Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-29
2002-09-03
Aulakh, Charanjit S. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S171000, C546S169000
Reexamination Certificate
active
06444684
ABSTRACT:
BACKGROUND OF THE INVENTION
Lavendamycin (A) was isolated from the fermentation broth of
Streptomyces lavendulae
by Doyle and co-workers. See Doyle et al.,
Tetrahedron Letters,
22, 4595 (1981) and Gould et al.,
Fortschr. Chem. Org. Naturst.,
41, 77 (1982). Lavendamycin has broad spectrum antitumor, antibacterial and antiviral activity. See, e.g., Shibata et al.,
J. Antibiot.,
33, 1231 (1980); Balitz et al.,
J. Antibiot.,
35, 259 (1982); Boger et al.,
J. Med. Chem.,
30, 1918 (1987).
Lavendamycin methyl ester (B) is also known. It can be prepared by esterification of lavendamycin. Doyle et al.,
Tetrahedron Letters,
22, 4595 (1981). The first total synthesis of lavendamycin methyl ester was reported by Kende and Ebetino in 1984. See Kende et al.,
Tetrahedron Letters,
25, 923 (1984) and Kende et al.,
Heterocycles,
21, 91 (1984). They accomplished the synthesis of lavendamycin methyl ester through a Bischler-Napieralski condensation of a substituted quinaldic acid with
b
-methyltryptophan methyl ester followed by cyclization and functionalization of the A ring. Boger and his co-workers have synthesized lavendamycin methyl ester by a Friedlander condensation of a functionalized aminoaldehyde with a b-carboline followed by other transformations. Boger et al.,
J. Org. Chem,
50, 5790 (1985). Formal syntheses of lavendamycin methyl ester have been reported in Hibino et al.,
Heterocycles,
23, 261 (1985) and Rao et al.,
Tetrahedron,
42, 5065 (1986). For a recent review of lavendamycin syntheses, see Rao, in
Recent Progress In Chemical Synthesis Of Antibiotics,
497-531 (Lukacs et al. eds., 1990).
Hibino's group has reported the synthesis of demethyllavendamycin methyl ester (C) in Hibino et al.,
Heterocycles,
20, 1957 (1983). Hibino's group synthesized demethyllavendamycin methyl ester by a Pictet-Spengler type cyclization of 8-benzyloxyquinoline-2-aldehyde with tryptophan methyl ester, followed by aromatization and hydrogenation to give an 8-hydroxyquinoline intermediate. This intermediate was brominated to give the 5,7-dibromo-8-hydroxyquinoline. Oxidation of the 5,7-dibromo-8-hydroxyquinoline yielded the 7-bromoquinolinequinone, and replacement of the bromine with sodium azide, followed by reduction of the azide with sodium hydrosulfite, yielded demethyllavendamycin methyl ester.
This synthetic scheme based on a Pictet-Spengler type cyclization was also used by Hibino's group for the formal synthesis of lavendamycin methyl ester mentioned above. Hibino et al. indicate that lavendamycin ethyl ester can be prepared using this same synthetic scheme. See Hibino et al.,
Heterocycles,
23, 261 (1985).
The Pictet-Spengler cyclization approach has further been used by Hibino's group to synthesize desaminodesmethyllavendamycin methyl ester (D) and eight other lavendamycin analogs. See Hibino et al.,
Chem. Pharm. Bull.,
34, 1376 (1986). This article reports that the relative mutagenic potency of the lavendamycin analogs was drastically influenced by the nature of the substituent (e.g., methyl and/or bromine) and that lavendamycin analogs having a methyl group at the 3′ position were more mutagenic.
The structures of lavendamycin and analogs B-D are presented below:
A: R=H, R′=CH
3
, R″=NH
2
B: R=CH
3
, R′=CH
3
, R″=NH
2
C: R=CH
3
, R′=H, R″=NH
2
D: R=CH
3
, R′=H, R″=H
During preliminary work aimed at the total synthesis of lavendamycin, Rao et al. synthesized two additional analogs (E) and (F) of lavendamycin. See Rao et al.,
Indian J. Chem.,
23
B,
496 (1984). The structures of lavendamycin analogs E-F are presented below:
E: R′=CH
3
F: R′=H
Lavendamycin is similar structurally to streptonigrin (G). Streptonigrin also has a broad spectrum of antitumor, antibacterial and antiviral activity. Balitz et al.,
J. Antibiot.,
35, 259 (1982); Rao et al.,
J. Am. Chem. Soc.,
85, 2532 (1986); Boger et al.,
J. Med. Chem.,
30, 1918 (1987). With notable exceptions, lavendamycin has been found to be comparable to, although less potent than, streptonigrin in its observed spectrum of activity. Id.; Balitz et al.,
J. Antibiot.,
35, 259 (1982). The structure of streptonigrin is presented below:
Streptonigrin and several streptonigrin derivatives have been synthesized. See Driscoll et al.,
Cancer Chemother. Rep
. (
Part
2), 4, 1(1974) (four streptonigrin derivatives and 1500 quinones including several quinolinequinone analogs of streptonigrin having various substituents at positions 2, 6 and 7); Rao,
Cancer Chemother. Rep
. (
Part
2), 4, 11 (1974) (streptonigrin derivatives and AB and ABC ring analogs thereof); Kende et al.,
Tetrahedron Lett.,
4775 (1978) (tetracyclic aminoquinone possessing full streptonigrin carbon skeleton but with different substituents on the C and D rings); Basha et al.,
J. Am. Chem. Soc.,
102, 3962 (1980) (streptonigrin); Kende et al.,
J. Am. Chem. Soc.,
103, 1271 (1981) (streptonigrin); Weinreb et al.,
J. Am. Chem. Soc.,
104, 536-44 (1982) (streptonigrin); Panek et al.,
Diss. Abs. Int'l,
46, 1176B (1985) (streptonigrin); Miyasaka et al.,
J. Chem. Soc. Perkin Trans.,
1, 479 (1986) (streptonigrin 2′-amide derivatives; also mentions a 7-position amide obtained by high-yield microbial synthesis of
Streptomyces griseus
); Tolstikov et al.,
J. Antibiot.,
45, 1020 (1992) (2′-amide, aminodicarboxylic acid and amino sugar derivatives of streptonigrin); Tolstikov et al.,
J. Antibiot.,
45, 1002 (1992) (2′-decarboxy-2′-amino streptonigrin); Preobrazhenskaya et al.,
J. Antibiot.,
45, 227 (1992) (streptonigrone from streptonigrin, streptonigrin and streptonigrone 8′-alkyl ethers, and other streptonigrin and streptonigrone derivatives); U.S. Pat. No. 3,372,090 (ester, 2′-amide, 2′-hydrazide, ether, dihydro, desamino and acetyl (O-acetyl, N-acetyl, tetraacetyl) derivatives of streptonigrin); U.S. Pat. No. 3,804,947 (isopropylidene azastreptonigrin, streptonigrin monoxime and esters and other derivatives thereof); and JP 61-280490 (streptonigrin 2′-amides).
The biological activities of several 2′-position streptonigrin derivatives have been studied. The derivatives include 2′-esters, 2′-amides, 2′-hydrazides, and 2-′amino acid derivatives. The effects of the substituents on the biological activity of streptonigrin varied depending on the substituent and the type of activity being studied. See Rivers et al.,
Cancer Chemotherapy Rep.,
46, 17 (1965); Harris et al.,
Cancer,
18, 49 (1965); Kremer et al.,
Biochem. Pharmacol.,
15, 1111 (1966); Kaung et al.,
Cancer,
23, 1280 (1969); Inouye et al.,
J. Antibiot.,
38, 1429 (1985); Okada et al.,
J. Antibiot.,
39, 306 (1986); Inouye et al.,
J. Antibiot.,
39, 550 (1986); Okada et al.,
J. Antibiot.,
40, 230 (1987); Take et al.,
J. Antibiot.,
42, 968 (1989); Tolstikov et al.,
J. Antibiot.,
45, 1020 (1992).
The biological properties of streptonigrin, streptonigrin methyl ester and isopropylidene azastreptonigrin have been compared. See Kremer et al.,
Cancer Chemother. Rep.,
51, 19 (1967); Mizuno,
Biochem. Pharmacol.,
16, 933 (1967); Chaube et al.,
Cancer Chemother. Rep
. (
Part
1), 53, 23 (1969) and Chirigos et al.,
Cancer Chemother. Rep
. (
Part
1), 57, 305 (1973). Again, the effects of the substituents varied depending on the activity being investigated.
The antibacterial activity of streptonigrin, streptonigrin methyl ester and streptonigrin 8′-alkyl ethers has been studied. See Preobrazhenskaya et al.,
J. Antibiot.,
45, 227 (1992). The 8′-alkyl ethers exhibited slightly greater antibacterial activity than streptonigrin methyl ester, but less than streptonigrin.
A naturally-occurring analog of streptonigrin, 10′-desmethoxystreptonigrin, has been discovered. U.S. Pat. No. 5,158,960; Liu et al.,
J. Antibiot.,
45, 454-57 (1992). In addition to 10′-desmethoxystreptonigrin, U.S. Pat. No.
Behforouz Mohammad
Behforouz Nancy C.
Aulakh Charanjit S.
Ball State University
Brinks Hofer Gilson & Lione
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