Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-12-07
1998-05-12
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 18, 544230, 514250, C07D45306, C07D49120, A61K 31435
Patent
active
057505330
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE
This application is a 371 of PCT/US94/06037 filed Jun. 7, 1994.
BACKGROUND OF THE INVENTION
The marcfortines are known compounds and are disclosed by Polonsky et al. in Journal of the Chemical Society Chemical Communications 1980 601-602 (Marcfortine A) and Tetrahedron Letters 1981 22 1977-1980 (Marcfortines B and C). The compounds are fungal metabolites of Penicillium roqueforti. The marcfortines are structurally related to the paraherquamides which are also known compounds. The paraherquamides are disclosed by Yamazaki et al. in Tetrahedron Letters 1981 22 135-136, and by Blanchflower et al., Journal of Antibiotics, 1991, 44, 492-497. U.S. Pat. Nos. 4,866,060 and 4,923,867 disclose the use of the marcfortines A, B, and C, and certain derivatives thereof as useful for the treatment and prevention of parasitic diseases in animals.
WO 92/22555 (published 23 Dec. 1992) generically discribes a marcfortine or paraherquamide derivative (i.e. partial formula (III) substituted at position 14 with methyl or methyl and hydroxy, however no description of how to prepare such 14-methyl-14-hydroxymarcfortine compounds is provided.
Paraherquamide has the following structure: ##STR2##
Marcfortine A has the following structure: ##STR3##
Marcfortine B has the following structure: ##STR4##
Marcfortine C has the following structure: ##STR5##
Marcfortine D has the following structure: ##STR6##
WO 91/09961 (published 11 Jul. 1991) discloses various derivatives of marcfortine and paraherquamide, and 12a-N-oxides thereof, as well as the production the production of VM 29919 (paraherquamide) and VM 55596 (the 12a-N-oxide of paraherquarnide) inter alia from Penicillium Sp. IMI 332995.
U.S. Pat. No. 4,873,247 discloses derivatives of paraherquamide and a strain of Penicillium charlessi MF 5123 (ATCC 20841) for the production of paraherquamide. U.S. Pat. No. 4,978,656 (as well as EP 390532-A, EP-301742-A) discloses various synthetic derivatives of paraherquamide as well as the production of paraherquamide from Penicillium charlessi MF 5123 (ATCC 20841).
SmithKline Beecham in International Publication No. WO 92/22555 (published 23 Dec. 1992) generically discloses 14.alpha.-hydroxy-marcfortine compounds and a process which uses the 14-hydroxy-14-methylmarcfortine compounds for the production of antiparasitic drugs. However, no enabling description of any means of preparation of 14.alpha.-hydroxy-marcfortine or 14.alpha.-hydroxy-14.beta.-methyl-marcfortine compounds is provided.
SUMMARY OF THE INVENTION
This invention is concerned with the synthesis of 14-substituted marcfortines A, B, C, and D and derivatives thereof and the use of these compounds as antiparasitic agents. Thus it is an object of this invention to describe these marcfortine derivatives. A further object of this invention is to describe processes for the preparation of these compounds. A still further object is to describe the use of the instant compounds as antiparasitic agents in the treatment and prevention of parasitic diseases. A still further object is to describe compositions for the treatment of parasitic diseases which contain the novel compounds of this invention as the active ingredient thereof. Further objects will become apparent from a reading of the following description.
DESCRIPTION OF THE INVENTON
The compounds of the instant invention are represented by Formula I: ##STR7## wherein:
m is 0 or 1;
Z is O or S;
Y is an oxygen atom (--O--) or a bond;
R.sub.1 is hydrogen, C.sub.1 -C.sub.7 alkyl, cyclo C.sub.3 -C.sub.8 alkyl, benzyl, C.sub.2 -C.sub.7 alkanoyl (--C(O)C.sub.2 -C.sub.7 alkyl) {optionally substituted with carboxy (--COOH), C.sub.1 -C.sub.7 alkanoyl, carboC.sub.1 -C.sub.7 alkoxy (--C(O)OC.sub.1 -C.sub.7 alkyl), --NR.sub.4 R.sub.5, aminocarbonyl (--C(O)NR.sub.4 R.sub.5)}, C.sub.10 -C.sub.24 alkanoyl (--C(O)C.sub.10 -C.sub.24 alkyl, cyclo C.sub.3 -C.sub.8 alkanoyl {optionally substituted with carboxy, C.sub.1 -C.sub.7 alkanoyl, carboC.sub.1 -C.sub.7 alkoxy, --NR.sub.4 R.sub.5, aminocarbonyl}, alkanoyloxymethylene (--CH.sub.
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Jameson William G.
Pharmacia & Upjohn Company
Rotman Alan L.
LandOfFree
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