CA1107739A - .beta.-LACTAM COMPOUNDS - Google Patents
.beta.-LACTAM COMPOUNDSInfo
- Publication number
- CA1107739A CA1107739A CA308,302A CA308302A CA1107739A CA 1107739 A CA1107739 A CA 1107739A CA 308302 A CA308302 A CA 308302A CA 1107739 A CA1107739 A CA 1107739A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- 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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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Abstract This invention provides a process for the preparation of a compound of the formula (II):
(II) or a salt or ester thereof, wherein R2 is a CH=CH2 or CH=CH-CH3 group, which comprises reacting an ester of clavulanic acid with a compound of the formula (III) or (IV):
R3 - O - CH = CH2 (III) R3 - O - CH = CH - CH3 (IV) wherein R3 is an alkyl group of up to 6 carbon atoms, in the presence of a mercuric ion catalyst, and thereafter, if desired, de-esterifying the result-ing ester of the compound of the formula (II); and when a compound of the formula (II) or a salt thereof is required, cleaving the corresponding p-nitrobenzyl ester of the compound of the formula (II); and when required converting the resulting compound to a salt of a compound of the formula (II);
and when required converting the resulting compound to a pharmaceutically acceptable salt of a compound of the formula (II). The compounds of the formula (II) and salts and esters thereof are novel and have ?-lactamase in-hibitory properties.
(II) or a salt or ester thereof, wherein R2 is a CH=CH2 or CH=CH-CH3 group, which comprises reacting an ester of clavulanic acid with a compound of the formula (III) or (IV):
R3 - O - CH = CH2 (III) R3 - O - CH = CH - CH3 (IV) wherein R3 is an alkyl group of up to 6 carbon atoms, in the presence of a mercuric ion catalyst, and thereafter, if desired, de-esterifying the result-ing ester of the compound of the formula (II); and when a compound of the formula (II) or a salt thereof is required, cleaving the corresponding p-nitrobenzyl ester of the compound of the formula (II); and when required converting the resulting compound to a salt of a compound of the formula (II);
and when required converting the resulting compound to a pharmaceutically acceptable salt of a compound of the formula (II). The compounds of the formula (II) and salts and esters thereof are novel and have ?-lactamase in-hibitory properties.
Description
1~77~9 ~ -Lactam Compound The present invention relates to a process for the preparation of certain ethers of clavulanic acid, to chemical intermediates in the process, to a process for the preparation of these intermediates, and to pharmaceutical compositions containing them.
Ethers of clavulanic acid are disclosed in Belgian Patent No: 847045, Japanese Patent Application No: 122725/76 and U.S.
Patent Application Serial No: 786345.* It has been found that 1~ ethyl and propyl ethers of clavulanic acid and derivatives thereof can conveniently be prepared via the vinyl and propenyl ethers of clavulanic acid.
Accordingly, in a divisional application there is provided a process for the preparation of the compounds of the formula (I):
H
N ~ (I) ~ C02H
and salts and esters thereof wherein Rl is a CH2CH3 or CH2CH2CH3 ~roup, which process comprises the reduction of an ester of a compound of the formula (II):
* U.S. Application Serial No. 786,345 corresponds to Canadian Patent App~ication Nos. 263,1~5 and 298,622.
~ 77~9 N ~ (II) ~ ~C0 H
wherein R2 is a CH=CH2 or CH=CH-CH3 group and there-after or simultaneously if desired converting the thus-formed ester of the compound of the formula (I~
to the corresponding acid or a salt thereof.
Most suitably, the reaction is performed on an ester of the compound of the formula (II) wherein ~ is a CH=CH2 group.
The reduction reaction is normally effected by hydro-genation in the presence of a catalyst such as a trans-ition metal catalyst, such as platinium oxide, pallad-ium or the like. An approximately atmospheric pressure of hydrogen is generally most convenient for laboratory useg but sub-atmospheric pressures may also be employed, so long as extreme conditions are avoided.
If a compound of the formula (I) per se or a salt thereof is required, this may be obtained by de-esteri-fying a suitable ester of the compound, for example, by the hydrolysis of a methoxymethyl or like ester or by the hydrogenation of a benzyl, p-methoxybenzyl or like ester optionally in the presence o~ a base, for example, as described in Belgian Patent No: 847045.
If desired, the hydrogenation of the vinyl or propenyl group and hydrogenolysis of the ester may occur at the same time, by selecting a suitable catalyst and solvent, ~1~77~9 for example, by using a tetrahydrofuran - containing solvent system and by using a palladium or mixed platinium oY~ide/palladium catalyst.
The present inver.tion provides the compounds of the formula (II) and salts and esters thereof.
Preferably, R2 is a CH=CH2 group.
Suitable esters of the compounds of the formula (II) include those wherein the esterifying moiety is a group Al or CHA2A3 wherein Al is an alkyl group of 1-8 carbon atoms optionally substituted by halogen or by a group of the formula oA4, oCoA4, SA4 So2A4 wherein A4 is a hydrocarbon group of up to 6 carbon atoms; A2 is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl group optionally substituted by halo~en or by a group A5 or oA5 where A5 is an alkyl group of up to 6 carbon atoms; and A3 is a phenyl group optionally substituted by halogen or nitro or by a group A5 or oA5 where A5 is an alkyl group.
Preferably, the ester of the compound of the for~ula (II) is such that the corresponding ester of the compound of the formula (I) is a readily hydrolysable or hydrogenolysable ester.
Suitable esters of this type include the methoxymethyl, ethoxymethyl, benzyl, methoxybenzyl, nitrobenzyl and the like esters.
b~
A particularly preferred ester of the compounds of the formula (II) is the p-nitrobenzyl ester.
Suitable salts of the compounds of the formula (II) include alkal metal, alkaline earth metal and ammonium and substituted ammonium salts.
Preferably, the salt is a pharmaceutically acceptable salt.
The novel compounds of this invention possess useful ~-lactamase inhihitory properties which allow them to be utilised in antibacterial compositions. Accordingly, this invention provides a pharmaceutical composition which comprises a compound of the formula (II) or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier.
The compositions of this invention may be utilised as described in the aforementioned patent specifica~ions and may advanta~eously contain a penicillin or cephalosporin.
This invention also provides a process for the preparation of the compounds of the formula (II) and salts and esters thereof which process comprises the reaction o an ester of clavulanic acid with a compound of the formula (III) or (IV):
R3 - 0 - CH = CH2 (III) R3 - 0 - CH = CH - CH3 ,~
~77~9 wherein R3 is an al~yl group of up to 6 carbon atoms, in the presence of mercuric ions as catalyst, and thereafter, if desired, de-esterifying the resulting ester of the compound of the formula (II).
Most suitably, R3 in formulae (III) and (IV) is an ethyl group.
Most suitably, the catalyst is mercuric acetate or mercuric trifluoroacetate.
The reaction may take place in an inert organic solvent, or if a large excess of the compound of the formulae (III) or (IV) is used, this may act as solvent.
The reaction may be effected at a non-extreme temperature such as about -10 to 60 C, for example from about 0 to 30~ C. Low temperatures in this range are preferred ~Ihen using a compound of the formula (IV).
Compounds of the formula (II) and salts thereof may be formed by cleavage of the corresponding p-nitrobenzyl ester. This cleavage may be effected using a reducing agent which reduces the nitro group to an amino group, for example, as described in Dutch Patent Application No: 7702~27.* ~n example of a suitable reducing agent * corresponds to Belgian Patent No. ~51821 '~, ~ 7 ~
is iron powder/ammonium chloride solution.
The following Examples illustrate this invention-`773 Example 1 Benzyl 9-0-vinYlclavulanate H H
F~, C2H50~1 F~'~
C02CH2C6H5 CC)2CH2C6H5 Mercuric acetate (50 mg) was added to a solution o~
benzyl clavulanate (1g) in ethyl vinyl ether (10 ml).
The solution was refluxed for 6 hours, then allowed to stand at room temperature for 72 hours. The solvent was removed under vacuum and the product purified by column chromatography (Kieselgel G, cyclohexane:ethyl acetate 3:1). Yield 0.676g. I.r:~ ma~ (film) 1805, 1750, 1700, 1638, 1620 cm 1. N.m.r.: ~ (CDCl3) 3.00 (1H, d, J 17Hz), 3.43 (1H, dd, J 3Hz and 17 Hz), 3.95 (1H, dd, J 7Hz and 3Hz), 4.13 (1H, dd, J 3 and 14Hz), 4.26 (2H, d, J 7Hz), 4.81 (1H, broad t, J 7Hz), 5.05 (1H, s), 5.13 (2H, s), 5.64 (1H, d, J 3Hz), 6.33 (1H, dd, J 14 and 7Hz), 7.27 (5H, s).
1~"377~
_ 8 --Example 2 Benzvl 9-0-ethylclavulanate H H
F~~ p~- C2H~
"C0 CH C H "
Ethers of clavulanic acid are disclosed in Belgian Patent No: 847045, Japanese Patent Application No: 122725/76 and U.S.
Patent Application Serial No: 786345.* It has been found that 1~ ethyl and propyl ethers of clavulanic acid and derivatives thereof can conveniently be prepared via the vinyl and propenyl ethers of clavulanic acid.
Accordingly, in a divisional application there is provided a process for the preparation of the compounds of the formula (I):
H
N ~ (I) ~ C02H
and salts and esters thereof wherein Rl is a CH2CH3 or CH2CH2CH3 ~roup, which process comprises the reduction of an ester of a compound of the formula (II):
* U.S. Application Serial No. 786,345 corresponds to Canadian Patent App~ication Nos. 263,1~5 and 298,622.
~ 77~9 N ~ (II) ~ ~C0 H
wherein R2 is a CH=CH2 or CH=CH-CH3 group and there-after or simultaneously if desired converting the thus-formed ester of the compound of the formula (I~
to the corresponding acid or a salt thereof.
Most suitably, the reaction is performed on an ester of the compound of the formula (II) wherein ~ is a CH=CH2 group.
The reduction reaction is normally effected by hydro-genation in the presence of a catalyst such as a trans-ition metal catalyst, such as platinium oxide, pallad-ium or the like. An approximately atmospheric pressure of hydrogen is generally most convenient for laboratory useg but sub-atmospheric pressures may also be employed, so long as extreme conditions are avoided.
If a compound of the formula (I) per se or a salt thereof is required, this may be obtained by de-esteri-fying a suitable ester of the compound, for example, by the hydrolysis of a methoxymethyl or like ester or by the hydrogenation of a benzyl, p-methoxybenzyl or like ester optionally in the presence o~ a base, for example, as described in Belgian Patent No: 847045.
If desired, the hydrogenation of the vinyl or propenyl group and hydrogenolysis of the ester may occur at the same time, by selecting a suitable catalyst and solvent, ~1~77~9 for example, by using a tetrahydrofuran - containing solvent system and by using a palladium or mixed platinium oY~ide/palladium catalyst.
The present inver.tion provides the compounds of the formula (II) and salts and esters thereof.
Preferably, R2 is a CH=CH2 group.
Suitable esters of the compounds of the formula (II) include those wherein the esterifying moiety is a group Al or CHA2A3 wherein Al is an alkyl group of 1-8 carbon atoms optionally substituted by halogen or by a group of the formula oA4, oCoA4, SA4 So2A4 wherein A4 is a hydrocarbon group of up to 6 carbon atoms; A2 is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl group optionally substituted by halo~en or by a group A5 or oA5 where A5 is an alkyl group of up to 6 carbon atoms; and A3 is a phenyl group optionally substituted by halogen or nitro or by a group A5 or oA5 where A5 is an alkyl group.
Preferably, the ester of the compound of the for~ula (II) is such that the corresponding ester of the compound of the formula (I) is a readily hydrolysable or hydrogenolysable ester.
Suitable esters of this type include the methoxymethyl, ethoxymethyl, benzyl, methoxybenzyl, nitrobenzyl and the like esters.
b~
A particularly preferred ester of the compounds of the formula (II) is the p-nitrobenzyl ester.
Suitable salts of the compounds of the formula (II) include alkal metal, alkaline earth metal and ammonium and substituted ammonium salts.
Preferably, the salt is a pharmaceutically acceptable salt.
The novel compounds of this invention possess useful ~-lactamase inhihitory properties which allow them to be utilised in antibacterial compositions. Accordingly, this invention provides a pharmaceutical composition which comprises a compound of the formula (II) or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier.
The compositions of this invention may be utilised as described in the aforementioned patent specifica~ions and may advanta~eously contain a penicillin or cephalosporin.
This invention also provides a process for the preparation of the compounds of the formula (II) and salts and esters thereof which process comprises the reaction o an ester of clavulanic acid with a compound of the formula (III) or (IV):
R3 - 0 - CH = CH2 (III) R3 - 0 - CH = CH - CH3 ,~
~77~9 wherein R3 is an al~yl group of up to 6 carbon atoms, in the presence of mercuric ions as catalyst, and thereafter, if desired, de-esterifying the resulting ester of the compound of the formula (II).
Most suitably, R3 in formulae (III) and (IV) is an ethyl group.
Most suitably, the catalyst is mercuric acetate or mercuric trifluoroacetate.
The reaction may take place in an inert organic solvent, or if a large excess of the compound of the formulae (III) or (IV) is used, this may act as solvent.
The reaction may be effected at a non-extreme temperature such as about -10 to 60 C, for example from about 0 to 30~ C. Low temperatures in this range are preferred ~Ihen using a compound of the formula (IV).
Compounds of the formula (II) and salts thereof may be formed by cleavage of the corresponding p-nitrobenzyl ester. This cleavage may be effected using a reducing agent which reduces the nitro group to an amino group, for example, as described in Dutch Patent Application No: 7702~27.* ~n example of a suitable reducing agent * corresponds to Belgian Patent No. ~51821 '~, ~ 7 ~
is iron powder/ammonium chloride solution.
The following Examples illustrate this invention-`773 Example 1 Benzyl 9-0-vinYlclavulanate H H
F~, C2H50~1 F~'~
C02CH2C6H5 CC)2CH2C6H5 Mercuric acetate (50 mg) was added to a solution o~
benzyl clavulanate (1g) in ethyl vinyl ether (10 ml).
The solution was refluxed for 6 hours, then allowed to stand at room temperature for 72 hours. The solvent was removed under vacuum and the product purified by column chromatography (Kieselgel G, cyclohexane:ethyl acetate 3:1). Yield 0.676g. I.r:~ ma~ (film) 1805, 1750, 1700, 1638, 1620 cm 1. N.m.r.: ~ (CDCl3) 3.00 (1H, d, J 17Hz), 3.43 (1H, dd, J 3Hz and 17 Hz), 3.95 (1H, dd, J 7Hz and 3Hz), 4.13 (1H, dd, J 3 and 14Hz), 4.26 (2H, d, J 7Hz), 4.81 (1H, broad t, J 7Hz), 5.05 (1H, s), 5.13 (2H, s), 5.64 (1H, d, J 3Hz), 6.33 (1H, dd, J 14 and 7Hz), 7.27 (5H, s).
1~"377~
_ 8 --Example 2 Benzvl 9-0-ethylclavulanate H H
F~~ p~- C2H~
"C0 CH C H "
2 2 6 5 C02CH2C6H5 A solution of benzyl 9-0-vinylclavulanate (81 mg) in ethyl acetate (10 ml) was hydrogenated over Adams catalyst (10 mg) for 2 hours at room temperature and pressure. The solution was filtered and the filtrate evaporated, and the product separated from starting material by column chromatography (Kieselgel, cyclo-hexane:ethyl acetate 3:1) Yield 54.8 mg.
I.r~rmax(film) 1805, 1750, 1700cm 1 N m r ~(CDCl3) 1 16 (3H, t, J 7Hz), 2 98 (1H, d, J
17Hz), 3 37 (2H, q, J 7Hz), 3 41 (1H, dd, J 3 and 17Hz), 4 00 (2H, d, J 7Hz), 4.79 (1H, t, J 7Hz), 5.04 (1H, s), 5 14 (2H, s3 5.62 (1H, d, J 3Hz), 7.29 (5H, s) 77~
_ g _ xample 3 MethoxymethyI 9-0-vinylclavulanate H H
F ~ C2H50~ ~ o CH=CH2 `C02CH20CH3 C2CH2CH3 A mixture of methoxymethyl clavulanate (972 mg), ethyl vinyl ether (10 ml) and mercuric acetate (50 mg) was heated at reflux, with stirring, for 3~ hours. The mixture was allowed to stand at room temperature 5 overnight, a further portion of methyl vinyl ether (3ml) was added, and the mixture was reflwced for a further hour. The solvent was removed under vacuum, and the product was isolated using column chromatography 5Kieselgel 60, cyclohexane:ethyl acetate 3:1) Yield 10 550 mg as a pale yellow oil.
I.r:~ max (film) 1810, 1755, 1700, 1635, 1620 cm 1.
N-m-r- ~ (CDC13) 3.05 (1H, d, J 17Hz), 3.44 (3H, s),
I.r~rmax(film) 1805, 1750, 1700cm 1 N m r ~(CDCl3) 1 16 (3H, t, J 7Hz), 2 98 (1H, d, J
17Hz), 3 37 (2H, q, J 7Hz), 3 41 (1H, dd, J 3 and 17Hz), 4 00 (2H, d, J 7Hz), 4.79 (1H, t, J 7Hz), 5.04 (1H, s), 5 14 (2H, s3 5.62 (1H, d, J 3Hz), 7.29 (5H, s) 77~
_ g _ xample 3 MethoxymethyI 9-0-vinylclavulanate H H
F ~ C2H50~ ~ o CH=CH2 `C02CH20CH3 C2CH2CH3 A mixture of methoxymethyl clavulanate (972 mg), ethyl vinyl ether (10 ml) and mercuric acetate (50 mg) was heated at reflux, with stirring, for 3~ hours. The mixture was allowed to stand at room temperature 5 overnight, a further portion of methyl vinyl ether (3ml) was added, and the mixture was reflwced for a further hour. The solvent was removed under vacuum, and the product was isolated using column chromatography 5Kieselgel 60, cyclohexane:ethyl acetate 3:1) Yield 10 550 mg as a pale yellow oil.
I.r:~ max (film) 1810, 1755, 1700, 1635, 1620 cm 1.
N-m-r- ~ (CDC13) 3.05 (1H, d, J 17Hz), 3.44 (3H, s),
3.48 (1H, dd, J 3 and 17Hz), 4.97 (1H, dd, J 2 and 7Hz), 4.16 (1H, dd, J 2 and 14Hz), 4.31 (2H, d, J 7Hz),
4.90 (1H, broad t, J 7Hz), 5.06 (1H, broad s), 5.22 (1H, d, J 5Hz), 5.33 (1H, d, J 5Hz), 5.68 (1H, d, J
3Hz), 6.36 (lH, dd, J 7 and 14 Hz).
~ 77~9 Example 4 Benzy~ 9-0-propenylcla~rulanate H~ H
J~)H ~ ~ ~ C~=C~C~3 ~C02CH2C6H5 H3 ~C02CH2C6H5 A stirred solution of benzyl clavulanate (578 mg) in ethyl propenyl ether (5 ml) was cooled to 0C and treat-ed with mercuric trifluoroacetate (20 mg). After 2 hours at 0C, the mixture was allowed to warm to room
3Hz), 6.36 (lH, dd, J 7 and 14 Hz).
~ 77~9 Example 4 Benzy~ 9-0-propenylcla~rulanate H~ H
J~)H ~ ~ ~ C~=C~C~3 ~C02CH2C6H5 H3 ~C02CH2C6H5 A stirred solution of benzyl clavulanate (578 mg) in ethyl propenyl ether (5 ml) was cooled to 0C and treat-ed with mercuric trifluoroacetate (20 mg). After 2 hours at 0C, the mixture was allowed to warm to room
5 temperature for 16 hours. The solvent was removed under reduced pressure and the product was isolated by COlD chromatography (Kieselgel 60, cyclohexane:
ethyl acetate 4:1) Yield 246 mg as a pale yellow oil.
I.r:~ max (film) 1800, 1750, 1695, 1670 cm 1.
N-m-r-: S (CDC13) 1.45 - 1.65 (3H, m), 2.99 (1H, d, J
17Hz), 3.44 (1H~ dd, J 3 and 17Hz~, 4.1 - 4.5 and 4.6 -4 95 (4H, m), 5.05 (1H, s), 5.13 (2H, s~, 5.62 (1H, d, J 3Hz), 5.8 - 6.2 (1H, m), 7.28 (5H, s).
Example 5 Benzyl 9-0-Propyl clavulanate H~ H
0-C = H3 ~ O--CH2CH2CH3 `C02CH2C6H5 2CH2C6H5 A solution of benzyl 9-0-propenylclavulanate (42.2 mg) in ethyl acetate (3ml) was hydrogenated over Adams catalyst (10 mg) for 3 hours at room temperature and pressure. The solution was filtered and evaporated to yield the title compound (40.9 mg).
1 spot by t.l.c (cyclohexane:ethyl acetate 3:1) I.R. max(film) 1805, 1755 and 1700cm 1, N.m~r. (CDCl3) 0.88 (3H, t, J 7Hz) 1 55 (2H, sextet J 7Hz). 2 99 (1H, d, J 17Hæ), 3.27 (2H, t, J 7Hz), 3.42 (1H, dd, J 3 and 17Hz), 3.99 (2H, d, J 7Hz), 4.78 (1H, broad t, 7Hz), 5.04 (1H, s), 5.14 (2H, s), 5.62 (1H, d, J 3Hz), 7.78 (5H, s)~
7;~9 _ 12 _ Example 6 Sodium 9-0-propyl clavulanate H H
"~ O ~
~ ~ 0 ~ CH = CHCH3 ~ ~ 0 -CH2CH2CH3 ~02CH2C6H5 ` C02Na A solution of benzyl 9-0-propenylclavulanate (117 mg) in tetrahydrofuran (4 ml) was hydrogenated over 10%
palladium on charcoal (40 mg) at room temperature and presssure for 10 minutes. The solution was filtered throu~l celite and the residue washed with tetrahydro-furan. The combined filtrates were treated with a solution of sodium bicarbonate (29.9 mg~ in distilled water (4 ml). The tetrahydrofuran was then removed on a rotary evaporator. The residual aqueous solution was extracted twice with ethyl acetate and ~iltered through celite. The solution was evaporated on a rotary evaporator and the residue dried over phosporus pent-oxide to yield the title compound (77.5 mg).
N.m.r. (D20) 0.84 (3H, t, J 7Hz), 1.53 (2H, sextet, J 7Hz~, 3.05 (1H, d, J 17Hz), 3 41 (2H, t, J 7Hz3, 3.54 (1H, dd, J 3 and 17Hz), 4.07 (2H, d, J 7Hz), 4.86 (1H, broad t, J 7Hz), 4.91 (1H, s3, 5.69 (1H, d, J 3Hz).
1~377~9 Example 7 Pivaloyloxymethyl 9-0-vinyIclavulanate O ~ O
~02CH20.CO.C(CH3)3 " C02CH2~.C0.C( A mixture of pivaloyloxymethyl clavulanate (700 mg of crude material) ethyl vinyl ether (5 ml) and mercuric acetate (50 mg) was refluxed for 6 hours and left to stand at room temperature overnight. The solvent was removed under vacuum and the product isolated by column chromatography (Kieselgel 60, cyclohexane:ethyl acetate 3:1). Yield 19 mg.
I.r:~ max (~ilm) 1810, 1760, 1700, 1635, 1620 cm 1 N.m.r.s ~ (CDC13) 1.19 (9H, s), 3.02 (1H, d, J 17Hz), 3.46 (1H, dd, J 3 and 17Hz), 3.96 (1H, dd, J 2.5 and 7Hz), 4.05 - 4.35 (3H, m), 4.84 (1H, broad t, J 7Hæ), 5 04 (1H, broad s), 5~66 (1H, d, J 3Hz), 5.71 (1H, d, J 5Hz), 5.78 (1H, d, J 5Hz), 6.35 (1H, dd, J 7 and 14Hz).
1~77;~9 - 14 ~
Example 8 .
Methyl 9-0-vinYlclavuianate H C2H5 ~ H
~ ~r ~C02cH3 ' C2CH3 A mixture of methyl clavulanate (426 mg), ethyl vinyl ether (5 ml) and mercurir acetate (25 mg) was heated at re~lux for 4 hours. The solvent was removed on a rotary evaporator and the product purified b~ column chromato-graphy. (K$eselgel, cyclohexane:ethyl acetate 1:1) Yield 168 mg.
I.r.:~ maX (film) 1800, 1750, 1700, 1632, 1618 cm 1.
N.m.r: ~ (CDCl3) 3.02 (1H, d, J 17Hz), 3.46 (1H, dd, J
3 and 17Hz), 3.74 (3H, s), 3.97 (1H, dd, J 3 and 7Hz), 4.16 (1H, dd, J 3 and 14Hz), 4.28 (2H, d, J 8Hz), 4.85 (1H, broad t, J 8Hz), 5.04 (1H, s), 5.66 (1H, d, J 3Hz), 6.36 (1H, dd, J 7 and 14Hz).
Analysis: Found C 55.19, H5.70, N 5.93%
C11H13N05 requires C 55.23, H 5.48, N 5.86%.
~77~9 Example 9 P-Nitrobenzyl 9-0-vinyl-clavulanate ~ -Nitrobenzyl clavulanate (3.34g) was dis-solved in dry tetrahydrofuran (30ml). Ethyl vinyl ether (50ml) and mercuric acetate (0.5g) were added to this solution and the resulting mixture was stirred and refluxed (bath temperature 40-50) with exclusion of moisture ~or 24 hours. The mixture was filtered and the solvent was evaporated from the filtrate to yield a bright yellow gum. The gum was chromatographed on silica gel (25 g) using ethyl acetate/petroleum ether (b.p. 60-80). The appropriate fractions, which were recognised using t.l.c., were combined and the solvent was evaporated to give the title compound as a pale yellow gum (270mg). [a]D = + 31.6 (c 1.0, CHC13).
~ max (CHC13): 1802, 1750, 1700, 1620, 1615, 1525, 1350 cm 1 ~ (CDC13): 3.07 (1H, d, J 16Hz), 3.51 (1H, dd, J 16 and 2Hz), 3.95-4.15 (2H, m) 4.32 (2H, d, J 8Hæ), 4.88 (1H, t, J 8Hz), 5.15 (1H, br.s3, 5.28 (2H, s), 5.70 (1H, d, J 2Hz), 6.39 (1H, dd, J 14 and 7Hz), 7.49 (2H, d, J 8.5Hz), 8.22 (2H~ d, J 8.5Hz).
1~773g _ 16 -Example 10 Lithium 9-0-vinyl-clavulanate H H
~H - ~ ~ 0-CH=CH2 p-Nitrobenzyl 9-0-vinyl-clavulanate (190mg) was dissol~ed in tetrahydrofuran (6ml) and to the result-ing stirred solution 1M ammonium chloride solution (6ml) and iron powder (0.8g) were added. The mixture was stirred for 20 minutes and then more iron powder (0.8g) and 1M ammonium chloride solution (0.5ml) were added.
The mixture was stirred for a further 15 minute~ and was then diluted with ethyl acetate (100ml). The resulting mixture was stirred rapidly while hydrogen sulphide was bubbled through it for 5 minutes. The mixture was filtered and the solid was washed well with water. The aqueous layer of the filtrate was saturated with sodium chloride and the mixture was filtered again. me filtrate was treated with 1N HCl (3ml), was shaken, and the layers were separated. The organic layer was dr~ed (sodium sulphate) and filtered. The resulting solution was extracted with 1/15 M phosphate buffer (pH 7; ~ x 3~ml).
The combined extracts were overlayed with ethyl acetate (50ml) and were treated with 1N HCl (5ml). The mixture was shaken and the layers were separated. The organic layer was dried Smagnesium sulphate) and the solvent was evaporated under reduced pressure. The resulting residue was immediately dissolved in tetrahydrofuran (5ml). This 77;~9 solution was diluted with water (5ml) and the pH was ad~usted to 7 by dropwise addition of 0.1M lithium hydroxide solution (ca 2ml). The neutralised solution was filtered and the solvent was evaporated from the filtrate under reduced pressure. The resulting residue was stirred with a mixture of acetone (3ml) and ether (6ml). The resulting solid was collected by filtration, washed with ether, and dried in vacuo.
The title compound was thus obtained as a very pale yellow powder which appeared to be 70-80%
pure as judged by t.l.c. and n.m.r.
Y max (B r): 1770, 1690, 1610 cm 1. ~(D20); inter alia:
3.02 (1H, d, J 17Hz), 3.50 (1H, dd, J 17 and 2.5Hz), 4.00-4.25 (2H, m), 5.68 t1H, d, J 2.5Hz), 6.42 (1H, dd, J 14 and 7Hz).
11~7739 De~.orlstration of ~-Lactamase Inhibitor~ Activit~
~ he minimum inhibitory concentrations (MIC) of certain compounds of this invention and of ampicillin, alone or in -the presence of compounds of the invention, were determined _ vitro for a range of micro-organisms.
The results are shown in Table 1.
773g rrable 1 Compound o~ Conc. ~IC Ampicillin ExarDple No. ~u~/ml ~O~/ml .. _ SAR KA PM EC
0.63.1 8 8 1 1.25 3.162.5 16 0 250 62.5 500 250 Compound alone 125 500 250 500 _ _ __ 0.08 3.12 2 4 1 0.33.12 8 8 0 1000 1000~2000 2000 Compound alone 15.631.2 _ 31.2 *
SAR : Staph~lococcus aureus Russell KA : Klebsiella aero~enes E70 PM : Proteus mirabilis C889 EC : E. coli JT39
ethyl acetate 4:1) Yield 246 mg as a pale yellow oil.
I.r:~ max (film) 1800, 1750, 1695, 1670 cm 1.
N-m-r-: S (CDC13) 1.45 - 1.65 (3H, m), 2.99 (1H, d, J
17Hz), 3.44 (1H~ dd, J 3 and 17Hz~, 4.1 - 4.5 and 4.6 -4 95 (4H, m), 5.05 (1H, s), 5.13 (2H, s~, 5.62 (1H, d, J 3Hz), 5.8 - 6.2 (1H, m), 7.28 (5H, s).
Example 5 Benzyl 9-0-Propyl clavulanate H~ H
0-C = H3 ~ O--CH2CH2CH3 `C02CH2C6H5 2CH2C6H5 A solution of benzyl 9-0-propenylclavulanate (42.2 mg) in ethyl acetate (3ml) was hydrogenated over Adams catalyst (10 mg) for 3 hours at room temperature and pressure. The solution was filtered and evaporated to yield the title compound (40.9 mg).
1 spot by t.l.c (cyclohexane:ethyl acetate 3:1) I.R. max(film) 1805, 1755 and 1700cm 1, N.m~r. (CDCl3) 0.88 (3H, t, J 7Hz) 1 55 (2H, sextet J 7Hz). 2 99 (1H, d, J 17Hæ), 3.27 (2H, t, J 7Hz), 3.42 (1H, dd, J 3 and 17Hz), 3.99 (2H, d, J 7Hz), 4.78 (1H, broad t, 7Hz), 5.04 (1H, s), 5.14 (2H, s), 5.62 (1H, d, J 3Hz), 7.78 (5H, s)~
7;~9 _ 12 _ Example 6 Sodium 9-0-propyl clavulanate H H
"~ O ~
~ ~ 0 ~ CH = CHCH3 ~ ~ 0 -CH2CH2CH3 ~02CH2C6H5 ` C02Na A solution of benzyl 9-0-propenylclavulanate (117 mg) in tetrahydrofuran (4 ml) was hydrogenated over 10%
palladium on charcoal (40 mg) at room temperature and presssure for 10 minutes. The solution was filtered throu~l celite and the residue washed with tetrahydro-furan. The combined filtrates were treated with a solution of sodium bicarbonate (29.9 mg~ in distilled water (4 ml). The tetrahydrofuran was then removed on a rotary evaporator. The residual aqueous solution was extracted twice with ethyl acetate and ~iltered through celite. The solution was evaporated on a rotary evaporator and the residue dried over phosporus pent-oxide to yield the title compound (77.5 mg).
N.m.r. (D20) 0.84 (3H, t, J 7Hz), 1.53 (2H, sextet, J 7Hz~, 3.05 (1H, d, J 17Hz), 3 41 (2H, t, J 7Hz3, 3.54 (1H, dd, J 3 and 17Hz), 4.07 (2H, d, J 7Hz), 4.86 (1H, broad t, J 7Hz), 4.91 (1H, s3, 5.69 (1H, d, J 3Hz).
1~377~9 Example 7 Pivaloyloxymethyl 9-0-vinyIclavulanate O ~ O
~02CH20.CO.C(CH3)3 " C02CH2~.C0.C( A mixture of pivaloyloxymethyl clavulanate (700 mg of crude material) ethyl vinyl ether (5 ml) and mercuric acetate (50 mg) was refluxed for 6 hours and left to stand at room temperature overnight. The solvent was removed under vacuum and the product isolated by column chromatography (Kieselgel 60, cyclohexane:ethyl acetate 3:1). Yield 19 mg.
I.r:~ max (~ilm) 1810, 1760, 1700, 1635, 1620 cm 1 N.m.r.s ~ (CDC13) 1.19 (9H, s), 3.02 (1H, d, J 17Hz), 3.46 (1H, dd, J 3 and 17Hz), 3.96 (1H, dd, J 2.5 and 7Hz), 4.05 - 4.35 (3H, m), 4.84 (1H, broad t, J 7Hæ), 5 04 (1H, broad s), 5~66 (1H, d, J 3Hz), 5.71 (1H, d, J 5Hz), 5.78 (1H, d, J 5Hz), 6.35 (1H, dd, J 7 and 14Hz).
1~77;~9 - 14 ~
Example 8 .
Methyl 9-0-vinYlclavuianate H C2H5 ~ H
~ ~r ~C02cH3 ' C2CH3 A mixture of methyl clavulanate (426 mg), ethyl vinyl ether (5 ml) and mercurir acetate (25 mg) was heated at re~lux for 4 hours. The solvent was removed on a rotary evaporator and the product purified b~ column chromato-graphy. (K$eselgel, cyclohexane:ethyl acetate 1:1) Yield 168 mg.
I.r.:~ maX (film) 1800, 1750, 1700, 1632, 1618 cm 1.
N.m.r: ~ (CDCl3) 3.02 (1H, d, J 17Hz), 3.46 (1H, dd, J
3 and 17Hz), 3.74 (3H, s), 3.97 (1H, dd, J 3 and 7Hz), 4.16 (1H, dd, J 3 and 14Hz), 4.28 (2H, d, J 8Hz), 4.85 (1H, broad t, J 8Hz), 5.04 (1H, s), 5.66 (1H, d, J 3Hz), 6.36 (1H, dd, J 7 and 14Hz).
Analysis: Found C 55.19, H5.70, N 5.93%
C11H13N05 requires C 55.23, H 5.48, N 5.86%.
~77~9 Example 9 P-Nitrobenzyl 9-0-vinyl-clavulanate ~ -Nitrobenzyl clavulanate (3.34g) was dis-solved in dry tetrahydrofuran (30ml). Ethyl vinyl ether (50ml) and mercuric acetate (0.5g) were added to this solution and the resulting mixture was stirred and refluxed (bath temperature 40-50) with exclusion of moisture ~or 24 hours. The mixture was filtered and the solvent was evaporated from the filtrate to yield a bright yellow gum. The gum was chromatographed on silica gel (25 g) using ethyl acetate/petroleum ether (b.p. 60-80). The appropriate fractions, which were recognised using t.l.c., were combined and the solvent was evaporated to give the title compound as a pale yellow gum (270mg). [a]D = + 31.6 (c 1.0, CHC13).
~ max (CHC13): 1802, 1750, 1700, 1620, 1615, 1525, 1350 cm 1 ~ (CDC13): 3.07 (1H, d, J 16Hz), 3.51 (1H, dd, J 16 and 2Hz), 3.95-4.15 (2H, m) 4.32 (2H, d, J 8Hæ), 4.88 (1H, t, J 8Hz), 5.15 (1H, br.s3, 5.28 (2H, s), 5.70 (1H, d, J 2Hz), 6.39 (1H, dd, J 14 and 7Hz), 7.49 (2H, d, J 8.5Hz), 8.22 (2H~ d, J 8.5Hz).
1~773g _ 16 -Example 10 Lithium 9-0-vinyl-clavulanate H H
~H - ~ ~ 0-CH=CH2 p-Nitrobenzyl 9-0-vinyl-clavulanate (190mg) was dissol~ed in tetrahydrofuran (6ml) and to the result-ing stirred solution 1M ammonium chloride solution (6ml) and iron powder (0.8g) were added. The mixture was stirred for 20 minutes and then more iron powder (0.8g) and 1M ammonium chloride solution (0.5ml) were added.
The mixture was stirred for a further 15 minute~ and was then diluted with ethyl acetate (100ml). The resulting mixture was stirred rapidly while hydrogen sulphide was bubbled through it for 5 minutes. The mixture was filtered and the solid was washed well with water. The aqueous layer of the filtrate was saturated with sodium chloride and the mixture was filtered again. me filtrate was treated with 1N HCl (3ml), was shaken, and the layers were separated. The organic layer was dr~ed (sodium sulphate) and filtered. The resulting solution was extracted with 1/15 M phosphate buffer (pH 7; ~ x 3~ml).
The combined extracts were overlayed with ethyl acetate (50ml) and were treated with 1N HCl (5ml). The mixture was shaken and the layers were separated. The organic layer was dried Smagnesium sulphate) and the solvent was evaporated under reduced pressure. The resulting residue was immediately dissolved in tetrahydrofuran (5ml). This 77;~9 solution was diluted with water (5ml) and the pH was ad~usted to 7 by dropwise addition of 0.1M lithium hydroxide solution (ca 2ml). The neutralised solution was filtered and the solvent was evaporated from the filtrate under reduced pressure. The resulting residue was stirred with a mixture of acetone (3ml) and ether (6ml). The resulting solid was collected by filtration, washed with ether, and dried in vacuo.
The title compound was thus obtained as a very pale yellow powder which appeared to be 70-80%
pure as judged by t.l.c. and n.m.r.
Y max (B r): 1770, 1690, 1610 cm 1. ~(D20); inter alia:
3.02 (1H, d, J 17Hz), 3.50 (1H, dd, J 17 and 2.5Hz), 4.00-4.25 (2H, m), 5.68 t1H, d, J 2.5Hz), 6.42 (1H, dd, J 14 and 7Hz).
11~7739 De~.orlstration of ~-Lactamase Inhibitor~ Activit~
~ he minimum inhibitory concentrations (MIC) of certain compounds of this invention and of ampicillin, alone or in -the presence of compounds of the invention, were determined _ vitro for a range of micro-organisms.
The results are shown in Table 1.
773g rrable 1 Compound o~ Conc. ~IC Ampicillin ExarDple No. ~u~/ml ~O~/ml .. _ SAR KA PM EC
0.63.1 8 8 1 1.25 3.162.5 16 0 250 62.5 500 250 Compound alone 125 500 250 500 _ _ __ 0.08 3.12 2 4 1 0.33.12 8 8 0 1000 1000~2000 2000 Compound alone 15.631.2 _ 31.2 *
SAR : Staph~lococcus aureus Russell KA : Klebsiella aero~enes E70 PM : Proteus mirabilis C889 EC : E. coli JT39
Claims (30)
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula (II) (II) or a salt or ester thereof, wherein R2 is a CH=CH2 or CH=CH-CH3 group, which comprises reacting an ester of clavulanic acid with a compound of the formula (III) or (IV):
R3 - O - CH = CH2 (III) R3 - O - CH = CH - CH3 (IV) wherein R3 is an alkyl group of up to 6 carbon atoms, in the presence of a mercuric ion catalyst, and thereafter, if desired, de-esterifying the result-ing ester of the compound of the formula (II); and when a compound of the formula (II) or a salt thereof is required, cleaving the corresponding p-nitrobenzyl ester of the compound of the formula (II); and when required, converting the resulting compound to a salt of a compound of the formula (II);
and when required converting the resulting compound to a pharmaceutically acceptable salt of a compound of the formula (II).
R3 - O - CH = CH2 (III) R3 - O - CH = CH - CH3 (IV) wherein R3 is an alkyl group of up to 6 carbon atoms, in the presence of a mercuric ion catalyst, and thereafter, if desired, de-esterifying the result-ing ester of the compound of the formula (II); and when a compound of the formula (II) or a salt thereof is required, cleaving the corresponding p-nitrobenzyl ester of the compound of the formula (II); and when required, converting the resulting compound to a salt of a compound of the formula (II);
and when required converting the resulting compound to a pharmaceutically acceptable salt of a compound of the formula (II).
2. A process as claimed in claim 1 wherein R3 is an ethyl group.
3. A process as claimed in claim 1 wherein the catalyst is mercuric acetate or mercuric trifluoroacetate.
4. A process as claimed in claim 1, 2 or 3 for the preparation of a compound of the formula (II) or a pharmaceutically acceptable salt thereof comprising the cleavage of the corresponding p-nitrobenzyl ester.
5. A process as claimed in claim 1, 2 or 3 and wherein the cleavage of the ester is effected using a reducing agent which reduces the nitro group to an amino group.
6. A process as claimed in claim 1, 2 or 3 for the preparation of a compound of the formula (II) or a pharmaceutically acceptable salt thereof comprising the cleavage of the corresponding p-nitrobenzyl ester and wherein the cleavage is effected using a reducing agent which is iron powder/ammonium chloride solution.
7. A process as claimed in claim 1 for the preparation of esters of the compounds of formula (II) wherein the ester of clavulanic acid is selected such that the esterifying moiety is a group A' or CHA2A3 wherein A' is an alkyl group of 1-8 carbon atoms optionally substituted by halogen or by a group of the formula OA4, OCOA4, SA4, SO2A4 wherein A4 is a hydrocarbon group of up to 6 carbon atoms; A2 is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl group optionally substituted by halogen or by a group A5 or OA5 wherein A5 is an alkyl group optionally substituted by halogen or nitro or by a group A5 or OA5 where A5 is an alkyl group.
8. A process as claimed in claim 1 wherein the ester of clavulanic acid is selected from readily hydrolysable or hydrogenolysable esters.
9, A process as claimed in claim 1 wherein the ester of clavulanic acid is selected from methoxymethyl, ethoxymethyl, benzyl, methoxybenzyl and nitrobenzyl esters.
10. A process as claimed in claim 1 wherein the salts prepared are selected from alkali metal, alkaline earth metal and ammonium salts.
11. A process as claimed in claim 10 wherein the salts prepared are selected from pharmaceutically acceptable salts.
12. A process for the preparation of benzyl 9-0-vinylclavulanate which comprises reacting mercuric acetate and a solution of benzyl clavulanate in ethyl vinyl ether and isolating the required product.
13. A process for the preparation of methoxymethyl 9-0-vinylclavu-lanate which comprises reacting methoxymethyl clavulanate, ethyl vinyl ether and mercuric acetate and isolating the required product.
14. A process for the preparation of benzyl 9-0-propenylclavulanate which comprises reacting benzyl clavulanate and ethyl propenyl ether with mercuric trifluoroacetate and isolating the required product.
15. A process for the preparation of pivaloyloxymethyl 9-0-vinyl-clavulanate which comprises reacting pivaloyloxymethyl clavulanate and ethyl vinyl ether with mercuric acetate and isolating the required product.
16. A process for the preparation of methyl 9-0-vinylclavulanate which comprises reacting methyl clavulanate and ethyl vinyl ether with mercuric acetate and isolating the required product.
17. A process for the preparation of p-nitrobenzyl 9-0-vinylclavu-lanate which comprises reacting p-nitrobenzylclavulanate in dry tetrahydrofuran with ethyl vinyl ether and mercuric acetate and isolating the required product.
18. A process for the preparation of lithium 9-0-vinylclavulanate which comprises reacting p-nitrobenzyl 9-0-vinylclavulanate in tetrahydro-furan with ammonium chloride and iron powder, isolating the desired compound and neutralised with lithium hydroxide to obtain the required product.
19. A compound of the formula (II) as defined in claim 1 or a pharmaceutlcally acceptable salt or ester thereof whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.
20. An ester of a compound of the formula (II) as set forth in claim 1 wherein the esterifying moiety is as defined in claim 7 whenever prepared by the process of claim 7 or an obvious chemical equivalent thereof.
21. An ester of a compound of the formula (II) as set forth in claim 1 selected from the resdily hydrolysable or hydrogenolysable esters whenever prepared by the process of claim 8 or an obvious chemical equivalent thereof.
22. An ester of a compound of the formula (II) as set forth in claim 1 selected from methoxymethyl, ethoxymethyl, benzyl, methoxybenzyl and nitrobenzyl esters whenever prepared by the process of claim 9 or an obvious chemical equivalent thereof.
23. A pharmaceutically acceptable alkali metal, alkaline earth metal and ammonium salt of a compound of the formula (II) as defined in claim 1 wlenever prepared by the process of claim II or an obvious chemical equivalent thereof.
24. Benzyl 9-0-vinylclavulanate whenever prepared by the process of claim 12 or an obvious chemical equivalent thereof.
25. Methoxymethyl 9-0-vinylclavulanate whenever prepared by the process of claim 13 or an obvious chemical equivalent thereof.
26. Benzyl 9-0-propenylclavulanate whenever prepared by the process of claim 14 or an obvious chemical equivalen thereof.
27. Pivaloyloxymethyl 9-0- vinylclavulanate whenever prepared by the process of claim 15 or an obvious chemical equivalent thereof.
28. Methyl 9-0-vinylclavulanate whenever prepared by the process of claim 16 or an obvious chemical equivalent thereof.
29. p-Nitrobenzyl 9-0-vinylclavulanate whenever prepared by the process of claim 17 or an obvious chemical equivalent thereof.
30. Lithium 9-0-vinylclavulanate whenever prepared by the process of claim 18 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000368746A CA1121360A (en) | 1977-08-04 | 1981-01-16 | .beta.-LACTAM COMPOUNDS |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3269977 | 1977-08-04 | ||
| GB32699/77 | 1977-08-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1107739A true CA1107739A (en) | 1981-08-25 |
Family
ID=10342695
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA308,302A Expired CA1107739A (en) | 1977-08-04 | 1978-07-27 | .beta.-LACTAM COMPOUNDS |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0000804B1 (en) |
| JP (1) | JPS5427595A (en) |
| CA (1) | CA1107739A (en) |
| DE (1) | DE2862385D1 (en) |
| ES (1) | ES472335A1 (en) |
| IT (1) | IT1106618B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1501643A (en) * | 1974-10-28 | 1978-02-22 | Beecham Group Ltd | Antibacterial substituted azetidinones |
| GB1565209A (en) * | 1975-10-13 | 1980-04-16 | Beecham Group Ltd | Clavulanic acid derivatives |
| US4230622A (en) * | 1975-12-17 | 1980-10-28 | Glaxo Laboratories Limited | Halogen derivatives of clavulaic acid |
-
1978
- 1978-07-10 EP EP78300135A patent/EP0000804B1/en not_active Expired
- 1978-07-10 DE DE7878300135T patent/DE2862385D1/en not_active Expired
- 1978-07-27 CA CA308,302A patent/CA1107739A/en not_active Expired
- 1978-08-01 JP JP9501178A patent/JPS5427595A/en active Pending
- 1978-08-02 IT IT50575/78A patent/IT1106618B/en active
- 1978-08-03 ES ES472335A patent/ES472335A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IT1106618B (en) | 1985-11-11 |
| IT7850575A0 (en) | 1978-08-02 |
| EP0000804B1 (en) | 1984-03-07 |
| ES472335A1 (en) | 1980-03-01 |
| JPS5427595A (en) | 1979-03-01 |
| EP0000804A1 (en) | 1979-02-21 |
| DE2862385D1 (en) | 1984-04-12 |
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