Enzyme interacting agents

Patent metadata

Field	Value
Publication number	US-2017190698-A1
Application number	US-201515321693-A
Country	US
Kind code	A1
Filing date	Jun 26, 2015
Priority date	Jun 26, 2014
Publication date	Jul 6, 2017
Grant date	—

Abstract

The present disclosure relates generally, but not exclusively, to compounds and their use as enzyme interacting agents, in particular, agents which interact with one or more enzymes in the sphingolipid biosynthesis pathway. The disclosure further relates to the use of such compounds as research tools, use in therapy, to compositions and agents comprising said compounds, and to methods of treatment using said compounds.

First claim

1 . A compound of Formula (I);

wherein
Q is a 5-membered heteroaromatic ring having 2 or 3 ring heteroatoms, at least one of which must be N and the remaining selected from N, O and S;
L is absent or a bivalent linker group selected from —NH—, —*NH—CH 2 —, —*CH 2 —NH—, *NH—NH—, and —*C(═O)—NH—, wherein the linker atom labelled * is bonded to Q;
R a is selected from hydrogen, halo, haloalkyl, haloalkoxy, alkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, carbocyclyl, carbocyclylalkyl, carbocyclyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy or heteroaryloxy, and wherein each of carbocyclyl, carbocyclylalkyl, carbocyclyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy or heteroaryloxy may be optionally substituted;
A is N or C—R b ,
wherein R b is selected from OH, B(OH) 2 , BF 3 .M (M=Na, K, Ca, or Mg), C(═NR c )NHR d , and, —C(═O)NHR d ;
wherein R c and R d are independently selected from hydrogen, hydroxy, alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl or acyl, each of which may be optionally substituted; or
R b is a cyclic group selected from formulae (i)-(iii):

wherein
Y is C or S,
X is O, S or NH;
A′ is C—R′ or N;
R′ is hydrogen or alkyl, such as C 1 -C 6 alkyl
each Z is independently H or OH; and
n is an integer from 0-6

or a pharmaceutically acceptable salt or solvate thereof;
provided that:
(i) when L is absent, then R b is not OH or C(═O)NHR d ;
(ii) when L is absent, and R b is C(═NR c )NH d , then R a must be a heteroatom or attached to the phenyl ring via a heteroatom, and Q is not

(iii) when L is absent and R b is a cyclic group of formula (iii) then Q is not

(iv) when L is NH, and A is N, then Q is not

(v) when L is NH and R b is OH, then Q is not

(vi) when L is NH and R b is C(═O)NHR d , then Q is not

(vii) when L is *C(═O)—NH and A is N, then Q is not

(viii) when L is *C(═O)—NH, then R b is not a cyclic group of formula (ii);
(ix) when L is *C(═O)—NH and R b is OH, then Q is not

(x) when L is *C(═O)—NH and R b is C(═O)NHR d , then Q is not

(xi) when L is *CH 2 —NH and R b is OH, then Q is not

(xii) when L is *CH 2 —NH, then R b is not C(═O)NHR d ;
(xiii) when L is *NH—CH 2 and A is N, then Q is not

(xiv) when L is *NH—CH 2 and R b is OH, then Q is not

(xv) when L is *NH—CH 2 and R b is C(═O)NHR d , then Q is not

where in the Q groups depicted in (i)-(xv) the bond labelled # is attached to L.

2 . The compound according to claim 1 wherein A is N.

3 . The compound according to claim 1 wherein A is C—R b .

4 . The compound according to claim 3 wherein R b is selected from C(═NR c )NHR d
and a cyclic group of formula (i), (ii), and (iii).

5 . The compound according to claim 4 wherein R b is selected from C(═NH)NH 2 , C(═N—OH)NH 2 , and a cyclic group selected from

where n is 0 or 1.

6 . The compound according to claim 1 wherein Q contains 2 ring heteroatoms.

7 . The compound according to claim 1 wherein Q contains 3 ring heteroatoms.

8 . The compound according to claim 7 wherein Q has at least 2 nitrogen ring atoms.

9 . The compound according to claim 8 wherein Q is an oxadiazolyl group.

10 . The compound according to claim 9 wherein Q is 1,3,4-oxadiazolyl.

11 . The compound according to claim 1 wherein L is a bivalent linker group selected from —NH—, —*NH—CH 2 —, —*CH 2 —NH—, *NH—NH—, and —*C(═O)—NH—, wherein the linker atom labelled * is bonded to Q.

12 . The compound according to claim 1 wherein R a is selected from hydrogen, halo (chloro, fluoro, bromo, iodo), C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-6 alkyl, C 3-6 cycloalkoxy, phenyl, phenylC 1-6 alkyl, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl.

13 . The compound according to claim 1 having the Formula (Ia):

wherein
L is a bivalent linker group selected from —NH—, —*NH—CH 2 —, —*CH 2 —NH—, *NH—NH—, and —*C(═O)—NH—, wherein the linker atom labelled * is bonded to Q;
A is C—R b , where R b is selected from C(═NR c )NHR d and a cyclic group selected from formula (i)-(iii).

14 . A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive.

15 . A compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, or a composition comprising said compound or a pharmaceutically acceptable salt or solvate thereof, for use as an sphingolipid enzyme agent for interacting with an enzyme in the sphingolipid pathway.

16 . A compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, or a composition comprising said compound or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

17 . A compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, or a composition comprising said compound or a pharmaceutically acceptable salt or solvate thereof treating a disease or condition in which excessive or undesirable sphingolipid enzyme activity is implicated.

18 . A compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, or a composition comprising said compound or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting undesirable cell proliferation, or treati

Assignees

• Univ Monash
• Univ South Australia
• Sa Pathology

Inventors

• Flynn Bernard Luke
• Aurelio Luigi
• Scullino Carmen Vittoria
• Wang Bing Hui
• Pitson Stuart Maxwell
• Pitman Melissa Rose

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• C07D271/10

  1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title