Patent EA-002706-B1 (EA)
Title: Echinocandin derivatives, preparation method and application as anti-fungal agents
Inventor: COURTIN OLIVER
IPC: A61K38/00
Filed: 1998-12-09
Abstract: 1. A compound of formula (I):   their possible isomer forms or mixtures thereof, in which or R1 and R2, identical or different, are a hydrogen atom, hydroxyl; linear, branched or cyclic alkyl, alkenyl or alkynyl radical, comprising up to 8 carbon atoms optionally interrupted by an oxygen atom, optionally substituted by a halogen atom, hydroxyl, radical   where a and b, identical or different, are a hydrogen atom or alkyl, alkenyl or alkynyl radical, comprising up to 8 carbon atoms, wherein a and b under known conditions together with a nitrogen atom can form a heterocycle, optionally comprising one or several supplementary heteroatoms; or R1 with an endocyclic carbon atom, bearing a radical    forms a double bond and or R2 is a XRa radical where X is an oxygen atom or a NH radical or N-alkyl, alkenyl or alkynyl, comprising up to 8 carbon atoms; and Ra is a hydrogen atom, linear, branched or cyclic alkyl, alkenyl or alkynyl radical, comprising up to 8 carbon atoms optionally substituted by one or several halogen atoms, one or several OH radicals, CO2H, CO2alc, a radical    where a' and b' are a hydrogen atom or alkyl, alkenyl or alkynyl radical, comprising up to 8 carbon atoms, wherein a' and b' can form a heterocycle, optionally comprising one or several supplementary heteroatoms; and/or heterocycle, comprising one or several heteroatoms; or R2 is a radical   in which  d, e, f and g are a hydrogen atom or alkyl, alkenyl or alkynyl radical, comprising up to 8 carbon atoms, wherein f and g, besides, can be an acyl radical, comprising up to 8 carbon atoms; e and f can also form a cycle, optionally comprising one or several heteroatoms; R3 is a hydrogen atom, methyl or hydroxyl; R4 is a hydrogen atom or hydroxyl; R is a linear, branched or cyclic chain, comprising up to 30 carbon atoms, optoinally comprising one or several heteroatoms, one or several heterocycles; or a linear, branched or cyclic acyl radical, comprising up to 30 carbon atoms, optoinally comprising one or several heteroatoms, one or several heterocycles; T is a hydrogen atom, methyl, a CH2CONH2 radical, CH2C [triple bond] N, (CH2)NH2 radical or (CH2)Nalc<+>X<->, wherein X is a halogen atom and alc is a linear, branched or cyclic chain, comprising up to 8 carbon atoms; Y is a hydrogen atom, hydroxyl or a halogen atom, or a OSO3H, or one of said radicals salts; W is a hydrogen atom or a OH radical; Z is a hydrogen atom or methyl; and addition salts of acids thereof of the compounds of formula (I). 2. The compounds of formula (I) of claim 1, in which T is a hydrogen atom. 3. The compounds of formula (I) of claim 1 or 2, in which W is a hydrogen atom. 4. The compounds of formula (I) of any of claims 1 to 3, in which Z is methyl. 5. The compounds of formula (I) of any of claims 1 to 4, in which Y is a hydrogen atom. 6. The compounds of formula (I) of any of claims 1 to 5, in which R3 is methyl. 7. The compounds of formula (I) of any of claims 1 to 6, in which R4 is hydroxyl. 8. The compounds of formula (I) of any of claims 1 to 7, in which R is a radical:   9. The compounds of formula (I) of claim 1, in which R is a chain:   10. The compounds of formula (I) of claim 1, in which R is a chain:   11. The compounds of formula (I) of any of claims 1 to 10, in which R1 together with an endocyclic carbon atom, bearing a NR1R2 radical forms a double bond. 12. The compounds of formula (I) of claim 11, in which R2 is a O(CH2)nNY'2 radical, in which n is an integer from 1 to 8, and Y' is a hydrogen atom or an alkyl radical, comprising up to 8 carbon atoms. 13. The compounds of formula (I) of claim 12, in which n is 2. 14. The compounds of formula (I) of claim 8, in which R2 is a    radical. 15. The compounds of formula (I) of any of claims 1 to 10, in which R2 is a (CH2)nNY'' radical, in which Y'' is a hydrogen atom or an alkyl radical, comprising up to 8 carbon atoms, and p is an integer from 1 to 8. 16. The compounds of formula (I) of any of claims 1 to 10 and 15, in which R1 is a hydrogen atom. 17. The compounds of formula (I) of claim 15, in which p is 2. 18. The compounds of formula (I) of claim 1, which are: 1-[(S)-N2-(12-methyl-1-oxotetradecyl) 4-[[(3-piperidinyl) oxy] imino]-L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B; 1-[4-[( 2-aminoethyl) amino]-N2-(12-methyl-1-oxotetradecyl)-L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B (isomer A and isomer B); 1-[4-[(aminoiminomethyl) hydrazono]-N2-(12-methyl-1-oxotetradecyl)-L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B; 1-[4-[(2-aminoethoxy) imino]-N2-(12-methyl-1-oxotetradecyl)-L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B and corresponding isomer Z; 1-[4-[ (2-aminoeethyl) amino]-N2-[ [4'-(octyloxy) [1,1'-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B (isomer A); and addition salts of acids thereof. 19. The compounds of formula (I) of any of claims 1 to 18, in which the compound of formula (II):   in which R, R3, R4, T, Y, W and Z are as defined above, are subjected to an action of amine or a derivative thereof, capable to introduce a    radical, in which R1and R2 are as defined above, and, if desired, are subjected to an action of a reducer, and/or to an agent of amine functionization , and/or to an acid to form a salt of the obtained product, and/or to an agent to separate different obtained isomers, and thus obtaining the aimed compound of formula (I):   in which R1, R2, R3, T, Y, W, R and Z are as defined above, then, if desired, the compound of formula (I) is subjected to an action of an acid and, if desired, separate different obtained isomers. 20. The compounds of formula (II) of claim 19 as new chemical products. 21. The compounds of formula (II) of claim 20, which are: 1-[-4-oxo-N2-(12-methyl-l-oxotetradecyl) L-ornithine] 4-[4-(4-hydroxyphenyl)-L-threonine] -5-L-serine-echinocandine B; 1-[N2-[[4'-(octyloxy)-[1,1'-biphenyl]-4-yl]carbonyl]-4-oxo-L-ornithine]-4-[4-{4-hydroxyphenyl)-L-threonine]-5-L-serine-echinocandine B; 1-[N2- [ [4- [4- [4-(pentyloxy)phenyl]-1-piperazinyl]-phenyl]-carbonyl]4-oxo-L-ornithine] -4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandine B. 22. A method of claim 19, characterized in that the compound of formula (II) is obtained by treating a compound of formula (III):   in which different substituents are as defined above, by an agent capable to substitute NH2 for NHR, where R is as defined above to obtain a compound of formula (IV):   which is subjected to an action of trimethylsilyl to obtain a corresponding compound of formula (II):   23. Use a compound of formula (III) of claim 22 as intermediate compounds to obtain compounds of formula (I). 24. Use of claim 23, in which a compound of formula (III) is a deoxymulundocandine nucleus of formula: .     25. Use a compound of formula (IV) as intermediate compounds to obtain compounds of formula (I). 26. A compound of formula (IV), in which R is C(O)-Ph_Ph-OC8H17, the rest of radicals are as defined in claim 1. 27. Use compounds of formula (I) of any of claims 1 to 18 and their salts of acid additions as antifungal preparations. 28. Pharmaceutical compositions, comprising as a medicament at least one compound of formula (I) of any of claims 1 to 18, and addition salts of pharmaceutically acceptable acids thereof.