TW200829242A - Penem prodrugs - Google Patents

Abstract

The invention relates to prodrugs of sulopenem of formula (I): wherein R1 is -(C2-C8)alkyl, or a solvate or hydrate thereof. The invention also relates to the preparation, formulation, and use of the prodrugs of sulopenem to treat a disorder such as an infection in a patient in need thereof.

Description

200829242 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to thiopenem prodrugs and compositions thereof. The invention is also directed to the use of thiopenic uranium in the treatment of patients in need thereof. [Prior Art] U.S. Patent No. 5,0 13,729 describes thiopenem as a broad-spectrum antibiotic, which can be named (5R,6S)-6-[(lR)_i_hydroxyethyl]-7-side Oxy-3-[(1R,3S)-tetrahydro-1-oxo bridge_3-thienylthio]thia-[ azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. See also j Shaorong c/2ew, 57, 4352_ 4361 (1992) 硫 Pre-clinical and clinical studies have been conducted with thiopenem and some of its prodrugs. Sulpenem itself alone is largely unusable for biological use. Thioprene methyl ester prodrug (or p〇M ester) of thiopenem as a crystalline solid with a melting point and solubility suitable for medical use, has been shown to be at the highest dose of about 500 mg Good oral bioavailability. Therefore, there is a need for thiopenem prodrugs having high oral bioavailability and physicochemical properties suitable for medical use. SUMMARY OF THE INVENTION The present invention relates to thiopenem prodrugs. In particular, the present invention relates to a thiopenem prodrug of the formula (1), and solvates and hydrates thereof: 126137.doc 200829242

Wherein R1 is a -(C2-C8) succinyl group. Unless otherwise stated, the phrase "the thiopenic prodrug of the invention" refers to a compound of formula 1 and solvates and hydrates thereof. In another embodiment, the invention is directed to a composition comprising one or more of the thiopenems of the present invention. In another embodiment, the invention relates to the use of one or more of the thiopenic prodrugs of the invention to treat an infection. In one embodiment, the invention is directed to a method of preparing a thiopenic prodrug of the invention. In one embodiment, the present invention is directed to a process for the preparation of a thiopenic prodrug of Formula I, and solvates and hydrates thereof, which comprises reacting a compound of formula (II)

Reaction with thiopenem (B9): 126137.doc 200829242

Wherein R1 is -(C2-C8)alkyl and X is a leaving group. [Embodiment] As described above, in one embodiment, the present invention relates to a sulfur "'Penan prodrug as described above. As used herein, the term "(匸2_匸8)alkyl) refers to a straight or branched chain group of 2 to 8 carbon atoms (eg ethyl, n-propyl, isopropyl, n-butyl). Base, isobutyl, second butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl). In one embodiment, the thiopenem prodrug is a chelate (compound 1) wherein R1 is -CH2CH3. In another embodiment, the thiopenem prodrug is a compound of formula I (compound 2) wherein R1 is -CH2CH3CH3 I). In another embodiment, the thiopenem prodrug is a compound of formula I (compound 3) wherein R1 is ·CH2Ch(cH3)2. The thiopenic prodrugs of the present invention may exist in unsolvated as well as solvated forms. Thus, it is to be understood that the compounds of the present invention also include the form of the compounds as well as the solvates. Water as described below

126137.doc is used herein to describe a non-covalent or easily reversible combination between a solvent and a solute. It should be understood that the solvent may be in the form of a solid, a liquid (such as a suspension or dispersion) or a solution. Non-limiting examples of solvents include ethanol, decyl alcohol, propanol, acetonitrile, methyl ether, diethyl ether, tetrahydrofuran, dichloromethane, and water. The term, hydrate, is used when the solvent is water. The currently accepted classification system for organic hydrates is a classification system that defines separation sites or channel hydrates. See P〇lym〇rphism

Pharmaceutical Solids by K. R. Morris (Editor: h. G. Brittain, Marcel Dekker, 1995). The separation position hydrate is a hydrate in which water molecules are separated from each other without being directly contacted by insertion of an organic molecule. In channel hydrates, water molecules are in the lattice channel where they are next to other water molecules. When the solvent or water is tightly bound, the complex will have a defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound (as in channel solvates and hygroscopic compounds), the water/solvent content will depend on the humidity and drying conditions. In such cases, the non-stoichiometric basis shall prevail. The invention also includes isotopically labeled compounds which are identical to the compounds of the thiopenem prodrugs of the invention, but in fact one or more of the atoms have been replaced by atomic masses which differ from the atomic mass or amount of f common in nature or Quality (four) material. Examples of isotopes in the compounds of the present invention include strontium; isotopes of stone, mouse, oxygen, and sulfur, such as: h'; h'13c'I4c'15-18〇-7〇^s〇^ ^, the above-mentioned sulphur and/or other isotopes of the sulfur of the invention: cap = within the material of the invention. Certain isotopically-labeled inventions of the present invention (for example, incorporating radioisotopes (such as 4 and 14 thiophene 126137.doc 200829242 shovel) are suitable for use in medicines and/or receptors, In the distribution test of the shellfish, the isotope isotope (ie, 3Η) and the carbon 14 isotope (ie, "c) are particularly preferred because of its ease of preparation and detectability. Such as 汛, that is, 2h) substitution can provide grasses that are produced by greater metabolic stability, Λ 叼, and advantages of oral therapy, such as increased in vivo or reduced dose requirements, and therefore in some cases The isotope-labeled prodrug of the present invention can be obtained by the process disclosed in the "process" and/or, examples, and the like The thiopenem prodrug of the present invention can be prepared by the use of a non-isotopic labeling reagent. The thiophene prodrug of the present invention exhibits a sinister phenomenon. ... prepared under the conditions of the invention to crystallize the prodrug of the present invention. For example, ... The mixture of ° recrystallizes; at different temperatures. ^ No door to 5 tob days μ, and ... day, during the crystallization, extremely fast cooling to a variety of Α τ Ρ in the range of extremely k cooling. Or melting the prodrug, then gradually cooling or each sputum can be served by lilfw 7. The presence of polymorphs is determined by solid-state probe NMR spectroscopy, 扒古绿, Α 卜 九 ° ° ° ° 不 不 不C> Ten-knife ray diffraction or other such techniques are used for the determination. The present invention also relates to the inclusion of a type of 1 & \ a ^ ming thiopenic prodrug and the preparation of the ingredients of 至 禋 έ "The composition of the present invention (hereinafter, the composition of the present invention)". In a % therapeutically effective amount, the composition of the present invention comprises the thiophene of the present invention of Kang Baizhenli Non-limiting examples of the at least one other ingredient file include impurities (in the case of the crude thiosalth Abbé of the present invention (for example, the presence of a central active drug axis in the heart of the South is as described below) a form or a solvent or a plurality of solvents (for example, as in this case) The pharmaceuticals described in 126137.doc -11 - 200829242 acceptable carriers. The term "solvent" as used in connection with the compositions of the invention includes organic solvents (eg, methanol, ethanol, isopropanol, ethyl acetate). And the solvent may be present in a non-stoichiometric amount, for example as a trace impurity, or in an excess amount sufficient to dissolve the compound of the invention. Alternatively, in the present invention The or the solvent may be present in stoichiometric amounts (e.g., 〇·5:1, 1:1 or 2:1 molar ratio).

In one embodiment, at least one other component present in the compositions of the present invention is an organic solvent.另一 In another embodiment, at least one other component present in the composition ♦ of the present invention is water. In one embodiment, at least one other component present in the compositions of the present invention is a pharmaceutically acceptable carrier. In another embodiment, at least one of the other ingredients present in the compositions of the present invention is a pharmaceutically acceptable excipient as described below. In one embodiment, the composition of the invention is a solution. In another embodiment, the composition of the invention is a suspension. In another embodiment, the composition of the invention is a solid. The present invention suitable for administration to a patient (e.g., a human) in need thereof is also referred to herein as a pharmaceutical composition of the present invention. Composition: Kill: The pharmaceutical composition can be in any form suitable for administration to a patient. For example, the medical composition may be in a form suitable for oral administration, such as a tablet, a capsule, a powder, a sustained release formulation, a solution and a suspension; a suitable form for injection administration, such as a sterile solution or suspension. Or emulsion; suitable for 126137.doc -12- 200829242 in the form of topical administration, such as ointment or cream; or suitable for rectal administration, such as laurel. The topsheet composition can be in a unit dosage form suitable for single administration of precise dosages. An exemplary parenteral administration form comprises a solution or suspension of the active compound in a sterile aqueous solution such as propylene glycol or aqueous dextrose. Such dosage forms may be suitably buffered as needed. In one embodiment, the pharmaceutical composition of the invention may be in the form of an oral dosage form. Non-limiting examples of oral dosage forms include, for example, chewable tablets, capsules, pills, buccal preparations, tablets, sachets, powders, syrups, elixirs, solutions and suspensions, and the like, in accordance with standard pharmaceutical practice. In another embodiment, the pharmaceutical compositions of the present invention may also be delivered directly to the gastrointestinal tract of a patient via the nasal gastrointestinal tract. The thiopenic prodrugs of the present invention may be present in the pharmaceutical compositions of the present invention in an amount sufficient to provide the desired dosage within the ranges described herein. The ratio of prodrug to excipient will of course depend on the chemical nature of the active ingredient 'solubility and stability and the dosage form being considered. In general, the pharmaceutical compositions of the present invention may contain from about 20% to about 95% by weight of the prodrug. In one embodiment, the amount of thiopenem prodrug present in the pharmaceutical composition of the invention is from about 200 mg to about 4000 mg of thiopenem prodrug. In another embodiment, the amount of the thiopenem prodrug present in the composition of the invention is from about 200 mg to about 3000 mg of the sulphuric prodrug. In another embodiment, the amount of the thiopenic prodrug present in the pharmaceutical composition of the invention is from about 200 mg to about 2000 mg of thiopenem a 〇. In another embodiment, the thiopenem 126137.doc -13 - 200829242 present in the composition of the invention is from about 400 mg to about 4000 mg of the sulphuric prodrug. In the examples, the amount of thiopenicin present in the pharmaceutical composition of the present invention is from about 400 mg to about 3000 mg of thiopenem prodrug. The amount of the thiopenic prodrug present in the pharmaceutical composition of the present invention in the 2-example is from about 400 mg to about 2000 mg of the thiopenem prodrug. In one embodiment, the thiopenic prodrug used in the compositions of the present invention is a thiopenem prodrug 1. In another embodiment, the thiopenic prodrug used in the compositions of the present invention is a thiopenem prodrug 2. In another embodiment, the thiopenem prodrug used in the compositions of the present invention is a thiopenem prodrug 3. The preparation and drug administration technology of the prior medicine of the present invention can be seen in the addition

Science and Practice 〇f pharmacy, i9, (4)

Co., Easton, Pa. (1995) An agent that can be combined with a thiopenic prodrug to prepare a pharmaceutical composition or an inert form of an oral pharmaceutical dosage form. The term "pharmaceutically acceptable excipient" means that the excipient must be compatible with the other ingredients of the composition and that it is in the mouth of the composition. Pharmaceutically acceptable excipients are selected based on the intended dosage form. Tablets, pills, capsules and the like may contain excipients selected from the group consisting of binders such as polyethylene (tetra), propylmethylcellulose (HPMC), hydroxypropylcellulose (Hpc). ), sucrose, gelatin, gum arabic, tragacanth or corn starch; fillers such as microcrystalline cellulose, lactose # sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine and starch; disintegration 126137.doc - 14- 200829242 Agent, f such as corn powder, horse starch starch, alginic acid, sodium thioglycolate, sodium carboxymethyl cellulose and some complex citrate; lubricants, u, 12 sodium sulphate and talc, and sweeteners such as sucrose, sugar or saccharin. When the unit dosage form is a capsule, in addition to the above types: material: it may also contain a liquid carrier such as a fatty oil. A variety of other materials may be present as a l-form or as a physical form of a modified unit dosage form. For example, a tablet can be coated with shellac, sugar or both. In the case of pediatric sputum suspensions and sachets, such excipients may comprise, for example, disaccharide or hydroxypropylmethylcellulose; glidants, such as colloidal monoxide, and diluents; A bulking agent, such as a dioxide dioxide; a flavoring agent such as a bubble gum, a dial, a money, a raspberry and a yellow syrup or a mixture thereof; a sweetener such as aspartame or a sugar; and a stable 4J such as Butyric acid. Powder or granule formulations, such as pediatric suspension formulations and sachets, can be prepared in the preparation of dry formulations for the preparation of aqueous suspensions using the formulation of pharmaceutical formulations. For example, a suitable technique is a technique of mixing a dry powder component or a particulate component. As described above, the present invention is also directed to a method of preparing a thiopenem prodrug of the present invention. The method comprises reacting a hydrazine compound with thiopenem (Β9). The reaction is carried out under conditions sufficient to form the thiopenic prodrug of the present invention. Usually, the reaction between the compound of formula 1 and thiopenem is carried out in an organic solvent and is carried out under examination. Non-limiting examples of suitable organic solvents include ketones such as acetone and mercaptoethyl ketone. Non-limiting examples of suitable bases include amines such as dialkylamines and dialkylamines. In an embodiment for the preparation of the thiopenic prodrug of the present invention 126137.doc -15- 200829242 the base is diisopropyl, the base is a trialkylamine; in another embodiment the ethylamine. The reaction for preparing the thiopentan prodrug is carried out at a time and temperature sufficient to form the (9) southern prodrug of the present invention. For example, when the reaction is carried out, it is usually about 0.25 hours to about 72 hours. The temperature at which the reaction is carried out may be from about the temperature at the freezing point of the agent to the reflux temperature of the solvent. The degree is usually about η: to about 1〇η:; more usually it is about 45t. '…solitary

In an embodiment for the preparation of the thiopenic prodrug of the invention, the formula is a compound wherein R1 is -CH2CH3; in another embodiment, r1 is -ch2ch3ch3; and in another embodiment, Rl is _CH2CH(CH3)2. In the examples used to prepare the thiopenic prodrugs of the present invention, the formula lnb is a compound wherein the X system is selected from the group consisting of: _· group, -methanesulfonate, -trifluoro Mesylate and _p-toluenesulfonate. In the examples used in the preparation of the thiopenic prodrugs of the present invention, the formula is a compound wherein X is a bromo group. The thiopenic prodrugs and hydrazine compounds of the present invention can be prepared in a manner similar to that described in the preparation of 3 described in the Examples section and in the manner described in U.S. Patent No. 5, No. 13,729, the entire contents of which is incorporated herein by reference. The citations are incorporated herein by reference. Other suitable methods for preparing the thiopenic prodrugs of the present invention can be found in U.S. Patent Nos. 3,951,954, 4,234,579, 4,287,181, 4'452'796, 7,342,693, and 4,348,264. No. 4,416,891, 4,457,924, and 5, the disclosure of each of which is incorporated herein by reference. These patents describe methods for the reaction of the free acid of 126137.doc -16 - 200829242 t ^ South or the cationic salt of thiopenem. The cationic salt of the sphagnum saponin is tetra-n-butylammonium or diisopropylethylammonium salt, which are respectively beneficial: &&& + sulphuric acid and tetrabutyl hydrogensulfate The preparation of money (n Bii^4N HS〇4· or diisopropylethylamine (diea) can be carried out. Then, the cation can be reacted with an appropriate _ sinter to form the desired prodrug. In one embodiment, the oral bioavailability of the thiopenem prodrug of the present invention (the erection is human oral bioavailability) (absorption fraction, % F) is at least about 4 G/°, 50%, 60°/〇 or Larger. Oral bioavailability can be predicted by factors such as one or more of the following factors: (1) GI stability; (2) Cac〇_2 permeability; (7) thiopenic conversion efficiency and high solubility Assessing the stability of the thiopenicin of the present invention in human intestinal juice _), the transformation efficiency of the squirrel perennial in human liver tissue homogenization, the whole blood conversion rate, and the following Solubility measured in pH 5•transate buffer. The thiopenem prodrug of the present invention was tested according to the following general procedure and the results are shown in Table 2. Liver S9 and whole blood conversion efficiency study: Liver S9 was prepared from the liver block stored under -7 (TC) for the completion of each analysis. About 5g cold bundle liver tissue should be chilled in the 15 machine. Homogenize to the solution in the solution (pH 7.4). Then centrifuge the homogenate (8) layer for 2 ' minutes to separate the S9 supernatant fraction. The % supernatant is in (10) potassium sulphate buffer (positive) 7.4) The 1:1 () transfer of the towel was carried out for each incubation. The reaction was initiated by adding a substrate (5 〇 _ final concentration) under the pit. The stability of the 1 mL heparinized whole blood culture at 37t: 126137.doc -17- 200829242

C conversion efficiency. For S9 grout and whole blood cultures, aliquots were obtained at 〇, 〇5, 】3, 5, H) and 2 〇 minutes (75 y, and (9) called internal standard (Ambiscillin) (ampieUHn), 5 call) 8g/2〇 B guess / 100 mM acetic acid (pH 4_5) to stop. Centrifuge the sample for 3 〇〇〇 1 minute and transfer the supernatant to the injection bottle In the following, the pro-drug degradation reaction of the prodrug was monitored by LC/MS/MS. The thiopenem conversion rate can be expressed as the percentage of the molar equivalent (5 〇 _) in the intensive sample. S9 and whole blood are stable. The results of the sex and conversion studies are shown in Table 2, where a single value represents the average of two replicates. The results (Table 2) show that the heparan conversion of liver (7) is about 67% or greater. Human intestinal fluid ( HI J) Study: In the HIJ experiment, the "out of each individual subject" was combined with the 600 mM potassium phosphate buffer (pH 74) of the mL mL. After the concentration of 〇〇, 3〇, 10, 3, and i _ is strengthened, an aliquot of 3〇〇μίχ6 buffered human intestinal juice is incubated at 3rc. Both prodrugs can be processed simultaneously. Compound: Take 35 samples at 0, 〇·5, i, 2, 2 () minutes, and use 70 μΐ^ containing internal standard (ampicillin, 5 called /1111〇8〇/2〇acetonitrile) /100 mM ammonium acetate (ΡΗ 4.5) was stopped. The sample was centrifuged at 3 ° C for 10 minutes and the supernatant was transferred to a vial. The prodrug was monitored by LC/MS/MS as described below. First-order degradation reaction. The relationship between the residual percentage of prodrugs at each concentration and time is fitted to the first-order decay function to determine the deceleration rate constant or kdep. The equation is fitted with a linear logarithmic curve of kdep with concentration. : 126137.doc -18- 200829242 fdep[S]^0 _[S]_ kdep value at a low inferior substrate concentration (where kdep is approximately kdep[s]1) indicates the maximum rate of consumption or intrinsic clearance of the system And (7) is the concentration at which half of the maximum speed of the system is reached. In the Michaelis-Menton terminology, the intrinsic clearance CLint indicates when [s] is much lower than the ratio. The quality unit used for these studies is reported in μΜ The intrinsic clearance (Clint) is reported in mL/min. The results of these studies are shown in Table 2.

Caco·2 Permeability Study: c The degree of intestinal absorption is proportional to the rate or penetration of the compound across the intestinal epithelium from the lumen of the intestine to the blood (when the solubility is not limited). This penetration can be predicted to the extent that the intestines are to be absorbed. The Cac〇_2 model is an in vivo tissue culture model of human intestinal epithelium that can be used to study the apparent permeation or permeability (Papp) of a compound across the intestinal epithelium. This model forms a monolayer that is self-differentiated, and the apical (A) domain and the bottom phase (B) domain that define the bright green are separated by a cellular indirect complex. Each domain contains distinct biochemical features (e.g., membrane composition, transporters, and enzymes) similar to those found in the intestinal epithelium. The intestinal lumen side was simulated by the A compartment and the intestinal mucosa (4) compartment was simulated. will~. -] The model is cultured in a two-compartment format, allowing measurement from the donor compartment (applied by the experimental solution = compartment) (rather than disappearing, which is usually measured in vivo or on the spot) to the body to Compounds in appropriate transfer buffers). Therefore, the apparent permeability (1_) of the true traversing polarized epithelium can be determined by this type. This Papp is primarily determined by the combination of the passive permeability of the compound with any potential cellular biochemical activity that can affect the transport of the compound over the early layer. 126137.doc •19· 200829242. By using this model (which is similar in structure and biochemical activity to the intestinal epithelium), the distribution of the compound across the human intestinal epithelium can be understood (in terms of penetration and mechanism of infiltration). Since cells contain a variety of esterases that hydrolyze prodrugs, the quantification of prodrugs and thiopenem (B9) is an important aspect of quality transfer and recovery within the evaluation system. A-B assays were performed to evaluate Papp (intestinal to intestinal mucosa; Papp, A_B) of the test compound in the direction of absorption transport. In the A-B assay, the compound was placed in chamber A and the relationship between the appearance of compounds in zone B and time was monitored. ##·· Caco-2 cells were obtained from the American Type Culture Collection; Rockville, MD. Cell culture medium (Dulbeccc^s Modified Eagles Medium with 20% fetal bovine serum, 1% non-essential amino acid, 1% Glutamax-Ι and 0.08% only damycin) Gentamycin)) and transport buffer (Hank's balanced salt solution with 25 mM dextrose monohydrate, 1.25 mM CaCl2 & 0.5 mM MgCl2) A (with 20 mM 2-[N- Morpholinyl]ethanesulfonic acid (MES) transport buffer; pH 6.5) and B (transport buffer with 20 mM N-hydroxyethylpiperazine-N'-2-ethanesulfonate (HEPES); pH 7.4) Obtained from Invitrogen (Gibco Laboratories, Grand Island, NY). HTS 24-porous insertion system cell culture plates (polyethylene terephthalate (PET) membrane, 0.28 cm2 growth zone, 1 μιη pore size) were obtained from BD Falcon (Bedford, MA). (7 〇-2 细游培妻··Caco-2 cells in Nuaire incubator (Plymouth, MN) at 37 ° C in 10% C02 atmosphere and 90% relative humidity 126137.doc -20- 200829242 The cells were cultured in a cell culture medium, and after about 75% to 85% of fullness in a flask, the cells were subcultured with 0.05% trypsin-EDTA (Invitrogen, Gibco Laboratories, Grand Island, NY). Kl was seeded in 100,000 cells/ml cell suspension in cell culture medium, and Caco-2 cells were seeded on each pet membrane of HTS 24-porous insertion system. 25 mL cell culture medium was added to the feeding tray. Cell culture medium was changed for two weeks. One time and 24 hours before the experiment was replaced. The Caco-2 cell monolayer was used for the experiment on the 26th day after the inoculation.

Ο 飨定才案··Caco-2 cell culture medium was removed from two compartments and 300 μM transport buffer A was placed in compartment A and 5〇〇pL transport buffer B was placed in In the room of Zone B. The cell monolayer is rotated by 1〇〇 rprn〇rbital

EnvironShaker (Lab-Line; Dubuque, 10) was incubated at 37 ° C for 1 hour. After 1 hour, the buffer was removed from both compartments. For the A-B assay, 300 μl of a 1 μμΜ prodrug solution containing fluorescein (〇1 mg/mL) as a single layer integrity standard in transport buffer A was added to the sputum compartment and 500 μl of transport buffer Β was added to the sputum compartment (n = 3 monolayers per experimental condition). The monolayer was incubated for 1 hour at 1 〇〇 rPm and 37 ° C in a sway shaker. Transfer the entire transfer well insertion system to a new 24-well plate containing fresh Transfer Buffer B (pre-incubated at 3rc) and place it back into the shaker at 1 rpm and 37. 〇 〇 〇 。 。 。. After the small dryness, the test sample was collected from the compartment B (the hole of the 24-well plate), and the sample was removed from the two compartments at the end of the first hour of the sample analysis and left for analysis. The first ja was captured from the B compartment. The sample is a test sample and a sample obtained from Zone A is collected for the recovery assay. The thiopenic prodrug and thiopenem (Eg) in all samples obtained from the 126137.doc -21 - 200829242 sputum and sputum were quantified by the LC/MS/Ms method. Based on the contribution of the complete prodrug and thiopenem, the total mass of each compartment was calculated. Fluorescent yellow content is achieved by using the Wallac Victor II Fluorescence Detector (Turku,

Finland), measured at an excitation wavelength of 430 nm and an emission wavelength of 535 nm. 0 #存分舞· Papp(xl〇 6 cm/sec) is calculated using Equation 1:

Pa Equation 1 〇PP Area^CD{0) dt

Where Area is the surface area of the cell monolayer (〇·3 cm2), Cd(〇) is the initial concentration of the compound applied to the donor chamber, t is time, is the mass of the compound in the receptor compartment, and dMr/dt The flux of the compound across the cell monolayer. Fluorescence Yellow Flux is determined using Equation 2: Flux °/〇, C Λ CD(0) 100 Equation 2 where &amp; is the concentration of fluorescent yellow in the receptor compartment after 1 hour and Cd(〇) is applied The initial concentration of fluorescent yellow in the donor cavity to the middle. A cell monolayer with &lt;3 %/h fluorescent yellow flux was determined to be intact. Data from a single layer of fluorescent yellow flux &gt; 3%/h was not included. The compound recovery was determined using Equation 3: ^R(l) + CR(2) + CD(2) + CM ^< cD(9) *100 Equation 3 where Cr(1) is the concentration of the compound in the receptor compartment after 1 hour CR(2) is 2 small, the concentration of the compound [the concentration of the compound] Cd(2) is the concentration of the compound in the donor compartment after 2 hours, and CM is the concentration of the drug remaining in the monolayer, and 126137. Doc -22- 200829242 cD (〇) is the initial concentration of the compound in the donor compartment. The recovery rate is usually 90% or more. Solubility: The equilibrium solubility is determined in ambient temperature at 25 mM phosphate buffer (pH 5). The vial containing the excess prodrug in phosphate buffer was spun for up to 48 hours. After the equilibration period, the samples were withdrawn, filtered through a 0.45 u Gelman Acrodisc Nylon syringe, filtered, and analyzed for drug concentration using HPLC. HPLC conditions were: column: C18, SymmetryShield RP, Waters, 4.6 x 150 mm, 3.5 micron; mobile phase A: acetonitrile; mobile phase B: 0. 1% TFA in water; flow rate: 1 mL/min; Time: 30 minutes; injection volume 20 μΐ; detection: 350 nm; retention time = 16 min; solvent: acetonitrile/water (50:50). Gradient used: Time %A %B Omin 5 95 25 min 95 5 27 min 5 95 30 min 5 95 Melting point: The melting point was determined via a MEL_TEMP 3·0 capillary melting point apparatus and was uncorrected. The results are shown in Table 2. Method of Use: The thiopenic prodrug of the present invention can be used to treat a patient suffering from a disease such as a bacterial infection. 126137.doc -23- 200829242 As used herein, the term "patient" refers to a mammal, such as a human, a dog, a cat, a horse, a pig, a cow, and the like. In one embodiment, the patient is a human. Bacterial infections suitable for treatment by the thiopenic prodrugs of the invention, pharmaceutical compositions and methods of the invention include infections caused by a wide variety of pathogens such as, but not limited to, Staphylococcus aureus awrews) , Staphylococcus aureus, otitis dysplasia, Streptococcus pyogenes/^yogena), Streptococcus agalactiae, Viridans, penicillin-sensitive pneumococcal p, anti-penicillin-type pneumonia Cocci, anti-Celebrex (/eV〇//(9Xad/7) type Streptococcus pneumoniae, Z^ier/α monocytogenes ^ iiversws, Freund's Citrobacter (C/ί π acier /re (10) (i / z ·), Enterobacter aerogenes aerogwes), Enterobacter cloacae (five c / oacae), Escherichia coli (five alpha / ζ ·), acid production Klebsiella (strain, Klebsiella pneumoniae (especially ae), Klebsiella pneumoniae (including those encoding broad-spectrum β-endosaminolase (hereinafter referred to as nESBLn)), Mohs Morgan Window [Morganella morganii), Proteus mirabilis (household Mirabilis), Salmonella/Shigella (10)e//a/67n.ge//a), β-endoprostase-negative Haemophilus influenzae {Haemophilus (9)zae), β-endotropin-positive influenza bloodthirsty Rod 126137.doc -24 - 200829242 bacteria, β-lactamase-negative mucosa Moraxella cakrr/za/), β-endotriamine-positive mucosa Moraxella, Legionella pneumophila, meninges Neisseria faecalis, Bacteroides fragilis, Clostridium perfringens (C/oWrMz'wm j^r/Wng(9)*y), Plasmodium (corpse spp.) and enterobacteriaceae (£^roZmcier) /acMe) member (expressing ESBL and AmpC type β-indoleamine for resistance to cephalosporin, cephamycin, and β-endoamine/β-endotriamine inhibitor combination Enzyme). Thiopenem and its prodrugs do not have activity against the following bacteria: Pseudomonas aerwgkwa, Acinetobacter spp., Stenotrophomonas, multi-resistant enterococci (mz//&quot;· ewierococc/) and methicillin-resistant staphylococcus {met hie ill ίη-res ist ant staphylococci) ° In one embodiment, the prodrug of the invention has anti-gram-positive bacteria (gram -positive bacteria) In another embodiment, the drug of the present invention has Gram-negative bacteria against Pseudomonas aeruginosa, Acinetobacter and A. maltophilia (gram-negative) Bacteria) activity. Based on the minimum inhibitory concentration (MIC), the activity of thiopenem (B9) (parentic acid) in vitro against 40 communities and pathogens involved in nosocomial infections was assessed as outlined in Table 1. Table 1: MIC9 硫 value of thiopenem bg/mL) oxacillin sensitive gold yellow glucosinolate. 125 126137.doc -25- 200829242 Staphylococcus aureus 0.5 otitis differential cocci 1 S. pyogenes (Group A) 0.03 Streptococcus agalactiae (Group B) 0.125 Bovisus group 0.06 Green Streptococcus group 0.25 Penicillin-sensitive Streptococcus pneumoniae 〇3 Penicillin Moderately sensitive Streptococcus pneumonia 0.25 Anti-penicillin type Streptococcus pneumoniae 1 Anti-Celebrex Streptococcus pneumoniae 0.5 Listeria monocytogenes 0.125 Corynebacterium (except for C. serrata (C.) C. citrate 〇. 〇6 Citrobacter freundii 0.25 Enterobacter aerogenes 0.5 Enterobacter cloacae Escherichia coli 1 Escherichia coli 0.06 Acid-producing Klebsiella spp. 0.125 Klebsiella pneumoniae 0.125 ESBL-positive Klebsiella pneumoniae 0.25 Moraxella burgdorferi 2 Proteus mirabilis .5 Salmonella/Shigella 0.125 β-endoprostase-negative Haemophilus influenzae 0.25 β-endoprolase-positive Haemophilus influenzae 0.5 β-endoprostase-negative mucosa Moraxella 0.03 β - endoprolylase positive M. catarrhalis 0.125 126137.doc -26- 200829242 Legionella pneumophila 0.06 Neisseria meningitidis 0.06 Bacteroides fragilis 0.5 Clostridium perfringens 0.06 Pleurotus sp. 0.125 In one embodiment, the invention The thiopenic prodrug can be used to treat a variety of hospital and community acquired infections in humans, such as respiratory infections, surgical infections, central nervous system infections, gastrointestinal infections, genitourinary infections, gynecological infections, skin and soft tissue infections, and eye infections, and Community acquired pneumonia (hereinafter referred to as "infection"). In the case of Bega, the infection is selected from the group consisting of acute exacerbations of chronic bronchitis, sinusitis, otitis media, brain abscess, pharyngitis, meningitis, Non-complex/complexity urinary tract infections, pyelonephritis 'hospital acquired pneumonia, community acquired pneumonia, surgical prophylaxis, uncomplicated/complex skin and skin structure infections, intra-abdominal infections, prostatitis, obstetrics and gynecological infections, Bone and joint infection, diabetic foot and bacteremia. In another embodiment, the infection is selected from the group consisting of the following infections Complex and non-complex urinary tract infections, complex skin and skin structure infections, diabetic foot infections, cluster-acquired pneumonia, hospital-acquired pneumonia, intra-abdominal infections, and obstetric and gynecological infections. The minimum amount of a prodrug is a therapeutically effective amount. The term &quot;therapeutically effective amount&quot; means preventing the onset of bacterial sensation in a mammal (e.g., a human), slowing the symptoms of bacterial infection, stopping the progression of bacterial infection, and/or eliminating bacteria. The dose before infection. The maximum dosage of the sputum medicinal prodrug of the present invention is toxicologically acceptable. 126137.doc -27- 200829242 盖' In the embodiment of the carp, the dosage of the thiopenem prodrug of the present invention is An interval between administrations of at least about 3% (preferably at least about 40%) (dosing interval) maintains the antibiotic concentration of the thiopenem to a level above the MIC of the infectious agent. In a more preferred embodiment, the thiopenic prodrug of the present invention is administered in an amount such that the plasma antibiotic concentration of thiopenem is maintained above the MIC of the infectious agent at a dose interval of at least 4%. Generally, the effective daily dose of the thiopenic prodrug of the present invention for use in an adult (i.e., the total dose in about 24 hours) is from about 400 mg to about 6000 mg of thiopenem 4; in another embodiment, An effective daily dose of from about 8 mg to about 6000 mg of the thiopenic prodrug; and in another embodiment, an effective daily dose of from about 800 mg to about 4000 mg of the sulphuric prodrug. This daily dose is administered from about one week to about two weeks. In some cases, doses other than these limits may be required. The amount of effective daily dose can be adjusted according to body mass. In one embodiment, the thiopenic prodrug of the present invention is used in an effective daily dose for an adult (ie, a total dose in about 24 hours) of from about 5 mg to about 85 mg per kg body weight. a thiopenic prodrug; in another embodiment, an effective daily dose of from about 10 mg to about 85 mg of thiopenem prodrug per kilogram of body weight; and in another embodiment, an effective daily dose per dose The kilogram weight is from about 1 mg to about 60 mg of sulphuric prodrug. This dose is administered over a period of about _week to about two weeks. In some cases it may be necessary to use doses outside of these limits. The daily dose of the thiopenem prodrug of the present invention is usually administered in an equal dose of 2 to 4 times a day. 126137.d〇 ( -28 - 200829242 In one embodiment, a single dose of thiopenem prodrug (i.e., QD) is administered daily (i.e., within about 24 hours); in another embodiment, each曰 administer two doses of sulphuric prodrug (ie, BID); in another embodiment, a second dose of thiopenem prodrug (ie, TID) is administered per sputum; and in another embodiment In the present embodiment, the mother is administered with four doses of the thiopenic prodrug (i.e., QID). In one embodiment, the effective dose of the thiopenem prodrug of the present invention is administered at about 12 hours intervals BID. In an embodiment, the effective dose of the thiopenem prodrug of the present invention is administered at a TID of about 8 hours apart. In another embodiment, the effective dose of the thiopenem prodrug of the present invention is administered at a 6 hour interval QID. In one embodiment, the effective dose of the thiopenic prodrug of the present invention is from about 400 mg to about 3000 mg administered at about 12 hours intervals Bm. In another embodiment, the thiopenem of the present invention An effective dose of the prodrug is from about 400 mg to about 2000 mg, which is administered at about 8 hour intervals. In another embodiment, the effective dose of the thiopenem prodrug of the present invention From about 400 mg to about 1500 mg, which is administered at about 6 hours intervals. The thiopenem prodrug of the present invention is easily hydrolyzed in vivo after absorption to form an antibacterial active form of thiopenem. The drug has a high oral bioavailability in humans that is sufficient to achieve a drug exposure greater than the desired level (eg, 1 pg/mL) at a dose interval of at least 4% to effectively treat the bacterial infection. In one embodiment, the thiopenic prodrug used to treat the infection is sulphur 126137.doc -29- 200829242. In another embodiment, the thiopenic prodrug used to treat the infection is thiopenic prodrug 2. In one embodiment, the thiopenic prodrug for treating infection is a thiopenem prodrug 3. Oral administration is preferred. The thiopenem prodrug of the invention may be combined with one or more other pharmaceuticals or agents ("other active agents" π) combination administration. The combined use of the thiopenem prodrug of the present invention and other active agents can be used simultaneously, independently or sequentially. In one embodiment, the other active agent is an antibacterial agent. Examples include: Aminoglycosides such as streptomycin Streptomycin), gentamycin, kanamycin or amikacin; ansamycin, such as rifamycin; β-indoleamine , such as penicillin (such as amoxicillin and ampicillin), cephalosporin (such as cefipime, cefditoren pivoxil (Spectracef®), cephalothin, cephalosporin Cefaclor or cefixime; a combination of a beta-endoprostanase inhibitor and a beta-endoamine/beta-endoamine inhibitor, such as sulbactam, clavulanic Acid), three-seat tazobactam and piperacillin-tazobactam (Zosyn®); carbapenems such as ertapenem (Invanz®), imine Imipenem-cilastatin (Primaxin®) and meropenine 126137.doc • 30· 200829242 South (meropenem) (Merrem®); dihydrofolate reductase inhibitors, such as clapplin (iclaprim); Vinegar peptides, such as vancomycin (Vancocin®), darbamycin (dalbavancin) (Pfizer), oritavancin (Targenta Therapeutics), telavancin (Theravance), ramoplanin (Pfizer and Oscient), picomycin (teicoplanin) (Targocid®); _ lactones, such as telithromycin (Ketek8); lipopeptides, such as daptomycin (Cubicin®); lincosamides, such as Klinda Clindamycin and lincomycin;

LpxC inhibitors, such as those disclosed in WO2007069020 and WO200407444; macrolides, such as azithromycin, erythromycin or clarithromycin; sputum ketones, such as linac Linzolid (Zyvox®), lanbezolid (RBX 7644), DA 7867, AZD-2563; compounds disclosed in U.S. Patent No. 7,141,588; and U.S. Patent Application Publication No. 20040 176,610 And the compounds disclosed in No. 20060030609; polymyxins, such as polymyxin B sulfate and colistin; quinolones and fluoroquinolones, such as Norfloxacin, ciprofloxacin, Levaquin®, gemifloxacin 126137.doc -31 - 200829242 (gemifloxacin) (Factive®), moxifloxacin (Avelox®) ), nalidixic acid or enoxacin, phenylpropanoids, such as chloramphenicol; phosphonates, such as fosfomycin; amine , such as sulfapyridine; and tetracyclines, such as chlortetracycline, doxycycline, tigecycline (Tygacil®) 〇 other antibacterial agents Non-limiting examples can be found in Chemical Reviews 105 (2): 391-394 (2005); and Bush et al., Current Opinion in Microbiology 7: 466-476 (2004); each of which is incorporated herein by reference in its entirety herein. . In one embodiment, the other active agent is a probenecid. Without being bound by theory, it is believed that the combination of the thiopenic prodrug of the present invention in combination with probenecid may increase the half-life of the active form of the prodrug. In one embodiment, the or other active agents are administered, prior to administration to the thiopenic prodrugs of the invention. In another embodiment, the or other active agent, when used, is administered after administration of the thiopenic prodrug of the invention. In another embodiment, the or other active agents, when used, are administered at about the same time as the administration of the thiopenem prodrug of the present invention. Other active agents can be administered by any route suitable for administration of the other active agent. 126137.doc -32- 200829242 In one embodiment, the or other active agents are present in the pharmaceutical compositions of the present invention. Thus, in another embodiment, the invention is directed to a method of treating a patient with a pharmaceutical composition of the invention that progressively incorporates one or more additional active agents.乂下所长: For Examples and Preparations The compounds of the present invention and methods of preparing the same are further illustrated and exemplified. It is to be understood that the scope of the invention is not limited in any way by the following examples and the scope of preparation. All patents, applications, publications, test methods, documents, and other materials cited herein are hereby incorporated by reference in their entirety. EXAMPLES The invention will be further illustrated by the following non-limiting examples. Example 1 (5Κ,6δ)-6-[(1Κ)]-Hydroxyethyl]-7. oxo_3-[[(1R,3S)-tetrahydroxyl bridge 11 thiophene]thio]- 4-thia-1-azabicyclo[3·2·〇]hept-2-ene-in formic acid (5-(3-methylpropyl)-2-oxo-1,3-dioxan Preparation of cyclopentene-4-yl)methyl ester (3): Compound 3 was prepared according to the method depicted in Scheme 且 and detailed below: 126137.doc •33 - 200829242 Scheme 1

Step 1: Preparation of 5-methyl-3-oxoethyl hexanoate (B1): Feeding the malonic acid monoethyl ester potassium salt (3680 g, 21.62 mol) in acetonitrile (20 L) Mechanical stirrer, addition funnel, thermometer, nitrogen inlet, drying tube and cooling bath in a 50 L three-necked round bottom flask. The contents of the flask were cooled to 10 ° C and treated with triethylamine (2821 mL). Magnesium vapor (2090 g) was then added portionwise while maintaining the temperature below 15 °C. The reaction mixture was allowed to warm to ca. 25 and stirred for 2.5 h. The contents of the flask were cooled to 0 ° C and slowly treated with isoamyl chloride (1303 g, 10.81 mol) while maintaining the temperature of the reaction mixture below 5 °C. An additional amount of acetonitrile (4000 mL) was added to the resulting viscous mixture during this time. The contents of the flask were treated with a solution of triethylamine (2000 mL) in acetonitrile (3000 mL) and stirred at 25 ° C for 18 hours. The contents of the flask were concentrated at 50 ° C, and the obtained viscous oil was transferred to a 50 L three-necked round bottom flask equipped with a mechanical stirrer, an addition funnel, a thermometer, a nitrogen inlet, a drying tube and a cooling bath 126137.doc • 34- 200829242. The reactor contents were diluted with toluene (10 L), cooled to 1 (rc, and treated with hydrochloric acid (1 5%, 13 L). The contents of the reactor were warmed to 25. 〇 and remixed 1 hour. The organic layer was then collected, and the aqueous layer was extracted with toluene (2 mL). The combined organic layer was washed with hydrochloric acid (丨 5%, 2 χ 2 〇 (9) mL), water (2000 mL), and The mixture was dried over magnesium sulfate. The mixture was filtered, and the solid was washed with benzene (1000 mL). The combined filtrate was concentrated to give B1 as colorless oil. Yield: 1754 g (94%). It can be used in the following step 2 without further purification. Step 2: Preparation of 5-methyl-3-oxo-oxy-acid group (B2):

Bl (1754 g' 10.18 mol) in benzyl alcohol (1431 g, 13.23 mol) was fed into a 12 L three equipped with a mechanical sand thrower, heating mantle, nitrogen inlet, thermocouple and short condenser (uncooled) The neck is rounded and burned. The contents of the flask were then heated at 150 ° C for 8 hours. The by-product ethanol was collected during this period. The reaction mixture was then cooled to give a solution of B2 in benzyl alcohol which was used in the next step 3 without further purification. Yield: 2291 g (product contains about 15% benzyl alcohol). The calculated yield without benzyl alcohol: 1947 g (82%). Step 3: Preparation of 2-diazo-5-methyl-3-oxo-hexanoic acid benzyl ester (B3) · B2 (1465 g) and p-toluene azide (1233 g) in acetonitrile (9,250) The solution in mL) was fed into a 22 L three-necked round bottom flask equipped with a mechanical stirrer, addition funnel, temperature, nitrogen inlet, drying tube and cooling bath. The contents of the flask were cooled to 0 ° C and slowly treated with triethylamine (740 mL) while maintaining the reaction temperature below 1 °C. The reaction mixture was allowed to warm to 25 C and stirred at 25 C for 18 h. The reaction mixture was then concentrated at 25 C. The oily residue obtained was dissolved in 5 〇〇〇❿ 之 126 126137.doc -35 - 200829242 alkane: ΜΤΒΕ 1:2 mixture and stirred at 2 rc for 3 Torr. The resulting suspension was filtered and the solid was washed with EtOAc EtOAc (EtOAc): The combined filtrate is then concentrated, and the resulting residue is passed through a Shixi rubber plug (1G00 g diox, H_1Q&quot;, D5 5&quot;) with (10)% g of splicing, 0 /. The AcOEt/Geng Institute was purified by gradient elution. The product-containing eliminator was collected and concentrated to give B3 as a yellow oil. Yield: 1778 (100%) 〇8 Step 4: Preparation of 2-hydroxy-5-methyl_3_oxetyl hexanoate (B4): B3 (1627 g) in tetrahydroanion (13_mL) The solution was fed into a 50 L three-necked round bottom flask equipped with a mechanical stirrer, an addition funnel, a heating mantle, a reflux condenser and a thermocouple. The contents of the flask were then treated with water (6, 〇〇〇 mL) and hydrazine acetate (16 g). The resulting green two phase mixture was then heated at reflux temperature for about 18 hours. The reaction mixture was concentrated and extracted with ethyl acetate (3×3. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The solid was washed with ethyl acetate (5 mL) and the combined filtrate was concentrated. The residue obtained was purified via a plug (1000 g of cerium oxide, Η·10,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, B4. Yield: 1850 g (l〇〇%). Step 5: Preparation of benzyl-5-isobutyl-2-oxo-1,3-dioxalenyl-4-carboxylate (B5): B4 (666 g, 2.66 mol) , a mixture of THF (12 L) and diisopropylethylamine (13.3 mL; 9·87 g, 76·4 mmol) fed into a 22 L equipped with an overhead stirrer, nitrogen inlet and temperature probe In the flask. The contents of the flask were then treated with 1, hydrazine-carbonyldiimidazole (7.98 mol; 126137.doc -36 - 200829242 1.29 kg) (the initial portion was kept less than 10 gram) for 15 minutes and at 25 C It was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to remove about 9.5 L of solvent. The resulting slurry was then poured into a flask containing a mixture of 2 N HCl (5 L) and EtOAc (1 L), while maintaining the temperature below 20 °C. An additional amount of EtOAc (4 L) was added to the flask and the obtained organic layer was collected and washed with 2 N EtOAc (5 L). The organic phase was passed through a NadCU pad and concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc-EtOAc) elute elute Yield: 7 5 4 g, about 4 5 %. Step 6 · Preparation of 5-isobutyl-2-oxooxy-1,3-dioxacyclo- 4-carboxylic acid (B6): Pd(OH)2(44.〇g), ethanol (12〇l) &amp; B5 (44〇g) was fed into a 2 gallon parr pressure reactor. The reactor contents were then treated with hydrogen (40 psi) at 23 C for 1.5 hours. During this time, 3 〇·2 g of hydrogen was added to the reactor. The Pd catalyst was removed from the reactor and the reactor contents were treated with Pd(OH)2 (44.0 g). The reactor contents were then treated with helium (20-40 psi) for 20 minutes at 32C. The reactor was vented and purged with nitrogen. The contents of the reactor were then transferred to a jar (1 〇 L) which was treated with diatomaceous earth and filtered through a 2 L sintered glass funnel. The filter cake was washed with EtOH (2 L), and the combined filtrate was concentrated to give B6 as pale yellow solid. Yield: 262 g, 88.4%. Step 7: Preparation of 4-(hydroxymethyl)-5-isobutyl-1,3-dioxole (B7): 262 g, methane (39 〇L) and A mixture of dimethyl decylamine (1 〇·3 g) was cooled to -0.8 t; and it was treated with ethylene dichloride (196 126137.doc -37 - 200829242 g) for a minimum of 30 minutes while Keep the temperature in the generation to generation. The reaction mixture was placed in a crucible. Keep your armpit for 30 minutes and warm it to 23. The hydrazine was allowed to stand for 1 hour and/or to obtain a chloro-organic intermediate 5-isobutyl I-side oxy-indolyl pentene 1-methyl chlorobenzene (B7a) (not shown in Scheme 1). Yield: 289 g, 100 〇 / 〇〇 A solution of B7a (287 g) in chloroformic acid L) was cooled to the passage and used with tetrabutylammonium borohydride (98% by weight, 231 g). The mixture in methyl chloride (then mL) was treated for 13 days while maintaining the temperature at _5. 〇 to 5 °C. The reaction mixture was maintained at 〇r to 2 min and was treated with 〇M HCl (2.1 L) for 30 min while maintaining the temperature at </ RTI> </ RTI> <RTIgt; The reaction mixture was warmed to 2 31 for 3 min and maintained at 2 3 for 1 h. The resulting organic phase was collected and the aqueous phase was washed with dichloromethane. The combined organic phases were washed with brine (1 x 2.5 L) and passed through a 2 L crude fritted glass funnel containing Na.sub.2. The residue was purified by EtOAc (EtOAc:EtOAc) elute Yield: 149 g, 61.8%. Step 8: Preparation of 4-(bromomethyl)-5-isobutyl-^-dioxol-2-one (B8): Β7(1·03 mol) in DCM (1845 mL) The solution was cooled to 0 C and treated with dibromotriphenylphosphane (463.5 g, EtOAc). The mixture was warmed to about 25 ° C, stirred for 18 hours and concentrated. The residue was treated with heptane (3600 mL) and filtered, and then evaporated. The combined filtrate was concentrated and the resulting glabrid oil was dissolved in 25% ethyl acetate in heptane (1800 mL). The mixture was then filtered through a bed of silica gel (360.0 g), and the cerium oxide was washed with 25% ethyl acetate in hexane (18 〇〇 126 137. doc - 38 - 200829242 mL). The combined filtrate was then concentrated to give B8 as a brown viscous oil. Yield: 194 g, 75%. The residual diphenylphosphine oxide was re-extracted and the organic layer was concentrated to give an additional 22 g of 9. Yield (all): 216 g (84%). Step 9 - A mixture of B8 (216 g, 0.92 mol) in acetone (324 mL) was added to B9 (sulphuric acid) (324 g, 〇·93 mol) (prepared according to Example 11 in U.S. Patent No. 5,013,729 ) in a slurry of acetone (2592 mL). The mixture was then treated with diisopropylethylamine (125.3 g, 0.97 mol) in hexanes (324 mL) and stirred at 25t: The mixture was then treated with water (1123 mL) and heptane (1123 mL). The aqueous phase was then distilled under reduced pressure to remove acetone and then extracted with ethyl acetate (3.times.23 mL). The combined ethyl acetate extracts were washed with aqueous sodium thiosulfate (丨 447 mL, 0.31 molar), water (1447 mL) and brine (1447 mL). The organic phase was then treated with activated carbon (65 g) and diatomaceous earth (65 g). The filter and cake were washed with ethyl acetate (2 x 648 mL) and the combined filtrate was concentrated. The residue was treated with ethyl acetate (243 mL) and the resulting suspension was heated to about 70 °C. The resulting solution was then treated with tert-butyl methyl ether (486 mL) and allowed to cool until it was taken. The resulting suspension was granulated at a temperature of _5 to 15 C for a minimum of 1 hour. The solid was collected, washed with EtOAc (EtOAc) (EtOAc) Yield: 320 g (69 ° / 〇). NMR (400 MHz, CDC13) δ 5.69 (d, J = ι·4 Hz, 1 H), 4·99 (d, J = 13.9 Hz, 1 H), 4.91 (d, J = 13.9 Hz, 1 H ),4.4- 126137.doc -39- 200829242 4_1 (m,1 H),3.9-3.85 (m,1 H),3.8-3.65 9 J,m,2 H),3.15-3.1 (m,1 H) , 2.9-2.6 (m, 4 H), 2_37 (d, J = 7 〇 〇... , · υΗζ, 2 Η), 1.97- 1.90 (m, 1 H), 1.31 (d, J - 6.3 Hz, 3 H ) 〇95 〇 / ', m-0.93 (m, 6 H) ppm 〇13C NMR (100 MHz, CDC13) δ 21.36 21 Q4 , 丄·y4, 21.99, 26.42, 32.34, 33.29, 46.73, 52.58, 54.04, 61 〇i «〇Ul,65.G2,65.02, 65.28,71.69,117.15,133.90,143.16,152 24 158.89,172.07 ppm 0 '

Example 2 (5R,6S)-6-[(lR)-1-hydroxyethyl]-7-sideoxy·3·Mountain ir 3s)_tetrahydro-1-oxo bridge-3-thienyl]thio ]-4-thia-1-azabicyclo[3 2 〇]heptane 2 dilute-2-carboxylic acid (5-ethyl-2-oxo-U-dioxacyclohexane) Preparation of ester (1): Compound 1 was prepared in a gas atmosphere similar to that described above for the preparation of 3, except that 4-(bromomethyl)·5-ethylpyrazine-1,3_dioxy Heterocyclopenten-2-one replaces 4-(molyl)-5-isobutyl^dioxolane-2-ene. Example 3 (SIMSW-KIR)]-Phenylethyl]_7_sideoxy_3_[[(ir,3s)•tetrahydro-oxa bridge-3-thienyl]thio]_4-thia-1 -Azabicyclo[32〇]hept-2-ene-2-carboxylic acid (5-propyl-2-oxo-1,3-dioxolyl) decyl ester (2) Preparation: Compound 2 was prepared in a manner similar to the manner of Preparation 3 above, except that 4-(bromoindolyl)-5-propyl-indole, 3-di-dioxol-2-yl was substituted 4-( 5-曱-isobutyl q,3_m-dioxole _ 2 - Stuffed | 〇126137.doc -40- 200829242 The hemihydrate form of Compound 2 can be prepared as follows... 2(13 • 8 mg) was dissolved in 1-propanol (300 pL) and 1-propanol was slowly evaporated to give a clear colorless crystalline hemihydrate. Comparative Example 4 (5R,6S)_6-[(1R)-1-hydroxyethyl]·7_ sideoxy_3_[[(1R 3S)_ra hydride-1-oxo bridge-3-thienyl]thio] 4-thiazolyl;[_azabicyclo[32〇]hept-2-ene-2-carboxylic acid (5-methyl_2_sideoxy", m-dioxole-4) Preparation of methyl ester (C1):

The ruthenium C1 was prepared according to the method described in U.S. Patent No. 5,031,729. 2;, the biological, melting point and solubility data of L 圪南药1 to 3 are shown in Table 1. The data of the sputum a substance C1 (the methyl analog of the thiopenem prodrug of the present invention) is also shown in Table 2. in. 126137.doc -41 200829242 Table 2: Biological data of thiopenem prodrugs Cpd. HIJ CLint (mL/min) 0.13 HIJ Km _ S9 conversion (%) S9 half-life (min) Whole blood conversion efficiency (%) Caco -2 Permeability (cm/sec) clogP 氺 Melting point (°C) Solubility (pg/m L) Cl 172 90.3 2.10 77 5.00 xlO*7 -1.98 159- 160 453 1 0.14 120 95 3.11 75 2.00x1 Ο·6 - 1.45 136 1200 2 0.16 22 83 3.62 67 4.1 xlO'6 -0.92 119- 122** 507 3 0.16 41 67 6.09 84 5.02 xlO-6 -0.52 130- 132 809 * Use Biolog Corporation's ClogP v4.3 (available at www_biobyte .com obtained) calculations. ** The hemihydrate form of Compound 2 is used, and it exhibits a broad low temperature endothermic property caused by dehydration in the range of 25 °C to 65 °C. The second endothermic data (reported in Table 2) is the melting data for the dehydrated hemihydrate. The water solubility of the thiopenem prodrug of the present invention is measured in a phosphate buffer (pH 5) which mimics physiological conditions. The results in Table 2 show that the thiopenem prodrug of the present invention is readily soluble in phosphate buffer at ambient temperature compared to the comparative compound C1. This result is surprising because the replacement of the methyl group in C1 with ethyl (compound 1), propyl (compound 2) or isobutyl (compound 3) is expected to reduce water solubility. (See, for example, C. Goosen et al., corpse 19 (2002) 13_19; and D_Y. Hung et al., J. 153 (1997) 25-39.). The results (Table 2) also show that the thiopenem prodrug of the present invention has a higher Caco-2 permeability than the comparative compound C1. The permeability of Compound 1 was increased by about 4 times compared with C1, the permeability of Compound 2 was increased by about 8 times, and the permeability of Compound 3 was increased by about 10 times. The Caco-2 permeability increases with the increase in the length of the base chain of the alkane 126137.doc -42- 200829242 due to the increased lipophilicity which is not what we expected. However, for compounds with molecular weights in this range, the increase in Caco-2 permeability of compounds 1 to 3 (relative to C1) is surprising (G. Camenisch et al., J. P/zarm. 5^/. 6 (1998) 3 13-319) 〇

126137.doc -43-

Claims (1)

200829242 X. Patent application scope: 1. A compound of formula (I)·· OH Wherein R1 is a -(CVC8) graft, or a solvate or hydrate thereof. 2. A compound according to claim 1, wherein R1 is -CH2CH3, or a solvate or hydrate thereof. 3. If you are looking for something! A compound wherein Ri is _Ch2Ch2CH3, or a solvent b or hydrate thereof. 4. A compound according to item i, wherein Ri is _Ch2Ch(CH3)2, or a C-soluble composition or hydrate thereof. A composition comprising the compound of any one of claims 1 to 4 and one or more other ingredients. 6. The composition of claim 5, wherein the one or more additional ingredients are active agents. 7. The composition of claim 5, wherein the compound of claim 1 or a solvate or hydrate thereof is present in an amount of from about 200 mg to about 4000 mg. 8. The composition of claim 5, wherein R1 is _CH2CH(CH3)2. 126137.doc 200829242 9. 10 11. 12. 13. 14. 15. The use of a compound of any one of items 1 to 4, or a solvate or hydrate thereof, is used in the preparation of A drug used to treat bacterial infections. For example, the purpose of &quot;monthly item 9, where R1 is -CH2CH3. The use of claim 9, wherein Ri is _CH2CH2cH3. The use of claim 9, wherein Ri is -CH2cH(CH3)2. A compound (5R,6S)-6-[(lR)-l-hydroxyethyl]_7_sideoxy-3-[[(1R,3S)·tetrahydrogen bridge_3_thienyl]thio] _ heart thiazepine heteroquinone [3 ·2·〇]hept-2-ene-2-carboxylic acid (5-ethyl-2-oxo-i,3-dioxole-4- Base) methyl ester. A compound (5R,6S)-6-[(lR)-l-hydroxyethyl]oxyl_3_[[(1R,3S)-tetradec-1-oxo-3-phenylphenyl]thio Thio_ι_azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (5-propyl-2-oxo-i,3-dioxax-pentan-4-yl) ) A 3 purpose. A compound (5R,6S)-6-[(lR)-l-hydroxyethyl]_7_sideoxy_3_[[(1R,3S)·tetrahydro- 1 -oxy bridge_3_nonyl] Thio]-4-thia-1-azabicyclo[3.2.0]hept-2-dialdehyde-2-carboxylic acid (5-(3.methylpropyl)_2-sideoxy_ι,3-inter Dioxol-4-yl)methyl ester. 126137.doc 200829242 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 126137.doc