Bicyclic aryl sphingosine 1-phosphate analogs

Patent metadata

Field	Value
Publication number	US-10166250-B2
Application number	US-201715783809-A
Country	US
Kind code	B2
Filing date	Oct 13, 2017
Priority date	Aug 5, 2009
Publication date	Jan 1, 2019
Grant date	Jan 1, 2019

Abstract

Compounds that have agonist activity at one or more of the S1P receptors are provided. The compounds are sphin-gosine analogs that, after phosphorylation, can behave as agonists at S1P receptors.

First claim

The invention claimed is:

1. A method for treatment of neuropathic pain in a mammal comprising administering to said mammal an effective amount of a compound of formula (IIa), (IIIa) or (IIIb):

or a pharmaceutically acceptable salt thereof, wherein:
each of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 , independently, is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —N(R f R g ), —N(R f )SO 2 R g , —SO 2 R f , —S(O) 2 N(R f R g ), —CO 2 R f , trialkylamino, aryl, or heteroaryl;
W is —O—;
Cy has the formula:

wherein:
Z 1 is —CH 2 CH 2 —;
Z 2 is —CH 2 —;
Z 3 is a bond;
R 1a and R 1b , independently, are hydrogen, halo, hydroxy, nitro, cyano, —NR f R g , alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
or R 1a and R 1b , when taken together, are C 2 -C 5 alkylene or C 2 -C 5 alkenylene;
R 2a and R 2b , independently, are hydrogen, halo, hydroxy, nitro, cyano, —NR f R g , alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
or R 1a and R 2a , when taken together, are C 1 -C 5 alkylene or C 2 -C 5 alkenylene;

wherein R 1a , R 1b , R 2a , and R 2b are each, independently, substituted with 0-5 substituents selected from halo, hydroxy, nitro, cyano, —NR f R g , or —CO 2 R f ;
R 3 is -L 1 -J-L 2 -T 1 ;
L 1 is —C(R f R g )—;
J is —N(R f )—; or J is

wherein
each of D 1 and D 3 , independently, is

D 2 is —[C(R f R g )] k —, —[C(R f R g )] k —N(R f )—, —[C(R f R g )] k —O—, —N(R f )—, or —N(R f )—[(CR f R g )] k —; and
D 4 is —[C(R f R g )] m —;
wherein k is 1 or 2; and m is 0, 1, 2, or 3;
provided that no more than 2 ring atoms of D 1 -D 4 are N or O;

L 2 is —C(R f R g )—, —C(R f G)-, —C(G) 2 -, —C(R f R g )—C(R f R g )—, —C(R f R g )—C(R f G)-, —C(R f R g )—C(G) 2 -, or a bond;
T 1 is —C(O)(OR f ), —C(O)N(R f )S(O) 2 R f , tetrazolyl, —S(O) 2 OR f , —C(O)NHC(O)—R f , —Si(O)OH, —B(OH) 2 , —N(R f )S(O) 2 R f , —S(O) 2 NR f , —O—P(O)(OR f )OR f , or —P(O) 2 (OR f );
each G, independently, is hydrogen, hydroxy, a halogen, or trifluoromethyl;
each R f , independently, is hydrogen, hydroxy, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH 2 ; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CG 3 , —OH, —NO 2 , alkyl, —OCG 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl; and
each R g , independently, is hydrogen, hydroxy, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, —CG 3 , —OH, —NO 2 , alkyl, —OCG 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl.

2. The method of claim 1 , wherein T 1 is —C(O)(OR f ), —C(O)N(R f )S(O 2 R f ), —O—P(O)(OR f )OR f , —P(O 2 )(OR f ), tetrazolyl or —S(O) 2 OR f .

3. The method of claim 1 , wherein R 1a and R 2a are both hydrogen, and R 1b is fluoro, chloro, bromo, iodo, methyl, trifluorormethyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, isopentyl, 1,1-dimethylpropyl, neopentyl, cyclopentyl, n-hexyl, cyclohexyl, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, 1,1-dimethylpropoxy, neopentyloxy, cyclopentyloxy, n-hexyloxy, or cyclohexyloxy.

4. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
J is

T 1 is —C(O)(OR f ), —C(O)N(R f )S(O 2 R f ), —O—P(O)(OR f )OR f , —P(O 2 )(OR f ), tetrazolyl, or —S(O) 2 OR f .

5. The method of claim 1 , wherein the compound is selected from the group consisting of:
3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide;
3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide;
2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoic acid;
3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)butanoic acid;
2-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino) acetic acid;
3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoic acid;
3-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino) propanoic acid;
1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylic acid;
1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)pyrrolidine-3-carboxylic acid;
1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;
1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylic acid;
3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)propanoic acid;
3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2,2-difluoropropanoic acid;
2,2-difluoro-3-((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methylamino)propanoic acid;
2-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)acetic acid;
4-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)butyric acid;
4-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)butyric acid;
(R)-1-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)piperidine-3-carboxylic acid;
(S)-1-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)piperidine-3-carboxylic acid;
4-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)butyric acid;
5-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)pentanoic acid;
6-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)hexanoic acid;
4-(6-(trans-4-tert-butylcyclohexyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanoic acid;
4-(6-(cis-4-tert-butylcyclohexyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanoic acid;
2-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)ethylphosphonic acid;
2-(2-(5-(trans-4-ter

Assignees

• Biogen Ma Inc

Inventors

• Thomas Jermaine
• Liu Xiaogao
• Lin Edward Yin-Shiang
• Zheng Guo Zhu
• Ma Bin
• Caldwell richard d
• Guckian Kevin M
• Kumaravel Gnanasambandam
• Taveras Arthur G

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P5/48

  of the pancreatic hormones · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title