US 8,802,659 B2Granted

Bicyclic aryl sphingosine 1-phosphate analogs

AssigneeBiogen Idec MA Inc.

InventorsJermaine Thomas, Xiaogao Liu, Edward Yin-Shiang Lin, Guo Zhu Zheng, Bin Ma, Richard D. Caldwell, Kevin M. Guckian, Gnanasambandam Kumaravel, Arthur G. Taveras

Life of this patent

Estimating the term…

Abstract

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

Claims24

Dependent claims

A compound of:

formula (IIa)
formula (IIIa, IIIb, IIIc, IIIf, or IIIg)
formula (IVa), (IVb) or (IVc)
or formula (VIa), (VIb) or (VIc)
wherein:
each of X1, X2, X3, X4, X5, and X6, independently, is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —N(RfRg), —N(Rf)SO2Rg, —SO2Rf, —S(O)2N(RfRg), —CO2Rf, trialkylamino, aryl, or heteroaryl;
W is —O—;
Cy has the formula:
wherein:
Z1 is —CH2CH2—;
Z2 is —CH2—;
Z3 is a bond;
R1a and R1b, independently, are hydrogen, halo, hydroxy, nitro, cyano, —NRfRg, 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 R1a and R1b, when taken together, are C2-C5 alkylene or C2-C5 alkenylene;
R2a and R2b, independently, are hydrogen, halo, hydroxy, nitro, cyano, —NRfRg, 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 R1a and R2a, when taken together, are C1-C5 alkylene or C2-C5 alkenylene;
wherein R1a, R1b, R2a, and R2b are each, independently, substituted with 0-5 substituents selected from halo, hydroxy, nitro, cyano, —NRfRg, or —CO2Rf;
R3 is -L1-J-L2-T1;
L1 is —C(RfRg)—;
J is —N(Rf)—;
or J is
wherein
each of D1 and D3, independently, is
D2 is —[C(RfRg)]k—, —[C(RfRg)]k—N(Rf)—, —[C(RfRg)]k—O—, or —N(Rf)—[(CRfRg)]k—;
and
D4 is —[C(RfRg)]m—;
wherein k is 1 or 2;
and m is 0, 1, 2, or 3;
provided that no more than 2 ring atoms of D1-D4 are N or O;
L2 is —C(RfRg)—, —C(RfG)-, —C(G)2—, —C(RfRg)—C(RfRg)—, —C(RfRg)—C(RfG)—, —C(RfRg)—C(G)2—, or a bond;
T1 is —C(O)(ORf), —C(O)N(Rf)S(O)2Rf, tetrazolyl, —S(O)2ORf, —C(O)NHC(O)—Rf, —Si(O)OH, —B(OH)2, —N(Rf)S(O)2Rf, —S(O)2NRf, —O—P(O)(ORf)ORf, or —P(O)2(ORf);
each G, independently, is hydrogen, hydroxy, a halogen, or trifluoromethyl;
each Rf, independently, is hydrogen, hydroxy, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH2;
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, —CG3, —OH, —NO2, alkyl, —OCG3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
and
each Rg, 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, —CG3, —OH, —NO2, alkyl, —OCG3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
or a pharmaceutically acceptable salt thereof.

35 more elements

A compound 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-tert-butylcyclohexyloxy)indolin-1-yl)-2-oxoethylamino)ethylphosphonic acid;
3-amino-4-(5-(trans-4-tert-butylcyclohexyloxy)indolin-1-yl)-4-oxo-butanoic acid;
3-{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-propionic acid;
{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-acetic acid;
4-{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-butyric acid;
1-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-azetidine-3-carboxylic acid;
and
1-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylate;
or a pharmaceutically acceptable salt thereof.

31 more elements

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and compound of:

formula (IIa)
formula (IIIa, IIIb, IIIc, IIIf, or IIIg)
formula (IVa), (IVb) or (IVc)
or formula (VIa), (VIb) or (VIc)
or a pharmaceutically acceptable salt thereof, wherein:
each of X1, X2, X3, X4, X5, and X6, independently, is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —N(RfRg), —N(Rf)SO2Rg, —SO2Rf, —S(O)2N(RfRg), —CO2Rf, trialkylamino, aryl, or heteroaryl;
W is —O—;
Cy has the formula:
wherein:
Z1 is —CH2CH2—;
Z2 is —CH2—;
Z3 is a bond;
R1a and R1b, independently, are hydrogen, halo, hydroxy, nitro, cyano, —NRfRg, 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 R1a and R1b, when taken together, are C2-C5 alkylene or C2-C5 alkenylene;
R2a and R2b, independently, are hydrogen, halo, hydroxy, nitro, cyano, —NRfRg, 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 R1a and R2a, when taken together, are C1-C5 alkylene or C2-C5 alkenylene;
wherein R1a, R1b, R2a, and R2b are each, independently, substituted with 0-5 substituents selected from halo, hydroxy, nitro, cyano, —NRfRg, or —CO2Rf;
R3 is -L1-J-L2-T1;
L1 is —C(RfRg)—;
J is —N(Rf)—;
or J is
wherein
each of D1 and D3, independently, is
D2 is —[C(RfRg)]k—, —[C(RfRg)]k—N(Rf)—, —[C(RfRg)]k—O—, or —N(Rf)—[(CRfRg)]k—;
and
D4 is —[C(RfRg)]m—;
wherein k is 1 or 2;
and m is 0, 1, 2, or 3;
provided that no more than 2 ring atoms of D1-D4 are N or O;
L2 is —C(RfRg)—, —C(RfG)-, —C(G)2—, —C(RfRg)—C(RfRg)—, —C(RfRg)—C(RfG)—, —C(RfRg)—C(G)2—, or a bond;
T1 is —C(O)(ORf), —C(O)N(Rf)S(O)2Rf, tetrazolyl, —S(O)2ORf, —C(O)NHC(O)—Rf, —Si(O)OH, —B(OH)2, —N(Rf)S(O)2Rf, —S(O)2NRf, —O—P(O)(ORf)ORf, or —P(O)2(ORf);
each G, independently, is hydrogen, hydroxy, a halogen, or trifluoromethyl;
each Rf, independently, is hydrogen, hydroxy, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH2;
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, —CG3, —OH, —NO2, alkyl, —OCG3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
each Rg, 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, —CG3, —OH, —NO2, alkyl, —OCG3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl.

33 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/389,054Filed 5 Aug 2010 · us provisional application
Priority: 5 Aug 2009
Published: US 2012/0190649 A126 Jul 2012
Granted: 12 Aug 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification97 codes

A61K 31/695
Medicinal preparations containing organic active ingredients: silicon compounds
A61K 31/085
Ethers or acetals: having an ether linkage to aromatic ring nuclear carbon
A61K 31/11
Medicinal preparations containing organic active ingredients: aldehydes
A61K 31/137
Having aromatic rings , e.g. ketamine, nortriptyline: arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone

Family

Application61/231,539Us provisional application · filed 5 Aug 2009
US 2012/0190649 A1Pre-grant publication · published 26 Jul 2012
US 8,802,659 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

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

A compound of:

formula (IIa)
formula (IIIa, IIIb, IIIc, IIIf, or IIIg)
formula (IVa), (IVb) or (IVc)
or formula (VIa), (VIb) or (VIc)
wherein:
each of X1, X2, X3, X4, X5, and X6, independently, is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —N(RfRg), —N(Rf)SO2Rg, —SO2Rf, —S(O)2N(RfRg), —CO2Rf, trialkylamino, aryl, or heteroaryl;
W is —O—;
Cy has the formula:
wherein:
Z1 is —CH2CH2—;
Z2 is —CH2—;
Z3 is a bond;
R1a and R1b, independently, are hydrogen, halo, hydroxy, nitro, cyano, —NRfRg, 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 R1a and R1b, when taken together, are C2-C5 alkylene or C2-C5 alkenylene;
R2a and R2b, independently, are hydrogen, halo, hydroxy, nitro, cyano, —NRfRg, 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 R1a and R2a, when taken together, are C1-C5 alkylene or C2-C5 alkenylene;
wherein R1a, R1b, R2a, and R2b are each, independently, substituted with 0-5 substituents selected from halo, hydroxy, nitro, cyano, —NRfRg, or —CO2Rf;
R3 is -L1-J-L2-T1;
L1 is —C(RfRg)—;
J is —N(Rf)—;
or J is
wherein
each of D1 and D3, independently, is
D2 is —[C(RfRg)]k—, —[C(RfRg)]k—N(Rf)—, —[C(RfRg)]k—O—, or —N(Rf)—[(CRfRg)]k—;
and
D4 is —[C(RfRg)]m—;
wherein k is 1 or 2;
and m is 0, 1, 2, or 3;
provided that no more than 2 ring atoms of D1-D4 are N or O;
L2 is —C(RfRg)—, —C(RfG)-, —C(G)2—, —C(RfRg)—C(RfRg)—, —C(RfRg)—C(RfG)—, —C(RfRg)—C(G)2—, or a bond;
T1 is —C(O)(ORf), —C(O)N(Rf)S(O)2Rf, tetrazolyl, —S(O)2ORf, —C(O)NHC(O)—Rf, —Si(O)OH, —B(OH)2, —N(Rf)S(O)2Rf, —S(O)2NRf, —O—P(O)(ORf)ORf, or —P(O)2(ORf);
each G, independently, is hydrogen, hydroxy, a halogen, or trifluoromethyl;
each Rf, independently, is hydrogen, hydroxy, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH2;
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, —CG3, —OH, —NO2, alkyl, —OCG3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
and
each Rg, 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, —CG3, —OH, —NO2, alkyl, —OCG3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
or a pharmaceutically acceptable salt thereof.

35 more elements

Facts

Application

13/389,054Filed 5 Aug 2010 · us provisional application

Priority

5 Aug 2009

Published

US 2012/0190649 A126 Jul 2012

Granted

12 Aug 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification97 codes

A61K 31/695
Medicinal preparations containing organic active ingredients: silicon compounds
A61K 31/085
Ethers or acetals: having an ether linkage to aromatic ring nuclear carbon
A61K 31/11
Medicinal preparations containing organic active ingredients: aldehydes
A61K 31/137
Having aromatic rings , e.g. ketamine, nortriptyline: arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone