Cyclic peptide antifungal agents

Details Cyclic peptide antifungal agents Cyclic peptide antifungal agents

2001-08-30

2003-12-30

Brumback, Brenda (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

Reexamination Certificate

active

06670324

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to anti-fungal/anti-parasitic agents, in particular, derivatives of Echinocandin compounds and their use in the treatment of fungal and parasitic infections.
BACKGROUND OF THE INVENTION
A number of naturally occurring cyclic peptides are known in the art including echinocandin B (A30912A), aculeacin, mulundocandin, sporiofungin, L-671,329, and S31794/F1. In general, these cyclic peptides may be structurally characterized as a cyclic hexapeptide core (or nucleus) with an acylated amino group on one of the core amino acids. This acyl group is typically a fatty acid moiety forming a side chain off the nucleus. For example, echinocandin B has a linoleoyl side chain while aculeacin has a palmitoyl side chain.
These natural products have limited inherent antifungal and antiparasitic.properties. The natural compounds may be structurally modified in order to enhance these properties or to improve the compound's stability and/or water solubility. Turner, W. W., Rodriguez, M. J.,
Cur. Pharm. Des
., 2:209, 1996. For example, the fatty acid side chain may be removed from the cyclic peptide core to provide an amino nucleus which may then be re-acylated to provide semi-synthetic compounds. Furthermore, the homotyrosine moiety in the cyclic peptide may be O-glycosylated to provide further elaborated, novel, semi-synthetic compounds such as those claimed in the present application.
BRIEF SUMMARY OF THE INVENTION
This invention relates to compounds of formula I:
where:
R is independently at each occurrence hydrogen, hydroxy, or O—Pg;
R
1
is hydrogen, methyl, CH
2
C(O)NH
2
, CH
2
C(O)NH—Pg;
R
2
and R
3
are independently hydrogen or methyl;
R
4
is a moiety of the formula:
R
5
is a moiety of the formula:
A is independently at each occurrence phen-di-yl, pyridin-di-yl, pyridazin-di-yl, pyrimidin-di-yl, pyrazin-di-yl, furan-di-yl, or thiophen-di-yl rings;
X is independently at each occurrence a bond or C≡C;
R
6
is hydrogen, C
1
-C
12
alkyl, C
2
-C
12
alkynyl, C
1
-C
12
alkoxy, C
1
-C
12
alkylthio, halo, or —O—(CH
2
)
m
—[O—(CH
2
)
n
]
p
—O—(C
1
-C
12
alkyl), or —O—(CH
2
)
q
—Z—R
8
;
R
7
is independently at each occurrence hydrogen, hydroxy, amino, azido, OR
5
, O—Pg, or NH
p
—Pg;
R
7
′ is CHR
7
CH
2
R
7
, CHR
7
CH
2
OR
9
, ethyl, CHR
7
CO
2
H, CHR
7
CH
2
O—Pg, or CHR
7
C(O)—Pg;
R
7
″ is hydrogen, CH
2
R
7
, CH
2
O R
9
, methyl, CO
2
H, CH
2
O—Pg, CH
2
NH
p
—Pg, or C(O)—Pg;
m, n, and q are independently 2, 3 or 4;
p is 0 or 1;
Z is pyrrolidin-di-yl, piperidin-di-yl, or piperazin-di-yl;
R
8
is hydrogen, C
1
-C
12
alkyl, benzyl, or methyl(C
3
-C
12
cycloalkyl);
R
9
is SO
3
H or a moiety of the formula:
R
10
is hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, phenyl, phenoxy, p-halophenyl, p-halophenoxy, p-nitrophenyl, p-nitrophenoxy, benzyl, benzyloxy, p-halobenzyl, p-halobenzyloxy, p-nitrobenzyl, or p-nitrobenzyloxy; and
Pg is a hydroxy, amino, amido or carboxy protecting group; with the proviso that the total number of R
7
substituents that are OR
5
groups does not exceed two; or a pharmaceutical salt or solvate thereof,
which are useful as antifungal and antiparasitic agents or intermediates to such agents.
Furthermore, the present invention relates to pharmaceutical formulations comprising one or more pharmaceutical carriers, diluents or excipients and a compound of formula I.
Moreover, the present invention relates to methods for inhibiting fungal and parasitic activity comprising administering an effective amount of a compound of formula I to a host in need of such treatment.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The Compounds:
As used herein, the term “C
1
-C
12
alkyl” refers to a straight or branched saturated alkyl chain having from one to twelve carbon atoms. Typical C
1
-C
12
alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, 5-methylpentyl, hexyl, heptyl, 3,3-dimethylheptyl, octyl, 2-methyl-octyl, nonyl, decyl, undecyl, dodecyl and the like. The term “C
1
-C
12
alkyl” includes within its definition the terms “C
1
-C
16
alkyl”, “C
1
-C
4
alkyl”, and “C
3
-C
12
cycloalkyl”. The term “C
3
-C
12
cycloalkyl” refers to a cyclic saturated alkyl chain having from 3 to 12 carbon atoms. Moreover, the term “C
3
-C
12
cycloalkyl” includes within its definition the term “C
3
-C
7
cycloalkyl”.
The term “C
2
-C
12
alkynyl” refers to a straight or branched mono-alkynyl chain having from two to twelve carbon atoms. Typical C
2
-C
12
alkynyl groups include ethynyl, 1-propyn-1-yl, 1-propyn-2-yl, 1-butyn-1-yl, 1-butyn-3-yl, 1-pentyn-3-yl, 4-pentyn-2-yl, 1-hexyn-3-yl, 3-hexyn-1-yl, 5-methyl-3-hexyn-1-yl, 5-octyn-1-yl, 7-octyn-1-yl, 4-decyn-1-yl, 6-decyn-1-yl and the like.
The term “halo” refers to chloro, fluoro, bromo or iodo.
The term “C
1
-C
12
alkoxyl” refers to a C
1
-C
12
alkyl group attached through an oxygen atom. Typical C
1
-C
12
alkoxy groups include methoxy, ethoxy, propoxy, butoxy, sec-butoxy, n-pentoxy, 5-methyl-hexoxy, heptoxy, octyloxy, decyloxy dodecyloxy and the like. The term “C
1
-C
12
alkoxy” includes within its definition the terms “C
1
-C
6
alkoxy”, “C
3
-C
7
alkoxy”, and “C
1
-C
4
alkoxy”.
The term “C
1
-C
12
alkylthio” refers to a C
1
-C
12
alkyl group attached through a sulfur atom. Typical C
1
-C
12
alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, 3-methyl-heptylthio, octylthio, 5,5-dimethyl-hexylthio and the like. The term “C
1
-C
12
alkylthio” includes within its definition the terms “C
1
-C
6
alkylthio” and “C
1
-C
4
alkylthio”.
The symbol “O—Pg” and term “hydroxy protecting group” refer to a substituent of a hydroxy group that is commonly employed to block or protect the hydroxy functionality while reactions are carried out on other functional groups on the compound. This substituent, when taken with the oxygen to which it is attached, may form an ether, e.g., methyl, methoxymethyl, and benzyloxymethyl ether, a silyl ether, an ester, e.g. acetoxy, or a sulfonate moiety, e.g. methane and p-toluenesulfonate. The exact genus and species of hydroxy protecting group is not critical so long as the derivatized hydroxy group is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. A preferred hydroxy protecting group is acetyl. Specific examples of hydroxy protecting groups are described in T. W. Greene, “Protective Groups in Organic Synthesis,” John Wiley and Sons, New York, N.Y., (2nd ed., 1991), (hereafter referred to as Greene) chapters 2 and 3 and in the Preparations and Examples section which follows.
The symbol “NH
p
—Pg” and term “amino protecting group” as used in the specification refer to a substituent of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. When p is 0, the amino protecting group, when taken with the nitrogen to which it is attached, forms a cyclic imide, e.g., phthalimido and tetrachlorophthalimido. When p is 1, the protecting group, when taken with the nitrogen to which it is attached, can form a carbamate, e.g., methyl, ethyl, and 9-fluorenylmethylcarbamate; or an amide, e.g., N-formyl and N-acetylamide. The exact genus and species of amino protecting group employed is not critical so long as the derivatized amino group is stable to the condition of subsequent reaction(s) on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino protecting group(s). Preferred amino protecting groups are t-butoxycarbonyl (t-Boc), allyloxycarbonyl, phthalimido, and benzyloxycarbonyl (CbZ). Further examples of groups referred to by the above terms are described in Greene at chapter 7.
The symbol C(O)—Pg and the term “carboxy protecting group” refer to a substituent of a carbonyl that is commonly employed to block or protect the carboxy functionality while reactions are carrie

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