Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084

Isoda, Takeshi; Ushirogochi, Hideki; Satoh, Koichi; Takasaki, Tsuyoshi; Yamamura, Itsuki; Sato, Chisato; Mihira, Ado; Abé, Takao; Tamai, Satoshi; Yamamoto, Shigeki; Kumagai, Toshio; Nagao, Yoshimitsu

doi:10.1038/ja.2006.34

Cited by 21 publications

(11 citation statements)

References 17 publications

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“…12) In recent years, the development of new antibiotics has attracted the attention in the clinical realm for the treatment of severe infectious diseases. L-084 is one of several promising candidates for oral administration and is now under clinical trials.…”

Section: Resultsmentioning

confidence: 99%

Efficient Synthesis of Isothiocyanates Based on the Tandem Staudinger/aza-Wittig Reactions and Mechanistic Consideration of the Tandem Reactions

Isoda¹,

Hayashi²,

Tamai³

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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The reaction of organic azides with trivalent phosphorous compounds to afford the corresponding azaylides is known as the Staudinger reaction.1) This reaction proceeds via a primary imination adduct, phosphazide, which spontaneously decomposes into azaylide and nitrogen in most cases.2) The azaylide product can usually be isolated as a stable compound, which can be used to prepare various amines, imines, amides, isocyanates, isothiocyanates, 3,4) and so forth, 5) as a versatile synthetic intermediate. As for the isothiocyanate synthesis, a convenient one-pot procedure was reported by Tsuge et al. in 1984 as is to say the tandem Staudinger/azaWittig reaction.6,7) They used carbon disulfide (CS 2 ) as the co-solvent in the reaction of only (trimethylsilyl)methylazide with triphenylphosphine (PPh 3 ), 6) and the yield of the corresponding isothiocyanate was superior to that obtained from a stepwise method 8) in which CS 2 was added to the primary reaction mixture containing the azaylide product. Especially, the tandem method was recently utilized in a carbohydrate field in order to effectively obtain isothiocyanate-functionalized sugars.9-11) Herein, we investigated the substrate generality of the tandem and stepwise Staudinger/aza-Wittig reactions and their reaction mechanisms utilizing a 1 H-NMR analysis. Results and DiscussionOur first target was to prepare chloroethylisothiocyanate (3a), because 3a was an indispensable material for the synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1), useful for the pendant moiety of the oral carbapenem antibiotic L-084 (Chart 1).12) In recent years, the development of new antibiotics has attracted the attention in the clinical realm for the treatment of severe infectious diseases. L-084 is one of several promising candidates for oral administration and is now under clinical trials. During the course of our synthetic study of L-084, we established an efficient synthetic route for 1 from 2 and 3a, 13) but to the best of our knowledge, there was no application to prepare 3a without using the harmful and toxic thiophosgene. 14,15) Thus, we planned to develop an effective and harmless synthetic route for 3a in which scaleup production would be possible. Chloroethylisothiocyanate (3a) was initially prepared from the reaction of chloroethylazide (5a) 16) and PPh 3 followed by the aza-Wittig reaction with CS 2 , but 3a was obtained in only 16% yield from 5a due to the decomposition of the unstable intermediate 8a (Entry 1 in Table 1). As a result of the optimization of the reaction conditions, we found that the yield of 3a dramatically increased to 83% when CS 2 was used as the co-solvent in the reaction of 5a with Ph 3 P, compared to the above stepwise method.At this point, we investigated in detail the tandem Staudinger/aza-Wittig reactions (Method I) and the stepwise reactions (Method II), as shown in Table 1. Namely, several azides 5b-g were treated with Ph 3 P in a mixed solvent of CS 2 and CHCl 3 to afford the corresponding isothiocyanates in good yields except for th...

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Section: Resultsmentioning

confidence: 99%

Efficient Synthesis of Isothiocyanates Based on the Tandem Staudinger/aza-Wittig Reactions and Mechanistic Consideration of the Tandem Reactions

Isoda¹,

Hayashi²,

Tamai³

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Therefore, prodrug approaches have been undertaken to overcome the poor oral availability of carbapenems [4]. Some prodrugs have been reported to afford increases in the oral availability of parent carbapenems [5,6].…”

Section: Introductionmentioning

confidence: 99%

Possible Factors Involved in Oral Inactivity of Meropenem, a Carbapenem Antibiotic

Saito¹,

Sawazaki²,

Ujiie³

et al. 2012

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Meropenem, a carbapenem antibiotic, is inactive after oral administration and administered exclusively by injection. In this study, in order to address the factors involved in the oral inactivity of meropenem, in vitro permeation characteristics across rat ileal segments was investigated using diffusion cells. Moreover, stability of meropenem was evaluated in the Japanese Pharmacopoeia (JP) 1st and 2nd fluid for disintegration test. Cefotaxime, ceftibuten, and faropenem were used for comparison. The permeation of meropenem across rat ileal segments was approximately 5-fold greater in secretory direction than in absorptive direction. The secretory-oriented transport of meropenem markedly diminished by replacement of D-glucose in the experimental medium with unmetabolizing 3-O-methyl-D-glucose, suggesting that the secretory transport of meropenem was an energy-dependent process. Cefotaxime exhibited extensively secretory-oriented permeation. On the other hand, much weaker directionalities were observed in ceftibuten and faropenem. While meropenem as well as other three β-lactam antibiotics was stable in JP 2nd fluid (pH 6.8), it declined rapidly in JP 1st fluid (pH 1.2). These results suggest that, in addition to the hydrophilic property of meropenem, its instability at gastric pH and secretory transport in the small intestine are possible factors involved in the inactivity of meropenem after oral administration

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“…In the early stage of the development of L-084, thiol 1 was prepared from the acetylthio compound 9 according to the above method we previously reported. 28) As for a large-scale production, the oily compound 9 was considered not to be an appropriate precursor, and the second generation precursor, crystalline compound 10, was omitted due to the cost of a metal thiobenzoate (Chart 2). As a more convenient method for the preparation of 1, the introduction of a dithiosulfonate group was investigated.…”

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“…28) Compound 5 was obtained in two steps including cyclization of N-benzhydryl-3-chloro-2-hydroxypropylamine (3) and deprotection of the N-substituent according to the literature (Chart 2). 31,32) Although compound 5 has been well recognized as a useful building block for various bioactive molecules such as antimicrobial agent WQ-2743, 33) antiepileptic Dezinamide 34) and antihypertensive Azelnidipine, 35) it has been suggested that the above two-step procedure for 5 was too expensive to adopt for large-scale production.…”

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confidence: 99%

“…The title compound L-084 is one of the hopeful candidates among recently reported oral carbapenems such as CS-834, [7][8][9][10][11][12] GV-118819 [13][14][15][16][17] and DZ-2640. [18][19][20][21][22][23][24][25][26][27] L-084, an ester-type prodrug of the active metabolite LJC11,036 (2), shows high bioavailability in humans, 28) and exhibits high antimicrobial activity against Gram-positive and Gram-negative bacteria. 29) The structural feature of L-084 is an achiral azetidine moiety at the C-2 position of the 1b-methylcarbapenem skeleton, whereas CS-834 and DZ-2640 have a chiral pyrrolidine moiety as shown in Chart 1.…”

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A Practical and Facile Synthesis of Azetidine Derivatives for Oral Carbapenem, L-084

Isoda¹,

Yamamura²,

Tamai³

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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An orally active carbapenem L-084, which exhibits high bioavailability in humans, has a 1-(1,3-thiazolin-2-yl)azetidin-3-ylthio moiety at the C-2 position of the 1b b-methylcarbapenem skeleton. We established a practical and cost-effective synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1) for further scale-up production of L-084. This synthesis method entails an industry-oriented reaction of azetidine ring-closure to yield N-benzyl-3-hydroxyazetidine (16), which is eventually converted to 1 via key intermediates, Bunte salts 19 and 20.

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Syntheses and Pharmacokinetic Studies of Prodrug Esters for the Development of Oral Carbapenem, L-084

Cited by 21 publications

References 17 publications

Efficient Synthesis of Isothiocyanates Based on the Tandem Staudinger/aza-Wittig Reactions and Mechanistic Consideration of the Tandem Reactions

Efficient Synthesis of Isothiocyanates Based on the Tandem Staudinger/aza-Wittig Reactions and Mechanistic Consideration of the Tandem Reactions

Possible Factors Involved in Oral Inactivity of Meropenem, a Carbapenem Antibiotic

A Practical and Facile Synthesis of Azetidine Derivatives for Oral Carbapenem, L-084

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