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US 6,043,341 AGranted
Cyclic peptide antifungal agents
AssigneeEli Lilly and Company
InventorsUko Effiong Udodong, John Leo Grutsch, Jr., Marvin Martin Hansen, Allen Robert Harkness, Daniel Edward Verral, II
Life of this patent
Estimating the term…
Abstract
The present invention provides phosphonylating agents and phosphonylation conditions that are compatible with the acid- and base-sensitive compounds and which promote a regioselective and reproducible conversion to a phosphonate compound. Also provided are intermediates that may be used to prepare phosphonate derivatives of cyclic peptides antifungal agent and a process for converting the phosphonates to the desired phosphonic acid prodrugs.
Claims21
A compound of formula I:
- ##STR35## where:
- R is C.sub.1 -C.sub.6 alkyl or phenyl;
- R.sup.1 is phenyl, naphthyl, cyclohexyl or a compound of the formula ##STR36## where R.sup.1a is hydrogen, halo, trifluoromethyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, nitro, protected amino, phenyl, benzyl or benzyloxy;
- with the proviso that when R.sup.1 is ##STR37## then R.sup.1a cannot be hydroxy, C.sub.1 -C.sub.6 alkoxy or benzyloxy;
- or a pharmaceutically acceptable salt thereof.
2 more elements
A compound of formula II ##STR41## wherein:
- R' is hydrogen, methyl or NH.sub.2 C(O)CH.sub.2 --;
- R" and R'" are independently methyl or hydrogen;
- R.sup.x1, R.sup.x2, R.sup.y1, R.sup.y2, R.sup.y3, and R.sup.y4 are independently hydroxy or hydrogen;
- R is C.sub.1 -C.sub.6 alkyl, phenyl or benzyl;
- Z is --CH.sub.2 --R.sup.1 ;
- R.sup.1 is phenyl, naphthyl, cyclohexyl or a compound of the formula ##STR42## where R.sup.1a is hydrogen, halo, trifluoromethyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, nitro, protected amino, phenyl, benzyl or benzyloxy;
- R.sub.2 is acyl;
- with the proviso that when R.sup.1 is ##STR43## then R.sup.1a cannot be hydroxy, C.sub.1 -C.sub.6 alkoxy or benzyloxy;
- or a pharmaceutically acceptable salt thereof.
6 more elements
A process for preparing a compound of formula II ##STR49## wherein:
- R' is hydrogen, methyl or NH.sub.2 C(O)CH.sub.2 --;
- R" and R'" are independently methyl or hydrogen;
- R.sup.x1, R.sup.x2, R.sup.y1, R.sup.y2, R.sup.y3, and R.sup.y4 are independently hydroxy or hydrogen;
- R is C.sub.1 -C.sub.6 alkyl, phenyl or benzyl;
- Z is --CH.sub.2 --R.sup.1 ;
- R.sup.1 is phenyl, naphthyl, cyclohexyl or a compound of the formula ##STR50## where R.sup.1a is hydrogen, halo, trifluoromethyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, nitro, protected amino, phenyl, benzyl, or benzyloxy;
- R.sub.2 is an acyl side chain defined as
- I) a group of the formula ##STR51## where:
- A) R.sub.3 is C.sub.1 -C.sub.12 alkyl, C.sub.1 -C.sub.6 alkoxy or quinolyl;
- B) R.sub.3 is --O--(C.sub.2).sub.m --[O--(CH).sub.n ].sub.p --O--(C.sub.1 -C.sub.12 alkyl);
- m and n are independently 2, 3 or 4;
- p is 0 or 1;
- or
- C) R.sub.3 is --Y--(C.sub.1 -C.sub.12 alkyl);
- Y is --C.tbd.C-- or --CH.dbd.CH--;
- or
- D) R.sub.3 is --O--(CH.sub.2).sub.q --G;
- q is 2, 3 or 4;
- G is C.sub.7 -C.sub.10 bicycloalkyl or C.sub.7 -C.sub.14 tricycloalkyl;
- or
- II) a group of the formula ##STR52## where:
- Z is --O--, --C.tbd.C--, --CH.dbd.CH--, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 -- or a bond;
- A) R.sub.4 is hydrogen, C.sub.1-C.sub.12 alkyl, C.sub.1 -C.sub.12 substituted alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 substituted alkenyl, C.sub.2 -C.sub.12 alkynyl, C.sub.2 -C.sub.12 substituted alkynyl, C.sub.1 -C.sub.12 alkoxy, C.sub.3 -C.sub.12 cycloalkyl, C.sub.7 -C.sub.10 bicycloalkyl, C.sub.7 -C.sub.14 tricycloalkyl, 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, halo, 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, or phenyl substituted with a group of the formula --O--(CH.sub.2).sub.m --[O--(CH.sub.2).sub.n ].sub.p --O--(C.sub.1 -C.sub.12 alkyl) where m, n and p are as defined above;
- or
- C) R.sub.4 is C.sub.1 -C.sub.12 alkoxy substituted with halo, 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.6 alkoxy, C.sub.2 -C.sub.12 alkynyl, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, formamido, C.sub.2 -C.sub.12 alkanoylamino, or phenyl substituted with a group of the formula
- --[O--(CH.sub.2).sub.m [--O--(CH.sub.2).sub.n ].sub.p 13 O--(C.sub.1 -C.sub.12 alkyl)
- where m, n and p are as defined above;
- or
- D) R.sub.4 is --O--(CH.sub.2).sub.r --W--R.sub.5 ;
- r is 2, 3 or 4;
- W is pyrrolidino, piperidino or piperazino;
- 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
- E) R.sub.4 is --Y.sup.1 --R.sub.6 ;
- Y.sup.1 is --C.tbd.C-- or --CH.dbd.CH--;
- R.sub.6 is C.sub.3 -C.sub.12 cycloalkyl, C.sub.7 -C.sub.10 bicycloalkyl, C.sub.7 -C.sub.14 tricycloalkyl, C.sub.3 -C.sub.12 cycloalkenyl, naphthyl, benzothiazolyl, thienyl, indanyl, fluorenyl, or phenyl substituted with C.sub.1 -C.sub.12 alkylthio, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, halo(C.sub.1 -C.sub.6 alkoxy) or a group of the formula
- --O--(CH.sub.2).sub.r --W--R.sub.5
- where r, W and R.sub.5 are as defined above;
- or
- R.sub.6 is phenyl substituted with a group of the formula --O--(CH.sub.2).sub.m --[O--(CH.sub.2).sub.n ].sub.p --O--(C.sub.1 -C.sub.12 alkyl) where m, n and p are as defined above;
- or
- F) R.sub.4 is C.sub.1 -C.sub.12 alkoxy substituted with a group of the formula --NHC(O)R.sub.7 ;
- R.sub.7 is C.sub.1 -C.sub.6 alkoxy, or phenyl(C.sub.1 -C.sub.6 alkoxy);
- or
- III) a group of the formula ##STR53## where:
- R.sup.8 is C.sub.1 -C.sub.12 alkoxy or a group of the formula
- --O--(CH.sub.2).sub.m --[O--(CH.sub.2).sub.n ].sub.p --O--(C.sub.1 -C.sub.12 alkyl)
- where m, n and p are as defined above;
- or
- IV) a group of the formula ##STR54## where:
- Y and R.sub.6 are as defined above;
- R.sub.9 is phenyl C.sub.1 -C.sub.12 alkyl, or C.sub.1 -C.sub.12 alkoxy, or
- V) naphthoyl substituted with R.sub.4 where R.sub.4 is as defined above;
- with the proviso that when R.sup.1 is ##STR55## then R.sup.1a cannot be hydroxy, C.sub.1 -C.sub.6 alkoxy or benzyloxy;
- or a pharmaceutically acceptable salt thereof;
- which comprises
- a) reacting a compound of formula I ##STR56## with a compound of formula IIB ##STR57## in the presence of a base at a temperature of from about -30.degree. C. to about 40.degree. C. to provide a compound of formula II;
- b) optionally converting the compound of formula II to provide the compound of formula IIA where Z is hydrogen;
- and
- c) optionally forming a pharmaceutically acceptable salt.
59 more elements
A process for converting a compound of formula II:
- ##STR63## wherein:
- R' is hydrogen, methyl or NH.sub.2 C(O)CH.sub.2 --;
- R" and R'" are independently methyl or hydrogen;
- R.sup.x1, R.sup.x2, R.sup.y1, R.sup.y2, R.sup.y3, and R.sup.y4 are independently hydroxy or hydrogen;
- R is C.sub.1 -C.sub.6 alkyl, phenyl or benzyl;
- Z is --CH.sub.2 --R.sup.1 ;
- R.sup.1 is phenyl, naphthyl, cyclohexyl or a compound of the formula ##STR64## where R.sup.1a is hydrogen, halo, trifluoromethyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, nitro, protected amino, phenyl, benzyl or benzyloxy;
- R.sub.2 is acyl;
- with the proviso that when R.sup.1 is ##STR65## then R.sup.1a cannot be hydroxy, C.sub.1 -C.sub.6 alkoxy or benzyloxy;
- or a pharmaceutically acceptable salt thereof;
- to a compound of formula IIA:
- ##STR66## where:
- R', R", R'", R.sup.x1, R.sup.x2, R.sup.y1, R.sup.y2, R.sup.y3, R.sup.y4, R and R.sub.2 are as defined above;
- and
- Z is hydrogen,
- which comprises
- 1) hydrogenating the compound of formula II by
- a) exposure to hydrogen gas in the presence of a catalyst and a base;
- or
- b) reaction with an alkali metal in liquid ammonia;
- and
- 2) optionally forming a pharmaceutically acceptable salt.
19 more elements
Dependencies are inferred from the claim text.