OA10632A - Esters of carbapenems - Google Patents
Esters of carbapenems Download PDFInfo
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- OA10632A OA10632A OA70122A OA70122A OA10632A OA 10632 A OA10632 A OA 10632A OA 70122 A OA70122 A OA 70122A OA 70122 A OA70122 A OA 70122A OA 10632 A OA10632 A OA 10632A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/14—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D477/08—Modification of a carboxyl group directly attached in position 2, e.g. esterification
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
A compound of formula (I), wherein R is selected from the group consisting of isobutyryloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, and benzoyloxymethyl, is useful in the treatment of bacterial infections.
Description
ESTERS OF CARBAPENEMS 010632
This invention relates to novel antibacterial compounds, processes for theirpréparation, pharmaceutical and veterinary compositions comprising them, and theiruse in antibacterial therapy.
Carbapenems such as imipenem, the corapound of formula (A): HO H h
COjH
(A) hâve a potent, broad spectrum of antibacterial activity (see US 3 950 357 andUS 4 194 047; Merck and Co). Such carbapenems however tend to be vulnérable tohydrolysis by the enzyme rénal dehydropeptidase-1 (DHP-1) and this limits their usein chemotherapy. In the case of imipenem, this problem may be overcome by the co-administration of an inhibitor of DHP-1.
Stability towards DHP-1 may also be imparted by Chemical modification ofthe carbapenem nucléus, for instance by incorporating a Ιβ-methyl substituant, as inthe compound meropenem, the compound of formula (B): HO h h
CQ>H (B) (see Shih D.H. et al., Heterocycles, 1984,21,29 and Sunagawa M. et al., J. Antibiotics, 1990,43,519). More recently, this has been extended to a 1β-aminoalkyl substituent (see EP 0 433 759, Bristol-Meyers Squibb).
An alternative approach to imparting improved stability to DHP-1 utilises 2-carbon'spbstituted carbapenems, for instance, 2-aryl, 2-heteroaiyl and 2-heteroaromatic carbapenems (US 4 543 257, US 4 260 627, US 4 962 101, US 4 978 659, EP 0 14 493, EP 0 414 489, EP 0 010 316 and EP 0 030 032 Merck &Co) and 2-(substituted)methyl carbapenems (Schmidt et al, J.Antibiotics, 41,1988,780). UK Patent 1 593 524, Merck & Co. discloses a number of 5-membered heteroaromatic carbapenem dérivatives including diazolyl and tetrazolyl compounds.
However, in the case of the pyrazolyl dérivatives the heterocyclic compound is attached to the carbapenem nucléus through the C-4 position. 2 010632
Other structural modifications introduced ai position-2 include a substitutedvinyl group -C(Ra)=CHRfc in which, for instance, Ra is hydrogen or methyl and ishydrogen or lower alkyl (EP 0 330 108; Fujisawa) or Ra and R& are selected fromhydrogen, lower alkyl, aminocarbonyl, lower alkoxy, cyano, nitro and loweralkoxycarbonyl (EP 0 430 037, Banyu Pharmaceutical Co.). In the absence of a 1β-methyl substituent, such a modification does not however appear to impart DHP-1stability.
International Patent Application No. PCT/GB94/02347 describes compoundsof the general formula (C):
co2r (C) in which R is:
wherein
Ra is hydrogen, optionally substituted (Cj_g)alkyl or optionally substituted aryl; RP is hydrogen, optionally substituted (C j.glalkyl or optionally substituted aryl; orRa and RP together form an optionally substituted 5 or 6 membered heterocyclic rin, 'g with or without additional heteroatoms;
Rc is (C i_6)alkyl which is unsubstituted or substituted by fluoro, a hydroxy groupwhich is optionally protected by a readily removable hydroxy protecting group, or byan amino group which is optionally protected by a readily removable aminoprotecting group;
Rd is hydrogen or methyl; and -CO2Re is carboxy or a carboxylate anion or the group Re is a readily removable carboxy protecting group. 3 010632
According to the présent invention, there is provided the compound ofi G): formula G):
OH
COjR G) wherein R is selected from the group consisting of isobutyryloxymethyl, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl, and benzoyloxymethyl.
Particular compounds in accordance with the présent invention are:isobutyryloxymethyl (5R, 6S)-2-[ 1 -ethyl-5-methylpyrazol-3-yl]-6-[( IR)-1 - hydroxyethyl]-carbapen-2-em-3-carboxylate, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl (5R, 6S)-2-[l-ethyî-5-methylpyrazol-3-yl]-6-[(lR)-l-hydroxyethyl]-carbapen-2~em-3-carboxylate, and benzoyloxymethyl (5R, 6S)-2-[l-ethyl-5-methylpyrazol-3-yl]-6-[(lR)-l-hydroxyethyl]-carbapen-2-em-3-carboxylate.
Since each carbapenem compound of the présent invention is intended for usein pharmaceutical compositions, it will be understood that it is provided insubstantially pure form, for example at least 50% pure, more suitably at least 75%pure and preferably at least 95% pure (% are on a wt/wt basis). Impure préparationsof the compound may be used for preparing the more pure forms used in thepharmaceutical compositions. Preferably, whenever possible, each compound of theprésent invention is obtained in crystalline form
When each compound of this invention is allowed to crystallise or isrecrystallised from organic solvents, solvent of crystallisation may be présent in thecrystalline product. This invention includes within its scope such solvatés. Similarly,the compounds of this invention may be crystallised or recrystallised from solventscontaining water. In such cases water of hydration may be présent in the crystallineproduct. This invention includes within its scope stoichiometric hydrates.
The carbapenem antibiotic compounds according to the invention may beformulated for administration in any convenient way for use in human or veterinarymedicine, according to techniques and procedures perse known in the art withréférencé to other antibiotics, and the invention therefore includes within its scope apharmaceutical composition comprising an antibiotic compound according to theprésent invention together with a pharmaceutically acceptable carrier or excipient. 4 010632
The compositions may be formulated for administration by any suitable route, such asoral, parentéral or topical application, although the oral route is particularly preferred.The compositions may be in the form of tablets, capsules, powders, granules,lozenges, creams or liquid préparations, such as oral or stérile parentéral solutions orsuspensions. Tablets and capsules for oral administration may be in unit doseprésentation form and may contain conventional excipients such as binding agents,for example, syrup acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone;fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol orglycine; tabletting lubricants, for example magnésium stéarate, talc, polyethyleneglycol or silica; disintegrants, for example potato starch; or acceptable wetting agentssuch as sodium lauryl sulphate. The tablets may be coated according to methods wellknown in normal pharmaceutical practice. Oral liquid préparations may be in theform of, for example, aqueous or oily suspensions, solutions, émulsions, syrups orélixirs, or may be presented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid préparations may contain conventionaladditives such as suspending agents, for example sorbitol, methyl cellulose, glucosesyrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stéarategel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitanmonooleate, or acacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters, glycérine, propylene glycol, orethyl alcohol;preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, ifdesired conventional flavouring or colouring agents. Suppositories will containconventional suppository base, eg cocoa-butter or other glyceride. .
For parentéral administration, fluid unit dosage forms are prepared utilisingthe compound and a stérile vehicle, water being preferred. The compound, dependingon the vehicle and concentration used, can be either suspended or dissolved in thevehicle. In preparing solutions the compound can be dissolved in water for injectionand filter sterilised before filling into a suitable vial or ampoule and sealing.Advantageously, agents such as local anaesthetic, preservative and buffering agentscan be 'dissolved in the vehicle. To enhance the stability, the composition can befrozen after filling into the vial and the water removed under vacuum. The drylyophilised powder is then sealed in the vial and an accompanying vial of water forinjection may be supplied to reconstitute the liquid prior to use. Parentéralsuspensions are prepared in substantially the same manner except that the compoundis suspended in the vehicle instead of being dissolved and stérilisation cannot beaccomplished by filtration. The compound can be sterilised by exposure to ethyleneoxide before suspending in the stérile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniform distribution of thecompound. 5 010632
The composition may contain from 0.1% to 99.5% by weight, preferably from10-60% by weight, of the active material, depending on the method of administration.Where the compositions comprise dosage units, each unit will preferably containfrom 50-500 mg of the active ingrédient The dosage as employed for adult humantreatment will preferably range from 100 mg to 12 g per day for an average adultpatient (body weight 70 kg), for instance 1500 mg per day, depending on the routeand frequency of administration. Such dosages correspond to approximately 1.5 to170 mg/kg per day. Suitably the dosage is from 1 to 6g per day.
The daily dosage is suitably given by administering a compound of theinvention several times in a 24-hour period. Typically, 250 mg is administered 4times a day although, in practice, the dosage and frequency of administration whichwill be most suitable for an individual patient will vary with the âge, weight andresponse of the patients, and there will be occasions when the physician will choose ahigher or lower dosage and a different frequency of administration. Such dosageregimens are within the scope of this invention.
No toxicological effects are indicated when any compound of the invention isadministered in the above mentioned dosage range.
The présent invention also includes a method of treating bacterial infections inhumans and animais which method comprises administering a therapeuticallyeffective amount of an antibiotic compound of the présent invention of the formula (I).
In a further aspect, the présent invention also provides for the use of acompound of formula (I) for the manufacture of a médicament for treating bacterialinfection.
The compounds of the présent invention of formula (I) are active against abroad range of Gram-positive and Gram-negative bacteria, and may be used to treat awide range of bacterial infections including those in immunocompromised patients.
Amongst many other uses, the compounds of the invention are of value in thetreatment of skin, soft tissue, respiratory tract and urinary tract infections in humansand may-also be used to treat mastitis in cattle. A particular advantage of the antibacterially active compounds of thisinvention is their stability to β-lactamase enzymes and they are therefore effectiveagainst β-lactamase producing organisms.
The présent invention further provides a process for the préparation of acompound of formula (I) wherein R is isobutyryloxymethyl or benzoyloxymethyl,which process comprises treating a corresponding compound of formula (I), whereinR is an alkali métal cation, with a compound of formula XCH2OCOCHMe2 orXCH2OCOC6H5, wherein X is a leaving group such as halogen, more particularlybromine or iodine. 010632
The reaction is typically carried out at between 0 and 60 C, for example atambient température, under an inert, for example argon, atmosphère, in a suitableorganic solvent, for example, N-methylpyrrolidin-2-one. Other suitable solventSystems include N, N'-dimethylformamide and N, N’-dimethylacetamide.
The présent invention further provides a process for the préparation of acompound of formula (I) wherein R is (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl,which process comprises treating a corresponding compound of formula C0, whereinR is an alkali métal cation, with a compound of formula:
wherein X is a leaving group such as halogen, more particularly bromine or iodine:
The reaction is typically carried out at between 0 and 60 C, for example atambient température, in a suitable organic solvent, for example, N-methylpyrroIidin-2-one, and in the presence of an acid-binding agent, such as 2,6-lutidine. Othersuitable acid-binding agents include pyridine and diisopropylethylamine. Othersuitable solvents include N, N'-dimethylformamide and N, N’-dimethylacetamide.
Compounds of formula (I) wherein R is an alkali métal cation,, such assodium, are described in International Patent Application No. PCT/GB94/02347, andhereinbélow in Préparation 1.
The compound of formula ICH2OCOCHMe2 (iodomethyl isobutyrate) andiodomethyl benzoate can be prepared from the corresponding chlorides via theFinkelstein réaction, which is well known to those skilled in the art.
Chloromethyl isobutyrate and chloromethyl benzoate can be prepared byesterifying isobutyric acid or benzoic acid respectively with chloromethylchlorosulphate (Binderup et al., Synthetic Commun., 14(9), 857-864 (1984)).
The foflowing Examples illustrate the présent invention further:
General Instructions -Solutions were dried using anhydrous magnésium sulphate and solvents were removed by évaporation under reduced pressure using a rotary evaporator. Column chromatography on silica gel used Merck silica gel 60, particle size <0.063mm. 010632
Example 1
Isobutyryloxymethyl-(5/?, 6S)-2-(l-ethyl-5-methylpyrazol-3-yl)-6-[(lR)-l- 5 hydroxyethyl]carbapen-2-em-3-carboxylate
The product from Préparation 1 (200 rag, 0.61 mmol) was dissolved in N-methylpyrrolidin-2-one (2 ml). A solution of isobutyryloxymethyl iodide (360 mg, 1.6mmol) in N-methylpyrrolidin-2-one (0.5 ml) was added to this solution at room 10 température under argon and after 0.5 h the reaction mixture was diluted with ethylacetate (15 ml) and the solution was washed with water (3 x 15 ml), 5% sodiumthiosulfate solution (15 ml) and then saturated brine (15 ml). The organic extract wasdried (Na2SÛ4) and concentrated to an oil which was purified by chromatography onsilica gel eluting with an acetone/toluene gradient mixture to yield a pale yellow solid 15 which was recrystallised from diethyl ether to afford the title compound as paleyellow microneedles (100 mg, 40%), m.p. 107-8°C; (Found: M+, 405.1899.C20H27N3°6 requires M 405.1900); vmax(CHCl3) 3458,3019,1772 and 1734 cm" 1; 5H(CDC13) 1.19 (6H, d, /7.1 Hz), 1.36 (3H, d, /6.1 Hz), 1.40 (3H, t, /7.2 Hz), 1.76 (1H, d, /4.9 Hz), 2.29 (3H, s), 2.62 (1H, septet, /7.1 Hz), 3.18 (1H, dd, /2.7,6.5 20 Hz), 3.30 (1H, dd, /9.0,18.8 Hz), 3.64 (1H, dd, /9.8,18.8 Hz), 4.08 (2H, q, /7.2 Hz),4.16-4.30 (2H, m), 5.92 (1H, d, /5.6 Hz), 5.98 (1H, d, /5.6 Hz) and 7.02 (1H, s).
Example 2 25 (5-Methyl-2-oxo-l,3-dioxolen-4-yl)methyl (5K,6S)-6-[(7?)-l-hydroxyethyl]-2-(l-ethyl-5-methyl-pyrazol-3-yl)carbapen-2-em-3-carboxyIate
Sodium (5Æ,6S)-6-((Æ)-l-hydroxyethyl]-2-(l-ethyl-5-methylpyrazoi-3-yl)carbapen-2-em-3-carboxylate (300 mg) in 7V-methylpyrrolidinone (4 ml) was treated with 2,6-lutidine (ca. 30 mg) followed by 4-bromomethyl-5-methyl-l,3-dioxol-2-one (290 30 mg) [F.*Sakamoto, S. Ikeda and G. Tsukamoto, Chem. Pharm Bull. 32, (6), 2241 -2248 (1984)] in tetrahydrofuran (1 ml). The mixture was stirred for 1.25 h. Ethylacetate and water were added and the layers separated. The aqueous layer was re-extracted with ethyl acetate and the combined ethyl acetate layers were washed withwater, followed by saturated brine solution, and then dried (MgSÛ4). The filtered 35 solution was stored in a refrigerator ovemight and then evaporated and chromatographed on silica gel (230 - 400 mesh ASTM) (2.5 x 12 cm column), loading in CH2CI2 / hexane, and eluting with ethyl acetate. Fractions containing the product were combined and evaporated to give a colourless solid which was recrystallised from acetone to give crystals of (5-methyl-2-oxo-l,3-dioxolen-4- 8 010632 yl )methyl (5Æ,6S)-6-[(/?)-1 -hydroxyethyl]-2-( 1 -ethyl-5-methylpyrazol-3-yl)carbapen- 2-em-3-carboxylate, m. p. 148 - 151°C; Oraax(CH2Cl2) 3605,2975,1823, 1776,
1737 (sh), 1721,1598,1546,1314,1231, and 1182 cm-*; Xmax(EtOH/nm 325 (ε/dm^mol-W1 14,654), 260.5 (e/dnAnoHcnH 3404); 5(CDC13) 1.36 (3H, d, J 6.2 Hz), 1.40 (3H. t, J ca. 7.3 Hz), 1.76 (lH,d, /4.9 Hz), 2.21 (3H, s), 2.30 (3H, s), 3.19 (1H, dd, / 2.7 & 6.5 Hz), 3.31 (1H, dd, / 9.0 & 18.7 Hz). 3.61 (1H, dd, J 9.9 & 18.7 Hz), 4.08 (2H, q, /7.3 Hz), 4.16 - 4.30 (2H, m), 5.00 & 5.07 (2H, ABq, J 13.9Hz), 6.88 (1H, s) ppm; Found (El ms) m/z 417 (Λ/+).
Example 3
Benzoyloxymethyl (5Æ,6S)-2-(l-ethyl-5-methylpyrazol-3-yl)-6-[(LR)-l-hydroxyethyI]carbapen-2-em-3-carboxylate
The product from Préparation 1 (200 mg, 0.61 mmol) was dissolved in N-methylpyrrolidin-2-one (2 ml). A solution of benzoyloxymethyl iodide (336 mg, 1.28mmol) in N-methylpyrrolidin-2-one (0.5 ml) was added to this solution at roomtempérature under argon and after 0.5 h the reaction mixture was diluted with ethylacetate (15 ml) and the solution was washed with water (3 x 15 ml), 5% sodiumthiosulfate solution (15 ml) and then saturated brine (15 ml). The organic extract wasdried (Na2SO4) and concentrated to an oil which was purified by chromatography onsilica gel eluting with an acetone/toluene gradient mixture to yield a pale yellow solidwhich was recrystallised from acetone/diethyl ether to afford the title compound as awhite solid (143 mg, 53%), m.p. 131-4°C; (Found: M+, 439.1743. €22^5^05requîtes M 439.1743); umax(CHCl3) 3021,1740,1602,1452 and 1440 cm“l ; δh(CDC13) 1.34 (6H, m), 1.70 (1H, d, /4.9 Hz), 2.25 (3H,s), 3.19 (1H, dd, /2.4, 6.3Hz), 3.30 (1H, dd, /8:8,18.8 Hz), 3.64 (1H, dd, /10.1,18.8 Hz), 4.07 (2H, q, /7.2Hz), 4.18-4.31 (2H, m), 6.20 (2H, s), 7.42-7.48 (2H, m), 7.56-7.61 (1H, m), and 8.10(2H, d,/7.1 Hz) ppm.
Préparation 1
Sodium (5Æ,6S)-6-[CR)-l-hydroxyethyl]-2-(l-ethyl-5-methylpyrazoI-3- yl)carbapen-2-em-3-carboxylate (a) Ethyl l-ethyl-5-methylpyrazole-3-carboxylate jV-Ethylhydrazine oxalate (12 g) in glacial acetic acid (100 ml) was cooled in an ice- bath and treated with ethyl 2,4-dioxovalerate (11.24 ml). After addition was complété 9 010632 the mixture was stirred at room température; after ca. 45 min the mixture waswarmed to dissolve insoluble ethylhydrazine oxalate. The mixture was stirred for afurther 2 h and then poured into water( ca. 300 ml) / ethyl acetate (ca. 700 ml) andsolid K2CO3 was carefully added, with stirring, untiLthe pH was neutral. Afterséparation the aqueous layer was re-extracted with ethyl acetate. The combined ethylacetate extracts were dried (MgSC>4), 311(1 ^e solvents removed to leave an oil.Chromatography on silica gel, loading in CH2Cl2/hexane and eluting with a gradientelution of ethyl acetate/hexane mixtures (from 2:8 to 1:1) gave ethyl l-ethyl-5-methylpyrazole-3-carboxylate as an oil (13.2 g); Umax (CH2CI2) 1717,1446,1389,and 1219 cm-1; 5(CDCl3) 1.38 (3H, t, 77.2 Hz), 1.42 (3H, t, 77.3 Hz), 2.30 (3H, s),4.17 (2H, q, 77.3 Hz), 4.38 (2H, q, 77.1 Hz), 6.55 (1H, s); (Found m/z 182.1055.C9H14N2O2 requires m/z 182.1055). (b) l-Ethyl-5«methyIpyrazole-3-carboxylic acid
Ethyl l-ethyl-5-methylpyrazole-3-carboxylate (10.93 g) in éthanol (70 ml) wastreated with KOH (3.69 g), followed by water (30 ml), and the mixture was stirredand heated under reflux for 6 h. The éthanol was removed using a rotary evaporatorand ethyl acetate/water were added. The pH of the mixture was adjusted to 3.0 andthe layers were separated. The aqueous layer was re-extracted with ethyl acetate.
The combined ethyl acetate layers were extracted with excess aqueous NaHCO3· TheNaHCÛ3 extract was poured into excess acid, and the pH was then adjusted to 3, andNaCl was added to the solution. The mixture was then repeatedly extracted withethyl acetate, and the combined extracts were dried (MgSO4) and evaporated. Theresidue was triturated'with diethyl ether to give the acid as a solid (5.65 g); Dmax(CH2C12) 2754, 2598,1698,1498,1464,1387. and 1233 cm'1; Ô(CDC13) 1.40(3H, t,77.3 Hz), 2.32 (3H,s),4.19 (2H, q,77.3 Hz), 6.61 (lH,s) ppm; (Found m/z154.0740. C7H10N2O2 requires m/z 154.0742). (c)/V-Methoxy-2V-methyl-l-ethyl-5-methylpyrazole-3-carboxamide l-Ethyl-5-methylpyrazole-3-carboxylic acid (5.25 g) in dry dichloromethane (100 ml)containing tyJV-dimethylformamide (0.26 ml) was cooled in an ice-bath and treatedwith a solution of oxalyl chloride (3.27 ml) in dichloromethane (25 ml), addeddropwise. The mixture was stirred in the cold for 25 min, and then allowed to warmto room température, when évolution of a gas was observed. After 10 min the solventwas removed by évaporation in vacuo and toluene was added and removed (x 2) to l0 01 0632 ensure any residual HCl and oxalyl chloride had been removed. The résultant acidchloride was redissolved in dry dichloromethane and then treated with N,O-dimethylhydroxylamine hydrochloride (3.61 g). The mixture was cooled in an ice-bath and treated with pyridine (6.0 ml), the mixture was then allowed to stir at rooratempérature for 1.5 h and then diluted with ether (100 ml) and washed with brine.
The organic layer was then dried (MgSO4) and evaporated to leave an oil. This wasthe chromatographed on silica gel, loading in dichloromethane, and eluting with ethylacetate / hexane mixtures to give, after évaporation of requisite fractions, thehydroxamate (5.2 g) as a solid; t)raax(CH2cl2) 2982,2937,1641, 1489,1445,1379,and 975 cm’1; 5(CDCl3) 1.43(3H, t, JT.3 Hz), 2.29 (3H, s), 3.42 (3H, s), 3.76 (3H, s, ), 4.13 (2H, q, 77.3 Hz), 6.49 (1H, s); (Found m/z 197,1164. C9H15N3O2 requires m/z 197.1164). (d) 3-Acetyl-l-ethyl-5-methylpyrazole JV-Methoxy-N-methyl-l-ethyl-5-methylpyrazole-3-carboxamide (3.12 g) in dxytetrahydrofuran (60 ml) was cooled in an ice-bath and treated with a 3.0M solution ofméthylmagnésium bromide in ether (11.08 ml). After stirring for 1.5 h the mixturewas poured into a mixture of methanol (100 ml) and 5M aqueous HCl (10 ml) in anice-bath. The mixture was then evaporated to lower volume and treated with amixture of dichloromethane, water and saturated brine. After séparation the aqueouslayer was re-extracted with dichloromethane. The combined dichloromethaneextracts were dried (MgSÛ4) and evaporated to leave an oil (2.26 g), which solidifiedon standing; Omax (CH2CI2) 1680,1446,1425,1380,1324,1208, and 945 cm-1; δ(CDC13) 1.44 (3H, t, 77.3 Hz), 2.30 (3H, s), 2.53 (3H, s), 4.13 (2H, q, 77.3 Hz,),6.51 (1H,s); (Found: m/z 152.0949. CgH^O requires m/z 152.090). (e) (3S,4R)-4-l(1-ethyl-5-methylpyrazol-3-yl)carbonylmethyl]-3-[(/?)-l-/ezi-butyIdimethyïsiIyloxyethyl]azetidin-2-one 3-Acetyl-l-ethyl-5-methylpyrazole (3.51 g) in dry tetrahydrofuran (THF) (150ml) under an argon atmosphère was cooled in an acetone / solid carbon dioxide bathand then treated with a IM solution of lithium bis(trimethylsilyl)amide (50 ml). Themixture was stirred for 45 minutes and then (3/?,4/?)-4-acetoxy-3-[(lÆ)-l-iert-butyldimethylsilyloxyethyl]azetidinone (6.6 g) was added as a solid under a blanket // 010632 or argon. The mixture was stirred in the cold for 3.on. saturated aqueous ammoniumchloride was then added, followed by ethyl acetate, and the mixture was allowed towarm to room température. A little water was added and the layers were separatedand the aqueous layer was re-extracted with ethyl acetate. The combined ethylacetate extracts were washed with saturated brine, dried and evaporated.Chromatography on silica gel, eluting with ethyl acetate/hexane mixtures gave thetitlecompound (3.65 g), Omax (CH2Cl2) 3411,1761,1678,1376,1151, and 838 cnr1; 5(CDC13) 0.064 (6H, s), 0.86 (9H, s), 1.20 (3H,d, 76.3 Hz), 1.44 (3H, t, 77.3Hz), 2.31 (3H, s), 2.89 (1H, dd, 7 1.8 & 4.9 Hz), 3.15 (1H, dd, 710.0 & 17.1 Hz), 3.50 (1H, dd, 73.5 & 17.0 Hz), 4.06 - 4.25 (4H, m), 6.11 (1H. s), 6.53 (1H, s). (Found m/z 379.2296. C19H33N3O3S1 requires m/z 379.2291). (f) Allyl (2Λ and 25)-2-((35,4Æ)-4-[(l-ethyl-5-methylpyrazol-3- yl)carbonylmethyl]-3-((/?)-l-iert-butyldimethylsilyloxyethyl]-2-oxoazetidinyl}-2- hydroxyacetate. (35,4/?)-4-[(l-Ethyl-5-methylpyrazol-3-yl)carbonylmethyl]-3-[(/?)-l-ferf-butyldimethylsilyloxyethyl]azetidin-2-one (3.6 g) and allyl glyoxylate hydrate (1.66g) in toluene (100 ml) were heated under reflux in a Dean and Stark apparatus underan atmosphère of argon for 3.5h. T.l.c. of the reaction mixture showed the reactionhad almost prceeded to completion, so more allyl glyoxylate hydrate (190 mg) wasadded and the mixture was heated under reflux for a further 45 min. The mixture wascooled, the toluene was removed to give crude allyl (2Λ and 25)-2-( (3S,4/?)-4-[(l -ethyl-5-methylpyrazol-3-yl)carbonylmethyl]-3-[(Æ)-l-teri- butyldimethylsilyloxyethyl]-2-oxoazetidinyl}-2-hydroxyacetate, which was used inthe next stage; umax (CH2C12) 3681,3518,1758,1676,1448,1376,1326,1209,1148,1092,954, and 836 cm" h SiCDCty inter alia 0.035 (s), 0.061 (s) (together6H,), 0.858 (s), 0.865 (s) (together 9H), 1.21 (d, 76.2 Hz), 1.24 (d, 76.2 Hz),(together 3H), 1.44 (3H, t. 77.2 Hz), 2.31 (3H, s), 2.95 - 3.00 (1H, m), 3.25 - 3.64(2H, m), 6.53 (s), 6.56 (s) ppm. (g) Allyl 2-{(3S,4Æ)-4-[(l-ethyI-5-methylpyrazol-3-yl)carbonylmethyI]-3-[(R)-l- ierf-butyldimethylsilyloxyethyl]-2-oxoazetidinyl}-2-(tri-n- butylphosphoranylidene)acetate.
Allyl (2R and 25)-2-{(35,4/?)-4-[(l-ethyl-5-methylpyrazol-3- yl)carbonylmethyl]-3-[(J?)-l-/m-butyldimethylsilyloxyethyl]-2-oxoazetidinyl}-2- l2 01 0632 hydroxyacetate (crude from the above préparation) in dry THF (125 ml) under argonwas cooled to -20°C and treated with 2,6-lutidine (1.98 ml), followed by thionylchloride (1.24 ml). The mixture was stirred at -20°C for 30 minutes, and thenallowed to warm to room température and filtercd, washing the residue with THF (20rai). The filtrate was evaporated in vacuo, toluene (70ml) was added and removed invàcuo and the residual oil was dried in vacuo. The oil was then taken up in 1,4-dioxan (40 ml) under an argon atmosphère, and treated with tri-n-butylphosphine(3.11 ml). The mixture was stirred for 1 h. 2,6-Lutidine (1.59 ml) was then addedand the mixture was stirred for a further 30 minutes. The mixture was diluted withethyl acetate , washed with water, then with brine, and dried (MgSO4). Afterremoval of the ethyl acetate the crude product was chromatographed on silica gel,eluting with ethyl acetate/hexane mixtures to give the phosphorane, which was usedin the next stage. (h) Allyl 2-{(3S,4J?)>4-[(l-ethyl-5-methylpyrazol-3-yl)carbonylmethyl]-3-[(7?)-l-hydroxyethyl]-2-oxoazetidinyl}-2-(tri-n-butylphosphoranylidene)acetate.
The phosphorane prepared above was taken up in 1,4-dioxan (60 ml) andtreated with 5M HCl (20 ml). After 1 h the mixture was carefully treated with ca. 40ml saturated aqueous NaHCCfy followed by solid NaHCÛ3 until the pH was slightlyalkaline. Saturated brine was added and the mixture was extracted twice with ethylacetate. The combined extracts were dried (MgSÛ4) and evaporated. The residuewas chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures to givethe hydroxy compound, (2.60 g), Omax (CH2CI2) 3454,1741,1667,1606, 1448,1403,1379,1155,1087,953, and 811 cm’l. (i) Allyl (5Æ,6S)-6-I(Æ)-l-hydroxyethyl]-2-(l-ethyl-5-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate
I l3 01 0632
Allyl 2- {(35,4Λ)-4-[( l-ethyl-5-methylpyrazol-3-yl)carbonylmethyl]-3-[(/?)-l-hydroxyethyl]-2-oxoazetidinyl)-2-(tri-zi-butylphosphoranylidene)acetate (2.6 g), intoluene (120 ml) containing hydroquinone (20 mg) was heated under reflux in anargon atmosphère for 4 h, allowed to stand for 64 h, and then heated under reflux fora further 2 h. The mixture was cooled and then loaded onto a column (4.5 x 12 cm)of silica gel (particle size 0.040 -0.063 mm), eluting with ethyl acetate/hexanemixtures; 1:1; 6:4; 7:3; 8:2; 9:1 (250 ml of each). followed by ethyl acetate. This gavethe carbapenem (436 mg); Omax(CH2Cl2) 3604,2976,1774,1716,1600,1546,1311,1189 cm-1; Xma/EtOH)/nm 321.5 (e/dn^mol-W1 14,856), 5(CDC13) 1.36 (d, J 6.3 Hz), 1.39 (t, J 7.3 Hz) (together 5H), 1.80 (1H, d, J 5.0 Hz), 2.28(3H,s), 3.19 (1H, dd J 1.Ί & 6.7 Hz), 3.28 (1H, dd, J 9.0 & 18.6 Hz), 3.60 (1H, dd, J9.9 & 18.5 Hz), 4.08 (2H, q, J 7.3 Hz), 4.16 - 4.30 (2H, m), 4.68 - 4.90 (2H. m), 5.27(1H, m, approx d, J ca. 12 Hz), 5.46 (m, approx d, J ca. 17 Hz), 5.93 - 6.08 (1H, m),7.00 (1H, s) ppm; [Found m/z 345.1693. C18H23N3O4 requires m/z 345.1689]. (j) Sodium (57?,6S)-6-[(/?)-l-hydroxyethyI]-2-(l-ethyl-5-methyl-pyrazoI-3-yl)carbapen-2-em-3-carboxylate
Allyl (5Æ,65)-6-[(Æ)-l-hydroxyethyl]-2-(l-ethyl-5-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate (267 mg) in dichloromethane (3ml) and ethyl acetate(3 ml) under argon was treated with sodium 2-ethylhexanoate (183 mg), followed bytriphenylphosphine (24 mg), followed by tetrakis(triphenylphosphine)palladium(0) (35 mg) and the mixture was stirred for 45 min. Diethyl ether (100ml) was thenadded, and after stirring for 90 minutes, the mixture was centrifuged. The residualsolid was dried under a stream of argon, and then in a desiccator. The solid was thentaken up in water containing sodium chloride and chromatographed on DÎAIONHP20SS resin, eluting with water, followed by water/THF mixtures; 1%, 2%, and3%,THF. Fractions were monitored by HPLC, and those containing the product werecombined, reduced in volume and freeze-dried to give sodium (5/?,65)-6-[(Λ)-1-hydroxyethyl]-2-( 1 -ethyl-5-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate as asolid (168 mg); Omax(KBr) 1761,1608,1577,1381,1225 cm-1; Xmax(H2O)/nm 298(e/dm^mol -km-1 8.531); 8(D2O) 1.26 (d, Jeu. 6 Hz), 1.27 (d, J ca. 7 Hz) (together5H), 2.23 (3H, s), 3.17 (2H, approx d, J ca. 9 Hz), 3.44 (1H, dd, J 2.9 & 6.0 Hz), 4.04 (2H, q, JT3 Hz), 4.15 - 4.25 (2H, m), 6.41 (1H, s) ppm.
Claims (8)
14 010632 r 1. A compound of formula (I):
wherein R is selected from the group consisting of isobutyryloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, and benzoyloxymethyl.
2. Isobutyryloxymethyl (5R, 6S)-2-[1-ethyl-5-methylpyrazol-3-yl]-6-[(1R)-1-hydroxy-ethyl]-carbapen-2-em-3-carboxylate.
3. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl (5R, 6S)-2-[1-ethyl-5-methylpyrazol-3-ylJ-6-[( 1 R)-1 -hydroxyethylJ-carbapen-2-em-3-caboxylate.
4. Benzoyloxymethyl (5R,6S)-2-{1 -ethyl-5-methylpyrazol-3-yl]-6-{( 1 R)-1 -hydroxyethyl]-carbapen-2-em-3-carboxylate.
5. A pharmaceutical composition comprising a compound according to any one ofthe preceding daims together with a pharmaceutically acceptable carrier orexcipient.
6. Use of a compound according to any one of daims 1 to 4 for the manufactureof a médicament for treating bacterial infection.
7. A process for the préparation of a compound of formula (I) as defined in daim 1wherein R is isobutyryloxymethyl or benzoyloxymethyl, which process comprisestreating a corresponding compound of formula (I), wherein R is an alkali métal 010632 15 cation, with a compound of formula XCH2OCOCHMe2 or XCH2OCOC5H5 wherein Xis a leaving group.
8. A process for the préparation of a compound of formula (I) as defined in claim 1wherein R is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, which process comprisestreating a corresponding compound of formula (I), wherein R is an alkali métalcation, with a compound of formula: wherein X is a leaving group.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9508957.9A GB9508957D0 (en) | 1995-05-03 | 1995-05-03 | Novel compounds |
| GBGB9508955.3A GB9508955D0 (en) | 1995-05-03 | 1995-05-03 | Novel compounds |
| GBGB9508956.1A GB9508956D0 (en) | 1995-05-03 | 1995-05-03 | Novel compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA10632A true OA10632A (en) | 2002-09-16 |
Family
ID=27267696
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| OA70122A OA10632A (en) | 1995-05-03 | 1997-11-03 | Esters of carbapenems |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0823910A1 (en) |
| JP (1) | JPH11504910A (en) |
| KR (1) | KR19990008355A (en) |
| CN (1) | CN1185783A (en) |
| AR (1) | AR005416A1 (en) |
| AU (1) | AU5813996A (en) |
| BG (1) | BG102014A (en) |
| BR (1) | BR9608313A (en) |
| CA (1) | CA2217990A1 (en) |
| CZ (1) | CZ347597A3 (en) |
| EA (1) | EA199700293A1 (en) |
| HU (1) | HUP9801066A3 (en) |
| IL (1) | IL118092A0 (en) |
| MA (1) | MA23853A1 (en) |
| MX (1) | MX9708421A (en) |
| NO (1) | NO974994D0 (en) |
| OA (1) | OA10632A (en) |
| PE (1) | PE50697A1 (en) |
| PL (1) | PL323141A1 (en) |
| SK (1) | SK146497A3 (en) |
| TR (1) | TR199701286T1 (en) |
| WO (1) | WO1996034868A1 (en) |
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| FR2902659A1 (en) | 2006-06-23 | 2007-12-28 | Pierre Fabre Medicament Sa | DHA ESTER AND ITS USE IN THE TREATMENT AND PREVENTION OF CARDIOVASCULAR DISEASES |
| WO2013157583A1 (en) * | 2012-04-18 | 2013-10-24 | 大日本住友製薬株式会社 | Novel carbapenem compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB1593524A (en) * | 1976-11-19 | 1981-07-15 | Merck & Co Inc | 1-carba-2-penem-3-carboxylic acids |
| CA1212105A (en) * | 1980-04-30 | 1986-09-30 | Shoji Ikeda | Ampicillin esters and production thereof |
| AU7467194A (en) * | 1993-08-18 | 1995-03-14 | Sankyo Company Limited | Crystalline carbapenem derivatives |
| WO1995011905A1 (en) * | 1993-10-29 | 1995-05-04 | Smithkline Beecham Plc | 2-(pyrazol-3-yl)carbapenem derivatives |
-
1996
- 1996-05-01 IL IL11809296A patent/IL118092A0/en unknown
- 1996-05-02 WO PCT/EP1996/001880 patent/WO1996034868A1/en not_active Application Discontinuation
- 1996-05-02 MX MX9708421A patent/MX9708421A/en unknown
- 1996-05-02 EP EP96919678A patent/EP0823910A1/en not_active Withdrawn
- 1996-05-02 AU AU58139/96A patent/AU5813996A/en not_active Abandoned
- 1996-05-02 SK SK1464-97A patent/SK146497A3/en unknown
- 1996-05-02 MA MA24218A patent/MA23853A1/en unknown
- 1996-05-02 KR KR1019970707881A patent/KR19990008355A/en not_active Application Discontinuation
- 1996-05-02 CN CN96194191A patent/CN1185783A/en active Pending
- 1996-05-02 PL PL96323141A patent/PL323141A1/en unknown
- 1996-05-02 TR TR97/01286T patent/TR199701286T1/en unknown
- 1996-05-02 HU HU9801066A patent/HUP9801066A3/en unknown
- 1996-05-02 CZ CZ973475A patent/CZ347597A3/en unknown
- 1996-05-02 EA EA199700293A patent/EA199700293A1/en unknown
- 1996-05-02 BR BR9608313A patent/BR9608313A/en not_active Application Discontinuation
- 1996-05-02 JP JP8533020A patent/JPH11504910A/en active Pending
- 1996-05-02 CA CA002217990A patent/CA2217990A1/en not_active Abandoned
- 1996-05-03 AR ARP960102434A patent/AR005416A1/en unknown
- 1996-05-03 PE PE1996000312A patent/PE50697A1/en not_active Application Discontinuation
-
1997
- 1997-10-30 NO NO974994A patent/NO974994D0/en not_active Application Discontinuation
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- 1997-11-03 OA OA70122A patent/OA10632A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PE50697A1 (en) | 1997-12-18 |
| WO1996034868A1 (en) | 1996-11-07 |
| EA199700293A1 (en) | 1998-06-25 |
| MX9708421A (en) | 1998-02-28 |
| MA23853A1 (en) | 1996-12-31 |
| BR9608313A (en) | 1999-01-26 |
| BG102014A (en) | 1998-11-30 |
| TR199701286T1 (en) | 1998-02-21 |
| PL323141A1 (en) | 1998-03-16 |
| EP0823910A1 (en) | 1998-02-18 |
| JPH11504910A (en) | 1999-05-11 |
| KR19990008355A (en) | 1999-01-25 |
| SK146497A3 (en) | 1998-05-06 |
| NO974994L (en) | 1997-10-30 |
| CN1185783A (en) | 1998-06-24 |
| AU5813996A (en) | 1996-11-21 |
| NO974994D0 (en) | 1997-10-30 |
| IL118092A0 (en) | 1996-09-12 |
| HUP9801066A2 (en) | 1998-08-28 |
| CZ347597A3 (en) | 1998-08-12 |
| HUP9801066A3 (en) | 1999-01-28 |
| AR005416A1 (en) | 1999-06-23 |
| CA2217990A1 (en) | 1996-11-07 |
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