Ring modified cyclic peptide analogs

Details Ring modified cyclic peptide analogs Ring modified cyclic peptide analogs

2001-05-24

2003-11-25

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S317000, C530S338000

Reexamination Certificate

active

06653281

ABSTRACT:

TECHNICAL FIELD
The present invention relates to the preparation of ring modified cyclic peptide analogs by replacing peptide unit(s) in the cyclic peptide ring nucleus of natural products or semi-synthetic derivatives thereof, in particular, Echinocandin-type compounds, and novel semi-synthetic cyclic peptide compounds produced therefrom.
BACKGROUND ART
Echinocandin B is a natural product with antifungal activity that has been modified in the past in a variety of ways. For example, simple derivatives have been made including dihydro-and tetrahydro-reduction products and modification of active groups pendant from the ring nucleus. The most common approach has been replacement of the N-acyl side chain. For example, U.S. Pat. Nos. 4,293,489; 4,320,052; 5,166,135; and 5,541,160; and EP 359529; 448353; 447186; 462531; and 561639 describe a variety of N-acyl derivatized Echinocandin-type compounds that provide varying degrees of antifungal and antiprotozoal activities.
Other modifications have included acylation of the hydroxyl group of the pendant phenolic group. For example, GB 2,242,194; and EP 448343; 448354; 503960 and 525889 describe the introduction of acyl, phosphono and sulfo radicals having a charged group at neutral pH to impart water solubility.
GB 2,241,956 and EP 448355 describe hydrogen-reduction products of cyclohexapeptide compounds.
A review of the Echinocandin families and their semi-synthetic analogs may be found in Turner, W., et al,
Current Pharmaceutical Design
, 2, 209-224 (1996). The review compares the in vitro and in vivo activities of the Echinocandin natural products and their semi-synthetic analogs.
Each of the approaches described above are limited to reactions with active groups pendant to the cyclic peptide ring nucleus. Some have attempted to build the entire cyclic peptide nucleus synthetically. (See, i.e., U.S. Pat. No. 5,696,084
; J. Am. Chem. Soc
., 108, 6041 (1986); Evans, D. A., et al.,
J. Am. Chem. Soc
., 109, 5151 (1987);
J. Med. Chem
., 35, 2843 (1992); and Kurokawa, N., et al.,
Tetrahedron
, 49, 6195 (1993).) However, this approach is not cost effective and may lead to racemic mixtures. Therefore, there is a need to provide a more flexible and cost effective process for modifying the cyclic hexapeptide nucleus of natural products to broaden the scope of potential antifungal candidates.
Several investigators have disclosed the preferential cleavage of an amide bond in compounds bearing hydroxyl groups in the delta and gamma positions relative to the amide bond to provide asymmetric lactones using acids such as hydrochloric acid and trifluoroacetic acid; however, none have applied the process to the cleavage of a terminal amino acid group of a linear peptide. (See, i.e., K. Tanaka, et al.,
Tetrahedron Lett
, 26(10), 1337 (1985); N. Baba, et al.,
Chem Lett
(5), 889 (1989); H. Yoda, et al,
Chem Express
, 4(8), 515 (1989); and Y. Yamamoto, et al.,
J Org Chem
, 56(3), 112 (1991).)
BRIEF SUMMARY OF THE INVENTION
The present invention provides a method for modifying the cyclic peptide ring system of Echinocandin-type compounds to produce new analogs having antifungal activity. The inventive process allows one to make changes in the cyclic peptide structure of natural and semi-synthetic products that were previously not possible. For example, one may incorporate features such as water-solubility into the cyclic peptide ring nucleus, sites for further modification, increase or decrease the number of amino acid or peptide units within the ring nucleus, and increase or decrease the total number of members (or atoms) in the ring nucleus.
The process includes the steps of (i) providing a cyclic peptide compound comprising a peptide unit having a &ggr;-hydroxyl group; (ii) opening the ring of the cyclic peptide compound to provide a first linear peptide wherein the peptide unit having a &ggr;-hydroxyl group is the N-terminus peptide unit of the first linear peptide; (iii) cleaving-off the peptide unit having a &ggr;-hydroxyl group to provide a second linear peptide (preferably by adding trifluoroacetic acid or hydrochloric acid to the first linear peptide in an organic solvent); (iv) attaching at least one amino acid, a dipeptide unit or a synthetic unit to the second linear peptide to produce a third linear peptide; (v) cyclizing the third linear peptide to produce a modified cyclic peptide compound having a modified ring nucleus. Alternatively, a second peptide unit may be cleaved-off the second linear peptide produced in step (iii) prior to attaching the amino acid, dipeptide or synthetic unit(s) in step (iv) and subsequent cyclization in step (v). The addition of two or more units in step (iv) may be accomplished in a stepwise fashion (e.g., first one unit is attached then a second unit is attached). Of particular interest is the modification of Echinocandin-type compounds to produce novel cyclic hexapeptide and heptapeptide compounds that show inhibition of fungal and parasitic activity. The process also provides a convenient means to produce cyclic peptide compounds having the formulas I and II (including pharmaceutically acceptable salts, esters and hydrates thereof).
where
R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or heteroaryl group;
R2 is —H or —CH
3
;
R3 is —H, —CH
3
, —CH
2
CONH
2
or —CH
2
CH
2
NH
2
;
R4 is —H or —OH;
R5 is —OH, —OPO
3
H
2
, or —OSO
3
H;
R6 is —H or —OSO
3
H;
R7 is —CH
3
or —H;
(Y) is represented by the following formula
wherein
A is —(CH
2
)
a
— where a 1-4,
—CHR′—CHR″—(CH
2
)
b
—, where R′ and R″ are independently —H, —OH, C
6
H
5
O—, —SH,
—NH
2
, C
n
H
2n+1
NH—, C
n
H
2n+1
O—, C
n
H
2n+1
S— or C
n
H
2n+1
, where n=1-4 and b=0-1,
—(CH
2
)
c
—C(O)NH(CH
2
)
d
—, where c=1-2 and d=1-2,
—N=CH—(CH
2
)
e
— where e=0-2,
—NR′″(CH
2
)
f
—, where R′″ is —H, —C(O)CH
2
NH
2
, —C(O)CH(NH
2
)CH
2
NH
2
or —C
n
H
2n+1
where n=1-4 and f=1-3,
—(CH
2
)
g
—SO
2
—(CH
2
)
h
— where g=1-2 and h=1-2,
where j is 1 or 2 and Z is an amino group, alkylamino group, or piperidyl amino group;
B is a substituted or unsubstituted C1 to C6 alkyl group (e.g., isopropyl, p-hydroxybenzyl, hydroxymethyl, or &agr;-hydroxyethyl); and W is a hydrogen or C(O)R where R is as defined above.
In another embodiment of the present invention, novel cyclic peptide compounds are provided having the formulas I and II (above) wherein
A is —(CH
2
)
a
— where a=1, 2 or 4,
—CHR′—CHR″—(CH
2
)
b
— where R′ and R″ are independently —H, —OH, C
6
H
5
O—, —SH,
—NH
2
, C
n
H
2n+1
NH—, C
n
H
2n+1
O, C
n
H
2n+1
S—or C
n
H
2n+1
, where n=1-4 and b=0,
—(CH
2
)
c
—C(O)NH(CH
2
)
d
— where c=1-2 and d=1-2,
—N=CH—(CH
2
)— where e=0-2,
—NR′″(CH
2
)
f
— where R′″ is —H, —C(O)CH
2
NH
2
, —C(O)CH(NH
2
)CH
2
NH
2
or where n=1-4 and f=1-3,
—(CH
2
)—SO
2
—(CH
2
)
h
— where g=1-2 and h=1-2,
where j is 1 or 2 and Z is an amino group, alkylamino group, or piperidylamino group.
In yet another embodiment of the present invention, a pharmaceutical composition is provided comprising the novel compounds I and II described above (including pharmaceutically acceptable salts, esters and hydrates thereof) in a pharmaceutically inert carrier. Methods for using the novel compounds and pharmaceutical compositions described above for inhibiting fungal growth and parasitic activity are also provided, as well as a method for treating a fungal infection in a human comprising administering to a human in need of such treatment a therapeutically effective amount of the novel antifungal compound described above.
As used herein, the term “Echinocandin-type compounds” refers to compounds having the following general structure including any simple derivatives thereof:
wherein R is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or heteroaryl group; R
1
is —H or —OH; R
2
is

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