Adamantylmethyl Analogues of Chloramphenicol

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Adamantylmethyl Analogues of Chloramphenicol To the Editor: A fermentation product of Streptomyces venezuelae, chloramphenicol (11, was the first antibiotic having a broad spectrum of activity against various gram-positive and gramnegative bacteria that was introduced into medicinal use.1 Later, another synthetic analogue, thiamphenicol (2), was also reported to display a broad spectrum of antimicrobial activity.2 However, it was only the threo-diastereomers of both compoiinds that were found active; the corresponding erythro-anal.ogueswere devoid of any meaningful therapeutic activity. Among a number of unwelcomed side effects associated with the biological activity of chloramphenicol, the aplastic and hypoplastic anemias and thrombo- and granulocytopenias are considered to be most dangerous. The substitution of the para-nitro group on the phenyl ring of chloramphenicol with other substituents (most notably a methylsulfonyl group) was clearly beneficial in decreasing the toxicity of the drug. The great majority of substituents used to replace the para-nitro group on the phenyl ring of chloramphenicol represent ather polar groups, such as acetyl,3 perchloryl (C103),4chlorine,E bromine,5.6 and f l ~ o r i n e . To ~ - ~our knowledge, there are few reports in the literature describing chloramphenicol analogues bearing lipophilic functions. Therefore, it was of interest to prepare such derivatives and investigate the effect, if any, of a large lipophilic moiety on the nature and scope of antimicrobial activity. Based on our previous experience with the adamantane ring system,1&16 we decided to use the adamantylmethyl moiety as the nonpolar substituent in place of the para-nitro group of chloramphenicol. In the present communication we report the synthesis of two adammtylmethyl analogues of chloramphenicol, the threo- and erythro-4-{[2'-tricyclo[3.3.1.13.7]de~yl ]methyl-(1"3"-dihydroury-2-a,a-dichloroacetamido~propyl}benzenes (10a and lob, respectively). The synthesis of analogues 10a and 10b was straightforward and involved an initial reaction of 2-adamantanone (3) with the Grignard reagent of a-chloropara-xy1en.e to furnish the 2-[~ara-methylphenyl)methyl]tricyclo[3.3.1.13~71decan-2-ol (4). Dehydration with 85%phosphoric acid led to the preparation of the corresponding olefin derivative 5. The latter was brominated, and the resulting bromomethyl compound 6 was oxidized to the 4-[(2'-tricyclo[3.3.1.13~7]~decylidene)methylene]benzaldehyde (7). Reaction

A

OH NH~CHCI,

0

I 0a

of 7 with 2-nitroethanol yielded the 1,3-dihydroxy-2-nitropropylphenyl derivative 8 as a diastereomeric mixture which was conveniently separated by flash chromatography on silica gel. The erythro-diastereomer 8b was hydrogenated over platinum catalyst to provide the corresponding amino analogue 9b. Treatment of the latter with ethyl dichloroacetate completed the synthesis of erythro-4-{[2'-tricycloi3.3 . l .13~~ldecyllmethyl-(l",3"-dihydroxy-2"-a,a-dichloroacetamido)propyl}benzene(lob; Scheme I). The threo-diastereomer 10a was prepared in a similar way, starting with the nitrodiol precursor 8a.

Po

4

3

"h,

4

B

cno

no

OH NO,

7

1a.b

NHCCHCI,

II

0 NHCCHCI,

I1 0

NHt Vb

IOb

Scheme I

0022-3549/88/0700*0643$0 1.00/0 0 1988, American Pharmaceutical Association

Journal of Pharmaceutical Sciences I643 Vol. 77,No. 7, July 1988

siella pneumoniae, Bacteroides fragilis, and Clostridium histolyticum, respectively. Based on the above results, it becomes evident that replacing the polar para-nitro group on the phenyl ring of chloramphenicol with the nonpolar adamantylmethyl moiety was detrimental for antimicrobial activity.

Table CAsslgnment'of Protons In the NMR Spectra of Dlastereomers 10s and 10b and thrwChloramphenlcoI 0

II

NHCCHCI, 21

1

-cH-cH,oH

OH

References and Notes

11

Compound

c-2

c-1

c-3

rhrecShloramphenicol 11: R = NO2

5.40 ppm 4.35 ppm 4.08 ppm (1 doublet) (1 multiplet) (2 doublets) Jq.2 = 2.74 HZ 4 3 = 5.46 HZ

fhreeDiastereomer 10a

5.11 ppm

4.08 ppm 3.89 ppm ( 1 doublet) (1 multiplet) (2 doublets) J2,S = 4.14 HZ J1.2 = 3.30 HZ

11: R =

CHZ-

erythrdliastereomer 10b 5.16 ppm (1 doublet) 11: R =

4.26 ppm 4.06 ppm (1 multiplet) (1 doublet-

J2.3 = 4.72 HZ

CHZ-

doublet)

J2,3 = 3.94, 12.10 Hz 3.89 ppm (1 doublet-

doublet)

J2.3 = 3.55, 12.04 Hz ~~~~~~~

~

'These 'H NMR spectra were obtained on an IBM-WP-200SY (200 MHz) spectrometer using Me,Si as an internal standard. The stereochemical assignment of diastereomers 10a and 10b was accomplished by interpretation of their NMR spectra and comparison with the corresponding values for threochloramphenicol (Table I). When screened for antimicrobial activity in the disc diffusion assay, the threo-diastereomer 1Oa displayed weak activity at 500 pg against Staphylococcus aureus, Staphylococcus pyogenes, and Naisseria gonorrhoeae. As expected, the erythro-analogue 10b was essentially devoid of antimicrobial activity. By comparison, when tested under similar conditions, cephalothin and gentamycin showed broad spectrum activity at 30 and 10 pg, respectively. In the homogenized broth assay, both the threo- and erythro-diastereomers 10a and 10b were found to be weakly active at 1000 pglmL against Proteus vulgaris, Fusobacterium necrophorum, and Clostridium histolyticum, and Salmonella pneumoniae, Kleb-

644 / Journal of Pharmaceutical Sciences Vol. 77, No. 7, July 1988

1. Georgiev, V. St. Survey of Drug Research in Immunologic Disease, Vol. 2; S. Karger: Basel, 1983; pp 138-152. 2. Georgiev, V. St. Survey of Drug Research in Immunologic Disease. Vol. 2: S. Kareer: Basel. 1983: DD 153-156. in Immunologic 3. Georgiev, V. St. SuGey of Drug Re&&ch Disease,Vol. 2; S. Karger: Basel, 1983; pp 137-138. 4. Ziebell, G.; Gross, H.; Bradley, G. Phurmazie 1983,38, 587-589. 5. Badiger, V. V.; Jamakhandi, M. Y. M. J . Indian Chem. Soc. 1977; 54,39 1-393. 6. Badiger, V. V.; Jamakhandi, M. Y . M. Indian J . Chem. 1971,9, 198-200. 7. Neu, H. C.; Fu, K. P.; Kung, K. Curr. Chemother. Infect. Dis. Proceedings Znt. Con r Chenzother., 11th; Nelson, J . D.; Grassi, C., Eds.; American gociety of Microbiology: Washington, DC, 1980; pp 446-447. 8. Schafer, T. W.; Moss, E. L., Jr.; Nagabhushan, T. L.; Miller, G. H. Curr. Chemother. Infect. Dis. Proceedin s Znt. Congr. Chernother., 11th; Nelson, J. D.; Grassi, C., As.; American Societ of Microbiolo Washin ton, DC, 1980; pp 444-446. Nagel, Scholz, M. Abh. Akad. Wiss. 9. Ziebelr, G.; Bradler, DDR, Abt. Math., Naturwiss., Tech. 1978, p 233-237. R.; Griffith, R. C.; 10. Geor iev V. St.; Radov, L. A.; Kinsolving, Zazufak, W . I.; Kam , D K ; Trusso, L. A,; Mack, R. A. Eur. J . Med. Chem.-Chim. f h e r 1986,21, 315-319. 11. Georgiev, V. St.; Mullen, G. B; Acker, C. G. Heterocycles 1986, 24, 751-753. 12. Mullen, G. B.; Georgiev, V. St. Heterocycles 1986,24,3441-3446. 13. Mullen, G. B.; Georgiev, V. St. Heterocycles 1986,24,3447-3450. 14. Georgiev, V. St.; Acker, C. G.; Kinsolving, C. R. Heterocycles 1987,26,469-473. 15. Georgiev, V. St.; Bennett, G. A.; Radov, L. A.; Kamp, D. K.; Trusso, L. A. Arch. Pharm. (Weinheim) 1987, 320, 465-470. 16. Mullen, G. B.; Swift, P. A,; Georgiev, V. St. J.Pharm. Sct. 1987, 76, 930-934.

p;'

8;

8.

Acknowledgments The help of Mr. William J. Kuipers in running the 'H NMR spectra is gratefully acknowledged.

GEORGE 6. MULLEN VASSlL ST. GEORGIEV' Department of Organic Chemistry Pennwalt Corporation, Pharmaceutical Division Rochester, NY 14623 Received November 23, 1987. Accepted for publication February 8, 1988.