CA2217990A1 - Esters of carbapenems - Google Patents
Esters of carbapenems Download PDFInfo
- Publication number
- CA2217990A1 CA2217990A1 CA002217990A CA2217990A CA2217990A1 CA 2217990 A1 CA2217990 A1 CA 2217990A1 CA 002217990 A CA002217990 A CA 002217990A CA 2217990 A CA2217990 A CA 2217990A CA 2217990 A1 CA2217990 A1 CA 2217990A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- ethyl
- methyl
- formula
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
-
- 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
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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
This invention relates to novel antib~ct~ri~l eompounds, processes for their preparation, pharmaceutical and veterinary compositions comprising them, and their 5 use in antibacterial therapy.
Carbapenems such as imipenem, the compound of formula (A):
Ho H H
~-\
o~ ~S(CH2)2NHCH=NH
(A) have a potent, broad spectrum of antibacterial aetivity (see US 3 950 357 and US 4 194 047; Merck and Co). Such carbapenems however tend to be vulnerable to hydrolysis by the enzyme renal dehydropeptidase-l (DHP-l) and this limits their use in chemotherapy. In the case of imipenem, this problem may be overcome by the co-lmini.ctration of an inhibitor of DHP-l.
Stability towards DHP-l may also be imparted by chemical modif1cation of the carbapenem nucleus, for instance by incorporating a l~-methyl substitutent, as in the compound mel~,pene,l" the compound of formula (B):
HO H H CH3 ~ CON(CH3k ~S --C~NH
(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 1~-aminoalkyl substituent ~see EP 0 433 759, Bristol-Meyers Squibb).
An alternative approach to imparting improved stability to DHP-l utilises 2-carbon~substituted carbapenems, for in.ct~nce, 2-aryl, 2-heteroaryl and 2-heteroaromatic carbapenems (US 4 543 257, US 4 260 627, US 4 962 101, US4978659,EP014493, EP0414489,EP0010316andEP0030032Merck&
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 derivatives including diazolyl and tetrazolyl compounds.
However, in the case of the pyrazolyl derivatives the heterocyclic compound is attached to the carbapenem nucleus through the C-4 position.
Other structural modifications introduced at position-2 include a substituted vinyl group -C(Ra)=CHRb in which, for in.~f~nce, Ra is hydrogen or methyl and Rb is hydrogen or lower alkyl (EP 0 330 108; Fujisawa) or Ra and Rb are selected from hydrogen, lower alkyl, aminocarbonyl, lower alkoxy, cyano, nitro and lower alkoxycarbonyl (EP 0 430 037, Banyu Pharmaceutical Co.). In the absence of a l,B-methyl substituent, such a mo-lific~tion does not however appear to impart DHP-1stability.
TntP.rn~tional Patent Application No. PC r/GB94/02347 describes compounds of the general formula (C): -d H H R
c-~ ~ R
o~
(C) in which R is:
N--N
~ 'R~;
wherein Ra is hydrogen, optionally substituted (Cl 6)alkyl or optionally substituted aryl;
R~ is hydrogen, optionally substituted (Cl 6)aL~yl or optionally substituted aryl; or 20 Ra and R13 together form an optionally substituted 5 or 6 membered heterocyclic ring with or without additional heteroatoms;
Rc is (Cl 6)aLlcyl which is unsubstituted or substituted by fluoro, a hydroxy group which is optionally protected by a readily removable hydroxy protecting group, or by an amiRQ group which is optionally protected by a readily removable amino 25 protecting 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.
According to the present invention, there is provided the compound of formula (I):
OH
CH3 ~'", ~Me ~~ --~ N--NEt (I) wherein R is selected from the group consicting of isobutyryloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, and benzoyloxymethyl.
Particular compounds in accordance with the present invention are:
isobutyryloxymethyl (SR, 6S)-2-[ 1-ethyl-5-methylpyrazol-3-yl]-6-[( 1 R)- 1-10 hydroxyethyl]-carbapen-2-em-3-carboxylate, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (5R, 6S)-2-[1-ethyl-5-methylpyrazol-3-yl]-6 [(lR)-l-hyd,~,~yeLhyl]-carbapen-2-em-3-carboxylate, and benzoyloxymethyl (5R, 6S)-2-[1-ethyl-5-methylpyrazol-3-yl]-6-[(lR)-1-hydroxyethyl] -carbapen-2-em-3-carboxylate.
Since each carbapenem compound of the present invention is intended for use in ph~rm~ceutic~l compositions, it will be understood that it is provided in sllbst~nti~lly pure form, for ~Y~mple at least 50% pure, more suitably at least 75%
pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compound may be used for p~pa,ing the more pure forms used in the 20 pharmaceutical compositions. Preferably, whenever possible, each compound of the present invention is obtained in crystalline form When each compound of this invention is allowed to crystallise or is recrystallised from organic solvents, solvent of cryst~lli.c~tion may be present in the crystal~ine product. This invention includes within its scope such solvates. Similarly, 25 the compounds of this invention may be crystallised or recrystallised from solvents cont~ining water. In such cases water of hydration may be present in the crystalline product. This invention includes within its scope stoichiometric hydrates.
The carbapenem antibiotic compounds according to the invention may be formulated for ~-lmini.ctration in any convenient way for use in human or veterinary 30 medicine, according to Lechniques and procedures per se known in the art withreference to other antibiotics, and the invention therefore includes within its scope a ph~rm~ eutical composition complising an antibiotic compound according to the present invention together with a ph~rm~ceutically acceptable carrier or excipient.
The compositions may be formulated for a~lmini.etration by any suitable route, such as oral, pa elllel~l 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 preparations, such as oral or sterile parenteral solutions or 5 suspeneione Tablets and caps-lles for oral a~1minictration may be in unit dosepresrnt~tion form and may contain convention~l excipients such as binding agents, for example, syrup acacia, gelatin, sorbitol, tr~g~ nth, or polyvinylpyrollidone;
fillers, for example lactose, sugar, mai~-starch, calcium phosph~te, sorbitol orglycine; tabletting lubricants, for example m~gn~eillm stearate, talc, polyethylene 10 glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal ph~rrn~eutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other 15 suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hy~o~ye~llyl cellulose, carboxymethyl cellulose, ~ minium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for20 example almond oil, oily esters, glycerine, propylene glycol, or ethyl alcohol;
preservatives, for example methyl or propyl p-hydlu~yl,enzoate or sorbic acid; and, if desired conventional flavouring or colouring agents. Suppositories will contain conventional suppository base, eg cocoa-butter or other glyceride.
For parenteral arlminietration~ fluid unit dosage forms are prepared utili.cing 25 the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and se~1ing.
Advantageously, agents such as local an~sthf~.tic, preservative and buffering agents 30 can be~dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry Iyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound 35 is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
W 096/34868 PCT~EP9G/01880 The composition may contain from 0.1% to 99.5% by weight, preferably from 10-60% by weight, of the active m~t~ri~l, depending on the method of admini~tration.
Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human 5 treatment will preferably range from 100 mg to 12 g per day for an average adult patient (body weight 70 kg), for instance 1500 mg per day, depending on the route and frequency of atlm;ni.~tration. Such dosages correspond to approximately 1.5 to 170 mg/kg per day. Suitably the dosage is from 1 to 6g per day.
The daily dosage is suitably given by ~lmini.~tering a compound of the invention several times in a 24-hour period. Typically, 250 mg is ~-lmini.ctered 4 times a day although, in practice, the dosage and frequency of ~dmini.ctration which will be most suitable for an individual patient will vary with the age, weight and response of the p~tiP.nt.~, and there will be occasions when the physician will choose a higher or lower dosage and a different frequency of ~minist-ration. Such dosage regimens are within the scope of this invention.
No toxicological effects are inc1icated when any compound of the invention is mini.~tered in the above mentioned dosage range.
The present invention also includes a method of treating bacterial infections inhumans and ~nim~l.c which method comprises ~lminicte.ring a therapeutically effective amount of an antibiotic compound of the present invention of the formula (I).
In a further aspect, the present invention also provides for the use of a compound of formula (I) for the manufacture of a meAi~ment for treating bacterial infection.
The compounds of the present invention of formula (I) are active against a broad range of Gram-positive and Gram-negative bacteria, and may be used to treat a wide range of b~teri~l infections including those in immunocompromised patients.Amongst many other uses, the compounds of the invention are of value in the tre~tment of skin, soft tissue, respiratory tract and urinary tract infections in hllm~n.c and mày also be used to treat mastitis in cattle.
A particular advantage of the antibacterially active compounds of this invention is their stability to ,~-lact~m~ce enzymes and they are th'erefore effective against ,13-lactamase producing org~ni.~m.c The present invention further provides a process for the preparation of a compound of formula (I) wherein R is isobutyryloxymethyl or benzoyloxymethyl, which process comprises treating a corresponding compound of formula (I), wherein R is an aL~ali metal cation, with a compound of formula XCH20COCHMe2 or XCH2OCOC6Hs, wherein X is a leaving group such as halogen, more particularly bromine or iodine.
W 096/34868 PCT~P96/01880 The reaction is typically carried out at between 0 and 60 C, for example at ambient temperature, under an inert, for example argon, atmosphere, in a suitable organic solvent, for e~r~mplP, N-methylpyrrolidin-2-one. Other suitable solvent systems include N, N'-dimethylfommamide and N, N'-dimethyl~et~mi~e The present invention further provides a process for the preparation of a compound of fommula (I) wherein R is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, which process comprises treating a corresponding compound of formula (I), wherein R is an alkali metal cation, with a compound of fommula:
Me 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 at ambient temperature, in a suitable organic solvent, for e~mphP, N-methylpyrrolidin-2-one, and in the presence of an acid-binding agent, such as 2,6-lutidine. Othersuitable acid-binding agents include pyridine and diisopropylethylamine. Other suitable solvents include N, N'-dimethylfnrm~mide and N, N'-dimethyl~et~mi~P
Compounds of formula (I) wherein R is an aLkali metal cation" such as sodium~ are described in TntPm~tion~l Patent Application No. PCT/GB9~/02347, andhereinbélow in Preparation 1.
The compound of formula ICH2OCOCHMe2 (iodomethyl isobutyrate) and iodomethyl benzoate can be prepared from the corresponding chlorides via the FinkPlstein reaction, which is well known to those skilled in the art.
Chloromethyl isobutyrate and chloromethyl benzoate can be prepared by e~ iLying isobutyric acid or benzoic acid respectively with chloromethyl chlorosulphate (Binderup et al., Synthetic Comme~n., 14(9), 857-864 (1984)).
The fo~owing Examples illustrate the present invention further:
General Instructions - Solutions were dried using anhydrous m~nesillm sulphate and solvents were removed by evaporation under reduced pressure using a rotary evaporator. Column chromatography on silica gel used Merck silica gel 60, particle size <0.063mm.
CA 022l7990 l997-lO-3l W 096/34868 PCT~EP96/01880 FY~n~PIe 1 Isobutyryl~ yl-(5R, 6S~2-(1-ethyl-5-~-u:ll-yl~ ~ol-3-yl)-~t(lR)-l-S l~y~l~ oxyethyl]carbapen-2-em-3-carboxylate The product from Preparation 1 (200 mg, 0.61 mmol) was dissolved in N-methylpyrTolidin-2-one (2 ml). A solution of isobutyTyloxymethyl iodide (360 mg, 1.6 mmol) in N-methylpylTolidin-2-one (0.5 ml) was added to this solution at room 10 temperature under argon and after 0.5 h the reaction mixture was diluted with ethyl acetate (15 ml) and the solution was washed with water (3 x 15 ml), 5% sodium thios~llf~t~ solution (15 ml) and then saturated brine (15 ml). The organic extract was dried (Na2SO4) and concentrated to an oil which was purified by chromatography on silica gel eluting with an ~etonP/toluene gradient ~ Lult: to yield a pale yellow solid 15 which was recrystallised from diethyl ether to afford the title compound as pale yellow microneedles (100 mg, 40%), m.p. 107-8~C; (Found: M+, 405.1899.
C20H27N3o6 requires M 405.1900); vmax(cHcl3) 3458, 3019, 1772 and 1734 cm~
l; ~H(CDC13) 1.19 (6H, d, n.l Hz), 1.36 (3H, d, J6.1 Hz), 1.40 (3H, t, r7.2 Hz),1.76 (lH, d, J4.9 Hz), 2.29 (3H, s), 2.62 (lH, septet, J7.1 Hz), 3.18 (lH, dd, J2.7, 6.5 20 Hz), 3.30 (lH, dd, J9.0, 18.8 Hz), 3.64 (lH, dd, J9.8, 18.8 Hz), 4.08 (2H, q, J7.2 Hz), 4.16-4.30 (2H, m), 5.92 (lH, d, J5.6 Hz), 5.98 (lH, d, J5.6 Hz) and 7.02 (lH, s).
Example 2 25 (5-Methyl-2-oxo-1,3-clioxolen~-yl)methyl (5R,65)-~[(R)-l-lly~ Jx~ethyl]-2-(1- ethyl-5-methyl-pyrazol-3-yl)carbapen-2-em-3-carboxylate Sodium (5R,65)-6-[(R)- 1 -hydroxyethyl] -2-(1 -ethyl-5-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate (300 mg) in N-methylpyrrolidinone (4 ml) was treated with 2,6-luti-iine (ca. 30 mg) foIlowed by 4-bromomethyl-5-methyl-1,3-dioxol-2-one (290 30 mg) [P.~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. Ethyl acetate 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 with water, followed by saturated brine solution, and then dried (MgSO4). 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 CH2C12 / h~x~n~ and eluting with ethyl acetate. Practions cont~ining the product were combined and evaporated to give a colourless solid which was recrystallised from acetone to give crystals of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (SR,65)-6-~(R)-l-hydroxyethyl]-2-(l-ethyl-S-meLhyll,ylazol-3-yl)carbapen-2-em-3-carboxylate, m. p. 148 - 151~C; ~maX(cH2cl2) 3605, 2975, 1823, 1776, 1737 (sh), 1721, 1598, 1546, 1314, 1231, and 1182 cm~l; ~max(EtOH/nm 325 (~
/dm3mol~lcm~l 14,654), 260.5 (~/dm3mol~lcm~l 3404); ~CDC13) 1.36 (3H, d, J
6.2 Hz), 1.40 (3H, t, J ca 7.3 Hz), 1.76 (lH,d, J4.9 Hz), 2.21 (3H, s), 2.30 (3H, s), 3.19 (lH, dd, J2.7 & 65 Hz), 3.31 (lH, dd, J9.0 & 18.7 Hz), 3.61 (lH, dd, J 9.9 &
18.7 Hz), 4.08 (2H, q, J7.3 Hz), 4.16 - 4.30 (2H, m), 5.00 & 5.07 (2H, ABq, J 13.9 Hz), 6.88 (lH, s) ppm; Found (EI ms) m/z 417 (M+).
F.Y~mp~ 3 Benzoyloxyl-.elllyl (5R,6S)-2~ ethyl-5-~,~lhyl~ ~ol-3-yl)-6-[(lR)-l-hr~lroxy~lllyllcal b~e~l-2-em-3-carbox-ylate The product from Preparation 1 (200 mg, 0.61 mmol) was dissolved in N-methylpyrrolidin-2-one (2 ml). A solution of benzoyloxymethyl iodide (336 mg, 1.28 mmol) in N-methylpyrrolidin-2-one (0.5 ml) was added to this solution at room tempelature under argon and after 0.5 h the reaction mixture was diluted with ethyl acetate (15 ml) and the solution was washed with water (3 x 15 ml), 5% sodium thioslllf~tP solution (15 ml) and then saturated brine (15 ml). The organic extract was ~ 20 dried (Na2SO4) and concentrated to an oil which was purified by chromatography on silica gel eluting with an ~etonP/toluene ~ liPnt ~ Ul~ to yield a pale yellow solid which was recrystallised from acetone/diethyl e~er to afford the title compound as a white solid (143 mg, 53%), m.p. 131-4~C; (Found: M+, 439.1743. C22H2sN3O6 requires M439.1743); ~max(CHCl3) 3021, 1740, 1602, 1452 and 1440 cm~l; ~
H(CDC13) 1.34 (6H, m), 1.70 (lH, d, J4.9 Hz), 2.25 (3H,s), 3.19 (lH, dd, J2.4, 6.3 Hz), 3.30 (lH, dd, J8;8, 18.8 Hz), 3.64 (lH, dd, J10.1, 18.8 Hz), 4.07 (2H, q, J7.2 Hz), 4.18-4.31 (2H, m), 6.20 (2H, s), 7.42-7.48 (2H, m), 7.56-7.61 (lH, m), and 8.10 (2H, d, J7.1 Hz) ppm.
Prep~flon 1 Sodium (SR,65)-6-[(R)-l-hydroxyelhyl]-2-(1-ethyl-5-methyl~y~ol-~
yl)carbapen-2-em-3-carboxylate (a) Ethyl l-ethyl-5-melllyl~yl~;ole-3-carboxylate N-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 complete the mixture was stirred at room temperature; after ca. 45 min the mixture was warmed to dissolve insoluble ethylhydrazine oY~l~tP The mixture was stirred for a further 2 h and then poured into water( ca. 300 ml) / ethyl acetate (ca. 700 ml) and solid K2CO3 was carefully added, with stirring, untiLthe pH was neutral. After 5 ~paration the aqueous layer was re-extracted with ethyl ~cet~t~o The combined ethyl acetate extracts were dried (MgSO4), and the solvents removed to leave an oil.
Chromatography on silica gel, loading in CH2C12/hexane and eluting with a gradient elution of ethyl acetate/hexane mixtures (from 2:8 to 1:1) gave ethyl 1-ethyl-5-methylpyrazole-3-carboxylate as an oil (13.2 g); 1)max (CH2C12) 1717, 1446, 1389, and 1219 cm~l; ~(CDC13) 1.38 (3H, t, J7.2 Hz), 1.42 (3H, t, J7.3 Hz), 2.30 (3H, s), 4.17 (2H, q, J7.3 Hz), 4.38 (2H, q, J7.1 Hz), 6.55 (lH, s); (Found m/z 182.1055.CgH14N202 requires m/z 182.1055).
(b) l-Ethyl-5-metl-yl~yl azole-3-carboxylic acid Ethyl l-ethyl-S-methylpyrazole-3-carboxylate (10.93 g) in ethanol (70 ml) was treated with KOH (3.69 g), followed by water (30 ml), and the mixture was stirred and heated under reflux for 6 h. The ethanol was removed using a rotary evaporator and ethyl acetate/water were added. The pH of the mixture was adjusted to 3.0 and the layers were ~p~r~tl~-i The aqueous layer was re-extracted with ethyl ~cet~te20 The combin~.d ethyl acetate layers were extracted with excess aqueous NaHCO3. The NaHCO3 extract was poured into excess acid, and the pH was then adjusted to 3, and NaCl was added to the solution. The mixture was then repeatedly extracted with ethyl ~et~t~., and the combined extracts were dried (MgSO4) and evaporated. The residue was triturated~~ith diethyl ether to give the acid as a solid (5.65 g); l~max (CH2C12) 2754, 2598, 1698, 1498, 1464, 1387, and 1233 cm~l; ~(CDC13) 1.40 (3H, t, J7.3 Hz), 2.32 (3H,s), 4.19 (2H, q, J7.3 Hz), 6.61 (lH,s) ppm; (Found n2/z 154.0740. C7HloN202 requires n2/z 154.0742).
(c)N-Metho~y-N-methyl- l-ethyl-5-metl.yl~yl a~ole-3-carboY~m: lle 1-Ethyl-S-methylpyrazole-3-carboxylic acid (5.25 g) in dry dichloromethane (100 ml) cont~ining N,N-dimethylform~mi~ (0.26 ml) was cooled in an ice-bath and treated with a solution of oxalyl chloride (3.27 ml) in dichloromethane (25 ml), added dropwise. The mixture was stirred in the cold for 25 min, and then allowed to warm to room temperature, when evolution of a gas was observed. After 10 min the solvent was removed by evaporation in vacuo and toluene was added and removed (x 2) to g - ensure any residual HCl and oxalyl chloride had been removed. The reslllt~nt acid chlnritle was redissolved in dry dichlornmeth~n~- 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 room 5 temperature 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 was the chromatographed on silica gel, loading in dichloromethane, and eluting with ethyl acetate / hexane mixtures to give, after evaporation of requisite fractions, the ~=
hydroY~m~te (5.2 g) as a solid;
10 ~maX(cH2cl2) 2982, 2937, 1641, 1489, 1445, 1379,and 975 cm~l; ~(CDC13) 1.43 (3H, t, J7.3 Hz), 2.29 (3H, s), 3.42 (3H, s), 3.76 (3H, s, ), 4.13 (2H, q, J7.3 Hz), 6.49 (lH, s); (Found m/z 197.1164. CgHlsN3O2 requires m/z 197.1164).
(d) 3-Acetyl-l-ethyl-5-methylpyrazole 15 N-Methoxy-N-methyl-l-ethyl-5-methylpyrazole-3-carboxamide (3.12 g) in dry tetrahydrofuran (60 ml) was cooled in an ice-bath and treated with a 3.0M solution of methylm~gn~ci-lm bromide in ether (11.08 ml). After stirring for 1.5 h the mixture was poured into a mixture of methanol (100 ml) and SM aqueous HCl (10 ml) in an ice-bath. The mixture was then evaporated to lower volume and treated with a 20 mixture of dichloromethane, water and saturated bAne. After separation the aqueous layer was re-extracted with dichlornmeth~n,q. The combined dichloromethane extracts were dried (MgS04) and evaporated to leave an oil (2.26 g), which solidified on standing; l)max (CH2C12) 16~0, 1446, 1425, 1380, 1324, 1208, and 945 cm~l;
(CDC13) 1.44 (3H, t, J7.3 Hz), 2.30 (3H, s), 2.53 (3H, s), 4.13 (2H, q, J7.3 Hz,), 25 6.51 (lH,s); (Found: nz/z 152.0949. CgH12N2O requires m/z 152.090).
(e) (3S,4R)-4-t(l-ethyl-5-me~l-yl~yr~ol-3-yl)carbonylmethyl]-3-[(R)-l-tert-butyl~lim~thylsilyloxyethyl]azeffdin-2-one 3-Acetyl-l-ethyl-5-methylpyrazole (3.51 g) in dry tetrahydrofuran (THF) (150 ml) under an argon atmosphere was cooled in an acetone / solid carbon dioxide bath and then treated with a lM solution of lithium bis(trimethylsilyl)amide (50 ml). The mixture was stirred for 45 minutes and then (3R,4R)-4-acetoxy-3-[(lR)- l-tert-butyldimethylsilyloxyethyl]azetidinone (6.6 g) was added as a solid under a blanket OI argon. The mixture was stirred in the cold for 3.~n. ~hlr~tecl aqueous ammonium chloride was then added, followed by ethyl acetate, and the mixture was allowed to warm to room temperature. A little water was added and the layers were separatedand the aqueous layer was re-extracted with ethyl acetate. The combined ethyl 5 acetate extracts were washed with ~tnr~ted brine, dried and evaporated.
Chromatography on silica gel, eluting with ethyl acetate/hexane mixtures gave the title compound (3.65 g), ~max (CH2C12) 3411, 1761, 1678, 1376, 1151, and 838 cm~l; o~CDC13) 0.064 (6H, s), 0.86 (9H, s), 1.20 (3H,d, J 6.3 Hz), 1.44 (3H, t, J 7.3 Hz), 2.31 (3H, s), 2.89 (lH, dd, J 1.8 & 4.9 Hz), 3.15 (lH, dd, J 10.0 & 17.1 Hz), 3.50 (lH, dd, J3.5 & 17.0 Hz), 4.06 - 4.25 (4H, m), 6.11 (lH, s), 6.53 (lH, s).
(Found m/z 379.2296. ClgH33N303Si requires m/z 379.2291).
(f~ Allyl (2R and 25)--2-{(35,4R)-4-[(1-ethyl-5-metl.yll,yla~ol-3-yl)carbonylmethyl]-3-[(R)-l-tert-butyl~im~thylsilylox,~ll.yl]-2-oxo~7eti 1inyl}-2-hy~ll oxy ~et~te (3S,4R)-4-[( 1-Ethyl-5-methylpyrazol-3-yl)carbonylmethyl] -3-[(R)- l-tert-butyltiimethylsilyloxyethyl]azetidin-2-one (3.6 g) and allyl glyoxylate hydrate (1.66 g) in toluene (100 ml) were heated under reflux in a Dean and Stark apparatus under an atmosphere of argon for 3.5h. T.l.c. of the reaction mixture showed the reaction had almost prceeded to completion, so more allyl glyoxylate hydrate (190 mg) wasadded and the mixtur~ was heated under reflux for a further 45 min. The mixture was cooled, the toluene was removed to give crude allyl (2R and 25)-2-{(3S,4R)-4-[(1-ethyl-5-methylpyrazol-3-yl)carbonylmethyl]-3-[(R)- l-tert-butyldimethylsilyloxyethyl]-2-oxoazetidinyl }-2-hydroxy~cet~t~, which was used in the next stage; 1)max (CH2C12) 3681, 3518, 1758, 1676, 1448, 1376, 1326, 1209, 1148, 1092, 954, and 836 cm~l; ~(CDC13) inter alia 0.035 (s), 0.061 (s) (together 6H,), 0.858 (s), 0.865 (s) (together 9H), 1.21 (d, J 6.2 Hz), 1.24 (d, J 6.2 Hz), (togethe~ 3H), 1.44 (3H, t, J7.2 Hz), 2.31 (3H, s), 2.95 - 3.00 (lH, m), 3.25 - 3.64 (2H, m), 6.53 (s), 6.56 (s) ppm.
(g) Allyl 2-{(35,4R)4-[(1-ethyl-5-methyl~yr~ol-3-yl)carbonylmethyl]-3-t(R)-l-tert-butyldimethylsilyloxyethyl]-2-oxo~eti~linyl}-2-(tri-n-butylphosphoranylidene)~ret~t~
Allyl (2R and 25)-2-{(35,4R)-4-[(1-ethyl-5-methylpyrazol-3-yl)carbonylmethyl]-3-[(R)- l-tert-butyldimethylsilyloxyethyl]-2-oxoazetidinyl }-2-W 096/34868 PCTAEP96/01880hydroxyacetate (crude from the above preparation) ~n dry THF (12~ ml) under argon was cooled to -20~C and treated with 2,6-lutidine (l.g8 ml), followed by thionylchloAde (1.24 ml). The mixture was stirred at -20~C for 30 minl-t~s, and then allowed to warm to room temperature and filtered, washing the residue with THF (20 ml). The filtrate was evaporated in vacuo, toluene (70ml) was added and removed in vacuo and the residual oil was dried in vacuo. The oil was then taken up in 1,4-dioxan (40 ml) under an argon atmosphere, and treated with tri-n-butylphosphine (3.11 ml). The mixture was stirred for 1 h. 2,6-Lutidine (1.59 ml) was then added and the mixture was stirred for a further 30 minutes. The mixture was diluted with ethyl acetate, washed with water, then with bAne, and dried (MgS04). After removal of the ethyl acetate the crude product was chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures to give the phosphorane, which was used in the next stage.
(h) Allyl 2-{(3S,4R)-4-t(l-ethyl-5-J.Ietl~yl~yl ~ol-3-yl)carbonylmethyl]-3-t(R)- 1-I-,y~ x~ethyl]-2-n~o~ inyl~-2-(tr~-n-butylphosphoranylidene)?ret~te The phosphorane prepared above was taken up in 1,4-dioxan (60 ml) and treated with 5M HCl (20 ml). After 1 h the mixture was carefully treated with ca. 40 ml saturated aqueous NaHCO3, followed by solid NaHCO3 until the pH was slightly ~lk~lin.o Saturated brine was added and the mixture was extracted twice with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures to give the hydroxy compound, (2.60 g). l)max (CH2C12) 3454, 1741, 1667, 1606, 1448, 1403, 1379, 1155, 1087, 953, and 811 cm~l.
(i) Allyl (SR,6S)-6-[(R)-l-l-ylll o~y~ ,yl]-2-(1-ethyl-5-melllyi~yl azol-3-yl)carbapen-2-em-3-carboxylate W 096/34868 PCTnEP96/01880 Allyl 2- { (3S,4R)~[(l-ethyl-5-meth~l~yl~zol-3-yl)carbonylmethyl]-3-[(R)- 1-hyd~ yethyl~-2-oxoazetidinyl}-2-(tri-n-butylphosphoranylidene)acetate (2.6 g), in toluene (120 ml) co~t~ining hydroquinone (20 mg) was heated under reflux in an argon atmosphere for 4 h, allowed to stand for 64 h, and then heated under reflux for a further 2 h. The mixture was cooled and then loaded onto a column (4.5 x 12 cm) of silica gel (particle si~ 0.040 -0.063 mm), eluting with ethyl acetate/hexane mixtures; 1:1; 6:4; 7:3; 8:2; 9:1 (250 ml of each), followed by ethyl ~et~te This gave ~, the carbapenem (436 mg); ~maX(CH2C12) 3604, 2976, 1774, 1716, 1600, 1546, 1311, 1189 cm~l; ~max(EtOH)/nm 321.5 (~/dm3mol~lcm~l 14,856), ~(CDC13) 1.36 (d, J 6.3 Hz), 1.39 (t, J7.3 Hz) (together 5H), 1.80 (lH, d, J5.0 Hz), 2.28(3H,s), 3.19 (lH, dd J 2.7 & 6.7 Hz), 3.28 (lH, dd, J9.0 & 18.6 Hz), 3.60 (lH, dd, J
9.9 & 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 (lH, m, approx d, J ca 12 Hz), 5.46 (m, approx d, J ca 17 Hz), 5.93 - 6.08 (lH, m), 7.00 (lH, s) ppm; [Found m/z 345.1693. ClgH23N304 requires m/7 345.1689].
(j) Sodium (5R,65)-6-[(R)-1-1~yl1l oxy~ yl]-2-(1-ethyl-5-methyl-pyrazol-3-yl)carbapen-2-em-3-carbox-ylate Allyl (5R,6S)-6-[(R)-l-hydlo~yethyl]-2-(1-ethyl-5-methylpyrazol-3-yl)c~l,apen-2-em-3-carboxylate (267 mg) in dichlorom~pth~np (3ml) and ethyl acetate (3 ml) under argon was treated with sodium 2-ethylhexanoate (183 mg), followed by triphenylphosphine (24 mg), followed by tetrakis(triphenylphosphine)p~ m(O) (35 mg) and the mixture was stirred for 45 min. Diethyl ether (lOOml) was then added, and after stirring for 90 minutes, the mixture was centrifuged. The residual solid was dried under a stream of argon, and then in a desiccator. The solid was then taken up in water cont~ining sodium chloride and chromatographed on DIAION
HP20SS resin, eluting with water, followed by water/THF mixtures; 1 %, 2%, and 3%,THF. Fractions were monitored by HPLC, and those containing the product were combined, reduced in volume and freeze-dried to give sodium (SR,6S)-6-t(R)-l-hy~ yethyl]-2-(1-ethyl-5-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate as a solid (168 mg); ~max(KBr) 1761, 1608, 1577, 1381, 1225 cm~l; ~max(H20)/nm 298 (~/dm3mol~lcm~l 8,531); ~(D20) 1.26 (d, Jca. 6 Hz), 1.27 (d, Jca. 7 Hz) (together SH), 2.23 (3H, s), 3.17 (2H, approx d, J ca. 9 Hz), 3.44 (lH, dd, J 2.9 & 6.0 Hz), - 4.04 (2H, q, J7.3 Hz)~ 4.15 - 4.25 (2H, m), 6.41 (lH, s) ppm.
ESTERS OF CARBAPENEMS
This invention relates to novel antib~ct~ri~l eompounds, processes for their preparation, pharmaceutical and veterinary compositions comprising them, and their 5 use in antibacterial therapy.
Carbapenems such as imipenem, the compound of formula (A):
Ho H H
~-\
o~ ~S(CH2)2NHCH=NH
(A) have a potent, broad spectrum of antibacterial aetivity (see US 3 950 357 and US 4 194 047; Merck and Co). Such carbapenems however tend to be vulnerable to hydrolysis by the enzyme renal dehydropeptidase-l (DHP-l) and this limits their use in chemotherapy. In the case of imipenem, this problem may be overcome by the co-lmini.ctration of an inhibitor of DHP-l.
Stability towards DHP-l may also be imparted by chemical modif1cation of the carbapenem nucleus, for instance by incorporating a l~-methyl substitutent, as in the compound mel~,pene,l" the compound of formula (B):
HO H H CH3 ~ CON(CH3k ~S --C~NH
(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 1~-aminoalkyl substituent ~see EP 0 433 759, Bristol-Meyers Squibb).
An alternative approach to imparting improved stability to DHP-l utilises 2-carbon~substituted carbapenems, for in.ct~nce, 2-aryl, 2-heteroaryl and 2-heteroaromatic carbapenems (US 4 543 257, US 4 260 627, US 4 962 101, US4978659,EP014493, EP0414489,EP0010316andEP0030032Merck&
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 derivatives including diazolyl and tetrazolyl compounds.
However, in the case of the pyrazolyl derivatives the heterocyclic compound is attached to the carbapenem nucleus through the C-4 position.
Other structural modifications introduced at position-2 include a substituted vinyl group -C(Ra)=CHRb in which, for in.~f~nce, Ra is hydrogen or methyl and Rb is hydrogen or lower alkyl (EP 0 330 108; Fujisawa) or Ra and Rb are selected from hydrogen, lower alkyl, aminocarbonyl, lower alkoxy, cyano, nitro and lower alkoxycarbonyl (EP 0 430 037, Banyu Pharmaceutical Co.). In the absence of a l,B-methyl substituent, such a mo-lific~tion does not however appear to impart DHP-1stability.
TntP.rn~tional Patent Application No. PC r/GB94/02347 describes compounds of the general formula (C): -d H H R
c-~ ~ R
o~
(C) in which R is:
N--N
~ 'R~;
wherein Ra is hydrogen, optionally substituted (Cl 6)alkyl or optionally substituted aryl;
R~ is hydrogen, optionally substituted (Cl 6)aL~yl or optionally substituted aryl; or 20 Ra and R13 together form an optionally substituted 5 or 6 membered heterocyclic ring with or without additional heteroatoms;
Rc is (Cl 6)aLlcyl which is unsubstituted or substituted by fluoro, a hydroxy group which is optionally protected by a readily removable hydroxy protecting group, or by an amiRQ group which is optionally protected by a readily removable amino 25 protecting 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.
According to the present invention, there is provided the compound of formula (I):
OH
CH3 ~'", ~Me ~~ --~ N--NEt (I) wherein R is selected from the group consicting of isobutyryloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, and benzoyloxymethyl.
Particular compounds in accordance with the present invention are:
isobutyryloxymethyl (SR, 6S)-2-[ 1-ethyl-5-methylpyrazol-3-yl]-6-[( 1 R)- 1-10 hydroxyethyl]-carbapen-2-em-3-carboxylate, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (5R, 6S)-2-[1-ethyl-5-methylpyrazol-3-yl]-6 [(lR)-l-hyd,~,~yeLhyl]-carbapen-2-em-3-carboxylate, and benzoyloxymethyl (5R, 6S)-2-[1-ethyl-5-methylpyrazol-3-yl]-6-[(lR)-1-hydroxyethyl] -carbapen-2-em-3-carboxylate.
Since each carbapenem compound of the present invention is intended for use in ph~rm~ceutic~l compositions, it will be understood that it is provided in sllbst~nti~lly pure form, for ~Y~mple at least 50% pure, more suitably at least 75%
pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compound may be used for p~pa,ing the more pure forms used in the 20 pharmaceutical compositions. Preferably, whenever possible, each compound of the present invention is obtained in crystalline form When each compound of this invention is allowed to crystallise or is recrystallised from organic solvents, solvent of cryst~lli.c~tion may be present in the crystal~ine product. This invention includes within its scope such solvates. Similarly, 25 the compounds of this invention may be crystallised or recrystallised from solvents cont~ining water. In such cases water of hydration may be present in the crystalline product. This invention includes within its scope stoichiometric hydrates.
The carbapenem antibiotic compounds according to the invention may be formulated for ~-lmini.ctration in any convenient way for use in human or veterinary 30 medicine, according to Lechniques and procedures per se known in the art withreference to other antibiotics, and the invention therefore includes within its scope a ph~rm~ eutical composition complising an antibiotic compound according to the present invention together with a ph~rm~ceutically acceptable carrier or excipient.
The compositions may be formulated for a~lmini.etration by any suitable route, such as oral, pa elllel~l 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 preparations, such as oral or sterile parenteral solutions or 5 suspeneione Tablets and caps-lles for oral a~1minictration may be in unit dosepresrnt~tion form and may contain convention~l excipients such as binding agents, for example, syrup acacia, gelatin, sorbitol, tr~g~ nth, or polyvinylpyrollidone;
fillers, for example lactose, sugar, mai~-starch, calcium phosph~te, sorbitol orglycine; tabletting lubricants, for example m~gn~eillm stearate, talc, polyethylene 10 glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal ph~rrn~eutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other 15 suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hy~o~ye~llyl cellulose, carboxymethyl cellulose, ~ minium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for20 example almond oil, oily esters, glycerine, propylene glycol, or ethyl alcohol;
preservatives, for example methyl or propyl p-hydlu~yl,enzoate or sorbic acid; and, if desired conventional flavouring or colouring agents. Suppositories will contain conventional suppository base, eg cocoa-butter or other glyceride.
For parenteral arlminietration~ fluid unit dosage forms are prepared utili.cing 25 the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and se~1ing.
Advantageously, agents such as local an~sthf~.tic, preservative and buffering agents 30 can be~dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry Iyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound 35 is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
W 096/34868 PCT~EP9G/01880 The composition may contain from 0.1% to 99.5% by weight, preferably from 10-60% by weight, of the active m~t~ri~l, depending on the method of admini~tration.
Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human 5 treatment will preferably range from 100 mg to 12 g per day for an average adult patient (body weight 70 kg), for instance 1500 mg per day, depending on the route and frequency of atlm;ni.~tration. Such dosages correspond to approximately 1.5 to 170 mg/kg per day. Suitably the dosage is from 1 to 6g per day.
The daily dosage is suitably given by ~lmini.~tering a compound of the invention several times in a 24-hour period. Typically, 250 mg is ~-lmini.ctered 4 times a day although, in practice, the dosage and frequency of ~dmini.ctration which will be most suitable for an individual patient will vary with the age, weight and response of the p~tiP.nt.~, and there will be occasions when the physician will choose a higher or lower dosage and a different frequency of ~minist-ration. Such dosage regimens are within the scope of this invention.
No toxicological effects are inc1icated when any compound of the invention is mini.~tered in the above mentioned dosage range.
The present invention also includes a method of treating bacterial infections inhumans and ~nim~l.c which method comprises ~lminicte.ring a therapeutically effective amount of an antibiotic compound of the present invention of the formula (I).
In a further aspect, the present invention also provides for the use of a compound of formula (I) for the manufacture of a meAi~ment for treating bacterial infection.
The compounds of the present invention of formula (I) are active against a broad range of Gram-positive and Gram-negative bacteria, and may be used to treat a wide range of b~teri~l infections including those in immunocompromised patients.Amongst many other uses, the compounds of the invention are of value in the tre~tment of skin, soft tissue, respiratory tract and urinary tract infections in hllm~n.c and mày also be used to treat mastitis in cattle.
A particular advantage of the antibacterially active compounds of this invention is their stability to ,~-lact~m~ce enzymes and they are th'erefore effective against ,13-lactamase producing org~ni.~m.c The present invention further provides a process for the preparation of a compound of formula (I) wherein R is isobutyryloxymethyl or benzoyloxymethyl, which process comprises treating a corresponding compound of formula (I), wherein R is an aL~ali metal cation, with a compound of formula XCH20COCHMe2 or XCH2OCOC6Hs, wherein X is a leaving group such as halogen, more particularly bromine or iodine.
W 096/34868 PCT~P96/01880 The reaction is typically carried out at between 0 and 60 C, for example at ambient temperature, under an inert, for example argon, atmosphere, in a suitable organic solvent, for e~r~mplP, N-methylpyrrolidin-2-one. Other suitable solvent systems include N, N'-dimethylfommamide and N, N'-dimethyl~et~mi~e The present invention further provides a process for the preparation of a compound of fommula (I) wherein R is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, which process comprises treating a corresponding compound of formula (I), wherein R is an alkali metal cation, with a compound of fommula:
Me 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 at ambient temperature, in a suitable organic solvent, for e~mphP, N-methylpyrrolidin-2-one, and in the presence of an acid-binding agent, such as 2,6-lutidine. Othersuitable acid-binding agents include pyridine and diisopropylethylamine. Other suitable solvents include N, N'-dimethylfnrm~mide and N, N'-dimethyl~et~mi~P
Compounds of formula (I) wherein R is an aLkali metal cation" such as sodium~ are described in TntPm~tion~l Patent Application No. PCT/GB9~/02347, andhereinbélow in Preparation 1.
The compound of formula ICH2OCOCHMe2 (iodomethyl isobutyrate) and iodomethyl benzoate can be prepared from the corresponding chlorides via the FinkPlstein reaction, which is well known to those skilled in the art.
Chloromethyl isobutyrate and chloromethyl benzoate can be prepared by e~ iLying isobutyric acid or benzoic acid respectively with chloromethyl chlorosulphate (Binderup et al., Synthetic Comme~n., 14(9), 857-864 (1984)).
The fo~owing Examples illustrate the present invention further:
General Instructions - Solutions were dried using anhydrous m~nesillm sulphate and solvents were removed by evaporation under reduced pressure using a rotary evaporator. Column chromatography on silica gel used Merck silica gel 60, particle size <0.063mm.
CA 022l7990 l997-lO-3l W 096/34868 PCT~EP96/01880 FY~n~PIe 1 Isobutyryl~ yl-(5R, 6S~2-(1-ethyl-5-~-u:ll-yl~ ~ol-3-yl)-~t(lR)-l-S l~y~l~ oxyethyl]carbapen-2-em-3-carboxylate The product from Preparation 1 (200 mg, 0.61 mmol) was dissolved in N-methylpyrTolidin-2-one (2 ml). A solution of isobutyTyloxymethyl iodide (360 mg, 1.6 mmol) in N-methylpylTolidin-2-one (0.5 ml) was added to this solution at room 10 temperature under argon and after 0.5 h the reaction mixture was diluted with ethyl acetate (15 ml) and the solution was washed with water (3 x 15 ml), 5% sodium thios~llf~t~ solution (15 ml) and then saturated brine (15 ml). The organic extract was dried (Na2SO4) and concentrated to an oil which was purified by chromatography on silica gel eluting with an ~etonP/toluene gradient ~ Lult: to yield a pale yellow solid 15 which was recrystallised from diethyl ether to afford the title compound as pale yellow microneedles (100 mg, 40%), m.p. 107-8~C; (Found: M+, 405.1899.
C20H27N3o6 requires M 405.1900); vmax(cHcl3) 3458, 3019, 1772 and 1734 cm~
l; ~H(CDC13) 1.19 (6H, d, n.l Hz), 1.36 (3H, d, J6.1 Hz), 1.40 (3H, t, r7.2 Hz),1.76 (lH, d, J4.9 Hz), 2.29 (3H, s), 2.62 (lH, septet, J7.1 Hz), 3.18 (lH, dd, J2.7, 6.5 20 Hz), 3.30 (lH, dd, J9.0, 18.8 Hz), 3.64 (lH, dd, J9.8, 18.8 Hz), 4.08 (2H, q, J7.2 Hz), 4.16-4.30 (2H, m), 5.92 (lH, d, J5.6 Hz), 5.98 (lH, d, J5.6 Hz) and 7.02 (lH, s).
Example 2 25 (5-Methyl-2-oxo-1,3-clioxolen~-yl)methyl (5R,65)-~[(R)-l-lly~ Jx~ethyl]-2-(1- ethyl-5-methyl-pyrazol-3-yl)carbapen-2-em-3-carboxylate Sodium (5R,65)-6-[(R)- 1 -hydroxyethyl] -2-(1 -ethyl-5-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate (300 mg) in N-methylpyrrolidinone (4 ml) was treated with 2,6-luti-iine (ca. 30 mg) foIlowed by 4-bromomethyl-5-methyl-1,3-dioxol-2-one (290 30 mg) [P.~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. Ethyl acetate 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 with water, followed by saturated brine solution, and then dried (MgSO4). 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 CH2C12 / h~x~n~ and eluting with ethyl acetate. Practions cont~ining the product were combined and evaporated to give a colourless solid which was recrystallised from acetone to give crystals of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (SR,65)-6-~(R)-l-hydroxyethyl]-2-(l-ethyl-S-meLhyll,ylazol-3-yl)carbapen-2-em-3-carboxylate, m. p. 148 - 151~C; ~maX(cH2cl2) 3605, 2975, 1823, 1776, 1737 (sh), 1721, 1598, 1546, 1314, 1231, and 1182 cm~l; ~max(EtOH/nm 325 (~
/dm3mol~lcm~l 14,654), 260.5 (~/dm3mol~lcm~l 3404); ~CDC13) 1.36 (3H, d, J
6.2 Hz), 1.40 (3H, t, J ca 7.3 Hz), 1.76 (lH,d, J4.9 Hz), 2.21 (3H, s), 2.30 (3H, s), 3.19 (lH, dd, J2.7 & 65 Hz), 3.31 (lH, dd, J9.0 & 18.7 Hz), 3.61 (lH, dd, J 9.9 &
18.7 Hz), 4.08 (2H, q, J7.3 Hz), 4.16 - 4.30 (2H, m), 5.00 & 5.07 (2H, ABq, J 13.9 Hz), 6.88 (lH, s) ppm; Found (EI ms) m/z 417 (M+).
F.Y~mp~ 3 Benzoyloxyl-.elllyl (5R,6S)-2~ ethyl-5-~,~lhyl~ ~ol-3-yl)-6-[(lR)-l-hr~lroxy~lllyllcal b~e~l-2-em-3-carbox-ylate The product from Preparation 1 (200 mg, 0.61 mmol) was dissolved in N-methylpyrrolidin-2-one (2 ml). A solution of benzoyloxymethyl iodide (336 mg, 1.28 mmol) in N-methylpyrrolidin-2-one (0.5 ml) was added to this solution at room tempelature under argon and after 0.5 h the reaction mixture was diluted with ethyl acetate (15 ml) and the solution was washed with water (3 x 15 ml), 5% sodium thioslllf~tP solution (15 ml) and then saturated brine (15 ml). The organic extract was ~ 20 dried (Na2SO4) and concentrated to an oil which was purified by chromatography on silica gel eluting with an ~etonP/toluene ~ liPnt ~ Ul~ to yield a pale yellow solid which was recrystallised from acetone/diethyl e~er to afford the title compound as a white solid (143 mg, 53%), m.p. 131-4~C; (Found: M+, 439.1743. C22H2sN3O6 requires M439.1743); ~max(CHCl3) 3021, 1740, 1602, 1452 and 1440 cm~l; ~
H(CDC13) 1.34 (6H, m), 1.70 (lH, d, J4.9 Hz), 2.25 (3H,s), 3.19 (lH, dd, J2.4, 6.3 Hz), 3.30 (lH, dd, J8;8, 18.8 Hz), 3.64 (lH, dd, J10.1, 18.8 Hz), 4.07 (2H, q, J7.2 Hz), 4.18-4.31 (2H, m), 6.20 (2H, s), 7.42-7.48 (2H, m), 7.56-7.61 (lH, m), and 8.10 (2H, d, J7.1 Hz) ppm.
Prep~flon 1 Sodium (SR,65)-6-[(R)-l-hydroxyelhyl]-2-(1-ethyl-5-methyl~y~ol-~
yl)carbapen-2-em-3-carboxylate (a) Ethyl l-ethyl-5-melllyl~yl~;ole-3-carboxylate N-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 complete the mixture was stirred at room temperature; after ca. 45 min the mixture was warmed to dissolve insoluble ethylhydrazine oY~l~tP The mixture was stirred for a further 2 h and then poured into water( ca. 300 ml) / ethyl acetate (ca. 700 ml) and solid K2CO3 was carefully added, with stirring, untiLthe pH was neutral. After 5 ~paration the aqueous layer was re-extracted with ethyl ~cet~t~o The combined ethyl acetate extracts were dried (MgSO4), and the solvents removed to leave an oil.
Chromatography on silica gel, loading in CH2C12/hexane and eluting with a gradient elution of ethyl acetate/hexane mixtures (from 2:8 to 1:1) gave ethyl 1-ethyl-5-methylpyrazole-3-carboxylate as an oil (13.2 g); 1)max (CH2C12) 1717, 1446, 1389, and 1219 cm~l; ~(CDC13) 1.38 (3H, t, J7.2 Hz), 1.42 (3H, t, J7.3 Hz), 2.30 (3H, s), 4.17 (2H, q, J7.3 Hz), 4.38 (2H, q, J7.1 Hz), 6.55 (lH, s); (Found m/z 182.1055.CgH14N202 requires m/z 182.1055).
(b) l-Ethyl-5-metl-yl~yl azole-3-carboxylic acid Ethyl l-ethyl-S-methylpyrazole-3-carboxylate (10.93 g) in ethanol (70 ml) was treated with KOH (3.69 g), followed by water (30 ml), and the mixture was stirred and heated under reflux for 6 h. The ethanol was removed using a rotary evaporator and ethyl acetate/water were added. The pH of the mixture was adjusted to 3.0 and the layers were ~p~r~tl~-i The aqueous layer was re-extracted with ethyl ~cet~te20 The combin~.d ethyl acetate layers were extracted with excess aqueous NaHCO3. The NaHCO3 extract was poured into excess acid, and the pH was then adjusted to 3, and NaCl was added to the solution. The mixture was then repeatedly extracted with ethyl ~et~t~., and the combined extracts were dried (MgSO4) and evaporated. The residue was triturated~~ith diethyl ether to give the acid as a solid (5.65 g); l~max (CH2C12) 2754, 2598, 1698, 1498, 1464, 1387, and 1233 cm~l; ~(CDC13) 1.40 (3H, t, J7.3 Hz), 2.32 (3H,s), 4.19 (2H, q, J7.3 Hz), 6.61 (lH,s) ppm; (Found n2/z 154.0740. C7HloN202 requires n2/z 154.0742).
(c)N-Metho~y-N-methyl- l-ethyl-5-metl.yl~yl a~ole-3-carboY~m: lle 1-Ethyl-S-methylpyrazole-3-carboxylic acid (5.25 g) in dry dichloromethane (100 ml) cont~ining N,N-dimethylform~mi~ (0.26 ml) was cooled in an ice-bath and treated with a solution of oxalyl chloride (3.27 ml) in dichloromethane (25 ml), added dropwise. The mixture was stirred in the cold for 25 min, and then allowed to warm to room temperature, when evolution of a gas was observed. After 10 min the solvent was removed by evaporation in vacuo and toluene was added and removed (x 2) to g - ensure any residual HCl and oxalyl chloride had been removed. The reslllt~nt acid chlnritle was redissolved in dry dichlornmeth~n~- 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 room 5 temperature 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 was the chromatographed on silica gel, loading in dichloromethane, and eluting with ethyl acetate / hexane mixtures to give, after evaporation of requisite fractions, the ~=
hydroY~m~te (5.2 g) as a solid;
10 ~maX(cH2cl2) 2982, 2937, 1641, 1489, 1445, 1379,and 975 cm~l; ~(CDC13) 1.43 (3H, t, J7.3 Hz), 2.29 (3H, s), 3.42 (3H, s), 3.76 (3H, s, ), 4.13 (2H, q, J7.3 Hz), 6.49 (lH, s); (Found m/z 197.1164. CgHlsN3O2 requires m/z 197.1164).
(d) 3-Acetyl-l-ethyl-5-methylpyrazole 15 N-Methoxy-N-methyl-l-ethyl-5-methylpyrazole-3-carboxamide (3.12 g) in dry tetrahydrofuran (60 ml) was cooled in an ice-bath and treated with a 3.0M solution of methylm~gn~ci-lm bromide in ether (11.08 ml). After stirring for 1.5 h the mixture was poured into a mixture of methanol (100 ml) and SM aqueous HCl (10 ml) in an ice-bath. The mixture was then evaporated to lower volume and treated with a 20 mixture of dichloromethane, water and saturated bAne. After separation the aqueous layer was re-extracted with dichlornmeth~n,q. The combined dichloromethane extracts were dried (MgS04) and evaporated to leave an oil (2.26 g), which solidified on standing; l)max (CH2C12) 16~0, 1446, 1425, 1380, 1324, 1208, and 945 cm~l;
(CDC13) 1.44 (3H, t, J7.3 Hz), 2.30 (3H, s), 2.53 (3H, s), 4.13 (2H, q, J7.3 Hz,), 25 6.51 (lH,s); (Found: nz/z 152.0949. CgH12N2O requires m/z 152.090).
(e) (3S,4R)-4-t(l-ethyl-5-me~l-yl~yr~ol-3-yl)carbonylmethyl]-3-[(R)-l-tert-butyl~lim~thylsilyloxyethyl]azeffdin-2-one 3-Acetyl-l-ethyl-5-methylpyrazole (3.51 g) in dry tetrahydrofuran (THF) (150 ml) under an argon atmosphere was cooled in an acetone / solid carbon dioxide bath and then treated with a lM solution of lithium bis(trimethylsilyl)amide (50 ml). The mixture was stirred for 45 minutes and then (3R,4R)-4-acetoxy-3-[(lR)- l-tert-butyldimethylsilyloxyethyl]azetidinone (6.6 g) was added as a solid under a blanket OI argon. The mixture was stirred in the cold for 3.~n. ~hlr~tecl aqueous ammonium chloride was then added, followed by ethyl acetate, and the mixture was allowed to warm to room temperature. A little water was added and the layers were separatedand the aqueous layer was re-extracted with ethyl acetate. The combined ethyl 5 acetate extracts were washed with ~tnr~ted brine, dried and evaporated.
Chromatography on silica gel, eluting with ethyl acetate/hexane mixtures gave the title compound (3.65 g), ~max (CH2C12) 3411, 1761, 1678, 1376, 1151, and 838 cm~l; o~CDC13) 0.064 (6H, s), 0.86 (9H, s), 1.20 (3H,d, J 6.3 Hz), 1.44 (3H, t, J 7.3 Hz), 2.31 (3H, s), 2.89 (lH, dd, J 1.8 & 4.9 Hz), 3.15 (lH, dd, J 10.0 & 17.1 Hz), 3.50 (lH, dd, J3.5 & 17.0 Hz), 4.06 - 4.25 (4H, m), 6.11 (lH, s), 6.53 (lH, s).
(Found m/z 379.2296. ClgH33N303Si requires m/z 379.2291).
(f~ Allyl (2R and 25)--2-{(35,4R)-4-[(1-ethyl-5-metl.yll,yla~ol-3-yl)carbonylmethyl]-3-[(R)-l-tert-butyl~im~thylsilylox,~ll.yl]-2-oxo~7eti 1inyl}-2-hy~ll oxy ~et~te (3S,4R)-4-[( 1-Ethyl-5-methylpyrazol-3-yl)carbonylmethyl] -3-[(R)- l-tert-butyltiimethylsilyloxyethyl]azetidin-2-one (3.6 g) and allyl glyoxylate hydrate (1.66 g) in toluene (100 ml) were heated under reflux in a Dean and Stark apparatus under an atmosphere of argon for 3.5h. T.l.c. of the reaction mixture showed the reaction had almost prceeded to completion, so more allyl glyoxylate hydrate (190 mg) wasadded and the mixtur~ was heated under reflux for a further 45 min. The mixture was cooled, the toluene was removed to give crude allyl (2R and 25)-2-{(3S,4R)-4-[(1-ethyl-5-methylpyrazol-3-yl)carbonylmethyl]-3-[(R)- l-tert-butyldimethylsilyloxyethyl]-2-oxoazetidinyl }-2-hydroxy~cet~t~, which was used in the next stage; 1)max (CH2C12) 3681, 3518, 1758, 1676, 1448, 1376, 1326, 1209, 1148, 1092, 954, and 836 cm~l; ~(CDC13) inter alia 0.035 (s), 0.061 (s) (together 6H,), 0.858 (s), 0.865 (s) (together 9H), 1.21 (d, J 6.2 Hz), 1.24 (d, J 6.2 Hz), (togethe~ 3H), 1.44 (3H, t, J7.2 Hz), 2.31 (3H, s), 2.95 - 3.00 (lH, m), 3.25 - 3.64 (2H, m), 6.53 (s), 6.56 (s) ppm.
(g) Allyl 2-{(35,4R)4-[(1-ethyl-5-methyl~yr~ol-3-yl)carbonylmethyl]-3-t(R)-l-tert-butyldimethylsilyloxyethyl]-2-oxo~eti~linyl}-2-(tri-n-butylphosphoranylidene)~ret~t~
Allyl (2R and 25)-2-{(35,4R)-4-[(1-ethyl-5-methylpyrazol-3-yl)carbonylmethyl]-3-[(R)- l-tert-butyldimethylsilyloxyethyl]-2-oxoazetidinyl }-2-W 096/34868 PCTAEP96/01880hydroxyacetate (crude from the above preparation) ~n dry THF (12~ ml) under argon was cooled to -20~C and treated with 2,6-lutidine (l.g8 ml), followed by thionylchloAde (1.24 ml). The mixture was stirred at -20~C for 30 minl-t~s, and then allowed to warm to room temperature and filtered, washing the residue with THF (20 ml). The filtrate was evaporated in vacuo, toluene (70ml) was added and removed in vacuo and the residual oil was dried in vacuo. The oil was then taken up in 1,4-dioxan (40 ml) under an argon atmosphere, and treated with tri-n-butylphosphine (3.11 ml). The mixture was stirred for 1 h. 2,6-Lutidine (1.59 ml) was then added and the mixture was stirred for a further 30 minutes. The mixture was diluted with ethyl acetate, washed with water, then with bAne, and dried (MgS04). After removal of the ethyl acetate the crude product was chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures to give the phosphorane, which was used in the next stage.
(h) Allyl 2-{(3S,4R)-4-t(l-ethyl-5-J.Ietl~yl~yl ~ol-3-yl)carbonylmethyl]-3-t(R)- 1-I-,y~ x~ethyl]-2-n~o~ inyl~-2-(tr~-n-butylphosphoranylidene)?ret~te The phosphorane prepared above was taken up in 1,4-dioxan (60 ml) and treated with 5M HCl (20 ml). After 1 h the mixture was carefully treated with ca. 40 ml saturated aqueous NaHCO3, followed by solid NaHCO3 until the pH was slightly ~lk~lin.o Saturated brine was added and the mixture was extracted twice with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures to give the hydroxy compound, (2.60 g). l)max (CH2C12) 3454, 1741, 1667, 1606, 1448, 1403, 1379, 1155, 1087, 953, and 811 cm~l.
(i) Allyl (SR,6S)-6-[(R)-l-l-ylll o~y~ ,yl]-2-(1-ethyl-5-melllyi~yl azol-3-yl)carbapen-2-em-3-carboxylate W 096/34868 PCTnEP96/01880 Allyl 2- { (3S,4R)~[(l-ethyl-5-meth~l~yl~zol-3-yl)carbonylmethyl]-3-[(R)- 1-hyd~ yethyl~-2-oxoazetidinyl}-2-(tri-n-butylphosphoranylidene)acetate (2.6 g), in toluene (120 ml) co~t~ining hydroquinone (20 mg) was heated under reflux in an argon atmosphere for 4 h, allowed to stand for 64 h, and then heated under reflux for a further 2 h. The mixture was cooled and then loaded onto a column (4.5 x 12 cm) of silica gel (particle si~ 0.040 -0.063 mm), eluting with ethyl acetate/hexane mixtures; 1:1; 6:4; 7:3; 8:2; 9:1 (250 ml of each), followed by ethyl ~et~te This gave ~, the carbapenem (436 mg); ~maX(CH2C12) 3604, 2976, 1774, 1716, 1600, 1546, 1311, 1189 cm~l; ~max(EtOH)/nm 321.5 (~/dm3mol~lcm~l 14,856), ~(CDC13) 1.36 (d, J 6.3 Hz), 1.39 (t, J7.3 Hz) (together 5H), 1.80 (lH, d, J5.0 Hz), 2.28(3H,s), 3.19 (lH, dd J 2.7 & 6.7 Hz), 3.28 (lH, dd, J9.0 & 18.6 Hz), 3.60 (lH, dd, J
9.9 & 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 (lH, m, approx d, J ca 12 Hz), 5.46 (m, approx d, J ca 17 Hz), 5.93 - 6.08 (lH, m), 7.00 (lH, s) ppm; [Found m/z 345.1693. ClgH23N304 requires m/7 345.1689].
(j) Sodium (5R,65)-6-[(R)-1-1~yl1l oxy~ yl]-2-(1-ethyl-5-methyl-pyrazol-3-yl)carbapen-2-em-3-carbox-ylate Allyl (5R,6S)-6-[(R)-l-hydlo~yethyl]-2-(1-ethyl-5-methylpyrazol-3-yl)c~l,apen-2-em-3-carboxylate (267 mg) in dichlorom~pth~np (3ml) and ethyl acetate (3 ml) under argon was treated with sodium 2-ethylhexanoate (183 mg), followed by triphenylphosphine (24 mg), followed by tetrakis(triphenylphosphine)p~ m(O) (35 mg) and the mixture was stirred for 45 min. Diethyl ether (lOOml) was then added, and after stirring for 90 minutes, the mixture was centrifuged. The residual solid was dried under a stream of argon, and then in a desiccator. The solid was then taken up in water cont~ining sodium chloride and chromatographed on DIAION
HP20SS resin, eluting with water, followed by water/THF mixtures; 1 %, 2%, and 3%,THF. Fractions were monitored by HPLC, and those containing the product were combined, reduced in volume and freeze-dried to give sodium (SR,6S)-6-t(R)-l-hy~ yethyl]-2-(1-ethyl-5-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate as a solid (168 mg); ~max(KBr) 1761, 1608, 1577, 1381, 1225 cm~l; ~max(H20)/nm 298 (~/dm3mol~lcm~l 8,531); ~(D20) 1.26 (d, Jca. 6 Hz), 1.27 (d, Jca. 7 Hz) (together SH), 2.23 (3H, s), 3.17 (2H, approx d, J ca. 9 Hz), 3.44 (lH, dd, J 2.9 & 6.0 Hz), - 4.04 (2H, q, J7.3 Hz)~ 4.15 - 4.25 (2H, m), 6.41 (lH, s) ppm.
Claims (9)
1. A compound of formula (I):
(I) wherein R is selected from the group consisting of isobutyryloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, and benzoyloxymethyl.
(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-hydroxyethyl]-carbapen-2-em-3-carboxylate.
3. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl (5R, 6S)-2-[1-ethyl-5-methylpyrazol-3-yl]-6-[(1R)-1-hydroxyethyl]-carbapen-2-em-3-carboxylate.
4. Benzoyloxymethyl (5R, 6S)-2-[1-ethyl-5-methylpyrazol-3-yl]-6-[(1R)-1-hydroxyethyl]-carbapen-2-em-3-carboxylate.
5. A pharmaceutical composition comprising a compound according to any one of the preceding claims together with a pharmaceutically acceptable carrier or excipient.
6. A method of treating bacterial infections in humans and animals which method comprises administering a therapeutically effective amount of a compound according to any one claims 1 to 4.
7. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for treating bacterial infection.
8. A process for the preparation of a compound of formula (I) as defined in claim 1 wherein R is isobutyryloxymethyl or benzoyloxymethyl, which process comprises treating a corresponding compound of formula (I), wherein R is an alkali metal cation, with a compound of formula XCH2OCOCHMe2 or XCH2OCOC6H5, wherein X is a leaving group.
9. A process for the preparation of a compound of formula (I) as defined in claim 1 wherein R is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, which process comprises treating a corresponding compound of formula (1), wherein R is an alkali metal cation, with a compound of formula:
wherein X is a leaving group.
wherein X is a leaving group.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9508957.9 | 1995-05-03 | ||
| GBGB9508957.9A GB9508957D0 (en) | 1995-05-03 | 1995-05-03 | Novel compounds |
| GB9508955.3 | 1995-05-03 | ||
| GBGB9508955.3A GB9508955D0 (en) | 1995-05-03 | 1995-05-03 | Novel compounds |
| GB9508956.1 | 1995-05-03 | ||
| GBGB9508956.1A GB9508956D0 (en) | 1995-05-03 | 1995-05-03 | Novel compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2217990A1 true CA2217990A1 (en) | 1996-11-07 |
Family
ID=27267696
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002217990A Abandoned CA2217990A1 (en) | 1995-05-03 | 1996-05-02 | 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) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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
- 1997-11-03 BG BG102014A patent/BG102014A/en unknown
- 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 |
| OA10632A (en) | 2002-09-16 |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH0853453A (en) | 2-(1-(1,3-thiazolin-2-yl)azetidin-3-yl)thiocarbapenem compound | |
| RU2097383C1 (en) | Carbopenem derivatives and a method of their synthesis | |
| JPH10507185A (en) | 2- (Imidazol-4-yl) carbapenem derivatives, their intermediates and use as antibacterial agents | |
| CA2175054C (en) | 2-(pyrazol-3-yl)carbapenem derivatives | |
| CA2217990A1 (en) | Esters of carbapenems | |
| CA2217885A1 (en) | Esters of carbapenems | |
| MXPA97008422A (en) | Carbapene steres | |
| US5606051A (en) | 2-(pyrazol-3-yl)carbapenem derivatives | |
| US5384317A (en) | Bridged biphenyl carbapenem compounds, compositions containing such compounds and methods of use | |
| MXPA97008421A (en) | Carbapene steres | |
| EP0376355A1 (en) | 2-Quaternary heteroarylalkythio carbapenems | |
| US7045619B2 (en) | 2-(pyrazol-3-yl)carbapenem derivatives | |
| CA1297110C (en) | 2-aza-substituted 1-carbadethiapen-2-em-3-carboxylic acids | |
| JP2003183281A (en) | Carbapenem compound | |
| KR870001743B1 (en) | Process for preparation of cabapenem | |
| PT99285B (en) | METHOD FOR THE PREPARATION OF DIETHYACETAL-SUBSTITUTED CARBENIC ACID ANTIBIOTICS IN CARBON 3 ATOM AND OF PHARMACEUTICAL COMPOSITIONS THAT CONTAINS THEM | |
| US5372993A (en) | Bridged carbapenem compounds, compositions containing such compounds and methods of use | |
| JPH05213953A (en) | 2-(n-imidazoliumphenyl)carbapenem | |
| JP2004043445A (en) | 1beta-METHYLCARBAPENEM DERIVATIVE FOR ORAL ADMINISTRATION |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |