Echinocandin derivatives, method for preparing same and use as antifungal agents
A subject of the invention is the compounds of formula (I): in which either R 1 and R 2 =H, OH, alkyl optionally substituted, or NR 1 form with the carbon carrying NR 1 R 2 a double bond and R 2 is XRa, X being O, NH OR N-alkyl and Ra being H, alkyl optionally substituted, or R 2 is e-N═C(—N-d)-N(f)-g R 3 =H, OH, CH 3 R 4 =H, OH R=chain containing up to 30 carbon atoms, optionally containing one or more heteroatoms, one or more heterocycles, T=H, CH 3 , CH 2 CONH 2 , CH 2 C≡N, (CH 2 ) 2 NH 2 , (CH 2 ) 2 Nalk + X − Y=H, OH, Halogen, OSO 3 H W=H, OH Z=H or CH 3 . The products have of the antifungal properties.
1. A compound selected from the group consisting of all possible steroisomeric forms and their mixtures of a compound of the formula
wherein either R 1 and R 2 are individually selected from the group consisting of hydrogen, hydroxyl, alkyl and cycloalkyl of up to 8 carbon atoms optionally interrupted by oxygen and optionally substituted by a member selected from the group consisting of
are individually hydrogen or alkyl of 1 to 8 carbon atoms or R 1 forms with the endocyclic carbon atom carrying
a double bond and R2 is —XRa, X is selected from the group consisting of oxygen, —NH— or —N-alkyl of 1 to 8 carbon atoms and Ra is selected from the group consisting of hydrogen, alkyl or cycloalkyl of up to 8 carbon atoms substituted by at least one member of the group consisting of halogen, —OH, —CO 2 H, —CO 2 alk,
a′ and b′ are hydrogen or alkyl of 1 to 8 carbon atoms or R 2 is
in which d, e, f and g are hydrogen or alkyl of 1 to 8 carbon atoms, f and g can also be acyl of up-to 8 carbon atoms,
R 3 is selected from the group consisting of hydrogen, methyl and hydroxyl,
R 4 is hydrogen or hydroxyl,
R is selected from the group consisting of
T is selected from the group consisting of hydrogen, methyl, —CH 2 CONH 2 , —CH 2 CN, —(CH 2 ) 2 NH 2 and —(CH 2 )Nalk + X − , X is halogen and alk is alkyl of up to 8 carbon atoms,
Y is selected from the group consisting of hydrogen, hydroxyl, halogen and OSO 3 H and a salt thereof,
W is hydrogen or —OH,
Z is hydrogen or methyl and a non-toxic, pharmaceutically acceptable acid addition salt thereof.
2. A compound of claim 1 in which T is hydrogen.
3. A compound of claim 1 in which W is hydrogen.
4. A compound of claim 1 in which Z is methyl.
5. A compound of claim 1 in which Y is hydrogen.
6. A compound of claim 1 in which R 3 is methyl.
7. A compound of claim 1 in which R 4 is hydroxyl.
8. A compound of claim 1 in which R is selected from the group consisting of
.
9. A compound of claim 1 in which R 1 is hydrogen.
10. A compound of claim 1 in which R 2 is
(CH 2 ) 2 NH 2 .
11. A compound of claim 1 in which R 2 is
12. A compound of claim 1 in which R 2 is selected from the group consisting of
.
13. A compound of claim 1 selected from the group consisting of
1-[4-[(2-aminoethyl)-amino]-N2-[[4-[5-[4-(pentyloxy)-phenyl]-3-isoxazolyl]-3-phenyl]-carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B trifluoroacetate,
trans-1-[4-[(2-aminocyclohexyl)-amino]-N2-[[4-[5-[4-(pentyloxy)-phenyl]-3-isoxazolyl]-phenyl]-carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B trifluoroacetate,
1-[4-[(2(S)-aminopropyl)-amino]-N2-[[4-[5-[4-(pentyloxy)-phenyl]-3-isoxazolyl]-phenyl]-carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B trifluoroacetate,
1-[4-[(2-aminoethyl)amino]-N2-[[4-[5-([4-(pentyloxy)-phenyl]-1,3,4-thiadiazol-2-yl]-phenyl]-carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B trifluoroacetate,
trans 1-[4-[(2-aminocyclohexyl)-amino]-N2-[[4-[5-[4-(pentyloxy)-phenyl]-1,3,4-thiadiazol-2-yl]-phenyl]-carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B trifluoroacetate and
trans 1-[4-[(2-aminocyclohexyl)-amino]-N2-[[4-[3-[4-(pentyloxy)-phenyl]-1,2,4-oxadiazol-5-yl]-phenyl-]-carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B trifluoroacetate.
14. A process for the preparation of a compound of claim 1 reacting a compound of the formula
in which R, R 3 , R 4 , T, Y, W and Z are defined as in claim 1 with an amine or of an amine derivative capable of introducing
in which R1 and R2 are defined as in claim 1
and optionally then with a reducing agent,
and/or a functionalization agent of the amine,
and/or an acid to form the salt of the product of claim 1 ,
and/or a separation agent of the different isomers obtained.
15. A compound of the formula
wherein R, R 3 , R 4 , T, Y, W and Z are defined as in claim 1 .
16. A process of claim 14 wherein a compound of the formula
R 3 , R 4 , T, W, Y and Z are defined as in claim 14 reacted with an agent capable of replacing —NH 2 by —NHR, R being defined as in claim 14 to obtain a compound of the formula
reacting the said compound with trimethylsilyl iodide to obtain the corresponding compound of the formula
.
17. A compound of claim 11 wherein R 2 is
.
18. A compound of the formula
wherein R, R 3 , R 4 , T, W, Y and Z are defined as in claim 1 .
19. An antifungal composition comprising an antifungally effective amount of a compound of claim 1 and an inert pharmaceutical carrier.
20. A method of treating fungal infections in warm-blooded animals comprising administering to warm-blooded animals in need thereof an antifungally effective amount of a compound of claim 1 .