WO2002048149A1

WO2002048149A1 - NOVEL ss-LACTAM COMPOUNDS AND PROCESS FOR PREPARING THE SAME

Info

Publication number: WO2002048149A1
Application number: PCT/JP2001/010826
Authority: WO
Inventors: Makoto Sunagawa; Paul Hebeisen
Original assignee: Sumitomo Pharmaceuticals Company, Limited
Priority date: 2000-12-12
Filing date: 2001-12-11
Publication date: 2002-06-20
Also published as: AU2002221114A1; JPWO2002048149A1

Abstract

Novel ß-lactam compounds represented by the general formula [1]: [1] [wherein R1 is lower alkyl or hydroxyl-substituted lower alkyl; R2 is hydrogen or lower alkyl; R3 is hydrogen, hydroxyl, optionally substituted lower alkyl, or the like; R?4 and R5¿ are each hydrogen, hydroxyl, an amino-protecting group, optionally substituted lower alkyl, or the like; A is optionally substituted phenylene; and X is O, S, or NH]. These compounds exhibit excellent antibacterial activity against Gram-positive bacteria, particularly methicillin -resistant staphylococci and methicillin-resistant coagulase -negative staphylococci.

Description

Description Novel β-lactam compound and method for producing the same

The present invention relates to a novel) 3-latatam compound represented by the following general formula [1]. Background art

With the widespread clinical application of third-generation cephalosporins, the frequency of isolation of Gram-positive bacteria has increased, and the frequency of isolation of methicillin-resistant staphylococci (hereinafter abbreviated as MRS II) has increased. Has become a major clinical problem due to intractable infections. In recent years, vancomycin, which is frequently used for MRSA infection, has difficulty in administration due to side effects and the like, and the number of daricopeptide-resistant bacteria is expected to increase in the future. Furthermore, in recent years, an increase in the frequency of isolation of methicillin-resistant coadalase-negative pseudostaphylococci (abbreviated as MR CNS) has been reported. Based on these facts, the development of a drug having a safer and stronger anti-MRSA activity and anti-MRCNS activity has been desired. Disclosure of the invention

An object of the present invention is to provide a 3-lactam drug having excellent antibacterial activity against Gram-positive bacteria, particularly MRSA and MR CNS.

As a result of various studies, the present inventors have found that the compound represented by the following general formula [1] has a strong potency against Gram-positive bacteria, and particularly shows excellent antibacterial activity against MRSA and MRCNS. To complete the present invention.

That is, the present invention

(1) General formula [1]

〗

[Wherein, R ¹ is a lower alkyl group or a lower alkyl group substituted with a hydroxyl group, R ² is a hydrogen atom or a lower alkyl group, and R ³ is a hydrogen atom, an optionally protected hydroxyl group, an imidoyl group. R ⁴ and R ⁵ are each independently a hydrogen atom, an optionally protected hydroxyl group, an amino group-protecting group, or a substituted lower alkyl group; R ³ , R ^4, and R ⁵ may be any two of them bonded together with one nitrogen atom, or with two nitrogen atoms and one carbon atom, It can also form a 5- or 7-membered heterocyclic ring which may be substituted, A is an optionally substituted phenylene group, and X represents O, S or NH. ]

I3_ ratatum compound represented by or a pharmaceutically acceptable salt or non-toxic ester thereof,

(2) X is S, (1) the monolatatum compound or a pharmaceutically acceptable salt or non-toxic ester thereof,

(3) The 3-lactam compound according to (1) or (2), wherein R ¹ is 11 (R) -hydroxyethyl, or a pharmaceutically acceptable salt or non-toxic ester thereof,

(4) General formula [1]

[Wherein, R ¹ is a lower alkyl group or a lower alkyl group substituted by a hydroxyl group, R ² is a hydrogen atom or a lower alkyl group, R ³ is a hydrogen atom, R ⁴ and R ⁵ each independently represent a hydrogen atom, an optionally protected hydroxyl group, an amino group, or a protecting group for an imidoyl group or a lower alkyl group which may be substituted. Or an optionally substituted lower alkyl group, and R ³ , R ^4, and R ⁵ may be any two of these bonded to form, together with, or with one nitrogen atom, May form a 5- to 7-membered heterocyclic ring with one carbon atom, A is an optionally substituted phenylene group, and X is ◦, S or NH Show. ]

When producing a 3-lactam compound or a salt thereof, the general formula [2]

[Wherein, R ^la is a lower alkyl group, a lower alkyl group substituted with a hydroxyl group, or a lower alkyl group substituted with a hydroxyl group protected with a protecting group, R ² has the same meaning as described above, and R ⁶ Represents a carboxyl protecting group, and L represents an active ester of a hydroxyl group. ]

And a compound represented by the general formula [3]

[Wherein, A, X, RR ⁴ and R ⁵ have the same meaning as described above. ]

Or a compound represented by the general formula [2] and a thiolate salt of the compound represented by the general formula [3] to react with the compound represented by the general formula [3].

[Wherein, A, X, RR ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meaning as described above. ]

Wherein R ^la , R ³ , R ⁴ and R ^{5 have} a hydroxyl group protecting group removal reaction, R ^{3 has} an imidoyl group protecting group removal reaction and R ⁴ and R ⁵ have an amino group protection Suitable for the reaction for removing the group and the reaction for removing the protective group for the carboxyl group in R ⁶ : a 3-lactam compound represented by the general formula [1] characterized by performing a combined reaction: ,

(5) a pharmaceutical containing the ratatam compound or the pharmaceutically acceptable salt or non-toxic ester thereof according to any one of the above (1) to (3), and

(6) An antibacterial agent containing the 3-latatam compound according to any one of (1) to (3) or a pharmaceutically acceptable salt or a nontoxic ester thereof. In the present invention, examples of the lower alkyl group include straight-chain or branched such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butylinole, n-pentyl or n-hexyl. Examples thereof include a chain having 1 to 6 carbon atoms.

Examples of the lower alkyl group substituted by a hydroxyl group include hydroxymethyl, 1-hydroxyethynole, 2-hydroxyxetinole, 1-hydroxy-11-methylethyl, 1-hydroxypropyl, and 2-hydroxypropyl. Having 1 to 6 carbon atoms.

Examples of the substituent of the optionally substituted lower alkyl group or the optionally substituted phenylene group include a hydroxyl group, a lower alkyloxy group, a lower alkylcarbonyl group, a lower alkylcarbonyloxy group and a lower alkyl group. Oxycarbonyl group, carbonyl group, halogen atom, cyano group, NR ⁶ R ⁷ (R ⁶ and R ⁷ each independently represent a hydrogen atom or a lower alkyl group, or R ⁶ and R ⁷ may be taken together with the nitrogen atom to form pyrrolidine, piperidine, monorephorin, piperazine, N-lower alkyl substituted piperazine or azepane. ), One CO NR ⁶ R ⁷ (where R ⁶ and R ⁷ have the same meaning as described above), one OCONR ⁶ R ⁷ (where R ⁶ and R ⁷ have the same meaning as described above),- SO ₂ NR ⁶ R ⁷ (however, R ⁶ and R ⁷ have the same meanings as described above), -NR ^6a S0 ₂ NR ⁶ R ⁷ (where R ^6a represents a hydrogen atom or a lower alkyl group; ⁶ and R ⁷ have the same meaning as described above.), -NR ^6a CONR ⁶ R ⁷ (however, R ^6a , R ⁶ and R ⁷ have the same meanings as described above), or _COOCH ₂ OCOR ⁸ (however, And R ⁸ represents a lower alkyl group. These substituents may be protected by a suitable protecting group. The substitution position is not limited as long as it is a chemically possible position, and-substitution or plural substitutions are possible.

Lower alkyloxy groups include, for example, straight-chain or branched carbons such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy. Examples of numbers 1 to 6 are given.

Examples of the lower alkyl carboxy group include methyl carbyl, ethyl carbonyl, n-propyl carbonyl, isopropyl carbole, n-butyl carbole, isoptinolecanolebonore, tert-butylcanolebonyl, Examples thereof include a linear or branched lower alkylcarboyl group having 2 to 7 carbon atoms such as pentinorecanolole-n- or n-hexylcarbonyl.

Examples of the lower alkylcarboxy group include, for example, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonoxy, isobutylcarbonyloxy, tert. Examples thereof include a linear or branched lower alkynolecarboxy group having 2 to 7 carbon atoms, such as xy, n-pentylcarboxy or n-hexynolecapillonyloxy.

Examples of the lower alkyloxycarbonyl group include methyloxycarbonyl, ethyloxypropyl, n-propyloxypropyl, isopropyloxycanoleponinole, n-butyloxycanoleponyl, and isobutyloxycarbonyl. , Tert Examples thereof include linear or branched lower alkyloxycarbonyl groups having 2 to 7 carbon atoms, such as monobutyloxycarbyl, n-pentyloxycarbonyl or n-hexylcarbocarber.

The halogen atom represents fluorine, chlorine, bromine or iodine.

Examples of the 5- to 7-membered hetero ring include a pyrrolidine ring, a piperidine ring, an azepane ring, a 3,4-dihydro-2H-pyrrole ring, a 2,3,4,5-tetrahydropyridine ring, Examples include 4,5,6-tetrahydro-12H-azepine ring, morpholine ring, thiomorpholine ring, piperazine ring, 2-imidazoline ring, 1,4,5,6-tetrahydropyrimidine ring and the like.

Examples of the substituent of the optionally substituted 5- to 7-membered hetero ring include a lower alkyl group, a hydroxyl group, a lower alkyloxy group, a lower alkylcarboxy group, a lower alkylcarboeroxy group, and a lower alkylo group. Examples include a carbonyl group, a carboxyl group, a halogen atom, and a cyano group.

The phenylene groups include 1,2-phenylene, 1,3-phenylene and 1,4-phenylene.

As the protecting group for the carbonyl group, various types of protecting groups which are usually used can be used. Preferably, the protecting group is linear or branched such as methyl, ethyl, isopropyl and tert-butyl. Lower alkyl groups having 1 to 5 carbon atoms, for example, lower alkyl groups having 1 to 5 carbon atoms, such as 2-ethylenoxytyl, 2,2,2-trichloromethyl, for example, methoxymethyl, ethoxymethyl, isobutoxy; 1 to 1 carbon atoms such as methyl

A lower alkoxymethyl group such as 5, for example, aceethoxymethyl, propionyloxymethyl, butyryloxymethyl, and bivaloyloxymethyl; a lower aliphatic acyloxymethyl group having 1 to 5 carbon atoms, for example, 1-ethoxy; carbonyl O 1--C ₅₎ lower alkoxycarbonyl Interview Ruo key shell ethyl group such as carboxymethyl Echiru, e.g. downy Njinore, .rho. methoxybenzylidene Honoré, o- Etro base Njinore, j) Ararukiru groups such as twelve Toroben Gilles Examples thereof include a lower alkenyl group having 3 to 7 carbon atoms such as aryl, 3-methylaryl, a benzhydryl group, or a phthalidyl group. Examples of the protecting group for the hydroxyl group, the protecting group for the imidoyl group, and the protecting group for the amino group include those capable of using various protecting groups which are usually used. A lower alkoxycarbonyl group having 1 to 5 carbon atoms such as cicarbonyl, for example, a carbon atom having 1 to 5 carbon atoms such as 2-iodyloxycarbonyl and 2,2,2-trichloroethylcarbonyl. A substituted or unsubstituted lower alkenyloxycarbonyl group having 3 to 7 carbon atoms such as aryloxycarboyl group, for example, benzyloxycarbonyl, p-methoxybenzyloxy group, o —Altoalkyloxycarbonyl groups such as benzodioxyoxycarbonyl, and p-toluene benzoyloxycarbonyl, for example, trialkylsilyl groups such as trimethylsilyl, triethylsilyl, and tert_butyldimethylsilyl Is mentioned. Examples of the protecting group for the imidoyl group and the protecting group for the amino group include, for example, (5_methyl-1,3-dioxolen-12-one-1-yl) methyloxycarbonyl group ゃ 3- (benzoylamino) propionyl group. Groups that can be completely hydrolyzed in vivo.

The pharmaceutically acceptable salt represented by the general formula [1] is a commonly used non-toxic salt. Examples of such salts include, as salts of carboxylic acids in the molecule, inorganic base salts such as sodium, potassium, calcium, magnesium, and ammonium, for example, triethylammonium, pyridium, and diisopropylammonium. Such an organic base salt, and an intramolecular salt formed with a positive charge such as a quaternary ammonium on the side chain at the 3-position are exemplified. And inorganic acid salts such as sulfuric acid and phosphoric acid, and organic acid salts such as formic acid, acetic acid, oxalic acid, methanesulfonic acid and benzenesulfonic acid.

— The non-toxic ester at the 2-carboxyl group of the general formula [1] means a conventional pharmaceutically acceptable ester, preferably, for example, acetoxmethyl, propionyloxymethyl, n-butylyloxymethyl, vivaloyl (Alkoxy alkenyl having 2 to 10 carbon atoms) such as oxymethyl, cyclohexyl acetooxymethyl, (1-methylcyclohexanyl propyloxy) methyl,

(Ethoxycarbonyloxy) ethyl, 1- (n-propyloxycarbo-loxy) ethynole, 1- (cyclohexynoleoxycanoleponinoleoxy) ~ 10 alkoxy) carbonyloxy] mono (alkyl having 1 to 3 carbon atoms) Ester, (5-methyl-1,3-dioxolen-l-2-one-41-yl) Those which are easily hydrolyzed in vivo such as methyl esters and phthalidyl esters are exemplified.

The -lactam compound represented by the general formula [1] or a pharmaceutically acceptable salt or non-toxic ester thereof may be an anhydride, hydrate or solvate thereof.

Hereinafter, the production method of the compound of the present invention will be described in detail.

General formula [2]

[Wherein, R ^la , R ² , R ⁶ and L represent the same meaning as described above. ]

And a compound represented by the general formula [3]

[Wherein, A, X, R ³ , R ⁴ and R ⁵ have the same meaning as described above. ]

Reacting the compound represented by the general formula [2] in the presence of a base, or reacting the compound represented by the general formula [2] with the thiolate salt of the compound represented by the general formula [3] in an inert solvent. By the general formula [4]

^{Wherein, A, X, RR 2,} R 3, R 4, R 5 and R ⁶ are have the same meanings as described above. ]

Can be obtained.

Here, an active ester of a hydroxyl group is, for example, a substituted or unsubstituted arylsulfonate such as benzenesulfonic acid ester, p-tonolenesnolefonic acid ester, nitrobenzenesnolefonic acid ester, and ρ-bromobenzenesulfonic acid ester. Acid esters such as lower alkanesulfonic acid esters having 1 to 5 carbon atoms such as methanesulfonic acid esters and ethanesulfonic acid esters, and halogenoalkane nolephones having 1 to 5 carbon atoms such as triphenylenolomethanesulfonic acid esters and the like Acid esters, for example, aryl phosphoric acid esters such as diphenyl phosphoric acid ester, and halides such as chlorinated, brominated, and iodo compounds, which are esters with hydrogen halide, and the like can be given. Among such reactive esters of hydroxyl groups, preferred are! ) Esterone monotonoleene sulfonic acid, ester methane sulfonic acid, trifluoromethane sulfonic acid ester, diphenyl phosphoric acid ester. The inert solvent used to obtain the compound represented by the general formula [4] in the presence of a base from the compound represented by the general formula [2] and the compound represented by the general formula [3] includes dioxane and tetrahydrofuran. And dimethyl sulfoxide, dimethyl honoleamide, acetonitrinole, benzene, toluene, hexametinole phosphoramide, and a mixed solvent thereof.

Examples of bases include inorganic bases such as sodium carbonate, carbonated lime, sodium hydride, hydrogenated lime, pyridine, dimethylaminopyridine, triethylamine, diisopropylethylamine, 1,8-diazavisic mouth [ 5. 4. 0] Organic bases such as van decay 7-ene (DBU). Particularly preferred is DBU. The base is required to be used in an amount sufficient for the reaction to proceed sufficiently, and the reaction can be usually performed using 1 to 3 equivalents to the mercaptan compound represented by the general formula [3].

The amount of the mercaptan compound represented by the general formula [3] needs to be sufficient to allow the reaction to proceed sufficiently, and a large excess can be used. It can be performed using 1-2 equivalents. The reaction is carried out at a temperature in the range of −100 ° C. to + 60 ° C., preferably in the range of −40 ° C. to + 40 ° C. After the completion of the reaction, the product can be taken out by a usual organic method.

The inert solvent used for producing the compound represented by the general formula [4] by reacting the compound represented by the general formula [2] with the thiolate salt of the compound represented by the general formula [3] includes: , Dioxane, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, acetoetrile, benzene, toluene, hexanemethylphosphoramide, and a mixed solvent thereof. The thiolate salt must be used in an amount sufficient for the reaction to proceed sufficiently, and can be used in a large excess. However, it is usually carried out using 1 to 2 equivalents to the compound represented by the general formula [2]. it can.

The reaction is carried out at a temperature in the range of 78 ° C to + 60 ° C, preferably in the range of 140 ° C to + 40 ° C. After the completion of the reaction, the product can be taken out by a usual organic chemical technique.

The thiolate salt can be produced by using a mercaptan compound represented by the general formula [3] and a base. Examples of the base include inorganic bases such as sodium hydride and potassium hydride, metal alkoxides such as potassium tert-butoxide and sodium methoxide, and metal amides such as sodium amide, lithium diisopropylamide and lithium disilazide. Can be

Then, obtained from the compounds represented by the general formula [4], according to known methods as needed, R ^la, removal of the protecting group for a hydroxyl group in R ^3, R ⁴ and R ^5, R ⁴ and removal of the protecting group of Amino groups in R ^5, or removal of the protecting groups Imidi Le group in R ^3, applies the removal of the protecting group of the carboxyl group in R ^3, RR ⁵ and R ^6: 13且combined viewed By performing the above reaction, a 3-latatam compound represented by the general formula [1] can be produced.

The method for removing these groups is a method known per se by treating with an acid, a base, a reducing agent, and the like.For example, see TWGreene: Protective Groups in Organic Synthesis, J. Wiley & Sons Inc., 1981. it can. The acid is preferably trifluoroacetic acid, formic acid, boron trifluoride, aluminum chloride, or a mixture thereof. Things can be mentioned. Preferred examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal sulfides such as sodium sulfide and potassium sulfide, and tetrabutylammonium fluoride. The reduction method preferably includes hydrogenolysis with zinc and acetic acid, hydrogen and palladium-carbon or platinum and the like. Further, a method using zero-valent palladium can also be used.

The solvent used is not particularly limited as long as it does not adversely affect the reaction, but water, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, fatty acids such as acetic acid, and the like. Can be used. The reaction temperature can be suppressed or promoted by appropriately cooling or heating, and the preferred temperature is from 130 ° C to 140 ° C. After completion of the reaction, the product can be removed by ordinary organic chemistry techniques.For example, the reaction mixture is adjusted to near neutrality, and then subjected to column chromatography using an adsorption resin or the like to obtain the target compound. The reaction product can be obtained by fractionating the eluted portion and freeze-drying.

The compound represented by the general formula [2] is known and can be produced, for example, by the method described in JP-B-63-55514.

The mercaptan compound represented by the general formula [3] can be prepared by various known methods, for example, K. Hofmann, Heterocyclic Chemistry vol. 6 (1953), JV Metzger, | RJ Vol. 34 (1979), IJ Turchi, ibid. 45 (1986), Interscience Publishers,

Inc. Alternatively AR Katritzky, Advanses in Hetrocyclic Chemistry, vol. 32 (1982), Academic Press, method of Monographs described such, Bioorganic & Medicinal Chemistry Letters 9 Certificates, 2 ⁹ 7 3 ²⁹ 76 pp (19 "years) such papers It can be produced by the methods described or by combining them.

The compound represented by the general formula [1]

As shown in the figure, there are optical isomers based on the asymmetric carbons at the 4-, 5-, and 6-positions of the carbane skeleton, and all of these isomers are represented by a single formula for convenience. However, the scope of the present invention is not limited thereby, and the present invention includes all isomers and isomer mixtures based on each asymmetric carbon atom. However, when R ² is hydrogen, a compound having a (5R, 6R) or (5R, 6S) configuration in which the carbon atom at the 5 position is an R configuration is preferred. In the case of a R ² force S lower alkyl group, the carbon atom at position 4 has an R configuration and the carbon atom at position 5 has an S configuration, or (4R, 5S, 6S) configuration, or (4R, 5 S, 6 R) -coordinated compounds. Further, when R ¹ is 1-hydroxyethyl,

As shown in the above, there are also R-coordination isomers and S-coordination isomers at the 8-position, and R coordination can be mentioned as a preferable one.

In the case of producing an isomer having such a coordination, the isomer can be produced using each of the corresponding isomers in the starting compound represented by the general formula [2].

The compounds of the present invention represented by the above general formula [1] are a novel group of] 3-lactam compounds having an azole thio group having various substituents at the 3-position of the carbane skeleton, and these compounds are excellent. It has antibacterial activity and is useful as a pharmaceutical. Specific examples of the compound having the general formula [1] obtained by the present invention include, for example, the compounds shown in Table 1 below.

Xiao 蕭

½) Γ shiny 28

Replacement form (Rule 26)

No. ¾ · 嗨 ^ 瓛

The compounds exemplified in Table 1 have stereoisomers as described above, and the exemplified compounds include all isomers.

The novel ratatam compounds represented by the general formula [1] of the present invention include gram proteins such as Staphylococcus' aureus, Staphylococcus' epidenoremidis, Streptococcus' pyogenes, Streptococcus sp. Some bacteria have antibacterial activity against a wide range of pathogenic bacteria including gram-negative bacteria such as live bacteria, Escherichia coli, Proteus bacteria, Klebsiella '2 humor, Hemophilus' influenza, gonococci, and Blanchamella, but dram-positive bacteria It is characterized by its excellent antibacterial activity against MRSA and also has excellent antibacterial activity against MRSA and MRCNS. Further, although the degree of the compound of the present invention varies depending on each compound, it can also be mentioned as a feature that the compound is further improved in physicochemical properties such as water solubility to be provided as a pharmaceutical. Dehydrobeptidase-I (DHP-I), a renal enzyme, is known to readily degrade naturally occurring carbamine compounds, but it is a compound of the general formula [1] Some of the compounds of formula (I) are stable against DHP-I and can be used as a single agent, but if necessary, they can be used in combination with DHP-IP and harmful agents.

The dosage form for using the compound of the present invention as an antibacterial agent for treating bacterial infections includes, for example, oral administration using tablets, capsules, powders, syrups, etc., or intravenous injection, intramuscular injection, rectal administration and the like. Parenteral administration is included.

The above-mentioned suitable dosage forms can be prepared by incorporating the active compound into acceptable carriers, excipients, binders, stabilizers and the like. When used in the form of an injection, acceptable buffers, dissolution aids, isotonic agents and the like can also be added. The dosage varies depending on symptoms, age, body weight, dosage form, number of administrations, etc., but usually 100 to 300 Omg / day is divided into one or several doses for adults. The dose can be reduced or increased as needed. Example

Next, the present invention will be described in more detail with reference to examples. They are not limited in any way.

The meanings of the abbreviations used in the following examples are as _follows.c

Ph: phenyl group

iPr: isopropyl group

Me: methyl group

TMS: Trimethinoresilinole group

AL0C: aryloxycarbonyl group Example 1

a) 0—aryl S— (4— {4-[(Z) 1 {[(aryloxy) carbonyl] imino} (dimethylamino) methyl] phenyl} 1-1,3-thiazol-2-yl) thiocar To a solution of Bonate (0.53 g, 1.23 mol) in THF (2.5 ml) at 0 ° C was added a solution of dimethylamine in tetrahydrofuran (2.0 M, 0.615 ml, 1.23 ramol). After 30 minutes, add a solution of dimethylhexamethyldisilazide in tetrahydrofuran (1.0 M, 1.23ral, 1.23fflmol). After stirring for 10 minutes, this solution was added to aryl (4R, 5R, 6S) 13-1 [(diphenoxyphosphino)] 1-4-methyl 1 7 -oxo 1 6-{(1 R)-1 -[(Trimethylsilyl) oxy] ethyl} 1-azabicyclo [3.2.0] heptoto-2-ene 2-hydroxypropyloxylate in acetonitrile

(30%, 2.5g, 0.40ramol) at 0 ° C and leave in the refrigerator for 15 hours. To the reaction solution At 0 ° C., water and subsequently 1N hydrochloric acid were added to adjust the pH to about 3, followed by stirring for 10 minutes. An aqueous solution of sodium hydrogen carbonate is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (chloroform / methanol) to give allyl (4R, 5S, 6S) 1-3— [(4— {4- [(Z)-

{[(Aryloxy) caprolponyl] imino} (dimethinoleamino) methyl] phenyl} — 1,3-thiazol-1-yl) sulfa-nore] — 6 — [(1R) —1-Hydroxetinole] —4-methyl 1-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-hydroxyloxylate (0.64 g) was obtained.

_{¾ NMR (300 MHz, CDC1 3} ) δ 1.13 (3 H, d, J = 7.1 Hz), 1.33 (3 H, d, J =

6.2 Hz), 2.89 (3 H, s), 3.21 (3 H, s), 3.27-3.31 (1 H, s), 3.58-3.68 (1 H, ra), 4.18-4.32 (2 H, ra), 4.39 (2 H, dt, J = 1.3, 5.7 Hz), 4.72-4.91 (2 H, m), 5.06-5.23 (2 H, ra), 5.27-5.32 (1 H, ra), 5.45-5.52 (1 H, m), 5.73- 6.07 (2 H, ra), 7.36-7.40 (2 H, ra), 7.62 (1 H, s), 7.93-7.96.

I (KC1) v 3434, 2971 , 1780, 1700, 1559, 1294, 1208 cm one ¹

b) Aryl (4R, 5S, 6S) -3-[(4- {4-[(Z) -I-[[(aryloxy) carbonyl] imino} (dimethylamino) methyl] phenyl) — 1,3-thiazole-2 —Yl) sulfanyl] —6— [(1R) —1-hydroxyethynole] 1-4-methyl-7-oxo-1-1-azabicyclo [3.2.0] heptoh-2-ene1-2—carboxylate (40w%, 0.259 g, 0.43 mmol), aniline (0.79 ml, 8.7 mol), dibutynoleic acid (181 mg, 0.86 mraol) in a benzene (4.3ral) solution at the mouth of a monochloride at 0 ° C and tetrakistripheninolephosphine palladium (24.8 mg , 0.02 mmol) and stir for 30 minutes. Water and dichloromethane are added and the mixture is separated. The organic layer is extracted three times with water, and the aqueous layer is washed with dichloromethane. After removing the organic solvent in the aqueous layer under reduced pressure, the residue was purified by polymer chromatography (CHP-20P), and the fraction eluted with an 8% THF aqueous solution was collected and lyophilized to form a white amorphous (4R, 5S, 6S) 1-[[4- {4-[(Dimethylamino) (imino) methyl] phenyl} —1,3_thiazol-2-yl) sulfaninole] 1 6 — [(1R) —1-Hydrox Chill] 1-4-methynole 1 7-oxo 1 1-azabicyclo [3.2.01 heptoto 2— Yield: 2-carboxylic acid (32.3 mg).

¾ NMR (300 MHz, D20) δ 0.93 (3 H, d, J = 7.5 Hz), 1.09 (3 H, d, J = 6.4 Hz), 2.99 (3 H, s), 3.15 (3 H, s) , 3.19 (1 H, dd, J = 13.9, 7.1 Hz), 3.31 (1 H, dd, J = 2.7, 5.7 Hz), 4.04-4.14 (2 H, m), 7.51 (2 H, d, J = 8.4 Hz), 7.86 (2 H, d, J = 8.4 Hz), 7.89 (1 H, s).

IR (KBr) v 3306, 2969, 1759, 1612, 1386, 1264 cm, ^1- starting material 0-aryl S— (4- {4 — [(Z) — {[(aryloxy) caprol] imino} Synthesis of (dimethylamino) methyl] phenyl} -1,3-thiazol-2-yl) thiocarbonate

a) To a suspension of 4-acetylbenzonitrile (1.24 g, 8.56 mmol) in ether (13 mL) is added aluminum chloride (160 mg, 1.2 mol) at 0-5 ° C. After 5 minutes, add bromine (1.37 g, 8.56 mmol) at 0-5 ° C over 3 minutes. After the addition is complete, warm to room temperature. Three hours later, toluene and a 2.5% aqueous solution of sodium dihydrogen phosphate are added to the reaction mixture, and the mixture is separated. The aqueous layer is extracted with ethyl acetate, and the organic layer is washed with saturated saline, dried over magnesium sulfate, and concentrated by an evaporator to obtain the desired 4- (bromoacetyl) benzonitrile (1.87 g, 97%). .

b) To a solution of 4- (promorecetinole) benzonitrile (1.87 g, 8.34 octol) in methylene chloride (13 mL) and ethanol (30 mL) at room temperature was added ammonia mudiocarbamide (0.92 g, 8.35 mmol) at room temperature. Add. After 23 hours, heat at 70 to 80 for 30 minutes, cool to room temperature, and evaporate the solvent under reduced pressure. Ethanore (30 mL), stirred for 30 minutes, filtered, and washed twice with cold ether. Dry in a vacuum line to obtain the desired 4- (2-mercapto-1,3-thiazono-41-yl) benzonitrile (1.45 g, 79.4%).

c) A solution of 4- (2-mercapto-1,3-thiazol-41-yl) benzonitrinole (10 g, 46 mmol) in tetrahydrofuran (92 ml) at 0 ° C was triethylamine.

(6.4 ml, 46 mmol) is added. Ten minutes later, isopropyl chloroformate (5.3 ml, 46 vol) was added, and the mixture was stirred for 1 hour. After stirring at room temperature for 1 hour, water, saturated saline, and ethyl acetate were added, and the layers were separated. The aqueous layer is extracted with ethyl acetate, and the organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is recrystallized from ether to give S- [4- (4-cyanophenyl) -l, 3-thiazol-l-yl] 0-isopropylthiocarbonate (8.08 g, 58%).

_{¾ NMR (300 MHz, CDC1 3} ) δ 1.38 (d, J = 6.2 Hz, 6 H), 5.24 (sept, J = 6.2 Hz, 1 H), 7.72 (d, J = 8.3 Hz, 2 H), 7.79 (s, 1 H), 8.01 (d, J = 8.3 Hz,

2 H).

d) Tetrahydrofuran (32 mL) of S- [4- (4-cyanophenyl) -l, 3-thiazol-2-yl] 0-isopropylthiocarbonate (4.13 g, 13.6 mmol) and methanol (0.58 ml, 14.3 mmol) Blow hydrogen chloride gas into the suspension for one and a half hours. When the suspension turned into a pale yellow solution, the solvent was distilled off under reduced pressure. Ether is added to the residue, and filtered when it crystallizes. The residue was washed three times with ether, and methyl 4- {2-[(isopropoxycarbonyl) sulfanyl] —1,

3 _thiazole_ 4-yl} Benzenecarboximidate (4.16 g, 82 ° /.) Is obtained as a yellow solid.

¾删_{R (300 MHz, CDC1 3)} 61.38 (d, J = 6.2 Hz, 6 H), 4.59 (s, 3 H), 5.24 (sept, J = 6.2 Hz, 1 H), 7.86 (s, 1 H ), 8.10 (d, J = 8.8 Hz, 2 H), 8.48 (d, J = 8.8 Hz, 2 H), 12.01 (s, 1 H), 12.73 (s, 1 H).

e) Methyl 4- {2-[(isopropoxycarbonyl) sulfanyl] 1-1,3-thiazol-4-yl} suspension of benzenecarboximidate (1.0 g, 2.7 mmol) in tetrahydrofuran (5 ml) / ethanol (10 ml) Dimethylamine in tetrahydrofuran (2.0 M, 7. Oral, 14 瞧 ol) was added to the mixture, and the mixture was stirred at 80-90 for 5 hours. Heat, then evaporate the solvent under reduced pressure. The residue was suspended in dimethylformamide (12 ml) I tetrahydrofuran (12 ml), and triethylamine (1.5 ml, llmmol) was added, followed by stirring for 1 hour. The mixture is cooled to 0 ° C, acryl chloroformate (1.15ral, llmmol) is added, and the mixture is stirred for 45 minutes, and further stirred at room temperature for 45 minutes. Water and black-mouthed form are added and the layers are separated, and the aqueous layer is extracted three times with black-mouthed form. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and 0-aryl S— (4- {4-[(Z) 1 {[(aryloxy) carbonyl] imino} (dimethylamino) methyl] phenyl} 1-3 —Thiazol-1-yl) thiocarbonate (1.48 g) is obtained as a colorless oil.

¾删_{R (300 MHz, CDC1 3)} 02.89 (3 H, s), 3.19 (3 H, s), 4.37 (2 H, dt, J = 1.1, 5.7 Hz), 4.83 (2 H, dt, J = 1.3, 6.0 Hz), 5.05-5.18 (2 H, ra), 5.33-5.44 (2 H, m), 5.75 (1 H, ddt, J = 5.9, 10.4, 17.2 Hz), 5.96 (1 H, ddt, J = 5.9, 10.4, 17.0 Hz), 7.35-7.40 (2 H, ra), 7.72 (1 H, s), 7.92-- 7.95 (2 H, m).

a) 4- [4- (4,5-dihydro-1H-imidazolone-2-(^ fnorre) pheninole] —1,3-triazole-12-mercaptan (258mg, 0.99 ol) tetrahydrofuran

(2 ml) / dimethylformamide (2 ml) At 0, add a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 0.99ral, 0.99ramol). After stirring for 5 minutes, stir at room temperature for 20 minutes. After cooling to 0 ° C, the solution was added to aryl (4R, 5R, 6S) —3 — [(diphenoxyphosphino) oxy] —4-methyl-7-oxo-1 6— {(1R) -1- [( Trimethylsilinole) oxy] ethyl} 1-aza bicyclo [3. 2. 0] hept-1-ene 2- 2-acetonitrile Solution (28 ° /., 2.0 _g , 0.99 mmol) and let stand in a refrigerator for 15 hours. Add water and then 1N hydrochloric acid to the reaction solution at 0 ° C to adjust the pH to about 3, and stir for 35 minutes. 1N aqueous sodium hydroxide solution was added to adjust the pH to 7.3, and the mixture was extracted twice with chloroform / ethyl acetate.The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and depressurized. The solvent is distilled off. The residue was dissolved in benzene (10 ml) with monochrome mouth, aniline (0.79 ral, 8.7 mol), dibutyl phosphoric acid (181 mg, 0.86 ramol) were added, and then tetrakistriphenylphosphine palladium (24.8 mg, 0.02 mmol) was added with. Stir for 30 minutes. Water and dichloromethane are added and the mixture is separated. The organic layer is extracted three times with water, and the aqueous layer is washed with dichloromethane. The organic solvent in the aqueous layer after removed under reduced pressure, and purified by polymer chromatography (CHP 20P), as a white Amorufasu by lyophilization Fractions eluted with 8~1 2 ⁰ / oTH F solution ( 4R, 5S, 6S) 1-3-({4- [4-1 (4, 5-dihydro- 1 1-imidazole-2-inole) funoré] 1-1, 3-thiazonole _ 2-inore} Snorrefal)-6 -[(1R) -11-Hydroxyethyl] 1-4-methyl-7-oxo_1-azabisik mouth [3.2.0] Heptoh 2_en-2-hydroxycarboxylate (11.8 mg) is obtained.

¾ 丽 (300 MHz, DMS0-d ₆ ) δ 0.99 (3 H, d, J = 7.0 Hz), 1.10 (3 H, d, J = 6.2 Hz), 3-3.50 (2 H, m), 4.90- 5.00 (1 H, ra), 3.98 (4 H, s), 4.17 (1 H, dd, J = 2.4, 9.7 Hz), 5.00 (1 H, s), 8.05 (2 H, d, J = 8.4 Hz ), 8.18 (2 H, d, J = .8.4 Hz), 8.43 (1 H, s).

IR (KBr) v 3405, 2970, 1759, 1621, 1385, 1242, 1090 cm- ¹ Example 3

a) 0—aryl S— (4- {4 -— ((Z) — {[(aryloxy) carbonyl] imino} (1 pyrrolidyl) methyl] phenyl} —1,1,3-thiazol-2-yl Chocabone To a solution of dimethylamine (0.33 g, 0.71 mmol) in THF (2 ml) at 0 was added a solution of dimethylamine in tetrahydrofuran (2.0 M, 0.178 ml, 0.35 mmol). Thirty minutes later, a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 0.35ral, 0.35 mmol) was added. After stirring for 30 minutes, aryl (4R, 5R, 6S) —3 — [(diphenoxyphosphino) oxy] —4-methyl-7-oxo-6 — {(1R) -1-[(trimethylsilinole) oxy] ethyl} — Add 1-azabicyclo [3,2,0] heptaw-2-ene-2-canolepoxylate in acetonitrile (28 ° C, 1.45 g, 0.71 mraol), and allow to stand in a refrigerator for 15 hours. Water and then 1N hydrochloric acid are added to the reaction solution at 0 ° C to adjust the pH to about 3, and the mixture is stirred for 35 minutes. After adding 1N aqueous sodium hydroxide solution to adjust the pH to 7.4, the mixture is extracted twice with chloroform / ethyl acetate, and the organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure. Dissolve the residue in monochrome mouth benzene (7 ml), aniline (1.3 ml, 14 ol), diptyl phosphate

(294 mg, 1.4 mmol), followed by tetrakistriphenylphosphine palladium (41 rag, 0.035 olol) at 0 ° C and stirring for 40 minutes. Water and dichloromethane were added, and the mixture was separated. The organic layer was extracted three times with water, and the aqueous layer was washed with dichloromethane. After removing the organic solvent in the aqueous layer under reduced pressure, the residue was purified by polymer chromatography (CHP-20P), and the fractions eluted with 8 to 2% aqueous THF solution were collected and freeze-dried to form a white amorphous (4R , 5S, 6S) —6— [(1R) — 1—Hydroxyethyl] -3- [(4- {4— [imino (1-pyrrolidinyl) methyl] phenyl] 1,1,3-thiazo1 Sulfur] 1-4-Methynole 17-oxo-1 1-azabicyclo [3.2.0] heptoto-2-en-2 _forcenolevonic acid (52.8 mg) is obtained.

¾ NMR (300 MHz, DMSO- d ₆ ) δ 0.95 (3 H, d, J = 7.1 Hz), 1.10 (3 H, d, J = 6.2 Hz), 1.83-1.90 (2 H, m), 2.00- 2.07 (2 H, m), 3.15 (1 H, dd, J = 2.9, 6.6 Hz), 3.20-3.45 (1 H, m), 3.52-3.57 (6 H, m), 3.91 (1 H, brt, J = 6.4

Hz), 4.10 (1 H, dd, J = 2.7, 9.9 Hz), 5.00 (1 H, s), 7.70 (2 H, d, J = 8.4 Hz), 8.14 (2 H, d, J = 8.4 Hz) ), 8.34 (1 H, s).

IR (KBr) v 3416, 2970, 1764, 1667, 1613, 1463, 1383, 1260 cm- ¹ Example 4

1.00 § of (41 ?, 5S, 6S) _3- {4- [4- (arinoleoxycarbonilimino-amino-methyl) -phenyl] -thiazonole-2-ylsulfur in 10 Om 1 of dichloromethane} -6- [(R) -1-hydroxy-ethyl] -4-methyl _7_oxo-1 -aza-bicyclo

[3.2.0] 0.123 g of bis (triphenyl / lephosphine) palladium dichloride and 5.11 g of triptyl hydride were dissolved in a solution of hept-2-ene_2-carboxylate. Add tin. The mixture is stirred at room temperature for 20 minutes. A 20 Om 1 mixture of water: acetonitrile = 3: 1 is added to the reaction mixture with stirring. Phase separation occurs. The aqueous layer is washed three times with 10 Oml of dichloromethane. Concentrate the 7 layers slightly to remove organic solvents. The solid was collected by filtration and 0.585 g of (4R, 5S, 6S) -3_ [4- (4-carbamimidoyl-phenyl) -thiazole-2-inolelesulfanyl] -6-[(R ) -1-hydroxy - Echiru] -4 - methyl-7-Okiso - 1 - § the - Bishiku port ^[3 .2.0] hept - ² - 93 with a ² _ carboxylic acid HPLC (area) as a yellow solid - E down Obtained in% purity. Analytically pure samples are obtained by chromatography on MCI gel using acetone with up to 30% water content.

HNMR (400 MHz, DMSO d6, δ ppra): 1.00 (d, J = 7.2 Hz, 3H); 1.13

(d, J = 6.4Hz, 3H); 3.15-3.22 (m, 1H); 3.30—3.40 (ra, 1H); 3.90-4.00 (m, 1H); 4.10-4.20 (ra, 1H); 4.98 (d , J = 4.8Hz, 1H); 7.91 (d, J = 8.4 Hz, 2H); 8.17

(d, J = 8.4 Hz, 2H); 8.41 (s, 1H); 9.2 (s, very broad, 2H); 10.50 (s, very broad, 2H).

IR (MIR): vl741 cm— ¹

MS (ISP) M + H = 445.3

Starting material (4R, 5S, 6S) -3- {4- [4- (aryloxycarbo-imino-amino-methyl) -phenyl] -thiazole-2-ylsulfurinyl} -6- [(R ) -1-Hydroxy [Tyl] -4-methyl-7-oxo-aza-bisic [3.2.0] hept-2-ene-2-carboxylic acid aryl ester is obtained by the following continuous process.

Synthesis of (Z) -N-t-butoxycarbonyloxy-4- (2-thioxo-2,3-dihydro-thiazol-4-yl) -benzamidine

In a solution of 133 g of 4- (2,3-dihydro-2-thioxo-thiazolyl) -benzo-tolyl in 3 000 ml of ethanol, 62 g of hydroxyamine hydrochloride and 14 1 Add m 1 of triethylamine and heat the mixture to reflux for 1 hour. An additional 30 g of hydroxylamine hydrochloride and 70 ml of triethylamine are added and the mixture is heated to reflux for at least 2 hours. After concentrating the mixture to a volume of 800 ml, add 200 ml of ethyl acetate and 500 ml of water. The precipitate formed was collected by filtration and recrystallized from ethyl acetate / ethyl ether to give 99.2 g of (Z) -N-hydroxy-4- (2-thioxo-2,3-dihydro-thiazole -4-yl) -Get Benzamidine. To a solution of 2.287 g of this material in 100 Oml of methanol is added 20.0 g of di-l-butyl-dicarbonate and the mixture is stirred at room temperature for 6 hours. Evaporate the solvent and dissolve the residue in 1000 ml of dichloromethane and 400 ml of water. Separate, dry the organic layer over magnesium sulfate, evaporate, purify by chromatography on silica gel using ethyl acetate: cyclohexane = 1: 1, and crystallize from ethyl acetate / ethyl ether / hexane. , 12.5 g of (Z) -N-1-butoxycarbonyloxy-4- (2-thioxo-2,3-dihydro-thiazonole-

₄ _ I Lumpur) one base Nzuamijin obtained as a yellow solid. Image R (250 MHz, DMSO d6, δ ppm): 1.48 (s, 9H); 6.80 (s, broadened, 2H); 7.5 (s, broad, 1H); 7.77 (d, J = 8.5 Hz, 2H); 7.85 (d, J = 8.5Hz, 2H) 13.75 (s, broad, 1H). IR (NJL): v 1749 1637 cm " ¹

MS (ISP): M + H = 352.3

Synthesis of 4- (2-Thioxo-2,3-dihydro-thiazole-4-yl) -benzamidine

2. Dissolve 6.15 g of (Z) -N-1-butoxycarponyloxy-4- ( ² -thioxo-2,3-dihydro-thiazol-4-yl) -benzamidine in 50 ml of methanol Melted 6.18 g of tin (II) chloride and 4.0 g of molecular sheep (4A) are added to the solution, and the mixture is heated to reflux for 1 hour. The solid is removed by filtration and the mother liquor is evaporated. Dissolve the residue in 50 Om1 of water and adjust the pH to 7.30. Wash the aqueous layer twice with 250 ml ethyl acetate. When placed in the freezer for 1 庫, a precipitate formed, which was collected by filtration and 3.70 g of 4_ (2-thioxo-2,3-dihydro-thiazol-4-yl) -benzamidine was yellowed. Obtained as crystals.

HNMR (250 MHz, DMSO d6, δppra): 7.63 (s, 1H); 7.88 (d, J = 8.5 Hz, 2H); 8.02 (d, J = 8.5 Hz, 2H); 9.10 (s, broad, 2H) ); 9.40 (s, broad, 2H).

IR (NJL): v 1671 cm- ¹

MS (ISP): M + H = 236.2

Synthesis of {imino- [4- (2-thioxo-2,3-dihydro-thiazol-4-yl) -phenyl] -methinole) -aryl canolebamic acid ester

In a solution of 1.00 g of 4_ (2-thioxo-2,3-dihydro-thiazonole-4-inole) -benzamidine in 2 Om 1 tetrahydrofuran, 0.40 g of hydroxylation in 2 ml of water Add a solution of sodium dissolved. While stirring at 0 ° C. for 10 minutes, a solution of 1.13 g of arylalkylform in 5 ml of tetrahydrofuran is added to the resulting mixture. Stirring is continued for 1.5 hours and the reaction mixture is partitioned between water and ethyl acetate. The organic layer is washed with brine and solids are removed by filtration. Evaporate the organic layer, leaving 1.32 g of a yellow solid. This solid is dissolved in 5 ml of methanol, 3 ml of a saturated solution of ammonia in methanol is added, and the mixture is stirred at room temperature for 1 hour. The solvent is evaporated and the residue is purified by chromatography on silica gel using ethyl acetate, ethyl acetate: methanol = 1: 1 and methanol and, after crystallization from ethyl acetate, 0.98 g of ( Imino- [4- ( ² -thioxo-2,3-dihydro-thiazol-4-inole) -pheninole] -methyl} -methylarylamine is obtained as a yellow solid.

H MR (250 MHz, DMSO d6, δ ppm): 4.57 (d, J = 7.2 Hz, 2H); 5.15-5.40 (m, 2H); 5.90-6.05 (m, 1H); 7.53 (s, 1H); 7.89 (d, J = 8.5Hz, 2H); 8.06 (d, J = 8.5Hz, 2H) 9.20 (s, broad, 2H); 13.75 (s, broad, 2H). MA calc for C ₁₄ H ₁₃ N ₃ 0 ₂ S ₂ C: 52.65, H: 4.10, N: 13.16, S: 20.08 found C: 52.70, H-.4.13, N: l3.04, S: 19.86

(4R, 5S, 6S) -3- {4- [4- (Aryloxycarbonilimino-amino-methyl) -phenyl] -thiazonole-2-ylsulfanyl} -4--methyl-7-oxo -6- [(R)-1-Trimethylsilyloxy-ethyl)-1-aza-bicyclo mouth [3.2.0] Synthesis of hept-2-ene-2-carboxylic acid allyl ester

7.83 g of {imino- [4- (2-thioxo-2,3-dihydro-thiazol-4-yl) -phenyl] -methyl} -amyl carbamic acid ester is added to 8 Om 1 of acetonitrile. 1.07 g of sodium hydride are added to the suspended suspension at 0 ° C. and the mixture is stirred at this temperature for 30 minutes. 15.57 _§ of (45R, 6S) -3- (bis-phenoxy-phosphoryloxy) -4-methyl-7-oxo-6-[(R) -1-trimethylsilyloxy- [3.2.0] Hept-2-ene-2-carboxylic acid aryl ester is added, and the mixture is stored in a refrigerator at 24 ° C for 72 hours. Solids are removed by filtration. The mother liquor is partitioned between 3 Oml of 10% sodium bicarbonate and 3 Om1 of ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue is purified by chromatography on silica gel using hexane: ethyl acetate = 1: 1 to give 10.10 of (45S, 6S) -3- (4- [4- (aryloxycarbocarboxy). 2-Ilumino-amino-methyl) -phenyl] -thiazonor-2-ylsulfanyl} -4-methyl-7-oxo-6-[(R) -1-trimethylsilyloxy-ethyl) -1-aza -Bissik [3.2.0] Hept-2-ene_2-carboxylate arylester is obtained as a light yellow foam.

HNMR (250 MHz, CDC13, 6 ppm): —0.11 (s, 9H); 1.12 (d, J = 7.5 Hz, 3H); 1.23 (d, J = 6 Hz, 3H); 3.20-3.30 (ra, 1H) 3.49-3.63 (m, 1H); 4.14-4.28 (ra, 2H); 4.60-4.90 (m, 4H); 5.20-5.53 (m, 4H); 5.90-6.10 (m, 2H); 7.70 (s, 1H) 7.98

(s, 4H).

IR (MIR): 1774cm- ¹

MS (ISP): M + H = 641.1 (4R, 5S, 6S) -3- {4- [4- (aryloxycarbonilimino-amino-methyl) -fuel] -thiazonole-2-ylsulfanyl} -6-[(R)- 1-Hydroxy-ethyl] -4-methyl-7-oxo-1-aza-bisic mouth [3.2.0] Synthesis of heptyl-2-en-2-aryl allylic ester

3.80 g of (4R, 5S, 6S) -3- {4- [4- (aryloxyl-propionoleimino-amino-methyl) -phenole] -thiazole-2-inolesnorefurinole in 40 ml of ethyl acetate} -4- Methyl-7-oxo-6-[(R) -1-trimethylsilyloxy-ethyl) -taza-bicic [3.2.0] Hept-2-ene-2-carboxylic acid aryl ester solution To this is added 40 ml of 0.5 M hydrochloric acid at 0 ° C. and the mixture is stirred for 10 minutes at room temperature. To the resulting mixture is added 60 ml of a 10% sodium bicarbonate solution. And separated, washed with organic layer with brine, dried over magnesium sulfate and purified using acetic Echiru on sheet Rikageru by chromatography, 2. _{93 8 (4 5S, 6S)} -3- { 4- [4- (allyloxy-propyl-imino-amino-methyl) -phenyl] -thiazole-2-ylsulfal} -6-[(R) _l-hydroxy-ethyl] -4-methyl-7- Oxo-1-aza-bisic mouth [3.2.0] Hept-2-ene-2-carboxylic acid aryl ester is obtained as a white foam.

Yuzuru _{R (250 Ifflz, CDC1 3,} 6 ppm): 1.18 (d, J = 7.5Hz, 3H); 1.36 (d, J = 6Hz, 3H); 3.22-3.34 (m, 1H); 3.52-3.70 (m 4.20-4.40 (m, 2H); 4.64-4.96 (ra, 4H); 5.20-5.67 (m, 4H); 5.90-6.16 (m, 2H); 7.70 (s, 1H) 7.97 (s, 4H).

IR (MIR): v 1768cm " ¹

MS (ISP): M + H = 569.4 Example 4a

0.1 ml of (4R, 5S, 6S) -3- [4- (4-carbamimidoyl-phenyl) -thiazol-2-ylsulfanyl] -6-[(R) in 1 ml of dimethylsulfoxide -1-Hydroxy-ethyl] -4-methyl-7-oxo-1-aza-bisic mouth [3.2.0] Hept-2-ene-2-force 0.06 6 g of (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl carbonate, 4-ditrophenyl ester are added. Store the resulting clear solution at room temperature for 24 hours. The reaction mixture is diluted with 6 ml of 2% sodium bicarbonate solution, purified by chromatography on MC I gel using acetonitrile with a water content of up to 50% and, after lyophilization, 0.048 g of sodium ( 4R, 5S, 6S) -3- (4- {4- [Amino- (5-methyl_2-oxo-1- [1,3] dioxol-4-ylmethoxycarburimino) -methyl] -phenyl} -Thiazole-2-ylsulferyl) -6-[(R) -1-hydroxy-ethyl) -4-methyl-7-oxo-1-aza-bisic [3.2.0] hept-2-ene- The 2-carboxylate is obtained as a yellow powder.

_{HNMR (400 MHz, D 2 0} , δ ppm): 1.09 (d, J = 7.2Hz, 3H); 1.25 (d, J = 6.4Hz, 3H); 2.23 (s, 3H); 3.30-3.40 (m, 3.45-3.50 (m, 1H); 4.20-4.30 (m, 2H); 5.09 (s, 2H); 7.81 (d, J = 8.4 Hz, 2H); 7.92 (d, J = 8.4 Hz, 2H) ); 8.03 (s, 1H).

IR (MIR): v 1757 1815 cm— ¹

MS (ISP) M + H = 60L 4 Example 4 b

0.04 g of (4R, 5S, 6S) -3- [4- (4-force-no-re-bamiimi-dino-ferenole) -thiazono-le-2-inores-zole-fane-no-le] in 0.5 ml of DMSO 1-Hydroxyethyl] -4-methyl-7-oxo-1-aza-bisic-mouth [3.2.0] hept-2-en-2-carboxylic acid and 0.025 g of ethyl carbonate, The solution in which 4-phenyl phenyl ester is dissolved is brought to room temperature. For 24 hours without light. The reaction mixture was diluted with 3 ml of 2% sodium bicarbonate, purified by chromatography on MCI gel using acetate with a water content of up to 50% and, after lyophilization, 0.020 g of sodium (4R, 5S, 6S) -3- {4- [4-Amino-ethoxycanolepodinoliminomethyl) -phenyl] -thiazole-2-ylsulfanyl} -6-[(R) -1-hydroxyethyl) -4-methyl -7-oxo-1-aza-bisic mouth [3.2.0] Hept-2-en-2-carboxylate is obtained. HNMR (400 MHz, DMSO d6, δ ppm): 0.98 (d, J = 7.2 Hz, 3H); 1.12

(d, J = 6.4Hz, 3H); 1.23 (t, J = 6.8Hz, 3H); 3.10-3.25 (ra, 1H); 3.25-3.40 (ra, 1H); 3.88-4.00 (m, 1H); 4.08 (qu, J = 6.8Hz, 2H), 4.05-4.20 (m, 1H) 4.95

(d, J = 5Hz, 1H); 7.00 (s, broad 1H); 8.06 (s, 4H); 8.33 (s, 1H) 9.10

(s, broad, 2H).

IR (MIR): v 1751 cm- ¹

MS (ISP) M + H = 517.4 Example 4c

In 0.5 ml of DMSO, 0.044 g of (4R, 5S, 6S) _3— [4- (4-carbamimidyl-diphenyl) -thiazol-2-ylsulfanyl] —6— [(R) 1 —Hydroxy-ethyl] -4-Methyl-7-oxo-1-aza-bis [3.2.0] hept-2-ene-2-carboxylic acid and 0.035 g of N-benzoyl-] Stir the mixture with the 3-alanine p-ditrophenyl ester at room temperature until a clear solution is obtained (about 30 minutes). Keep the solution light-free at room temperature for 6 days. The reaction mixture was diluted with 3 ml of 2% sodium bicarbonate, purified by chromatography on MCI-gel (CHP-20) using acetonitrile with a water content of up to 50%, and lyophilized to 0.1%. 009 g of sodium; (4R, 5S, 6S) -3- (4- {4- [amino- (3-benzoylamino-propiolimino) -methyl] -phenyl} -thiazole-2-ylsulfanyl) -6- [(R) -l-Hydroxy-ethyl] -4-methyl-7-oxo-1-aza-bisic mouth [3.2.0] Hept-2-ene-2-carboxylate is a yellow powder Get as.

HNMR (400 MHz, DMSO d6, δ ppm): 0.95 (d, J = 7.2 Hz, 3H); 1.12

(d, J = 6.4Hz, 3H); 3.00-3.10 (ra, 2H); 3.10-3.15 (m, 1H); 3.25-3.40 (m, 1H);

3.53-3.63 (m, 2H); 3.87-3.96 (m, 1H); 4.05-4.12 (m, 1H), 4.94

(d, j = 4.8Hz, 1H); 7.40-7.60 (m, 3H) 7.85 (d, 7.2Hz, 2H); 7.99

(d, J = 8.4Hz, 2H); 8.06 (d, J = 8.4Hz, 2H); 8.31 (s, 1H); 8.60 (s, broad, 2H);

11.0 (s, broad, 1H).

IR (MIR): v 1751 cm " ¹

MS (ISP) M + H = 620.4 Example 5

0.15 g of (4R, 5S, 6S) -3-{4-[3- (aryloxycarbo-lamino-imino-methyl) in 5 ml of ethyl acetate and 5 ml of 0.51 \ ^ hydrochloric acid -Phenyl] -thiazole-2-ylsulfanyl} -4-methyl-7-oxo-6 _ [(R) -1-trimethylsilyloxy-ethynole) -1-aza-bisic mouth [3.2.0] hepto- Stir the solution mixture in which 2-ene-2-carboxylic acid aryl ester is dissolved at 0 ° C for 10 minutes. The layers are separated, the organic layer is washed with sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue is dissolved in 5 ml of dichloromethane and 0.0153 g of bis (triphenylphosphine) palladium dichloride and 0.64 g of triptyltin hydride are added with stirring. The mixture is stirred at room temperature for 20 minutes. To the reaction mixture; add a phosphoric acid buffer solution at pH 7.00. Separate the aqueous layer and chromatographically extract the water content on the MC I gel. Purify with up to 30% acetonitrile and freeze-dry 0.025 g of (4R, 5S, 6S) -3- [4- (3-carbamimidoyl-phenyl) -thiazol-2-ylsulfanyl ] -6-[(RU-Hydroxy-ethyl) -4-methyl-7-oxo_1-aza-bisic mouth [3.2.0] hept-2-ene-2-carboxylic acid is obtained as a white powder.

HNMR (400 MHz, DMSO d6, δ ppra): 1.00 (d, J = 7.2 Hz, 3H); 1.13

(d, J = 6.4Hz, 3H); 3.15-3.25 (ra, 1H); 3.30-3.45 (ra, 1H); 3.85-4.00 (m, 1H); 4.10-4.20 (m, 1H); 5.00 (d , J = 4.8Hz, 1H); 7.60-7.85 (ra, 2H); 8.23

(d, J = 8Hz, 1H); 8.32 (s, 1H); 8.39 (s, lH).

IR (MIR): v 1753cm- ¹

MS (ISP) M + H = 445.3 Starting material (4R, 5S, 6S) -3- {4- [3- [aryloxycarbonylamino] -imino-methyl) -pheninole] -thiazole-2 -Ylsulfur} _4-Methyl-7-oxo-6-[(R) -1-trimethylsilyloxy-ethyl) -1-aza-bisic mouth [3.2.0] hept-2-ene-2- The carboxylic acid aryl ester is obtained by the following successive steps.

Synthesis of (Z) -N-t-butylcarponyloxy-3- (2-S-1-butylbutylcarbonyl-thiazole-4-inole) -benzamidine

A mixture of 1.14 g of 3- (2,3-dihydro-2-thioxo-thiazolyl) -benzonitrinole, 0.53 g of hydroxynoreamine hydrochloride and 0.88 g of triethylamine was added to 35 ml of ethanolanol. Heat and reflux for 2 hours. Water and ethyl acetate are added to the resulting suspension to adjust the pH to 6.8. Filter off solids. Separate, dry the organic layer over magnesium sulfate and evaporate. The residue is dissolved in 8 ml of tetrahydrofuran. To the resulting solution at 0 ° C. is added a solution of 0.35 g of sodium hydroxide in 2 ml of water. At 0 ° C the resulting mixture is 1.

00 g of pivaloyl chloride are added and the mixture is stirred at the same temperature for 1 hour. The mixture was partitioned between water and ethyl acetate, the organic layer was washed with brine, dried over magnesium sulfate and purified by chromatography on silica gel using dichloromethane: ethyl acetate = 9: 1, 0.97 g of (Z) -N-l-butylcarbonyloxy- 3- (2-S-t-butylcarbonylthio-thiazol-4-yl) -benzamidine is obtained as a white solid.

HNMR (250 MHz, DMSO d6, 6 ppra): 1.26 (s, 9H); 1.32 (s, 9H); 6.70

(s, broad, 2H); 7.47-7.60 (m, IH); 7.65-7.75 (ra, IH); 8.00-8.12 (ra, IH); 8.22-8.30 (ra, IH); 8.50 (s, IH) .

MS ((ISP): M + H = 420.2

IR (MIR): -v 1740 and 1688 cm one ¹

Synthesis of {imino- [3_ (2-mercapto-thiazol-4-yl) -phenyl] -methyl} -carpamic acid aryl ester

A suspension obtained by adding 0.95 g of (Z) -N-1_butylcarboxy-roxy-3- (2-St-butylcarbonylthio-thiazole-4-inole) -benzamidine to 20 ml of isopropanol To this, 1.00 g of molecular sheep (A) and 0.85 g of tin (II) dichloride are added and the mixture is heated at 80 ° C. for 1 hour. The solid is removed by filtration and the mother liquor is evaporated. The residue is dissolved in 2 Oml of tetrahydrofuran. To the resulting solution is added 5.64 ml of 2N sodium hydroxide at 0 ° C., and then over 5 minutes, a solution of 0.60 g of allyl chromate formate in 2 ml of tetrahydrofuran is added. The mixture is stirred at 0 ° C. for 1 hour. The reaction mixture is partitioned between water and ethyl acetate at pH 7.4. Separate, dry the organic layer over magnesium sulfate and evaporate. Dissolve the residue in 5 ml of methanol. 0 ° to the resulting solution. Then 5 ml of an ammonia saturated methanol solution are added and the mixture is stirred for 30 minutes at this temperature. The solvent is evaporated and the residue is purified by chromatography on silica gel with hexane: ethyl acetate = 1: 1, crystallized under t-butyl methyl ether and 0.138 g of { Imino- [3- (2-mercapto-thiazol-4-yl) -phenyl] -methyl} -carboxyl rubamic acid ester is obtained.

HNMR (250 MHz, DMSO d6, δ ppm): 4.58 (d, J = 7.2 Hz, 2H); 5.18-5.40 (ra, 2H); 5.90-6.10 (m, lH); 7.40 (s, IH); 7.5 -7.63 (m, IH); 7.85-8.02 (m, 2H); 8.22- 8.34 (m, IH); 9.20 (s, broad, 2H); 13.75 (s, broad, 2H).

_{_{MA calc for C 14 H 13 N}} 3 0 2 S 2 C: 52.65, H: 4.10, N: 13.16 found C: 52.80, H: 4.37, N: 12.90

MS ((ISP): M + H = 320.3

IR (MIR): v 1619 cm— ¹ (4R, 5S, 6S) -3- 3- [4- [3- (aryloxypropylaminopyrimino-imino-methyl) phenyl] -thiazole-2-ylsulfanyl}-4- Synthesis of methyl-7-oxo _6 _ [(R) _1-trimethylsilyloxy-ethyl) -1 -aza-bis [3.2.0] hept-2-ene-2-carboxylate

To a suspension of 0.13 g of {imino- [3- (2-mercapto-thiazol-4-yl) -phenyl] -methyl} -methylarylamine in 5 ml of acetate At 0 ° C., 0.018 g of sodium hydride (about 65% in mineral oil) are added and the mixture is stirred at 0 ° C. for 30 minutes. 0.259 g of (4R, 5R, 6S) -3- (bis-phenoxy-phosphoryloxy) -4-methinole-7-oxo-6-[(R) -1-tri) was added to the resulting mixture. Methylsilyloxy-ethyl) -1-aza-bisic-mouth [3.2.0] Hept-2-ene-2-carboxylate allylic ester is added and the mixture is stored in a refrigerator at 24 ° C. for 48 hours. The reaction mixture is partitioned between 10% sodium bicarbonate and ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate and concentrated under aspirator vacuum. The residue was purified by chromatography on silica gel using hexane: ethyl acetate = 1: 1 to give 0.14 g of (4R, 5S, 6S) -3- {4- [3- (aryloxycarbonyl). Amino

-Imino-methyl) -feel] -Thiazol-2-ylsulfanyl} -4-methyl-7-oxo-6-[(R) -1_trimethylsilyloxy-ethyl] -1 -aza-bisic mouth [3.2.0] heptene toe ₂ _ En ₂ - obtain carboxylic acid Ariruesuteru as a pale yellow foam.

_{HNMR (250 fflz, CDC1 3,} δ ppm): -0.11 (s, 9H); 1.12 (d, J = 7.5Hz, 3H); 1.23 (d, J = 6Hz, 3H); 3.20-3.30 (m, 1H ); 3.45-3.60 (m, 1H); 4.17-4.30 (ra, 2H);

4.64-4.90 (m, 4H); 5.22-5.52 (m, 4H); 5.88-6.10 (m, 2H); 7.50-7.60 (m, 1H); 7.70 (s, lH); 7.89-7.95 (m, 1H ); 8.02-8.10 (ra, 1H); 8.26-8.32 (ra'lH).

IR (MIR): v 1774cm— ¹ MS (ISP): M + H = 641.4 Industrial Potential

The compounds of the present invention exhibit excellent antibacterial activity against Gram-positive bacteria, particularly MDSA and MRCNS, and are useful as antibacterial agents.

Claims

Scope of claim General formula [1]

[Wherein, R ¹ is a lower alkyl group or a lower alkyl group substituted with a hydroxyl group, R ² is a hydrogen atom or a lower alkyl group, and R ³ is a hydrogen atom, an optionally protected hydroxyl group, an imidoyl group. R ⁴ and R ⁵ are each independently a hydrogen atom, a protected or unsubstituted hydroxyl group, a protecting group for an amino group, or a substituted alkyl group; R ³ , R ^4, and R ⁵ may be any two of these bonded to form a substituent with one nitrogen atom, or with two nitrogen atoms and one carbon atom. It can also form a 5- to 7-membered heterocycle, A is an optionally substituted phenylene group, and X represents O, S or NH. ]

Represented by 5 — a ratatum compound or a pharmaceutically acceptable salt or non-toxic estenole.

2. The 3-latatam compound according to claim 1, wherein X is S, or a pharmaceutically acceptable salt or non-toxic ester thereof.

3. The 3-0 ratatam compound according to claim 1 or 2, wherein R ¹ is 1- (R) -hydroxyethyl, or a pharmaceutically acceptable salt or non-toxic esternole thereof.

4. General formula [1]

[Wherein, R ¹ is a lower alkyl group or a lower alkyl group substituted with a hydroxyl group, R ² is a hydrogen atom or a lower alkyl group, and R ³ is a hydrogen atom, an optionally protected hydroxyl group, an imidoyl group. R ⁴ and R ⁵ are each independently a hydrogen atom, a protected 1 /, a hydroxyl group, an amino group protecting group, or a substituted alkyl group; Sa

In addition, R ³ , R ⁴ and R ⁵ are substituted with any one of them, together with one nitrogen atom, or with two nitrogen atoms and one carbon atom. May form a 5- to 7-membered hetero ring, A is an optionally substituted phenylene group, and X represents 0, S or NH. ]

In producing a 3-lactam compound or a salt thereof, the general formula [2]

And a compound represented by the general formula [3]

The compound represented by the general formula [4] is reacted with the compound represented by the general formula [2] or the thiolate salt of the compound represented by the general formula [3] is reacted with the compound represented by the general formula [2]

Wherein R ^la , R ³ , R ⁴ and R ^{5 have} a hydroxyl group protecting group removal reaction, R ^{3 has} an imidoyl group protecting group removal reaction and R ⁴ and R ⁵ have an amino group protection Suitable for the reaction for removing the group and the reaction for removing the protecting group for the carboxyl group in R ⁶ : a method for producing a lactam compound or a salt thereof represented by the general formula [1], characterized by performing a combined reaction: .

5. A medicament comprising the _ ratatam compound according to claim 1, 2 or 3, or a pharmaceutically acceptable salt or non-toxic ester thereof.

6. An antibacterial agent comprising the monolactam compound according to claim 1, 2 or 3, or a pharmaceutically acceptable salt or non-toxic ester thereof.