Details for Patent: 5,932,543

Title:	Cyclic peptide antifungal agents and process for preparation thereof
Abstract:	Provided are compounds of the formula (1): ##STR1## wherein R' is hydrogen, methyl or NH.sub.2 C(O)CH.sub.2 --; R" and R'" are independently methyl or hydrogen; R and R.sup.Y are independently hydroxy or hydrogen; R.sub.1 is hydroxy, hydrogen, or hydroxysulfonyloxy; R.sub.7 is hydroxy, hydrogen, hydroxysulfonyloxy or phosphonooxy; R.sub.2 is a novel acyl side chain. Also provided are novel formulations, methods of inhibiting fungal and parasitic activity, and a process for preparing dideoxy (R=H) forms of the compounds.
Inventor(s):	Burkhardt; Frederick J. (Indianapolis, IN), Debono; Manuel (Indianapolis, IN), Nissen; Jeffrey S. (Indianapolis, IN), Turner, Jr.; William W. (Bloomington, IN)
Assignee:	Eli Lilly and Company (Indianapolis, IN)
Filing Date:	Jun 12, 1997
Application Number:	08/873,480
Claims:	1. A compound of the formula ( 1): ##STR251## wherein R' is hydrogen, methyl or NH.sub.2 C(O)CH.sub.2 --; R" and R'" are independently methyl or hydrogen; R and R.sup.y are independently hydroxy or hydrogen; R.sub.1 is hydroxy, hydrogen, or hydroxysulfonyloxy; R.sub.7 is hydroxy, hydrogen, or hydroxysulfonyloxy; and I) R2 is a substituted benzoyl group represented by the formula ##STR252## wherein A) R3 is a polyoxa-alkyl group represented by the formula wherein m and n are integers of from 2 to 4, and p is 0 or 1; or B) R3 is an unsaturated hydrocarbon group represented by the formula wherein Y is --C.tbd.C-- or --C.dbd.C--; or C) R3 is a group of the formula --O(CH.sub.2).sub.m --G, wherein m is as defined and G is C.sub.7 -C.sub.10 bicycloalkyl or C.sub.7 -C.sub.14 tricycloalkyl; or D) R3 is quinolyl; or II) R2 is naphthoyl substituted with R.sub.4 wherein A) R.sub.4 is hydrogen, C.sub.2 -C.sub.12 alkynyl, C.sub.2 -C.sub.12 substituted alkynyl, C.sub.3 -C.sub.12 cycloalkyl, C.sub.7 -C.sub.10 bicycloalkyl, C.sub.7 -C.sub.14 tricycloalkyl, C.sub.1 -C.sub.12 alkoxy, C.sub.3 -C.sub.12 cycloalkoxy, naphthyl, pyridyl, thienyl, benzothienyl, quinolyl or phenyl; or B) R.sub.4 is phenyl substituted by amino, C.sub.1 -C.sub.12 alkylthio, halogen, C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.1 -C.sub.12 substituted alkyl, C.sub.2 -C.sub.12 substituted alkenyl, C.sub.2 -C.sub.12 substituted alkynyl, C.sub.1 -C.sub.12 alkoxy, trifluoromethyl, phenyl, substituted phenyl, phenyl substituted with a polyoxa-alkyl group represented by the formula wherein m and n are integers of from 2 to 4, and p is 0 or 1; or C) R.sub.4 is phenyl substituted with C.sub.1 -C.sub.6 alkoxy substituted by fluoro, bromo, chloro or iodo; or D) R.sub.4 is C.sub.1 -C.sub.12 alkoxy substituted with C.sub.3 -C.sub.12 cycloalkyl, C.sub.7 -C.sub.10 bicycloalkyl, C.sub.7 -C.sub.14 tricycloalkyl, C.sub.2 -C.sub.12 alkynyl, amino, C.sub.1 -C.sub.4 alkylamino, di-(C.sub.1 -C.sub.4 alkyl) amino, C.sub.1 -C.sub.12 alkanoylamino, phenyl substituted with a polyoxa-alkyl group represented by the formula wherein m, n and p are as defined above; or E) R.sub.4 is C.sub.1 -C.sub.12 alkoxy substituted with a group of the formula ##STR253## wherein R.sub.8 is C.sub.1 -C.sub.6 alkoxy optionally substituted with phenyl; or F) R.sub.4 is a group represented by the formula wherein p' is an integer of from 2 to 4; W is pyrrolidino, piperidino or piperazino, and R.sub.5 is hydrogen, C.sub.1 -C.sub.12 alkyl, C.sub.3 -C.sub.12 cycloalkyl, benzyl or C.sub.3 -C.sub.12 cycloalkylmethyl; or G) R.sub.4 is a group represented by the formula wherein Y is --C.tbd.C-- or --CH.dbd.CH--; and R.sub.6 is C.sub.1 -C.sub.12 alkyl, C.sub.1 -C.sub.12 substituted alkyl; C.sub.3 -C.sub.12 cycloalkyl, C.sub.7 -C.sub.10 bicycloalkyl, C.sub.7 -C.sub.14 tricycloalky, phenyl, C.sub.3 -C.sub.12 cycloalkenyl, naphthyl, benzothiazolyl, thienyl, indanyl, fluorenyl, phenyl substituted by amino, C.sub.1 -C.sub.12 alkylthio, halogen, C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.1 -C.sub.12 alkoxy, trifluoromethyl, --O--(CH.sub.2).sub.p' --W--R.sub.5, or C.sub.1 -C.sub.6 alkoxy substituted by fluoro, bromo, iodo or chloro; or R.sub.6 is phenyl substituted by a polyoxa-alkyl group represented by the formula wherein m, n and p are as defined above; or III) R2 is a group having the formula ##STR254## wherein R.sup.x is C.sub.1 -C.sub.12 alkoxy or a polyoxa-alkyl group represented by the formula wherein m, n and p are as defined above; or IV) R2 is a group having the formula ##STR255## wherein R.sub.9 is phenyl, C.sub.1 -C.sub.12 alkyl, or C.sub.1 -C.sub.12 alkoxy; and the pharmaceutically acceptable non-toxic salts thereof; with the proviso that when R' is methyl or NH.sub.2 C(O)CH.sub.2 --; R" is methyl; R'" is methyl; R.sup.y is hydroxy or hydrogen; and either a) or b) or c) a) R.sub.1 is hydroxysulfonyloxy and R.sub.7 is hydroxy or hydroxysulfonyloxy; b) R.sub.1 is hydrogen or hydroxysulfonyloxy and R.sub.7 is hydroxysulfonyloxy; c) R.sub.1 is hydroxy and R.sub.7 is hydroxy: R.sub.2 is not ##STR256## wherein R3 is wherein p=0; nor ii) naphthoyl substituted by R.sub.4 wherein R.sub.4 is hydrogen, phenyl, or C.sub.1 -C.sub.12 alkoxy. 2. The compound as recited in claim 1 wherein R', R" and R'" are methyl, R.sub.1 is hydrogen, and R.sub.7 and R.sup.y are OH. 3. The compound as recited in claim 1 wherein R is hydrogen. 4. A method for inhibiting parasitic activity comprising contacting a compound of claim 1 with a parasite. 5. A method for inhibiting fungal activity comprising contacting a compound of claim 1 with a fungus. 6. A method for inhibiting the growth of organisms responsible for opportunistic infections in immunosuppressed individuals comprising administering a compound of claim 1 to said immunosuppressed individuals. 7. A method for inhibiting the growth of pneumocystis carinii comprising contacting a compound of claim 1 with said pneumocystis carinii. 8. A pharmaceutical formulation comprising a compound of claim 1 and suitable pharmaceutical carrier.