EP0000645B1 - Isopénicillines, procédés pour leur préparation et compositions qui les contiennent - Google Patents

Isopénicillines, procédés pour leur préparation et compositions qui les contiennent Download PDF

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Publication number
EP0000645B1
EP0000645B1 EP78300169A EP78300169A EP0000645B1 EP 0000645 B1 EP0000645 B1 EP 0000645B1 EP 78300169 A EP78300169 A EP 78300169A EP 78300169 A EP78300169 A EP 78300169A EP 0000645 B1 EP0000645 B1 EP 0000645B1
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Prior art keywords
compound
oxo
mmol
heptane
thia
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EP78300169A
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German (de)
English (en)
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EP0000645A1 (fr
Inventor
Ralph Floyd Hall
William Francis Huffman
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GlaxoSmithKline LLC
SmithKline Beecham Corp
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SmithKline Corp
SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • This invention relates to isopenicillins showing antibacterial activity, to processes for their preparation, and to pharmaceutical compositions containing them.
  • the acyl group is preferably an acyl group known to impart antibacterial activity as a substituent in the 7- or 6-positions of cephalosporins or _penicillins respectively.
  • acyl refers to acyl groups represented by the general formulae where
  • the 5- or 6-membered heterocyclic rings referred to above include thienyl, furyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, and pyrimidyl.
  • Each heterocyclic group may be unsubstituted or substituted with one or two substituents selected from lower alkyl, halo, hydroxy, nitro, lower alkoxy, aryl such as phenyl, or lower aralkyl.
  • the terms lower alkyl or lower alkoxy refer to groups containing one to six carbon atoms.
  • acyl groups include the following examples:
  • the isopenicillin compounds of this invention decompose rapidly when the 2-carboxylic acid group is present in the free acid form. However, the compounds are stable when the acid is present as a salt or is protected with a protective ester group. Therefore, it is apparent to the skilled chemist that all chemical reactions performed on these compounds must be done under conditions which take this fact into account.
  • a carboxylic acid protective ester residue refers to those ester groups which are commonly employed to block or protect the carboxylic acid functionality while reactions are carried out on other functional groups within the molecule.
  • the term has acquired a definite meaning within the f3- lactam and organic chemical arts and many useful groups within this term are known in the art. These protective groups are known for the ease with which they may be cleaved to regenerate the carboxylic acid group.
  • the term refers to those groups known in the art which can be cleaved by mild basic hydrolysis and/or hydrogenation in basic solution.
  • ester protecting groups include lower alkyl such as methyl, 2,2,2-trichloroethyl, f3-iodoethyl, C1-Ca-alkanoylmethyl, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, methylbenzoylmethyl, methanesulfonylbenzoylmethyl, phenylbenzoylmethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, and benzhydryl.
  • the choice of which ester group to use is well within the ability of one skilled in the art. Factors which are considered include what subsequent reaction conditions the group must withstand and what conditions for removing the protecting ester are desirable. Particularly preferred esters are methyl, benzyl and benzhydryl.
  • the selection of the proper protecting group is not critical to our invention since the point of novelty of our invention lies within the new isopenicillin nucleus and not within the ester groups substituted thereon
  • carboxyl protecting groups are not intended to be exhaustive. A person skilled in the art knows the purpose of these groups and is able to properly choose from the groups known and described in the art. Many articles and books have described the subject of protecting reactive groups, for example J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, 1973.
  • salts of carboxylic acids for pharmaceutical formulations. These salts have improved properties, such as solubility, over the free acids.
  • useful cations include alkali metals such as sodium and potassium, alkaline earth metals and ammonium cations from inorganic or organic amine bases. These salts are prepared when the protective ester groups are hydrolyzed by base or when the isopenicillin nucleus is formed by base treatment as described below.
  • salts of other acid moieties present within the acyl group of the compounds are prepared in the same manner as described above.
  • the compounds of this invention may exist in hydrate or solvate form.
  • the amount of water or solvent may vary.
  • the compounds of this invention where R is acylamino and M'is hydrogen or a pharmaceutically acceptable cation have antibacterial activity against Gram-positive and Gram-negative organisms.
  • Minimum inhibitory concentrations (MIC's) against a variety of bacteria are shown in Table 1 for representative compounds. Data for standard antibacterial agents, penicillin V and 2-thienylmethyl- penicillin are included.
  • the active compounds or their salts can be dissolved in water and used to sterilize laboratory equipment or for the treatment or prevention of bacterial infections in warm-blooded mammals such as man.
  • R is acylamino and M is a carboxylic acid protecting ester group also exhibit antibacterial activity, for example against B. subtilis. These compounds may be used in the same manner as described for the compounds where M is not an ester group.
  • R is amino or azido and/or M is a carboxylic acid protecting ester group are useful as intermediates for the preparation of the therapeutically active compounds.
  • R is azido
  • reduction by chemical or catalytic methods also gives the useful free amino derivative.
  • halogen or halo shall mean fluorine, chlorine, bromine or iodine.
  • the compounds of this invention are novel bicyclic A-lactams which are prepared by a totally synthetic route.
  • the key starting materials are cis-3-azido-4-oxo-2-azetidinylmethyl iodide (1 a) and cis-3-t-butoxycarbonylamino-2-hydroxymethyl-4-oxoazetidine ⁇ 1b ⁇ .
  • These compounds can be prepared in good yield via a ketene-imine cyclization reaction of azidoacetic acid and methyl N-(2,4-dimethoxybenzyl)iminoacetate and subsequent chemical modification, all as set forth in Belgian Patent No. 841,234.
  • Schemes 1, 2 and 3 set forth different reactions which may be used to prepare compounds of this invention. It is readily apparent to one skilled in the art that the reactions set forth in these Schemes may be carried out by various methods in various sequences. In particular, at various points along the reaction pathway set forth in each of the Schemes, the R substituent may be converted from azido to amino and the amino group subsequently acylated with a desired acyl group. The most advantageous times to perform these conversions would be readily apparent to a person skilled in the art.
  • the reaction sequence set forth in Scheme 1 involves first, a condensation of the A-lactam 1 with an ester of glyoxylic acid to give the ⁇ -hydroxy- ⁇ -azetidinyl acetic acid derivative (2).
  • the hydroxy group of this compound is converted to a halo derivative, such as chloro by the reaction with thionyl chloride, and the halo derivative is reacted with a salt of thiolacetic acid to give the sulfur-containing compound (3).
  • Cyclization of compound (3) to the desired isopenicillin derivative can be effected by treatment with a base such as cyclohexylamine. If R is azido, reduction to the amino derivative followed by acylation with the desired acyl group gives the compounds of this invention. If M is a protecting ester group, it may be removed by base hydrolysis to give the compounds where M is a cation.
  • a preferred route to the antibacteriaf compounds of this invention involves treating compound 3 where R is acylamino and M is a cation such as sodium with a base such as cyclohexylamine.
  • R is t-butoxycarbonylamino
  • M is benzhydryl
  • thionyl chloride followed by potassium thiolacetate gives compound 3 (R and M are as above).
  • any organic primary and secondary amine which preferentially hydrolyzes the thiolacetate moiety over attacking the A-lactam moiety gives the desired product.
  • the selectivity of action is a result of choosing a base with the proper balance between basicity and nucleophilicity. The selection of the proper base is within the ability of a person skilled in the art.
  • the preferred route is run in an organic solvent, preferably an aprotic solvent.
  • the reaction is run at a temperature and a period of time which maximizes the formation of product and minimizes product decomposition. Temperatures may range from -30 to 30° with about 0° being a preferred temperature.
  • Scheme 2 sets forth a different reaction sequence for converting the ⁇ -hydroxy compound 2 into the isopenicillins.
  • the hydroxy group is converted into a chloro group as outlined above in Scheme 1.
  • the resulting chloro derivative is treated with sodium triphenylmethylmercaptide to give derivative 4.
  • Cyclization of derivative 4 can be effected by treatment with metal ions such as silver or mercury or by treatment with a strong acid such as trifluoroacetic acid.
  • the a-chloro compound (5) may also be converted directly into the desired isopenicillin as outlined in Scheme 3.
  • Reagents useful for this conversion include hydrogen sulfide, sodium hydrosulfide, sodium sulfide and tetramethylguanidinium hydrosulfide.
  • Acylations of the compounds of this invention are effected by standard methods.
  • the carboxylic acid group which will be the carbonyl group in the acyl moiety is activated by known methods including mixed anhydride, activated esters, and acid halides.
  • use of coupling reagents such as dicyclohexylcarbodiimide and carbonyldiimidazole is a possible method of acylation.
  • any sensitive group in the acyl moiety for example, hydroxyl or carboxyl, can be protected by a standard protecting group such as those described previously and/or known in the art.
  • acyl groups which are particularly useful in this invention contain an asymmetric carbon atom. It is understood that each optical isomer separately and as mixtures of the isomers are within the scope of this invention. It has been found that the D-isomer is particularly useful and therefore is a preferred isomer as with the mandelamido containing compounds.
  • the cis-fused isopenicillin ring system may exist as d and I isomers.
  • the carboxylic acid group at position 2 can be in the a or f3 configuration and results in an additional center of asymmetry. All possible stereoisomers are within the scope of this invention.
  • Benzyl glyoxylate (1.97 g, 12 mmol) was dissolved in toluene (25 ml) and a small amount was distilled out to dry the solution. The solution was cooled to 90° and the product of Preparation 1 (1 g, 3.97 mmol) was added. The reaction was heated for 5.5 hours under argon at 90°. The solution was evaporated in vacuo and the residue was chromatographed on silica gel (100 g). The product was eluted with 10% ethyl acetate in benzene, 1.28 g (78%).
  • the reaction mixture was extracted with ethyl acetate and the product isolated in the usual way to give crude material (16 g) which was dissolved in dichloromethane and allowed to crystallize overnight at -23°C. The solution was filtered and the crystals dried to give a white crystalline solid; 2.6 g, mp 159-160.5°. The mother liquors were combined and chromatographed on silica gel to afford additional semicrystalline product (3.71 g). The crystalline material was a single diastereoisomer while the material isolated by chromatography was a mixture of diastereoisomers.
  • the combined extracts are washed copiously with water and brine.
  • the dried extracts are distilled in vacuo to give 4.5 g of clear orange gum which was rapidly chromatographed on a column of 90 g of silica gel. with methylene chloride and 20% ethyl acetate in methylene chloride as eluants to give the condensation products, 1.66 g (64%).
  • Example 2 The compound from Example 2 (65 mg, 0.171 mmol) was hydrogenated at atmospheric pressure in ethyl acetate (2 ml) in the presence of Pt0 2 (130 mg) for three hours. The mixture was filtered and evaporated to give the title product, 60 mg.
  • Example 1 The compound of Example 1 (35 mg, 0.115 mmol) was hydrogenated in ethyl acetate with Pto 2 as catalyst (70 mg) in the same manner as in Example 3 to give the title product, 32 mg.
  • the compound of Preparation 12 (731 mg, 0.935 mmol) was dissolved in dichloromethane (30 ml) and anisole (4 ml), cooled to 0° under argon and treated with trifluoroacetic acid (36 ml). The mixture was stirred at 0° for 20 minutes and then was added rapidly to a cold mixture of aqueous NaHCO a layered with ethyl acetate. The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic phases were washed with brine, dried and evaporated to give the product which was chromatographed on silica gel (100 g).
  • the title compound was also prepared by dissolving the intermediate chloro compound prepared above in anhydrous dimethylformamide (1.5 ml) and cooling to -20 0 .-The cold solution was treated with a sodium sulfide-dimethylformamide solution (0.7 ml) which was prepared as follows:

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  • Chemical & Material Sciences (AREA)
  • 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)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Claims (13)

1. Composé de formule
Figure imgb0011
dans laquelle R représente un radical acylamino, azido ou amino et M représente un atome d'hydrogène, un cation pharmaceutiquement acceptable ou un groupe ester d'acide carboxylique protecteur éliminable.
2. Composé tel que revendiqué dans la revendication 1, dans laquelle le groupe acyle du radical acylamino est un groupe
Figure imgb0012
dans lequel
X représente un radical thiényle, furyle, cyclohexyle, cyclohexényle, cyclohexadiényle, phényle ou phényle substitué par un ou deux substituants alkyle inférieur, alcoxy inférieur, hydroxy, hydroxyméthyle, halo, nitro, mercapto, alkyl inférieur thio, trifluorométhyle, uréido, formamido ou carboxyméthylamino;
A représente un radical hydroxy, formyloxy, carboxy, sulfo ou (en l'absence d'alpha-hydrogène) un radical methoxyimino ou oximino;
Y représente un radical cyano, azido, phényle, phénoxy ou un noyau hétérocyclique à 5 ou 6 chaînons contenant du carbone et de 1 à 4 hétéroatomes choisis parmi l'azote, l'oxygène et le soufre;
Z représente un radical phényle, pyridyle, alkyl inférieur, trifluorométhyle, trifluoroéthyle ou cyanométhyle;
n a une valeur de 0, 1 ou 2; et
M représente un atome d'hydrogène ou un cation pharmaceutiquement acceptable.
3. Composé tel que revendiqué dans la revendication 1 ou dans la revendication 2, dans laquelle le groupe acyle du radical acylamino est un radical mandéloyle, a-formyloxyphénylacétyle, trifluoro- méthylmercaptoacétyle, méthylmercaptoacétyle, méthylsulfonylacétyle, 2,2,2-trifluoroéthylsulfinyl- acétyle, cyanoacétyle, cyanométhylmercaptoacétyle, a-carboxy-2-thiénylacétyle, β-carboxy-3-thiénylacétyle, a-carboxyphénylacétyle, a-sulfophénylacétyle, 2-thiénylacétyle, 1-tetrazolylacétyle, phénoxy- acétyle, phénylacétyle, 4-pyridylmercaptoacétyle, ce-syn-méthoXyimino (2-furyl)-acétyle ou α-oximino- phénylacétyle.
4. L'acide 6β-phénoxyacétamido-7-oxo-3-thia-1-azabicyclo-[3.2.0] heptane-2-carboxylique et son sel de cyclohexylamine, de sodium ou de potassium.
5. L'acide 6β-(2'-thiénylacétamido)-7-oxo-3-thia-1-azabicyclo-[3.2.0] heptane-2-carboxylique et son sel de cyclohexylamine, de sodium ou de potassium.
6. Composé tel que revendiqué dans la revendication 1 ou la revendication 2, dans laquelle R représente un radical amino et
M représente un radical méthyle, benzyle ou benzhydryle.
7. L'ester benzylique de l'acide 6β-amino-7-oxo-3-thia-1-azabicyclo [3.2.0]-heptane-2-carboxylique.
8. L'ester benzhydrylique de l'acide 6β-amino-7-oxo-3-thia-1-azabicyclo-[.2.0] heptane-2-carboxylique.
9. L'acide 6β-azido-7-oxo-3-thia-1-azabicyclo [3.2.0] heptane-2-carboxylique.
10. Composé tel que revendiqué dans la revendication 9, sous la forme de son ester benzhydrilique.
11. Composé tel que revendiqué dans la revendication 9, sous la forme de son ester benzylique.
12. Procédé de préparation d'un composé tel que revendiqué dans la revendication 1 dans laquelle
R représente un radical acylamino ou azido caractérisé en ce qu'on fait réagir un composé de formule
Figure imgb0013
dans laquelle
R représente un radical acylamino ou azido;
X représente un atome d'halogène; et
M représente un atome d'hydrogène, un cation d'un métal alcalin ou un groupe d'acide carboxylique protecteur éliminable, avec une base, et que, si l'on désire un composé tel que revendiqué dans la revendication 1 dans laquelle R représente un radical amino, on enlève un groupe acyle protecteur d'un groupe acylamino.
13. Composition pharmaceutique caractérisé en ce qu'elle contient un composé tel que revendiqué dans la revendication 2 en association avec un véhicule ou diluant pharmaceutiquement acceptable.
EP78300169A 1977-07-26 1978-07-20 Isopénicillines, procédés pour leur préparation et compositions qui les contiennent Expired EP0000645B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US05/819,197 US4122086A (en) 1977-07-26 1977-07-26 Isopenicillins
US819197 2001-03-28

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EP0000645A1 EP0000645A1 (fr) 1979-02-07
EP0000645B1 true EP0000645B1 (fr) 1981-01-28

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US (1) US4122086A (fr)
EP (1) EP0000645B1 (fr)
JP (1) JPS5424891A (fr)
DE (1) DE2860370D1 (fr)
DK (1) DK328578A (fr)
IE (1) IE47037B1 (fr)
IT (1) IT1097306B (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4257947A (en) * 1977-08-03 1981-03-24 Smithkline Corporation 3-Amino-2-hydroxy, halo or mercaptomethyl-4-oxoazetidines
US4174316A (en) * 1978-08-14 1979-11-13 Merck & Co., Inc. 4-Iodomethylazetidin-2-one
ATE6065T1 (de) * 1978-08-14 1984-02-15 Merck & Co. Inc. Verfahren zur herstellung von thienamycin und zwischenprodukten.
US4290947A (en) * 1979-04-27 1981-09-22 Merck & Co., Inc. Process for the preparation of thienamycin and intermediates
JPS62248766A (ja) * 1986-04-21 1987-10-29 タキゲン製造株式会社 扉用ハンドル装置
JPS63140464U (fr) * 1987-03-09 1988-09-16
PT611115E (pt) * 1993-02-10 2001-07-31 Shionogi & Co Preparacao de compostos beta-lactamicos e seus intermediarios
US5563264A (en) * 1993-02-10 1996-10-08 Shionogi & Co., Ltd. Preparation of βlactam compounds
US5496816A (en) * 1994-03-14 1996-03-05 Merck & Co., Inc. Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK194776A (da) * 1975-05-05 1976-11-06 Smithkline Corp Antibakterielle midler og mellemprodukter dertil

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DE2860370D1 (en) 1981-03-19
US4122086A (en) 1978-10-24
JPS5424891A (en) 1979-02-24
EP0000645A1 (fr) 1979-02-07
IT7826043A0 (it) 1978-07-24
IE47037B1 (en) 1983-11-30
DK328578A (da) 1979-01-27
IE781493L (en) 1979-01-26
IT1097306B (it) 1985-08-31
JPS6143357B2 (fr) 1986-09-26

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