Cyclic peptide antifungal agents and process for preparation...

Details Cyclic peptide antifungal agents and process for preparation... Cyclic peptide antifungal agents and process for preparation...

2002-02-27

2004-06-01

Seidel, Marianne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C514S009100, C530S317000, C530S329000

Reexamination Certificate

active

06743777

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to cyclic peptide antifungal agents. In particular, it relates to acyl derivatives of the echinocandin class of cyclic peptide antifungal agents; to methods for treating antifungal and parasitic infections, and to formulations useful in the methods.
The compounds provided by this invention are semi-synthetic antifungal agents in that they are derived from the cyclic peptide antifungals which are produced by culturing various microorganisms. A number of cyclic peptide antifungals are known. Among these are echinocandin B (A30912A), aculeacin, mulundocandin, sporiofungin, L-671,329, FR901379, and S31794/F1. All such antifungals are structurally characterized by a cyclic hexapeptide core, or nucleus, the amino group of one of the cyclic amino acids bearing a fatty acid acyl group forming a side chain off the core or nucleus. For example, echinocandin B has a linoleoyl side chain while aculeacin has a palmitoyl side chain. These fatty acid side chains of the cyclic hexa-peptides can be removed by enzymatic deacylation to provide the free nucleus. (Formula (1), hereinafter, wherein R
2
is hydrogen.) Reacylation of the amino group of the nucleus provides semisynthetic antifungal compounds. For example, the echinocandin B nucleus provides a number of antifungal agents when reacylated with certain unnatural side chain moieties (see Debono, U.S. Pat. No. 4,293,489). Among such antifungal compounds is cilofungin which is represented by the formula (1) wherein R is methyl, R
1
is hydrogen and R
2
is p-(n-octyloxy)benzoyl.
Enzymatic deacylation of the cyclic hexapeptides is carried out with deacylase produced by the organism
Actinoplanes utahensis
and related microorganisms as described by Abbott et al., U.S. Pat. No. 4,293,482.
The present invention provides acylated cyclic hexapeptides having unique side chain acyl groups which, inter alia impart enhanced antifungal and antiparasitic potency e.g. against pathogenic strains of
Candida albicans.
Also provided is a process for removing the aminal and benzylic hydroxy groups to result in a dideoxy compound of formula (1) (R=H).
SUMMARY OF THE INVENTION
The compounds provided by this invention are represented by the following formula (1):
wherein
R′ is hydrogen, methyl or NH
2
C(O)CH
2
—;
R″ and R′″ are independently methyl or hydrogen;
R and R
y
are independently hydroxy or hydrogen;
R
1
is hydroxy, hydrogen, or hydroxysulfonyloxy;
R
7
is hydroxy, hydrogen, hydroxysulfonyloxy or phosphonooxy; and
I) R
2
is a substituted benzoyl group represented by the formula
wherein.
A) R
3
is a polyoxa-alkyl group represented by the formula
—O—(CH
2
)
m
—[O—(CH
2
)
n
]
p
—O—(C
1
-C
12
alkyl)
wherein m and n are integers of from 2 to 4, and p is 0 or 1; or
B) R
3
is an unsaturated hydrocarbon group represented by the formula
—Y—(C
1
-C
12
alkyl)
wherein Y is —C≡C— or —CH═CH—; or
C) R
3
is a group of the formula —O—(CH
2
)
m
—G, wherein m is as defined and G is C
7
-C
10
bicycloalkyl or C
7
-C
14
tricycloalkyl; or
D) R
3
is quinolyl; or
II) R
2
is an acyl group represented by the formula
wherein
Z is —O—, —C≡C—, —CH═CH—, —CH
2
—CH
2
—, —CH
2
—, or a carbon to carbon bond;
A) R
4
is hydrogen, C
2
-C
12
alkynyl, C
2
-C
12
substituted alkynyl, C
3
-C
12
cycloalkyl, C
7
-C
14
bicycloalkyl, C
7
-C
14
tricycloalkyl, C
1
-C
12
alkoxy, C
3
-C
12
cycloalkoxy, naphthyl, pyridyl, thienyl, benzothienyl, quinolyl or phenyl; or
B) R
4
is phenyl substituted by amino, C
1
-C
12
alkylthio, halogen, C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl, C
1
-C
12
substituted alkyl, C
2
-C
12
substituted alkenyl, C
2
-C
12
substituted alkynyl, C
1
-C
12
alkoxy, trifluoromethyl, phenyl, substituted phenyl, phenyl substituted with a polyoxa-alkyl group represented by the formula
—O—(CH
2
)
m
—[O—(CH
2
)
n
]
p
—O—(C
1
-C
12
alkyl)
wherein m,n and p are as defined; or
C) R
4
is phenyl substituted with C
1
-C
6
alkoxy substituted by fluoro, bromo, chloro or iodo; or
D) R
4
is C
1
-C
12
alkoxy substituted with C
3
-C
12
cycloalkyl, C
7
-C
10
bicycloalkyl, C
7
-C
14
tricycloalkyl, C
2
-C
12
alkynyl, amino, C
1
-C
4
alkylamino, di-(C
1
-C
4
alkyl)amino, C
1
-C
12
alkanoylamino, phenyl substituted with a polyoxa-alkyl group represented by the formula
—O—(CH
2
)
m
—[O—(CH
2
)
n
]
p
—O—(C
1
-C
12
alkyl)
wherein m,n and p are as defined; or
E) R
4
is C
1
-C
12
alkoxy substituted with a group of the formula
wherein R
8
is C
1
-C
6
alkoxy optionally substituted with phenyl; or
F) R
4
is a group represented by the formula
—O—(CH
2
)
p′
—W—R
5
wherein p′ is an integer of from 2 to 4; W is pyrrolidino, piperidino or piperazino, and R
5
is hydrogen, C
1
-C
12
alkyl, C
3
-C
12
cycloalkyl, benzyl or C
3
-C
12
cycloalkylmethyl; or
G) R
4
is a group represented by the formula
—Y—R
6
wherein Y has the same meanings defined above; and
R
6
is C
1
-C
12
alkyl, C
1
-C
12
substituted alkyl; C
3
-C
12
cycloalkyl, C
7
-C
10
bicycloalkyl, C
7
-C
14
tricycloalkyl, phenyl, C
3
-C
12
cycloalkenyl, naphthyl, benzothiazolyl, thienyl, indanyl, fluorenyl, phenyl substituted by amino, C
1
-C
12
alkylthio, halogen, C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl, C
1
-C
12
alkoxy, trifluoromethyl, —O—(CH
2
)p′—W—R
5
, or C
1
-C
6
alkoxy substituted by fluoro, bromo, iodo or chloro; or
R
6
is a phenyl substituted by a polyoxa-alkyl group represented by the formula
—O—(CH
2
)
m
—[O—(CH
2
)
n
]
p
—O—(C
1
-C
12
alkyl)
wherein m,n and p are as defined above; or
III) R
2
is a group having the formula
wherein R
x
is C
1
-C
12
alkoxy or a polyoxa-alkyl group represented by the formula
—O—(CH
2
)
m
—[O—(CH
2
)
n
]
p
—O—(C
1
-C
12
alkyl)
wherein m,n and p are as defined above; or
IV) R
2
is a group having the formula
wherein R
9
is phenyl, C
1
-C
12
alkyl, or C
1
-C
12
alkoxy; or
V) R
2
is naphthoyl substituted with R
4
; and the pharmaceutically acceptable non-toxic salts thereof;
with the proviso that when
R′ is methyl or NH
2
C(O)CH
2
—;
R″ is methyl;
R′″ is methyl;
R
Y
is hydroxy;
R is hydroxy; and
either a) or b):
a) R
1
is hydroxysulfonyloxy and R
7
is hydroxy, hydroxysulfonyloxy or phosphonooxy;
b) R
1
is hydrogen or hydroxysulfonyloxy and R
7
is hydroxysulfonyloxy or phosphonooxy;
R
2
is not
wherein R
3
is
—O—(CH
2
)
m
—[O—(CH
2
)
n
]
p
—O—(C
1
-C
12
alkyl)
wherein p=O; nor
wherein Z is a carbon to carbon bond or —O— and R
4
is C
1
-C
12
alkoxy; nor
iii) naphthoyl substituted by R
4
wherein R
4
is hydrogen, phenyl, or C
1
-C
12
alkoxy.
Also provided are formulations and methods for inhibiting parasitic and fungal activity which employ the compounds of the invention, and a process for preparing the dideoxy form of the compounds.
DETAILED DESCRIPTION
The term: “C
1
-C
12
alkyl” refers to the straight or branched chain alkyl hydrocarbon groups such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups; and the like.
The term “C
2
-C
12
alkenyl” refers to groups such as vinyl, 1-propene-2-yl, 1-butene-4-yl, 1-pentene-5-yl, 1-butene-1-yl, and the like.
The term “C
2
-C
12
alkynyl” refers to such groups as ethynyl, propynyl, pentynyl, butynyl and the like.
The term “C
1
-C
12
alkylthio” refers to such groups as methylthio, ethylthio, t-butylthio, and the like.
The term “C
1
-C
12
alkoxy” refers to the straight or branched chain oxyalkyl groups such as, e.g. methoxy, ethoxy, propoxy, butoxy, heptoxy, octyloxy, dodecyloxy, and the like.
The term C
3
-C
12
cycloalkoxy” refers to such groups as cyclopropoxy, cyclobutoxy and the like.
The term “C
3
-C
12
cycloalkenyl” refers to such groups as cyclopropenyl, cyclobutenyl, cyclopentenyl, and the like.
The term “C
1
-C
12
substituted alkyl,” “C
2
-C
12
substituted alkenyl”, and “C
2
-C
12
substituted alkynyl”, denotes the above substituted one or two tim

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