Process for the conversion of echinocandin class of peptides...

Details Process for the conversion of echinocandin class of peptides... Process for the conversion of echinocandin class of peptides...

2001-03-29

2004-10-26

Wax, Robert A. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Cyclic peptides

C530S318000, C530S345000, C530S402000, C530S406000, C435S071300, C930S190000, C930S270000, C930SDIG722, C514S009100, C514S011400

Reexamination Certificate

active

06809177

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a process for the conversion of echinocandin class of peptides of the formula I
wherein W, X, Y, Z, R and R′ are as defined herein below:
W
X
Y
Z
R
R′
1. Echino-
OH
OH
OH
OH
CH
3
Linoleoyl
  candin B
2. Pneumo-
OH
OH
OH
OH
CH
2
—CONH
2
10,12-Di-
  candin A
0
methyl-
myristoyl
3. Pneumo-
H
OH
OH
OH
CH
2
—CONH
2
10,12-Di-
  candin A
1
methyl-
myristoyl
4. Pneumo-
OH
OH
H
H
CH
2
—CONH
2
10,12-Di-
  candin A
2
methyl-
myristoyl
5. Pneumo-
OH
OH
OH
OH
CH
2
—CONH
2
10,12-Di-
  candin B
0
methyl-
myristoyl
6. Pneumo-
OH
OH
H
H
CH
2
—CONH
2
10,12-Di-
  candin B
2
methyl-
myristoyl
7. Pneumo-
OH
OH
OH
OH
CH
2
—CONH
2
10,12-Di-
  candin C
0
methyl-
8. Mulundo-
OH
OH
OH
OH
H
12-Methyl-
  candin
tetradec
noyl
to their C4-homotyrosine monodeoxy analogues of the formula I wherein W, Y, Z, R and R′ are as defined herein below:
W
X
Y
Z
R
R′
1.
Deoxyechinocandin B
OH
H
OH
OH
CH
3
Linoleoyl
(Echinocandin C)
2.
Deoxypneumocandin A
0
OH
H
OH
OH
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
3.
Deoxypneumocandin A
1
H
H
OH
OH
CH
2
—CONH
2
10,12-Dimethyl-
myristoyl
4.
Deoxypneumocandin A
2
OH
H
H
H
CH
2
—CONH
2
10,12-Dimethyl-
myristoyl
5.
Deoxypneumocandin B
0
OH
H
OH
OH
CH
2
—CONH
2
10,12-Dimethyl-
myristoyl
6.
Deoxypneumocandin B
2
OH
H
H
H
CH
2
—CONH
2
10,12-Dimethyl-
myristoyl
7.
Deoxypneumocandin C
0
OH
H
OH
OH
CH
2
—CONH
2
10,12-Dimethyl-
myristoyl
8.
Deoxymulundocandin
OH
H
OH
OH
H
12-Methyl tetra-
decanoyl,
particularly to a process for the conversion of mulundocandin (compound of the formula II)
to deoxymulundocandin (compound of the formula III)
BACKGROUND OF THE INVENTION
1,3-&bgr;-glucan synthesis inhibitors are effective antifungal agents
Candida albicans
and also
Pneumocystis carini,
an opportunistic organism responsible for an often fatal pneumonitis among HIV patients and other immunocompromised hosts. Of all the structural classes of 1,3-&bgr;-glucan synthesis inhibitors, only the echinocandins received considerable attention [Ref: J. Med. Chem. 35, 198-200 (1992)]. Echinocandin class of peptides are cyclic hexapeptides having a lipophilic side chain.
Several methods for the conversion of echinocandins to the corresponding deoxy analogues under acidic conditions have been reported [Ref: Tetrahedron Letts., 33, 4529-4532 (1992); U.S. patent application Ser. No. 222,157 dated Apr. 4, 1994]. The above methods involve selective reduction of C4-htyr (homotyrosine) hydroxyl group of echinocandins to their monodeoxy analogues with prior protection/deprotection of the equally facile C5-Orn (ornithine) hydroxyl group.
Mulundocandin [J.Antibiotics, 40, 275-280 and 281-289 (1987)] and deoxymulundocandin [Indian patent No. IN I69830 ; J.Antibiotics. 45, 618-623 (1992)] having antifungal properties were isolated from
Aspergillus sydowii
(Bainier and Sartory) Thom and Church var. Nov. Mulundensis Roy (culture no.HIL Y-30462). Deoxymulundocandin was found to possess better antifungal activity than mulundocandin. However, the production of deoxymulundocandin during the fermentation was 200 times less than that of mulundocandin.
We have found out by extensive research and experimentation that echinocandin class of peptides of the formula I may be converted to the corresponding C4-htyr monodeoxy analogues, particularly mulundocandin to deoxymulundocandin under neutral conditions. Accordingly, the object of the present invention is to provide a process for the conversion of echinocandin class of peptides of the formula I to the corresponding C4-homotyrosin monodeoxy analogues, particularly mulundocandin (compound of formula II) to deoxymulundocandin (compound of formula III).
SUMMARY OF THE INVENTION
According to the invention, there is provided a process for the conversion of echinocandin class of peptides of the formula I
wherein W, X, Y, Z, R and R′ are as defined herein below:
W
X
Y
Z
R
R′
1.
Echinocandin B
OH
OH
OH
OH
CH
3
Linoleoyl
2.
Pneumocandin A
0
OH
OH
OH
OH
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
3.
Pneumocandin A
1
H
OH
OH
OH
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
4.
Pneumocandin A
2
OH
OH
H
H
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
5.
Pneumocandin B
0
OH
OH
OH
OH
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
6.
Pneumocandin B
2
OH
OH
H
H
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
7.
Pneumocandin C
0
OH
OH
OH
OH
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
8.
Mulundocandin
OH
OH
OH
OH
H
12-Methyl-
tetradecanoyl
to the C4-homotyrosine monodeoxy analogues of the formula I, wherein W, X, Y, Z, R and R′ are as defined herein below:
W
X
Y
Z
R
R′
1.
Deoxyechinocandin B
OH
H
OH
OH
CH
3
Linoleoyl
(Echinocandin C)
2.
Deoxypneumocandin A
0
OH
H
OH
OH
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
3.
Deoxypneumocandin A
1
H
H
OH
OH
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
4.
Deoxypneumocandin A
2
OH
H
H
H
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
5.
Deoxypneumocandin B
0
OH
H
OH
OH
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
6.
Deoxypneumocandin B
2
OH
H
H
H
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
7.
Deoxypneumocandin C
0
OH
H
OH
OH
CH
2
—CO—NH
2
10,12-Dimethyl-
myristoyl
8.
Deoxymulundocandin
OH
H
OH
OH
H
12-Methyl tetra-
decanoyl
particularly to a Process for the conversion of Mulundocandin (compound of the formula II
to deoxymulundocandin (compound of the formula III)
which consists of a single step selective reduction of C4-htyr (homotyrosine) hydroxyl group of echinocandins to their monodeoxy analogues particularly under neutral conditions without prior protection, deprotection of the equally facile C5-Orn (ornithe) hydroxyl group and purification of the monodeoxy compound from the crude reaction mixture.


REFERENCES:
patent: 5159059 (1992-10-01), Balkovec et al.
patent: 5677423 (1997-10-01), Rodriguez
patent: 5684128 (1997-11-01), Balkovec et al.
patent: 0 459 564 (1991-12-01), None
patent: 0 535 959 (1993-04-01), None
patent: 0 535 968 (1993-04-01), None
patent: 0 644 199 (1995-03-01), None
patent: 96/08266 (1996-03-01), None
Mukhopadhyay et al., The Journal of Antiniotics, vol. 40, No. 3, pp. 281-289, Mar. 1987.*
Mukhopadhyayet al., The Journal of Antibiotics, vol. 45, No. 5, pp. 618-623, May 1992.*
Balkovec et al., “Reduction Studies of Antifungal Echinocandin Lipopeptides. One Step Conversion of Echinocandin B to Echinocandin C.,”Tetrahedron Letters,33(32):4529-4532 (1992).

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