C-terminal Hsp90 inhibitors
Hsp90 C-terminal inhibitors and pharmaceutical compositions containing such compounds are provided. The compounds of the disclosure are useful for the treatment and/or prevention of neurodegenerative disorders such as diabetic peripheral neuropathy.
1. A method of preparing a compound of the formula:
wherein
R 1 is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, aralkyl, carboxyl, amido, amino, alkoxy, sulfanyl, sulfenyl, sulfonyl, or ether;
R 2 is hydrogen, halo, hydroxy, trifluoromethyl, alkoxy, alkyl, alkenyl, alkynyl, carbocyclic, alkylcarbocyclic, alkylheterocyclic, heterocyclic, or —R 9 —OR 10 , wherein R 9 is a covalent bond or alkyl, and R 10 is hydrogen, alkyl, C-amido or acyl; or R 2 together with R 3 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;
R 3 is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkoxy, sulfanyl, or —R 11 —O—R 12 , wherein R 11 is a covalent bond or alkyl, and R 12 is alkyl, C-amido, or acyl; or R 3 together with R 2 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;
R 4 is hydrogen or alkyl;
R 5 is hydrogen or alkyl;
R 6 is hydrogen, hydroxy, sulfanyl, alkyl, or alkoxy;
R 7 is hydrogen or hydroxyl;
R 8 is hydrogen or hydroxyl;
X is ═CR 21 — or ═N—, wherein R 21 is hydrogen, halo, trifluoromethyl, alkyl, alkenyl, alkynyl, alkoxy, or hydroxy;
R′ is hydrogen or alkyl;
R″ is alkyl;
Y is ═CR 3 — or ═N—;
Z is CH or Z—Z 1 is —C═C—;
Z 1 is CH or Z—Z 1 is —C═C—; and
n is 0, 1, 2, or 3;
comprising reacting an aglycone of the formula:
wherein:
R 1 is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, aralkyl, carboxyl, amido, amino, alkoxy, sulfanyl, sulfenyl, sulfonyl, or ether;
R 2 is hydrogen, halo, hydroxy, trifluoromethyl, alkoxy, alkyl, alkenyl, alkynyl, carbocyclic, alkylcarbocyclic, alkylheterocyclic, heterocyclic, or
—R 9 —OR 10 , wherein:
R 9 is a covalent bond or alkylene, and
R 10 is hydrogen, alkyl, C-amido, or acyl; or
R 2 together with R 3 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;
R 3 is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkoxy, sulfanyl, or
—R 11 —O—R 12 , wherein:
R 11 is a covalent bond or alkylene, and
R 12 is alkyl, C-amido, or acyl; or
R 3 together with R 2 and the atoms to which they are attached form a carbocyclic ring with 5 to 7 ring members or a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen; or
R 3 is absent when Y is ═N—;
R′ is H or alkyl;
R″ is alkyl, alkoxy, haloalkyl, alkylcycloalkyl, or alkylamidoalkyl;
X is ═CR 21 — or ═N—, wherein:
R 21 is hydrogen, halo, trifluoromethyl, alkyl, alkenyl, alkynyl, alkoxy, or hydroxy; and
Y is ═CR 3 — or ═N—;
with a sugar of the formula:
wherein:
R 4 is hydrogen or alkyl;
R 5 is hydrogen or alkyl;
R 6 is hydrogen, hydroxy, sulfanyl, alkyl, or alkoxy;
R 7 is hydrogen or hydroxyl;
R 8 is hydrogen or hydroxyl;
Z is CH or Z—Z 1 is —C═C—;
Z 1 is CH or Z—Z 1 is —C═C—; and
n is 0, 1, 2, or 3;
in the presence of a Lewis acid.
2. The method of claim 1 , wherein R 2 is halo.
3. The method of claim 2 , wherein R 2 is fluoro.
4. The method of claim 1 , wherein R 1 is hydrogen.
5. The method of claim 1 , wherein R 3 is hydrogen.
6. The method of claim 1 , wherein X is ═CR 21 —, wherein R 21 is hydrogen.
7. The method of claim 1 , wherein Y is ═CR 3 —.
8. The method of claim 1 , wherein R′ is hydrogen.
9. The method of claim 1 , wherein R″ is alkyl.
10. The method of claim 1 , wherein R 4 and R 5 are alkyl.
11. The method of claim 1 , wherein R 6 is alkoxy.
12. The method of claim 1 , wherein R 7 and R 8 are hydroxy.
13. The method of claim 1 , wherein the aglycone is:
14. The method of claim 1 , wherein the sugar is:
15. The method of claim 1 , wherein the compound is:
16. The method of claim 1 , wherein the Lewis acid is a boron compound.
17. The method of claim 16 , wherein the boron compound is BF 3 .
18. The method of claim 1 further comprising adding a base.
19. The method of claim 18 , wherein the base is triethylamine.
20. The method of claim 1 further comprising an alcohol.