Azacyclic constrained analogs of FTY720

Patent metadata

Field	Value
Publication number	US-10077236-B2
Application number	US-201414903579-A
Country	US
Kind code	B2
Filing date	Jul 15, 2014
Priority date	Jul 15, 2013
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

Abstract

Small molecules comprised of azacyclic constrained analogs of FTY720 are provided. Formulations and medicaments are also provided that are directed to the treatment of disease, such as, for example, leukemia, and other diseases. Therapeutics are also provided containing a therapeutically effective dose of one or more small molecule compounds, present either as pharmaceutically effective salt or in pure form, including, but not limited to, formulations for oral, intravenous, or intramuscular administration.

First claim

What is claimed is:

1. A compound of formula

or a pharmaceutically acceptable salt thereof
wherein:
R 1 is a group selected from hydrogen, an alkyl chain, (CH 2 ) n OH, (CH 2 ) n OPO 3 2− CHOH-alkyl, CHOH-alkyne, and (CH 2 ) n OMe;
R 2 is an aliphatic chain having six to ten carbons;
R 3 is one to four substituents selected from hydrogen, halogen, alkyl, alkoxy, azide (N 3 ), ether, NO 2 , or cyanide (CN);
R 4 is a group selected from hydrogen, CH 2 OPO 3 2− and CH 2 OH;
L is O—CH 2 ;
Me is an alkyl, alkene or alkyne;
n is an independently selected integer selected from the group of 1, 2, or 3; and
wherein the benzyl group through oxygen atom of the linker L is linked to the pyrrolidine ring at either position 3 or 4.

2. The compound of claim 1 , wherein the benzyl group through oxygen atom of the linker L is linked to the pyrrolidine ring at position 3.

3. The compound of claim 1 , wherein the stereochemistry of the compound is selected from the group consisting of S at position 2 and R at position 4, R at position 2 and S at position 4, R at position 2 and R at position 4, and S at position 2 and S at position 4.

4. The compound of claim 1 , wherein R4 is a group selected from CH 2 OH or CH 2 OPO 3 2− , and wherein the benzyloxy group attached to the pyrrolidine group is in one of either a cis or trans orientation relative to R4.

5. The compound of claim 1 , wherein R 2 is C 8 H 17 and R 1 is CH 2 OH.

6. A pharmaceutical comprising a therapeutically effective amount of a compound of formula

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is a group selected from hydrogen, an alkyl chain, (CH 2 ) n OH, (CH 2 ) n OPO 3 2− CHOH-alkyl, CHOH-alkyne, and (CH 2 ) n OMe;
R 2 is an aliphatic chain having six to ten carbons;
R 3 is one to four substituents selected from hydrogen, halogen, alkyl, alkoxy, azide (N 3 ), ether, NO 2 , or cyanide (CN);
R 4 is a group selected from hydrogen, CH 2 OPO 3 2− and CH 2 OH;
L is O—CH 2 ;
Me is an alkyl, alkene or alkyne;
n is an independently selected integer selected from the group of 1, 2, or 3; and
wherein the benzyl group through oxygen atom of the linker L is linked to the pyrrolidine ring at either position 3 or 4.

7. The pharmaceutical of claim 6 , wherein the benzyl group through oxygen atom of the linker L is linked to the pyrrolidine ring at position 3.

8. The pharmaceutical of claim 6 , wherein the stereochemistry of the compound is selected from the group consisting of S at position 2 and R at position 4, R at position 2 and S at position 4, R at position 2 and R at position 4, and S at position 2 and S at position 4.

9. The pharmaceutical of claim 6 , wherein R4 is a group selected from CH 2 OH or CH 2 OPO 3 2− , and wherein the benzyloxy group attached to the pyrrolidine group is in one of either a cis or trans orientation relative to R4.

10. The pharmaceutical of claim 6 , wherein R 2 is C 8 H 17 and R 1 is CH 2 OH.

Assignees

• Univ California
• The Univ De Montreal
• The Univ De Montreal

Inventors

• Edinger Aimee
• Hanessian Stephen

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07D207/12 Primary

  Oxygen or sulfur atoms · CPC title