2-Hydroxymethyl-3,4,5-trihydroxy-1-benzilpiperidine derivatives as inhibitors of glucosylceramide
View Patent ↗The present invention provides novel piperidine derivatives of formula (I), wherein R represents a substituted benzyl group, which are useful as inhibitors of glucosylceramide synthase (GCS). The compounds of the Invention are useful for treating various glycolipid storage diseases, such as Gaucher's disease, Sandhoff's disease, Tay-Schs disease, Fabry disease, and GM1 gangliosidosis; glycolipid accumulation disorders, such as Niemann-Pick disease, mucopolysaccharidoses, mucolipidosis type IV and α-mannosidosis; various cancers that involve abnormal glycolipid synthesis; and various infectious diseases that involve cell surface glycolipids as receptors for the infectious organisms or for their toxins; as well as a variety of other disorders involving glycolipid synthesis, including neuronal disorders, inflammatory diseases, obesity, and the like.
1. A compound of formula (I) in free or a pharmaceutically acceptable salt form:
wherein
R is phenylmethyl-, wherein phenyl is substituted by OR 1 ; and
R 1 is C 4-5 alkyl.
2. The compound as defined in claim 1 wherein the OR 1 substituent on the phenyl is on the 4 position.
3. The compound of claim 1 being 3,4,5-piperidinetriol, 2-(hydroxymethyl)-1-[(4-pentyloxyphenyl)methyl]-, (2S,3R,4R,5S), or a pharmaceutically acceptable salt form.
4. The compound of claim 1 being 3,4,5-piperidinetriol, 1-[(4-butoxyphenyl)methyl]-2-(hydroxymethyl)-, (2S,3R,4R,5S), or a pharmaceutically acceptable salt form.
5. A pharmaceutical composition comprising the compound as defined in claim 1 , together with one or more pharmaceutically acceptable carriers, excipients and/or diluents.
6. A process for the preparation of the compound as defined in claim 1 , which process comprises:
a) reacting a compound of formula (II):
with an aldehyde of formula R 2 CHO, wherein R 2 is phenyl which is substituted as defined in claim 1 , using NaBH 3 CN or a supported reagent in acetic acid-methanol or HCl-methanol, or using NaBH(OAc) 3 in a solvent, or
b) deprotecting a compound of formula (III):
wherein R is as defined in claim 1 , and P, which may be the same or different, are hydroxy protecting groups.