Fungicidal echinocandin derivatives and their preparation
The invention concerns compounds of general formula (I) wherein: R 1 represents a hydrogen atom, a hydroxy radical, Ob or Ncd; A represents an oxygen atom, a CH 2 radical or a NH radical; B represents the radical of a steroid; R 3 represents a hydrogen atom, a methyl or hydroxyl radical; R 4 represents a hydrogen atom or a hydroxyl radical; T represents a hydrogen atom, a methyl radical, a CH 1 CONH 2 , CH 2 C≡N radical, a (CH 2 ) 2 NH 2 or (CH 2 )2Nalk + X − radical; X being a halogen atom and alc an alkyl radical; Y represents a hydrogen atom, a hydroxyl radical or a halogen atom or a OSO 3 H radical; W represents a hydrogen atom or a OH radical; Z represents a hydrogen atom or a methyl radical. The compounds of formula (I) exhibit antifungal properties.
1. A compound of the formula:
wherein R 1 is selected from the group consisting of hydrogen, hydroxyl, Ob
b is selected from the group consisting of alkyl, alkenyl and alkynyl of up to 12 carbon atoms, optionally substituted by halogen;
b′ and b″ are individually selected from the group consisting of hydrogen, alkyl of up to 12 carbon atoms and unsubstituted or substituted aryl;
c and d are selected from the group consisting of hydrogen, alkyl and cycloalkyl of up to 8 carbon atoms, optionally interrupted by an oxygen atom and unsubstituted or substituted by a member selected from the group consisting of halogen, OH and
c 1 and d 1 are hydrogen or alkyl of up to 8 carbon atoms or c 1 and d 1 form with the nitrogen atom a heterocycle optionally containing at least one heteroatom,
A is selected from the group consisting of oxygen, —CH 2 — and NH,
B is a steroid linked at position 3,
R 3 is selected from the group consisting of hydrogen, methyl and hydroxyl,
R 4 is hydrogen or hydroxyl,
T is selected from the group consisting of hydrogen, methyl, —CH 2 —CONH 2 ),
—CH 2 ≡N, —(CH 2 ) 2 NH 2 and —(CH 2 ) 2 Alk + X, X is halogen and Alk is an alkyl of up to 8 carbon atoms,
Y is selected from the group consisting of hydrogen, hydroxyl, halogen and —OSO 2 H or a salt thereof,
W is hydrogen or —OH,
Z is hydrogen or methyl and its pharmaceutically acceptable acid addition salts.
2. The compound of claim 1 wherein T is hydrogen.
3. The compound of claim 1 wherein Y is hydrogen.
4. The compound of claim 1 wherein Z is methyl.
5. The compound of claim 1 wherein R 3 is methyl.
6. The compound of claim 1 wherein R 4 is hydroxyl.
7. The compound of claim 1 wherein R 1 is hydroxyl.
8. The compound of claim 1 wherein A is oxygen.
9. The compound of claim 1 wherein A is —CH 2 —.
10. The compound of claim 1 wherein B is selected from the group consisting of:
11. The compound of claim 10 wherein B is :
12. A compound of claim 1 selected from the group consisting of:
1-[(4R,5-dihydroxy-N2-[[[(3β22E)-ergosta-5,7,22-trien-3-yl]oxy]carbony]-L-ornithinel]-mulundocandin,
1-[(4R,5R)-4,5-dihydroxy-N2-[[[3β-lanosta-8,24-dien-3-yl]-L-ornithine]-deoxymulundocandin and
1-[(4R,5R)-4,5-dihyddroxy-N2-[[[(3β,22E)-ergosta-5,7,22-trien-3-yl]oxy]carbonyl]-L-ornithine]-deoxymulundocandin.
13. A process for the preparation of a compound of claim 1 comprising reacting a compound of the formula:
with a steroid BOH where B is defined as in claim 1 or of one of its derivatives in the presence of an activator of the alcohol function, or of a corresponding acid or of one of its derivatives, to obtain the corresponding compound of formula (I).
14. An antifungal composition comprising an antifungicidally effective amount of a compound of claim 1 and an inert carrier.
15. A method of treating fungal infections in warm-blooded animals comprising administering to warm-blooded animals in need thereof an antifungicidally effective amount of a compound of claim 1 .