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Claims for Patent: 5,965,525

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Claims for Patent: 5,965,525

Title: Cyclic peptide antifungal agents
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)
Application Number:08/449,056
Patent 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

R.sub.2 is an acyl group represented by the formula ##STR252## wherein: Z is --O--, --C.tbd.C--, --CH.dbd.CH--, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --, or a carbon to carbon bond;

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.12 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 tricycloalkyl, 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 a pharmaceutically acceptable salt 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; and

either a) or b)

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;

R.sub.2 is not ##STR254## wherein Z is a carbon to carbon bond or --O-- and R.sub.4 is hydrogen or C.sub.1 -C.sub.12 alkoxy.

2. A compound as recited in claim 1 where R.sub.2 is an acyl group represented by the formula ##STR255## wherein Z is --O--, --C.tbd.C--, --CH.dbd.CH--, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --, or a carbon to carbon bond;

R.sub.4 is phenyl or 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, C1-C12 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 R.sub.4 is phenyl substituted with C.sub.1 -C.sub.6 alkoxy substituted by fluoro, bromo, chloro or iodo;

or 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 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 tricycloalkyl, 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 a pharmaceutically acceptable salt thereof.

3. The compound as recited in claim 2 wherein R.sub.2 is of the formula ##STR256## wherein Z is --C.tbd.C--; and

R.sub.4 is phenyl substituted by C.sub.1 -C.sub.12 alkoxy or phenyl substituted with a polyoxa-alkyl group of the formula

4. The compound as recited in claim 2 wherein R.sub.2 is of the formula ##STR257## wherein Z is a carbon to carbon bond and R.sub.4 is a group of the formula

wherein W is a piperidino group.

5. The compound as recited in claim 4 wherein p' is 2.

6. The compound as recited in claim 5 wherein R.sub.5 is hydrogen, n-propyl, 4-benzyl, 4-cyclohexyl, or 4-cyclohexylmethyl.

7. 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.

8. The compound as recited in claim 1 wherein R.sub.2 is of the formula ##STR258## wherein Z is a carbon to carbon bond; and

R.sub.4 is C.sub.3 -C.sub.7 cycloalkoxy, C.sub.1 -C.sub.6 alkoxy substituted by C.sub.3 -C.sub.7 cycloalkyl; or

R.sub.4 is phenyl substituted by C.sub.1 -C.sub.12 alkoxy or phenyl substituted with a polyoxa-alkyl group of the formula

R.sub.4 is a group of the formula --Y--R.sub.6, wherein Y is an acetylenic bond and R.sub.6 is C.sub.1 -C.sub.6 alkyl, phenyl, or phenyl substituted with a polyoxa-alkyl group of the formula

9. The compound as recited in claim 1, wherein R is hydrogen.

10. The compound as recited in claim 1 wherein R.sub.2 is of the formula ##STR259##

11. A method for inhibiting parasitic activity comprising contacting a compound of claim 1 with a parasite.

12. A method for inhibiting fungal activity comprising contacting a compound of claim 1 with a fungus.

13. A method for inhibiting the growth of organisms responsible for opportunistic infections in immunosuppressed individuals comprising administering a compound of claim 1 to said individual.

14. A method for inhibiting the growth of Pneumocystis carinii comprising contacting a compound of claim 1 with Pneumocystis carinii.

15. A pharmaceutical formulation comprising a compound of claim 1 and a suitable pharmaceutical carrier.

16. A compound of the formula (1): 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) R.sub.2 is a group of the formula ##STR260## and pharmaceutically acceptable salts thereof.

17. The compound as recited in claim 16 wherein R', R" and R'" are methyl, R.sub.1 is hydrogen, R.sub.7 and R.sup.y are hydroxy, and R is hydroxy.

18. A method for inhibiting parasitic activity comprising contacting a compound of claim 16 with a parasite.

19. A method for inhibiting fungal activity comprising contacting a compound of claim 16 with a fungus.

20. A method for inhibiting the growth of organisms responsible for opportunistic infections in immunosuppressed individuals comprising administering a compound of claim 16 to said individual.

21. A method for inhibiting the growth of Pneumocystis carinii comprising contacting a compound of claim 16 with said Pneumocystis carinii.

22. A pharmaceutical formulation comprising a compound of claim 16 and a suitable pharmaceutical carrier.

23. A compound of the formula ##STR261##
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