Tricyclic cephems as inhibitors of human leukocyte elastase. Furo[3,4-c]cepham sulfones

Alpegiani, Marco; Bissolino, P.; Corigli, R.; Rizzo, Vincenzo; Perrone, Ettore

doi:10.1016/0960-894x(95)00094-a

Cited by 6 publications

(3 citation statements)

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“…[7a] Some tricyclic β-lactams acted as inhibitors of β-lactamases [10][11][12] and other medicinally relevant mammalian enzymes implicated in many diseases. [13,14] Thus, tricyclic β-lactams constituted a new generation of β-lactam antibiotics which are resistant to a wide range of β-lactamases and exhibit improved metabolic stability.…”

Section: Introductionmentioning

confidence: 99%

“…Few more structural analogs of sanfetrinem were synthesized and are known to possess a broad spectrum of antibacterial activities . Some tricyclic β‐lactams acted as inhibitors of β‐lactamases and other medicinally relevant mammalian enzymes implicated in many diseases . Thus, tricyclic β‐lactams constituted a new generation of β‐lactam antibiotics which are resistant to a wide range of β‐lactamases and exhibit improved metabolic stability.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of Chlorinated, Heteroatom‐Rich and Differently Fused Tricyclic β‐Lactams by Cu(I)‐Catalyzed Halogen Atom Transfer Radical Cyclization

Dawra¹,

Ram

Thakur

2020

ChemistrySelect

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The application of Cu (I)-catalyzed halogen atom transfer radical cyclization (ATRC) for the synthesis of two different series of chlorinated, heteroatom rich and differently fused tricyclic β-lactams has been demonstrated. N-substituted-3,4dihydropyrimidine-2(1H)-thiones synthesized by Biginelli reaction were used as starting materials for this synthetic pathway which upon S-allylation/alkylation furnished 2-allylthio/alkylthio-1,4-dihydropyrimidines (cyclic imines). Staudinger reaction of these cyclic imines with dichloroketene was employed to obtain the bicyclic dichloro-S-allyl/N-allyl-β-lactams, which upon subsequent Cu(I)-catalyzed ATRC produced two different series of tricyclic β-lactams. The difference in the relative behavior of N-allyl bicyclic dichloro-β-lactams and S-allyl bicyclic dichloro-β-lactams towards ATRC was also introspected in terms of their relative rates of cyclization, the amount of catalyst loading needed and the stabilities of tricyclic-β-lactams obtained after cyclization. To study the relative reactivity of Nallyl group and S-allyl group towards ATRC, the bicyclic dichloro-β-lactams having both S-allyl and N-allyl groups were synthesized. The intramolecular competitive experiments revealed the high reactivity of S-allyl group towards ATRC than the N-allyl group.[a] Dr. N. DawraMehr Chand Mahajan DAV College for Women Sector 36-A, Chandigarh,

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis of Chlorinated, Heteroatom‐Rich and Differently Fused Tricyclic β‐Lactams by Cu(I)‐Catalyzed Halogen Atom Transfer Radical Cyclization

Dawra¹,

Ram

Thakur

2020

ChemistrySelect

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“…Our investigation 3 has resulted in the disclosure of original 1,1dioxocephem 4-ketones 4 and tricyclic cephem sulfones. 5 As their synthesis mostly relies on the exploitation of the key-intermediates 1 and 2, we sought for improved methods of preparing both synthons: herein and in the accompanying paper 6 we report our findings on this subject. Scheme 1 outlines the retrosynthetic pathway according to which we had previously obtained cephem 1 starting from 7α-methoxy-3deacetoxycephalosporanic acid 3.…”

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Novel Preparation of 1,1-Dioxo-7α-methoxy-3-methyl-Δ³-cephem-4-yl Aryl Ketones

Alpegiani¹,

Bissolino²,

D'Anello³

et al. 1998

Synlett

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1,1-Dioxo-7α-methoxy-3-methyl-∆ 3 -cephem-4-yl phenyl ketone, a valuable precursor of potent HLE inhibitors, was obtained in an efficient way starting from 7α-methoxy-3-methyl-∆ 3 -cephem-4-carboxylic acid. By employing the same methodology a variety of 1,1-dioxocephem-4-yl aryl ketones were prepared.Until a decade ago cephem derivatives had long been known only for their antibacterial properties attained through inhibition of bacterial peptidases. 1 During the last decade the capability of modified cephalosporins to inhibit mammalian serine proteinases, and in particular human leukocyte elastase (HLE), has been ascertained. 2 The prospective use of cephems as antiinflammatory drugs in human therapy has fostered renewed efforts to explore the cephem field both from a chemical and a biological point of view.Our investigation 3 has resulted in the disclosure of original 1,1-dioxocephem 4-ketones 4 and tricyclic cephem sulfones. 5 As their synthesis mostly relies on the exploitation of the key-intermediates 1 and 2, we sought for improved methods of preparing both synthons: herein and in the accompanying paper 6 we report our findings on this subject.Scheme 1 outlines the retrosynthetic pathway according to which we had previously obtained cephem 1 starting from 7α-methoxy-3-deacetoxycephalosporanic acid 3. 7 Carbon-carbon bond formation was the critical step, and acid chloride 4, uneventfully obtained from acid 3, was converted into phenyl ketone 5 upon treatment with phenylmagnesium chloride/copper(I) iodide. 4 Scheme 1In developing an alternative synthetic plan we were guided by two main considerations elaborated on the basis of other researchers' and our own experience in the field of cephem chemistry. Firstly, cephem esters had been reported to undergo regioselective acylation at C-4. 8 Secondly we had observed the easy decarboxylation of 4-alkyl-4-carboxy-∆ 2 -cephem sulfones to provide 1,1-dioxo-4-alkyl-∆ 3 -cephems. 9 Both these features turned out to be the keystones of an efficient synthetic pathway, according to which the targeted 4-benzoyl cephem 1 was obtained in five steps from the cheap and commercially available 7β-amino-3-deacetoxycephalosporanic acid (7-ADCA) (Scheme 2).The methoxy-deamination reaction of 7-ADCA to provide 7α-methoxy-3-deacetoxycephalosporanic acid 3 7 was optimised in terms of safety and reproducibility by substituting methanesulfonic acid for perchloric acid in the diazotation of 7-ADCA; crude acid 3 was then protected 10 with p-methoxybenzyl chloride (NaBr, NaHCO 3 , DMF) affording ester 6 11 in satisfactory yield. Upon treatment of 6 with LDA (1.1 mol equiv, THF, -70 °C) and then with benzoyl chloride (1.5 mol equiv, -70 °C) the C-4 acylated ∆ 2 -cephem 7 was produced as a single diastereomer in about 75% yield. It is noteworthy that the delocalized carbanionic species, generated by removal of a cephem C-2 proton, undergoes Scheme 2Downloaded by: University of Liverpool. Copyrighted material. LETTERS SYNLETTacylation with remarkable regio-and stereoselectivity. On mechanistic g...

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ChemInform Abstract: Tricyclic Cephems as Inhibitors of Human Leukocyte Elastase. Furo(3,4‐ c)cepham Sulfones.

et al. 1995

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Tricyclic cephems as inhibitors of human leukocyte elastase. Furo[3,4-c]cepham sulfones

Cited by 6 publications

References 9 publications

Synthesis of Chlorinated, Heteroatom‐Rich and Differently Fused Tricyclic β‐Lactams by Cu(I)‐Catalyzed Halogen Atom Transfer Radical Cyclization

Synthesis of Chlorinated, Heteroatom‐Rich and Differently Fused Tricyclic β‐Lactams by Cu(I)‐Catalyzed Halogen Atom Transfer Radical Cyclization

Novel Preparation of 1,1-Dioxo-7α-methoxy-3-methyl-Δ³-cephem-4-yl Aryl Ketones

ChemInform Abstract: Tricyclic Cephems as Inhibitors of Human Leukocyte Elastase. Furo(3,4‐ c)cepham Sulfones.

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Tricyclic cephems as inhibitors of human leukocyte elastase. Furo[3,4-c]cepham sulfones

Cited by 6 publications

References 9 publications

Synthesis of Chlorinated, Heteroatom‐Rich and Differently Fused Tricyclic β‐Lactams by Cu(I)‐Catalyzed Halogen Atom Transfer Radical Cyclization

Synthesis of Chlorinated, Heteroatom‐Rich and Differently Fused Tricyclic β‐Lactams by Cu(I)‐Catalyzed Halogen Atom Transfer Radical Cyclization

Novel Preparation of 1,1-Dioxo-7α-methoxy-3-methyl-Δ3-cephem-4-yl Aryl Ketones

ChemInform Abstract: Tricyclic Cephems as Inhibitors of Human Leukocyte Elastase. Furo(3,4‐ c)cepham Sulfones.

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Novel Preparation of 1,1-Dioxo-7α-methoxy-3-methyl-Δ³-cephem-4-yl Aryl Ketones