness in a vacuum and get orange oil, when chromatographicaliy of which on silica gel with elution with a mixture of ethyl acetate in hexane get ethyl-2-(2-brometalia)imidazole-4(or 5)-carboxylate as a white solid (1.2 g, 4.3 mmol, 61%).

To a suspension of sodium hydride (206 mg of a 50% dispersion in oil, 4.3 mmol) in dry, re-distilled tetrahydrofuran (THF), in the atmosphere of argon at room temperature under stirring add portions obtained above white solids withstand 0.5 hours, the reaction mixture is cautiously treated with water (5 ml), filtered through celite. The filtrate is evaporated to dryness in vacuo, re-evaporated (2x) with ethanol, chromatographic on silica gel with elution by ethyl acetate and get a connection in the form of a white solid (0.72 g, 81%), so pl. 107-109oC (dichloromethane-hexane).

C8H10N2O2S.

Found: C, 48.25, H 4.87, N 14.17, S 16.34%, -1
.

H(250 MHz; CD3OD): 1.33 (3H, t, J 7 Hz), 3.92 (2H, t, J 7 Hz), 4.24-4.38 (4H, m), 7.81 (1H, c).

(b) 2,3-Dihydro-6-hydroxymethylimidazole [2.1-b]thiazole.

Alumaguard lithium (280 mg, 7.3 mmol) is suspended in dry fresh THF (20 ml) in an argon atmosphere, and treated dropwise with a solution of ethyl-2,3-dihydroimidazo[2,1-b] thiazole-6-carboxylate (1,32 g, 6.7 mmol) in THF (20 ml), incubated 2 hours, carefully add water until the termination of rapid gas evolution, the mixture is filtered through celite, the gasket of the filter is washed with THF and water. The filtrate and wash water are combined, evaporated to dryness in a vacuum. The residue evaporated twice from ethanol and receive a named connection in the form of a white solid (1.03 g, 100%).

H(250 MHz; CD3OD): 3.73-3.95 (2H, m), 4.06-4.30 (2H, m), 4.42 (2H, s), 7.04 (1H, c).

c) 2,3-Dihydroimidazo[2,1-b]thiazole-6-carboxaldehyde.

2,3-Dihydro-6-hydroxymethylimidazole[2,1-b]thiazole (1.47 g, 9.4 mmol) was dissolved in acetonitrile (30 ml) and addition of water (minimum volume), contribute manganese dioxide (to 4.41 g, 3 weight equivalents), the mixture is stirred for 1.5 hours at room temperature, filtered through diatomaceous earth, the filter is washed with water, and the combined filtrate and wash water is evaporated to dryness the LASS="ptx2">

max(CH2Cl2): 1685, 1528, 1272, 1260 and 1152 cm-1;

H(90 MHz; CD3OD): 3.84 - 4.19 (2H, m), 4.20-4.59 (2H, m), 7.97 (1H, s), 9.52 (1H, s).

Method 2

2,3-Dihydroimidazo[2,1-b]thiazole-6-carboxaldehyde

Ethyl-2,3-dihydroimidazo[2,1-b]thiazole-6-carboxylate (4,2 g, 21,21 mmol) dissolved in dry dichloromethane (150 ml), cooled to -70oC in a stream of dry argon, is treated with a solution of diisobutylaluminium in toluene (1.5 M, and 26.9 ml, 2 equivalents) for 40 minutes at -70oC. the Reaction mixture was stirred at -70oC additional 0.5 hour, bring water (10 ml), the mixture is stirred at room temperature for 0.5 hour, acidified with 5 M HCl, filtered through a pad of celite, laying celite, the gasket additionally washed with dichloromethane. The combined organic extracts dried over anhydrous magnesium sulfate, evaporated to dryness, chromatographic on silica gel with elution by ethyl acetate and get titled compound (1.4 g, 43%).

Method 2. 2,3-Dihydroimidazo[2,1-b]thiazole-6-carboxaldehyde-1-(R,S)-oxide

Method 1

2,3-Dihydroimidazo[2,1-b]thiazole-6-carboxaldehyde-1(R,S)-oxide

2,3-Dihydroimidazo[2,1-b] thiazole-6-carboxaldehyde (154 mg, 1 mmol) dissolved in dichloromethane (minimum volume) temperature 0.5 hour, add diethyl ether, dissolving the existing sediment, and eventually formed a new precipitate. This new precipitate is collected by filtration, washed with diethyl ether, air-dried (128 mg, 75%).

Found: M+170,0149, C6H6N2O2S

Required: M 170,0150

max(CH2Cl2): 1697, 1268, 1259 cm-1;

H(250 MHz, CD3OD: 3.69-3.88 (1H, m), 3.94 - 4.11 (1H, m), 4.50 - 4.90 (2H, m), 8.20 (1H, s), 9.81 (1H, s).

Method 2

a) 2,3-Dihydro-6-hydroxymethylimidazole[2,1-b]thiazole-1(R,S)-oxide

2,3-Dihydro-6-hydroxymethylimidazole[2,1-b] thiazole (1.5 g, 10 mmol) in dichloromethane (500 ml) cooled to 0-5oC handle m-chlormadinone acid (60% purity, is 2.88 g, 10 mmol), soak 15 minutes, the volatile components are removed under vacuum, the residue is treated with ether. The solvent is decanted, and the process repeated twice. The remaining solid residue was dissolved in methanol (minimum volume), filtered, the filtrate is evaporated to dryness in vacuo to education is not quite white foamy substance (1.64 g, 99%).

Found: M+172,0308; C6H8N2O2S.

Required: M 172,0306

H(250 MHz; (CD3)2O): 3.58-3.67 (1H, m), 3.89 - 4.01 (1H, m), 4.39 - 4.63 (4H, m), 5.14 (1H, t, J 6 is elimidate [2,1-b] thiazole-1 (R, S)-oxide (376 mg, 2.19 mmol) suspended in acetonitrile (10 ml), add water to obtain a clear solution, make dvuoksid manganese (1.13 g, 3 weight equivalents), the mixture is vigorously stirred at room temperature for 24 hours, make incremental dvuoksid manganese (1 g), and stirred for additional 24 hours. The reaction mixture was filtered through celite, the gasket of the filter is washed with water, the filtrate is evaporated to dryness in a vacuum and get more solid (340 mg, 91%).

Method 3. 2,3-Dihydroimidazo[2,1-b] thiazole-6-carboxaldehyde-1,1-dioxide

a) 6-Acetoxymethyl-2,3-dihydroimidazo[2,1-b]thiazole

2,3-Dihydro-6-hydroxymethylimidazole[2,1-b] thiazole (312 mg, 2 mmol) is suspended in dichloromethane (10 ml), treated with pyridine (174 mg, 2.2 mmol) and acetic anhydride (224 mg, 2.2 mmol), was added 4-dimethylaminopyridine (10 mg), the mixture is stirred for 4 hours at room temperature, the volatile components are evaporated in vacuum to dryness, the residue RUB clean with hexane, the hexane is decanted (2x), the remainder chromatographic on silica gel with elution with a mixture of ethyl acetate and hexane and receive the product (374 mg, 94%) as a white solid.

Found: M+198,0465. C8H10N2O2S

), 2.80 (2H, t, J 7 Hz), 4.15 (2H, t, J 7 Hz), 4.97 (2H, s), 7.11 (1H, s).

b) 6-Acetoxymethyl-2,3-dihydroimidazo[2,1-b]thiazole-1,1-dioxy

A solution of 6-acetoxymethyl-2,3-dihydroimidazo[2,1-b] thiazole (358 mg, is 1.81 mmol) in dichloromethane (10 ml) is treated at room temperature m-chlormadinone acid (60% purity, 936 mg, 3.78 mmol). After the initial sulfoximine the reaction mixture is boiled for 4 hours, left for 72 hours at room temperature, evaporated in vacuo, the residue RUB clean with diethyl ether, the solvent decanted. This process is repeated (2x) and the remaining white solid residue is dissolved in methanol, adsorb on silica gel, chromatographic on silica gel with elution with a mixture of ethyl acetate and hexane and get the named compound as a white solid (305 mg, 73%).

Found: M+230,0361. C8H10N2O4S

Required: M 230,0361

max(CH2Cl2): 1739, 1336, 1272, 1264 and 1258 cm-1;

H(250 MHz, CDCl3): 2.08 (3H, s), 3.94 (2H, t, J 6 Hz), 4.55 (2H, t, J 6 Hz), 5.07 (2H, c), 7.16 (1H, s).

C) 2,3-Dihydro-6-hydroxymethylimidazole[2,3-b]thiazole-1,1-dioxide

6-Acetoxymethyl-2,3-dihydroimidazo[2,1-b] thiazole-1,1-dioxy (305 mg, 1.33 mmol)is treated with methanolic ammonia is ω (20 ml) at room temperature, withstand 2.5 hours, evaporated volatile components in vacuo, the residue RUB clean with diethyl ether, the resulting solid precipitate is filtered off, washed with diethyl ether, air-dried (207 mg, 83%).

Found: M+188,0256. C6H8N2O3S.

Required: M 188,0256

max(Hujol) 3354, 1377, 1325 and 1133 cm-1;

H(250 MHz, (CD3)2O): 4.14 (2H, t, J 6 Hz), 4.40 (2H, d, J 6 Hz), of 4.54 (2H, t, J 6 Hz), 5.20 (1H, t, J 6 Hz, exchangeable), 7.36 (1H, s).

(d) 2,3-Dihydroimidazo[2,1-b]thiazole-6-carboxaldehyde-1,1-dioxide

A solution of 2,3-dihydro-6-hydroxymethylimidazole[2,1-b] thiazole-1,1-dioxide (207 mg, 1.1 mmol) in acetonitrile (minimum volume) is treated with manganese dioxide (621 mg, 3 weight equivalent), stirred vigorously at room temperature for 1 hour, pay an additional amount of manganese dioxide (621 mg), additionally stirred for 18 hours. The mixture is filtered through celite, the filter is washed with acetonitrile, and the filtrate and wash liquid unite, evaporated to dryness in vacuo, the residue clobber in dichloromethane, the resulting solid precipitate is filtered off, washed with dichloromethane, dried in air (108 mg, 53%).

Found: M+186,0103. C6H6N2O3
2O): 4.25 (2H, t, J 7 Hz), 4.68 (2H, t, J 7 Hz), 8.32 (1H, s), 9.81 (1H, s).

Method 4. 6,7-dihydro-5H-imidazo[2,1-b]1,3 thiazin-2-carboxaldehyde

a) Ethyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-2-carboxylate

A solution of ethyl-2-mercaptoimidazole-4(or 5)-carboxylate (860 mg, 5 mmol) in DMF (minimum volume) containing triethylamine (555 mg, 5.5 mmol), added dropwise to the rapidly stirred 1,3-dibromopropane (5 ml), incubated for 0.5 hours, the reaction mixture was partitioned between)dilatatum and water, the phases are separated, the organic layer washed with water (3x), saturated brine, dried over anhydrous magnesium sulfate, evaporated to dryness in a vacuum. The remainder chromatographic on silica gel with elution with a mixture of 25% ethyl acetate-hexane and receive the intermediate ethyl-2-(3-bromo-1-propylthio)imidazole-4 (or 5)-carboxylate, which was dissolved in dry fresh THF (minimum volume) and added dropwise with stirring to a suspension of sodium hydrate (60% dispersion in oil, 240 mg, 6 mmol) in dry fresh THF (20 ml) in an argon atmosphere, soak 10 minutes, carefully add water to the reaction mixture, which was filtered through celite. The filter was washed with THF, the filtrate and washing liquid are combined evaporated to dryness in vacuo,a white solid (635 mg, 60%), so pl. 99o-100oC (dichloromethane-hexane).

C9H12N2O2S.

Found: C, 50.86, H 5.74, N 13.14, S 15.07%; M+212.0619

Calculated: C, 50.94, H 5.66, N 13.21, S 15.09%; M 212.0619

max(CH2Cl2): 1720, 1212 and 1198 cm-1;

H(250 MHz, CDCl3): 1.34 (3H, t, J 7 Hz), 2.29-2.38 (2H, m), 3.13-3.17 (2H, m), 4.09 (2H, t, J6 Hz), 4.33 (2H, q, J 7 Hz), 7.53 (1H, s).

b) 6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-2-carboxaldehyde.

To a solution of ethyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-2-carboxylate (2,12 g, 1% mmol) in dry dichloromethane (40 ml) in an argon atmosphere at -70oC is added at a temperature below -68oC diisobutylaluminium (1.5 M in toluene, 12 ml, 18 mmol), stirred for 1 hour at -70oC, carefully add water, remove cooling, the reaction mixture was vigorously stirred at room temperature for 15 minutes and make a celite (2 g). The mixture is filtered through celite, the filter was washed with dichloromethane and water, the filtrate and washing liquid are combined evaporated to dryness in a vacuum. The residue is evaporated with ethanol (2x) and get the named compound as a white solid (1.31 g, 78%).

max(CH2Cl2): 1685, 1543 and 1453 cm-1.

H(250 MG what,3]thiazin-2-carboxaldehyde-8,8-dioxide

a) Ethyl-6,7-dihydro-5H-imidazo[2,1-b] [1,3]thiazin-2-carboxylate-8,8-dioxide.

A solution of ethyl-6,7-dihydro-5H-imidazo[2,1-b] [1,3] thiazin-2-carboxylate (212 mg, 1 mmol) in dichloromethane (20 ml) is treated with m-chlormadinone acid (50% purity, 690 mg, 2 mmole). The initial sulfoximine is quick and ectothermic when the reaction sulfoximine completed, the mixture is boiled for 2 hours, evaporated in vacuo volatile components and the remainder RUB clean with diethyl ether. The resulting white solid precipitate is filtered off, washed with diethyl ether, dried in air (226 mg, 93%).

C9H12N2O4S. Found: M+244, 0521, requires M 244,0515.

max(CH2Cl2): 1735, 1717, 1331, 1270, 1257, 1218, 1198, 1167, 1120 cm-1.

H(250 MHz, CDCl3): 1.36 (3H, t, J 7 Hz), 2.71 - 2.80 (2H, m), 3.54 - 3.59 (2H, m), 4.28 - 4.42 (4H, m), 7.65 (1H, s).

b) 6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-2-carboxaldehyde - 8,8-dioxide.

Ethyl-6,7-dihydro-5H-imidazo[2,1-b] [1,3] thiazin-2-carboxaldehyde - 8,8-dioxide (200 mg, of 0.82 mmole) dissolved in dry dichloromethane (minimum volume) in argon, cooled to a temperature of -70oC, add diisobutylaluminium (1.5 M in toluene, 1 ml, 1.5 mmol) at a temperature below -70oC is acetelyne number or no original material. Then make a careful water (5 ml), remove the cooling and the mixture is stirred for 1 hour at room temperature, contribute to a mixture of celite and the resulting mixture filtered through celite. Zletovo the pad washed with dichloromethane and water, the filtrate and washing liquid are combined evaporated to dryness in vacuo, the residue re-evaporated with ethanol (2x), then RUB clean with diethyl alcohol, the product is filtered, washed with diethyl ether, dried in air (274 mg, 30%).

C7H8N2O3S. Found: M+200.0256 requires: 200.0253.

max(II, OI): 1678, 1316, 1161 and 1191 cm-1.

H[250 MHz, (CD3)2O]: 2.50 - 2.57 (2H, m), 3.81 - 3.85 (2H, m), 4.31 (2H, t, J 6 Hz), 8.27 (1H, s), 9.80 (1H, s).

Example 1. ((5R)-6[(Z)-(2,3-Dihydroimidazo[2,1-b] thiazol-6-yl) methylene] - stump-3-carboxylate sodium

a) 4-Methoxybenzyl[5R,6S,8RS]-6-acetoxy(2,3-dihydroimidazo [2,1-b]thiazol-6-yl)methyl]-6-bromine-3-carboxylate.

Diphenylamine (604 mg, 3.57 mmol) was dissolved in dry, fresh THF (35 ml) in an argon atmosphere, cooled to -20oC, make a n-utility (1,48 M in hexane, 208 mg, 3.25 mmol), the mixture is stirred for 10 minutes at room temperature, cooled to -70oC, was added dropwise a solution of 4-methoxybenzaldehyde 10 minutes at -70oC, treated with a solution of 2,3-dihydroimidazo[2,1-b] thiazole-6-carboxaldehyde (500 mg, 3.25 mmol) in dry DMF (5 ml). The reaction mixture was stirred for 20 minutes at -70oC, treated with acetic anhydride (331 mg, 3.25 mmol) and 4-dimethylaminopyridine (100 mg). When the intermediate bromohydrin will turn into a named connection, the reaction mixture is concentrated to a smaller volume under vacuum and partitioned between dichloromethane and water. The organic layer was separated, washed again with water (5x), diluted with water, sodium bicarbonate, water, saturated brine, dried (MgSO4), evaporated to dryness in a vacuum and get a brown oil, which chromatographic on silica gel with elution with 50% ethyl acetate in hexane and get the named compound as a brown foamy substance (1.0 g, 55%).

max(CH2Cl2): 1801, 1753 and 1715 cm-1.

b) 4-Methoxybenzyl-(5R)-6-(2,3-dihydroimidazo[2,1-b] thiazol-6-yl)methylene-stump-3-carboxylate.

A solution of 4-methoxybenzyl[5R, 6RS, 8RS] -6-[acetoxy(2,3 - dihydroimidazo[2,1-b]thiazol-6-yl)methyl]-6-bromine-3 - carboxylate (930 mg, 1.65 mmol) in THF (20 ml) is treated with N,N,N',N'-tetramethylethylenediamine (TMEDA, 478 mg, 4.1 mmol), then add the powder CIN is these 10 minutes, make additional amount of glacial acetic acid (247 mg, 4.1 mmol), additionally stirred for 10 minutes, the resulting mass is distributed between ethyl acetate and water, the mixture is filtered through celite. The phases are separated, the organic layer washed with 1 M aqueous potassium bisulfate (3), saturated brine, saturated aqueous sodium bicarbonate (2x), saturated brine, dried (MgSO4), evaporated to dryness in a vacuum. The remainder chromatographic on silica gel with elution with 50% ethyl acetate in hexane and get the product as a yellow foamy substance (459 mg, 65%),

[]D25+522o(c = 0.1% in acetonitrile):

max(CH2Cl2): 1773, 1709, 1252 and 1232 cm-1;

H[250 MHz, (CD3)2CO]: 3.79 (3H, s), 3.93 (2H, t, J 7 Hz), 4.34 (2H, t, J 7 Hz), 5.16 (2H, Avkw, 1,25 Hz), 6.55 (1H, d, J 1 Hz), 6.91 - 6.96 (3H, m), 7.40 (2H, d, J 7 Hz), 7.45 (1H, s), 7.61 (1H, s).

c) (5R)-6-[(Z)-(2,3-dihydroimidazo[2,1-b] thiazol-6-yl)- methylene] - stump-3-carboxylate sodium.

The anisole (of 1.52 ml, 14 mmol) dissolved in dry dichloromethane (2 ml) in an argon atmosphere, cooled to -20oC add ethylaminoethanol (1.8 M in toluene, 147 mg, 1.16 mmol), stirred for 10 minutes at -20oC, cooled to -70oC, was added dropwise a solution of 4-methoxime is not (5 ml), stirred for 15 minutes at -70oC, treated with excess 0.5 M aqueous trisodium citrate, film cooling. When the reaction mixture is again reaches room temperature, treated with diethyl ether, acetone and water to the formation of two distinct phases with very small amounts of material on the surface of the partition. The phases are separated, the organic layer is extracted with dilute aqueous sodium bicarbonate. The combined aqueous extracts acidified with 5 M hydrochloric acid in the presence of ethyl acetate to pH 2, the phases are separated. The aqueous phase is additionally extracted with ethyl acetate, the combined extracts washed repeatedly with water (5x). The washed organic phase is stirred in the presence of water, the pH of the aqueous phase adjust to 6.6 by the addition of dilute aqueous sodium bicarbonate, the phases are separated. The organic phase is additionally extracted with water, aqueous extracts are combined and dried at a temperature below the freezing point. The resulting orange powder cleanse chromatographic resin Didanion HP20 SS when elution with a mixture of THF in water and get after drying at a temperature below the freezing point of the named compound as a yellow solid (56,2 mg, 44%).

max(CME;

H(250 MHz, D2O): 3.86 (2H, d, J 7 Hz), 4.22 (2H, t, J 7 Hz), 6.46 (1H, s), 6.86 (1H, s), 7.01 (1H, s), 7.47 (1H, s).

Example 2. (5R)-6-[(Z)-(2,3-Dihydro-1(R,S)-accomidate[2,1-b] thiazol-6-yl)methylene] - stump-3-carboxylate sodium

a) 4-Methoxybenzyl-(5R)-6-[(Z)-(2,3-dihydro-1(RS)-accomidate [2,1-b] thiazol-6-yl)methylene] - stump-3-carboxylate.

Diphenylamine (372 mg, 2.2 mmole) was dissolved in dry, fresh THF (10 ml) in an argon atmosphere, cooled to -20oC, make a n-utility (2.5 M in hexane, 128 mg, 2 mmole), the mixture is stirred at room temperature for 10 minutes. The resulting mass is then cooled to -70oC, was added dropwise a solution of 4-methoxybenzyl-(5R, 6R)-6-bromine-3-carboxylate (740 mg, 2 mmole) in dry, freshly THF (10 ml), incubated for 20 minutes at -70oC, the reaction mixture is treated with a solution of 2,3-dihydroimidazo[2,1-b]thiazole-6-carboxaldehyde-1(RS)-oxide (340 mg, 2 mmole) in dry DMF (5 ml), stirred at -70oC for 0.5 hours, then treated with acetic anhydride. The cooling is removed, the mixture is stirred for 1 hour at room temperature, and then distributed between ethyl acetate and water. The organic layer is washed well with water (5x), saturated brine, dried (MgSO4) and evaporated to dryness in a vacuum. The residue is purified is,8RS]-6-[acetoxy(2,3-dihydro-1(RS)- accomidate[2,1-b]thiazol-6-yl)methyl]-6-bromine-3 - carboxylate (527 mg, 45%, 0.9 mmol).

The above mixture of bromoacetate (0.9 mmol) dissolved in THF (10 ml), treated TMEDA (263 mg, 2.3 mmol), then powder zinc (148 mg, 2.3 g-atom), contribute glacial acetic acid (136 mg, 2.3 mmol), the mixture is vigorously stirred for 10 minutes, add the additional amount of glacial acetic acid (136 mg, 2.3 mmol), incubated an additional 10 minutes, diluted with ethyl acetate and water and filtered through celite. Phase in the filtrate is separated, the aqueous phase is additionally extracted with ethyl acetate, the extracts combined washed with 1 M aqueous potassium bisulfate (3), saturated brine, saturated aqueous sodium bicarbonate (2x), saturated brine, dried (MgSO4) and evaporated to dryness in a vacuum. The remainder chromatographic on silica gel with elution by ethyl acetate, then the mixture of ethanol in ethyl acetate and get a mixture of (E) and (Z)-isomers plus pure (Z)-isomer. The mixture of isomers re chromatographic on silica gel and two fractions of pure (Z)-isomer unite (236 mg, 27%).

[]D25+409o(c = 0.1% in acetonitrile);

max(KBr): 1772, 1703, 1233 and 1057 cm-1;H[250 MHz, (CD3)2CO]: 3.67 - 2.76 (1H, m), 3.81 (3H, s), 4.00 - 4.14 (1H, m), 4.62 -4.87 (2H, 2m), 5.18 (2H, s), 6.60 (1H, d, J 1 Hz), 6.65 (1H, d, J 7 SUP>+).

b) (5R)-6-[(Z)-(2,3-Dihydro-I(RS)-accomidate[2,1-b] thiazol-6-yl) methylene] - stump-3-carboxylate.

The anisole is dissolved in dry dichloromethane (0.5 ml) in an argon atmosphere, is treated with trichloride aluminum (61,5 mg, 0.45 mmol), cooled to -40oC after reconstitution, is treated with a solution of 4-methoxybenzyl-(5R)-6-[(Z)-(2,3-dihydro-I(RS)-accomidate [2,1-b]thiazol-6-yl)methylene] - stump-3-carboxylate (68 mg, 0.15 mmol) in dry dichloromethane (2 ml), incubated for 15 minutes at -40oC, add 0,5 M trinacria citrate (10 ml), film cooling. The mixture is stirred for 15 minutes at room temperature, the phases are separated. The aqueous layer was washed with dichloromethane, acidified to pH 25 M hydrochloric acid in the presence of ethyl acetate. The phases are separated, the aqueous phase is additionally extracted with ethyl acetate, washed with water (5x), vigorously stirred in the presence of water, adjust the pH of the aqueous layer to 6.8 with dilute aqueous sodium bicarbonate. The phases are separated, the organic layer extracted with water, the extracts combined, dried at a temperature below the freezing point and receive the product (23 mg, 43%).

max(H2O) 370,5 ( DM3mol-1cm-11761) and 301,5 (18,005) nm;

max(KBr): 1751, 1598, 1383, 1268, 1139, 1090 and 1047) 7.77 and 7.80 (each 1H, 2c).

Example 3. (5R)-6-[(Z)-(2,3-Dihydro-1,1-dioxole-azo[2,1-b]thiazol-6-yl) methylene] - stump-3-carboxylate sodium

a) 4-Methoxybenzyl-(5R)-6-[(Z)-(2,3-dihydro-1,1-dioxo-imidazo[2,1-b) thiazole-6-yl)methylene] - stump-3-carboxylate.

Diphenylamine (372 mg, 2.2 mmole) was dissolved in dry, fresh THF (10 ml) in an argon atmosphere; cooled to -20oC, treated with n-butyllithium (2.5 M in hexane, 128 mg, 2 mmole). The mixture is stirred for 10 minutes at room temperature, cooled to -70oC, was added dropwise a solution of 4-methoxybenzyl-(5R, 6R)-6-bromine-3-carboxylate (740 mg, 2 mmole) in dry, freshly THF (5 ml), incubated an additional 10 minutes at -70oC, add a solution of 2,3-dihydroimidazo [2,1-b]thiazole-6-carboxaldehyde-1,1-dioxide (372 mg, 2 mmole) in dry DMF (5 ml), stirred for 0.5 hours at -70oC, treated with acetic anhydride (204 mg, 2 mmole), film cooling, the mixture is stirred for 1.25 hours at room temperature and distribute the reaction mixture between ethyl acetate and water. The organic phase is washed with water (4x), saturated aqueous brine, dried (MgSO4), evaporated to dryness in a vacuum and are yellow-brown foamy substance that chromatographic on silica gel p is 504 mg, 0.84 mmol).

Diastereomer mixture of bromoacetate (504 mg, 0.84 mmol) dissolved in THF (5 ml), treated TMEDA (216 mg, 1.9 mmol), was added powdered zinc (121 mg, 1.9 grams-atoms), the mixture is vigorously stirred, treated with glacial acetic acid (112 mg, 1.9 mmol), incubated 10 minutes, make additional amount of glacial acetic acid (112 mg, 1.9 mmol), maintain the mixture an additional 0.5 hour, distribute the reaction mass between ethyl acetate and water, filtered through celite and separated phases. The organic phase is washed with 1M aqueous potassium bisulfate (3x), saturated brine, dried (MgSO4), evaporated to dryness in a vacuum. The remainder chromatographic on silica gel with elution with mixtures of ethyl acetate in hexane and get titled compound (250 mg, 27%).

[]D25+ 464o(C = 0.1% in acetonitrile);

max(CH2Cl2): 1770, 1714, 1274 and 1256 cm-1;

H[250 MHz, (CD3)2CO]: 3.81 (3H, s), 4.18 (1H, t, J 7 Hz), 4.87 (2H, t, J 7 Hz), 5.19 (2H, Shir.s), 6.57 (1H, c), 6.95 (2H, d J8 Hz), 7.41 (2H, d, J8 Hz), 7.65 (1H, s), 8.39 (1H, s);

m/z (F,A,b, + Ve ion xenon, NOBA sodium) 482 (MNa+).

b) (5R)-6-[(Z)-(2,3-Dihydro-1,1-dioximes [2,1-b] thiazol-6-yl)methylene] - stump-3-carboxylate sodium.

The anisole (1.8 g, 16,3 who should complete solution the mixture is cooled to -40oC, is treated with a solution of 4-methoxybenzyl-(5R)-6-[(Z)- (2,3-dihydro-1,1-dioximes [2,1-b]thiazol-6-yl)methylene] - stump-3-carboxylate (250 mg, 0,54 mmol) in dry dichloromethane (2 ml), stirred for 10 minutes at -40oC, add 0,5 M water trinacria citrate (15 ml) and remove the cooling withstand additional 15 minutes, the mixture is diluted with ditilinom ether, acetone and water to the formation of two distinct phases. The phases are separated, the aqueous phase washed with diethyl ether to pH 2 acidified with 5M hydrochloric acid in the presence of ethyl acetate. The phases are separated, the aqueous phase is additionally extracted with ethyl acetate, the extracts combined well washed with water (4x), vigorously stirred in the presence of water, adjust the pH of the aqueous phase to 6.8 by the addition of dilute sodium bicarbonate. The phases are separated, the organic phase is additionally extracted with water, the combined aqueous extracts are dried at a temperature below the freezing point, then chromatographic resin Dianion HP20 SS when elution with mixtures of THF in water and get a named connection (114 mg, 58%).

max(H2O) 370 ( DM3mol-1cm-12127) and 296.5 (25,942) nm;

max(CVG): 1755, 1599, 1389, 1322, 1269 and 1136 cm-1;

H(250 MHz, D2O): 4.20 (2H, T. 3] thiazin-2-yl)methylene] - stump-3-carboxylate sodium.

a) 4-Methoxybenzyl-(5R, 6RS, 8RS)-6-[acetoxy(6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-2-yl)methyl] -6-bromine-3-carboxylate.

Diphenylamine (598 mg, 3.5 mmol) dissolved in dry fresh THF (20 ml) under argon, cooled to -20oC, make a n-utility (2.5 M in hexane, 203 mg, 3.2 mmol), stirred for 10 minutes at room temperature, cooled to -70oC, are added dropwise at -70oC solution of 4-methoxybenzyl-(5R, 6R)-6-bromine-3-carboxylate (1,17 g, 3.2 mmol) in dry, distilled THF (10 mg), stirred for 10 minutes at this temperature, are added dropwise at -70oC a solution of 6,7-dihydro-5H-imidazo- [2,1-b][1,3]thiazin-2-carboxaldehyde (532 mg, 3.2 mmol) in dry, freshly THF (20 ml), stirred for 20 minutes at -70oC, make acetic anhydride (323 mg, 3.2 mmol), then 4-dimethylaminopyridine (20 mg), remove the cooled, allowed to stand for 1 hour at room temperature, evaporated in vacuo volatile components and the residue distributed between ethyl acetate and water. The organic phase is washed with saturated aqueous sodium bicarbonate, water, saturated brine, dried (MgSO4), evaporated to dryness in a vacuum. The remainder chromatographic on silicalite when elution with mixtures of ethyl acetate in hexane and get named the>: 1801, 1749, 1716 cm-1;

b) 4-Methoxy-(5R)-6-[(Z)-(6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-2-yl) methylene-stump-3-carboxylate.

4-Methoxybenzyl-(5R, 6RS, 8RS)-6-[acetoxy(6,7-dihydro-5H-imidazo[2,1-b] [1,3]thiazin-2-yl) methyl-6-bromine-3-carboxylate (1.04 g, 1.79 mmol) dissolved in THF (20 ml) with vigorous stirring, treated sequentially TMEDA (521 mg, 4,48 mmol), powdered zinc (293 mg, 4,48 g-atoms) and glacial acetic acid (296 mg, 4,48 mmol), stand for 10 minutes, add the additional amount of glacial acetic acid (296 mg, 4,48 mmol), stirred vigorously for 10 minutes. The reaction mixture is distributed between ethyl acetate and water, filtered through celite. The phases are separated, the organic layer was washed with 1M aqueous potassium bisulfate (3), saturated brine, saturated aqueous sodium bicarbonate, saturated brine, dried (MgSO4), evaporated to dryness in vacuo, the residue chromatographic on silica gel with elution with mixtures of ethyl acetate with hexane and get the product as a yellow foamy substance (532 mg, 67%).

max(CH2Cl2): 1773, 1710, 1270 and 1232 cm-1;

H[250 MHz, (CD3)2CO]: 2.30 - 2.42 (2H, m), 3.22 - 3.33 (2H, m), 3.80 (3H, s), 4.20 (2H, t, J6 Hz), 5.16 (2H, Shir. s), 6.55 (1H, d, J 11 Hz), 6.88 - 6.97 (3H, m), 7.38 - 7.53 (4H, Anisole (2,02 g, 18 mmol) dissolved in dry dichloromethane (2 ml) under argon, treated with trichloride aluminum (248 mg, 1.8 mmol), after receipt of the final solution, the mixture is cooled to -40oC, is added dropwise a solution of 4-methoxybenzyl-(5R)-6-[(Z)-(6,7-dihydro - 5H-imidazo[2,1-b][1,3]-thiazin-2-yl)methylene-stump-3-carboxylate in dry dichloromethane (10 ml), incubated 10 minutes at -40oC, treated with 0.5 M aqueous trinacria citrate (15 ml), film cooling, stirred for 15 minutes at room temperature, the mixture is diluted with diethyl ether, water and acetone to obtain a clear separation of phases. The phases are separated, the aqueous layer washed with diethyl ether, acidified to pH 2 with 5 M hydrochloric acid in the presence of ethyl acetate. The phases are separated, the aqueous phase is additionally extracted with ethyl acetate, the extracts are combined and washed well with water (4x). An ethyl acetate extracts are mixed in the presence of water, adjusting the pH value to 6.8 diluted aqueous sodium bicarbonate. The phases are separated, the aqueous layer is dried at a temperature below the freezing point, the remainder chromatographic resin Dianion HP20SS when elution with mixtures of THF in water or get a named connection in the form of bright yellow lyophilized solid (of 79.5 mg, 37%).

UP>;

H(250 MHz, D2O): 2.18-2.23 (2H, m), 3.17 (2H, t, J 6 Hz), 4.04 (2H, t, J 6 Hz), 6.44 (1H, s), 6.86 (1H, s), 7.35 (1H, s);

m/z (F. A. B., + Ve ion xenon, glycerin) 366 (MNa+) and 344 (NH+).

Example 5. (5R)-6[(Z)-(6,7-dihydro-8,8-dioxo-5H-imidazo[2,1 - b][1,3]thiazin-2-yl)methylene] - stump-3-carboxylate sodium

a) 4-Methoxybenzyl-(5R, 6RS, 8RS)-6-[acetoxy(6,7-dihydro-8,8 - dioxo-5H-imidazo[2,1-b][1,3]thiazin-2-yl)methyl]-6-bromine-3-carboxylate.

Diphenylamine (186 mg, 1.1 mmol) dissolved in dry, fresh THF (10 ml) under argon, cooled to -20oC add n-utility in hexane (2.45 M, 410 μl, 1 mmol), film cooling, soak 10 minutes, the mixture is cooled to -70oC, treated with 4-methoxybenzyl-(5R,6R)-6-bromine-3-carboxylate (370 mg, 1 mmol) in dry fresh THF (5 ml), stirred for 10 minutes at -70oC, is treated at this temperature with a solution of 6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-2-carboxaldehyde-8,8-dioxide (200 mg, 1 mmol) in dry THF (2 ml). This mixture is stirred for 20 minutes at -70oC, make acetic anhydride (102 mg, 1 mmol) and 4-dimethylaminopyridine (10 mg), film cooling, the reaction mixture is stirred for 1 hour at room temperature, evaporated in vacuo volatile components and the residue partitioned between etelaat what assalam, dried (MgSO4), evaporated to dryness in vacuo, the residue chromatographic on silica gel with elution with mixtures of ethyl acetate in hexane and get a named connection (229,6 mg, 37.5 per cent).

max(CH2Cl2): 1802, 1758, 1716, 1330, 1275, 1216 and 168 cm-1;

b) 4-Methoxybenzyl-(5R)-6-[(Z)-(6,7-dihydro-8,8-dioxo-5H - imidazo[2,1 - b][1,3]thiazin-2-yl)methylene] - stump-3-carboxylate.

A solution of 4-methoxy-(5R,6RS,8RS)-6-[acetoxy(6,7-dihydro-8,8 - dioxo-5H-imidazo[2,1-b] [1,3] thiazin-2-yl)methyl] -6-bromine-3-carboxylate (410 mg, 0.7 mmol) in THF (10 ml) is treated sequentially TMEDA (195 mg, 1.67 mmol), powdered zinc (109 mg, 1,67 g-atoms) and glacial acetic acid (101 mg, 1.67 mmol), after 10 minutes bring in added amount of glacial acetic acid (101 mg, 1.67 mmol), additionally stirred for 10 minutes, the reaction mixture is distributed between ethyl acetate and water. The organic layer was washed with 1 M aqueous sodium bisulfate (3x), saturated brine, saturated aqueous sodium bicarbonate, saturated brine, dried (MgSO4), evaporated to dryness in vacuo and the residue chromatographic on silica gel with elution by ethyl acetate and receive a bright yellow foamy substance (201 mg, 63%).

[]D25+446o(c=0.1% and the CH2Cl2): 3134, 1777, 1732, 1711, 1330 and 1235 cm-1;

H[250 MHz, (CD3)2CO)]: 2.68-2.77 (2H, m), 3.67-3.72 (2H, m), 3.81 (3H, s), 4.46 (2H, t, J 6 Hz), 5.18 (2H, s), 6.59 (1H, d, J 1 Hz), 6.94 (2H, d, J 9 Hz), 7.11 (1H, d, J 1 Hz), 7.41 (2H, d, J 9 Hz), 7.50 (1H, s), 7.74 (1H, s);

m/z (NH3DCl) 474 (MH+) and 491 (MNH4+).

c) (5R)-6-[(Z)-(6,7-dihydro-8,8-dioxo-5H-imidazo[2,1-b] [1,3] thiazin - 2-yl)methylene] - stump-3-carboxylate sodium.

A solution of anisole (1.2 g, 11.4 mmol) in dry dichloromethane (1 ml) under argon is treated with trichloride aluminum (152 mg, 1.14 mmol), after receipt of the final solution is cooled to -40oC, is treated at a temperature of -30oC a solution of 4-methoxybenzyl- (5R)-6-[(Z)-(6,7-dihydro-8,8-dioxo-5H-imidazo[2,1-b] [1,3] thiazin - 2-yl)methylene] - stump-3-carboxylate (180 mg, 0.38 mmol) in dry dichloromethane (5 ml), incubated for 10 minutes, add 0.5 M aqueous trisodium citrate (10 ml), film cooling, the mixture is left to warm to room temperature, diluted with diethyl ether, water and acetone to obtain two distinct phases. The phases are separated, the aqueous layer washed with diethyl ether, acidified to pH 2 with 5 M hydrochloric acid in the presence of ethyl acetate. The phases are separated, the aqueous phase is additionally extracted with ethyl acetate, the extracts obyedinennogo aqueous sodium bicarbonate and the phases are separated. The aqueous layer is dried at a temperature below the freezing point, resulting orange powder chromatographic resin JP20SS when elution with water to give the named compound as a bright orange powder (54,2 mg, 38%).

max(H2O) 298 ( DM3mol-1cm-122,462) nm;

max/(KBr): 1750, 1597, 1385, 1317 and 1165 cm-1;H[(250 MHz, D2O)]: 2.60-2.77 (2H, m), 3.76-3.80 (2H, m), 4.27 (2H, t, 7 Hz), 6.84 (1H, s), 6.96 (1H, s), 7.01 (1H, s), 7.56 (1H, s);

m/z (F. A. B., + Ve ion xenon, glycerin) 376 (MH+) and 398 (MNa+)

Example 6

(5R)-6-[(Z)-(2,3-dihydroimidazo[2,1-b] thiazol-6-yl)methylene] - stump - 3-carboxylate sodium (448 mg, 1.36 mmol) was dissolved in a minimum volume of water at room temperature, add acetone until the solution becomes turbid. The mixture is left for 24 hours at 4oC, the resulting yellow microcrystalline precipitate is filtered off, washed with acetone, dried in vacuum (327 mg, 67% of the degree of regeneration).

Example 7

(5R)-6-[(Z)-(2,3-dihydroimidazo[2,1-b] thiazol-6-yl)methylene] - stump - 3-carboxylate sodium (100 mg, 0.3 mmol) dissolved in minimum volume of water at room temperature, diluted with ethanol until the solution becomes turbid when mashing formed bright orangemen regeneration).

Example 8

4-Methoxybenzyl-(5R)-6-[(Z)-(2,3-dihydroimidazo[2,1-b] thiazol - 6-yl)methylene] - stump-3-carboxylate

A solution of diphenylamine (2,52 g, 14,85 mmol) in dry distilled THF (50 ml) is cooled to -20oC under stirring, treated with a solution of n-utility (5,7 ml of a 2.6 M solution in hexane), stirred for 10 minutes at -20oC, then cooled to -70oC, and then added dropwise a solution of 4-methoxybenzyl-6-bromo-stump-3-carboxylate (5 g, 13.5 mmol) in dry distilled THF (60 ml) while maintaining the reaction temperature -65oC, stirred for additional 15 minutes at this temperature, then add in 2-3 minutes a solution of 2,3-dihydroimidazo[2,1-b]thiazole - 6-carboxaldehyde (to 2.29 mg, 14,85 mmol) in dry dimethylformamide (approximately 25 ml), stirred for 30 minutes at a temperature of -65oC, make acetic anhydride (1,34 ml of 14.2 mmol), film cooling, the reaction vessel placed on a steam bath with ice, additionally stirred for 30 minutes, and then add the powdered zinc (1,34 g, 20.6 mmol), glacial acetic acid (2,32 ml, 40.5 mmol) and N,N,N',N'-tetramethylethylenediamine (3 ml, 20.2 mmol), the reaction is allowed to increase to room temperature (about 1 hour). The reaction mixture is then resbala, filtered, evaporated, the residue chromatographic on silica gel with elution with a gradient solvent of 50%--->75% ethyl acetate/hexane and get a named connection, identical to the analytical aspect that described in example 1 as a yellow foamy substance (4,01 g, 69.5 per cent).

(5R)-6-[(Z)-(2,3-dihydroimidazo[2,1-b] thiazol-6-yl)methylene] - stump - 3-carboxylate sodium

A solution of anisole (59,7 g, 60 ml, 0.55 mmol) in dry dichloromethane (DHM) (60 ml) is cooled to -20oC under stirring, treated with a solution of ethylaminoethanol (39 ml, 1.8 M solution in toluene, 70.2 mmol), stirred for 5 minutes, cool the reaction to -50oC, is added dropwise a solution of 4-methoxybenzyl-(5R)-6-[(Z)-(2,3-dihydroimidazo[2,1-b]thiazol - 6-yl)methylene] - stump-3-carboxylate (10 g, 23.4 mmol) in dry DHM (100 ml), keeping adding the reaction temperature below -50oC, further stirred for 15 minutes, make an aqueous solution of triacrylate (500 ml, 0.5 M), film cooling, add water (500 ml), the pH of the reaction mixture regulate at the level of 7.2 aqueous sodium bicarbonate, add diethyl ether (500 ml) and the phases are separated. The organic phase is additionally extracted with water (2 x 100 ml), the combined aqueous solution of proliferator additionally adjust to 7.5, then chromatographic resin Dianion HP20SS when the elution with water. The fractions are combined, evaporated in volume with reverse osmosis and get after drying at a temperature below the freezing point of the named compound as a yellow solid substances with identical analytical properties described for the compound in example 1c (to 4.98 g, 65%). The compound crystallizes in the conditions described in example 6.

Example 9

The table shows lactamase - inhibitory activity of the compound of example 1, expressed as the concentration of the compound of example 1, required to achieve 50% inhibition of the hydrolysis of the lactam with the help of/ number-lactamase enzymes (I50µm).

1. 6-(Substituted methylene)stump of General formula (I)

< / BR>
in which R2represents a condensed bicyclic heterocyclic system of rings General formula

< / BR>
where m = 2 or 3;

p= 0, 1, or 2;

R3means hydrogen, salt-forming cation, or a pharmaceutically acceptable hydrolyzable in vivo esters;

the symbol indicates that the double bond may be either E or Z configuration.

2. Connection on p. 1, having the structure IA

< / BR>
where R2and R3

4. Connection under item 1 or 2, where R3is sodium ion.

5. Connection on p. 1, selected from the group consisting of:

(5R)-6-[(Z)-(2,3-dihydroimidazo[2,1-b] thiazol-6-yl)methylene] - stump-3-carboxylate sodium,

(5R)-6-[(Z)-(2,3-dihydro-1-(R, S)-accomidate[2,1 -] thiazol-6-yl)methylene] - stump-3-carboxylate sodium,

(5R)-6-[(Z)-(2,3-dihydro-1,1-dioximes[2,1 -] thiazol-6-yl)methylene] - stump-3-carboxylate sodium,

(5R)-6-[(Z)-(6,7-imidazo[2,1-b] [1,3] thiazin-2-yl)methylene] - stump-3-carboxylate sodium and

(5R)-6-[(Z)-(6,7-dihydro-8,8-dioxo-5H-imidazo[2,1-b] [1,3] thiazin-2-yl)methylene] - stump-3-carboxylate sodium.

6. The compound according to any one of paragraphs.1 - 5 in crystalline form.

7. The method of obtaining the compounds of formula I on p. 1, characterized in that the compound of formula II

< / BR>
where R2matter specified in paragraph 1;

Rxrepresents a protective group for carboxypropyl;

X is a halogen atom;

Z means a halogen atom, a hydroxy-group, substituted by a hydroxy-group, - S(O)qR or -- Se(O)rR7where q is 0, vosstanovitelnogo elimination to remove elements of the group X and z

8. The compound of formula II

< / BR>
where R2, Rx, x and Z have the meanings given in paragraph 7.

9. The compound of formula IV

R2- SNO,

where R2defined under item 1.

10. Compound of formula VII

< / BR>
where R is a C1- C6-alkyl,

Y is halogen atom,

the value of m determined in paragraph 1,

or sulfon or sulfoxide.

11. The compound of formula VIII

< / BR>
where R is a C1- C6-alkyl;

m is defined in paragraph 1,

or sulfon or sulfoxide.

12. The compound of formula IX

< / BR>
or sulfon, or sulfoxide.

13. The compound of the formula X

< / BR>
where m is defined under item 1;

And is1- C6-acyl group,

or sulfon, or sulfoxide.

14. The pharmaceutical composition exhibiting inhibitory-lactamase activity, including an active ingredient and a pharmaceutically acceptable carrier, characterized in that it comprises as active ingredient an effective amount of the compounds of formula I on p. 1 or its pharmaceutically acceptable salt.

15. The method of inhibition-lactamase in the treatment of bacterial infections in humans and animals, OPTIChESKIE acceptable salt, or one, or in combination with-lactam antibiotic.

16. The compounds of formula I or its pharmaceutically acceptable salt p. 1 active inhibitor-lactamase.

 

Same patents:

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I

The invention relates to tricyclic derivatives of pyrrole General formula (I), where R1-R4denote hydrogen, halogen, lower alkyl, phenyl, cycloalkyl or lower alkoxy, a R2indicates additional lower alkoxycarbonyl, acyloxy or mesilate; R5denotes lower alkyl; R6, R7represent hydrogen or lower alkyl; X represents-CH2CH(C6H5), -CH= C(C6H5)-, -YCH2-, -CH=CH - (CR11R12)n; R11and R12denote hydrogen, phenyl, lower alkyl; h denotes 1-3 and Y denotes O or S, and pharmaceutically acceptable acid additive salts

The invention relates to new compounds having pharmacological activity, to a method of their preparation and use as pharmaceuticals

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

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

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
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