US 2013/0158093 A1 · GPR 17 Agonists and Screening Assay

Abstract

The present invention is related to a method of determining a test compound's ability to modify the biological activity of a GPR17. Said method comprises, among others, the step of contacting the test compound with a GPR17, or a functional GPR17 fragment in the presence of a suitable amount of a GPR17 agonist of formula I.

Claims14

Dependent claims

-7. (canceled)

A method of treating, alleviating or preventing of a GPR17 mediated disease, optionally selected from ischemic diseases, stroke or multiple sclerosis, in a patient in need thereof comprising the steps of

(a) identifying a compound that modulates GPR17 biological activity by
(i) contacting a compound with a GPR17, or a functional GPR17 fragment in the presence of a suitable amount of a GPR17 agonist of formula I
or a salt thereof,
(ii) measuring the biological activity of said GPR17 or said functional GPR17 fragment after addition of said compound, and
(iii) comparing the biological activity measured in step (ii) with the biological activity of said GPR17 or said functional fragment thereof in the presence of said GPR 17 agonist of formula I without the addition of said compound to identify whether the compound is one that modulates GPR17 activity,
wherein in formula I
R1 and R2 are independently selected from the group comprising hydrogen, halogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR6R7, carboxy, carbamoyl, (C1-C8)alkyl, (C1-C8) all yloxy, (C1-C8)alkylthio, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkloxy, (C3-C8)cycloalkylamino, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, trifluoromethyl, (C1-C8)alkylcarbonyl, (C1-C8) alkylaminocarbonyl, di(C1-C8)alkylaminocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl(C1-C8)alkyl, heteroaryl(C1-C8)alkyl, aryl(C1-C8)alkyloxy, heteroaryl(C1-C8)alkyloxy, aryl(C1-C8)alkylcarbonyl, heteroaryl(C1-C8)alkylcarbonyl, aryl(C1-C8)alkyloxycarbonyl, heteroaryl(C1-C8)alkyloxycarbonyl, (C1-C8)alkyloxycarbonyl, (C1-C8)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, sulfonylamino, (C1-C8)alkylaminosulfonyl, di(C1-C8)alkylaminosulfonyl, arylsulfonylamino, heteroarylsulfonylamino and (C1-C8)alkylsulfonylamino;
wherein each alkyl, alkenyl alkynyl or cycloalkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C5)alkyloxy, (C1-C3)alkyloxy(C1-C3)alkyloxy, halogen, and NR6R7;
and wherein each aryl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C5)alkyloxy, halogen, (C1-C5)alkyl, (C3-C8)cycloalkyl, carboxy, NR6R7, cyano, trifluormethyl and nitro;
R3 is selected from hydrogen, a group —(CH2)mCH2—COOH, OH, NH, and (C1-C5)alkyl which is optionally substituted with one or more halogens, one or two hydroxyl groups or (C1-C3)alkoxy;
R4 is selected from hydrogen and fluoro;
R5 is selected from hydrogen, halogen, (C1-C3)alkyl, (C1-C3)alkyloxy, (C1-C3)alkylthio, (C2-C4)alkenvl, (C2-C4)alkynyl, and NR6R7;
R6 and R7 are independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl;
wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C3)alkyloxy, phenyl, halo, carboxy, and NR8R9;
and wherein R6 and R7 may form a 5- to 7-membered cycle;
and wherein phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C3)alkyloxy, halogen, (C1-C3)alkyl, carboxy, NR8R9, cyano, trifluormethyl and nitro;
R8 and R9 are independently selected from among hydrogen and (C1-C3)alkyl;
n and m are independently 0, 1 or 2;
and
(b) administering said GPR17 modulating compound to the patient, optionally together with one or more pharmaceutically acceptable excipients.

17 more elements

A screening assay for the identification of GPR 17 modulators among a multitude of compounds, said screening assay comprising

(a) cells or membrane fractions expressing GPR17 or a functional GPR17 fragment and
(b) a suitable amount of a GPR17 agonist of formula I
wherein in formula I
R1 and R2 are independently selected from the group comprising hydrogen, halogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR6R7, carboxy, carbamoyl, (C1-C8)alkyl, (C1-C8) alkyloxy, (C1-C8)alkylthio, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyloxy, (C3-C8)cycloalkylamino, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, trifluoromethyl, (C1-C8)alkylcarbonyl, (C1-C8) alkylaminocarbonyl, di(C1-C8)alkylaminocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl(C1-C8)alkyl, heteroaryl(C1-C8)alkyl, aryl(C1-C8)alkyloxy, heteroaryl(C1-C8)alkyloxy, aryl(C1-C8)alkylcarbonyl, heteroaryl(C1-C8)alkylcarbonyl, aryl(C1-C8)alkyloxycarbonyl, heteroaryl(C1-C8)alkyloxycarbonyl, (C1-C8)alkyloxycarbonyl, (C1-C8)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, sulfonylamino, (C1-C8)alkylaminosulfonyl, di(C1-C8)alkylaminosulfonyl, arylsulfonylamino, heteroarylsulfonylamino and (C1-C8)alkylsulfonylamino;
wherein each alkyl, alkenyl, alkynyl or cycloalkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C5)alkyloxy, (C1-C3)alkyloxy(C1-C3)alkyloxy, halogen, and NR6R7;
and wherein each aryl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C5)alkyloxy, halogen, (C1-C5)alkyl, (C3-C8)cycloalkyl, carboxy, NR6R7, cyano, trifluormethyl and nitro;
R3 is selected from hydrogen, a group —(CH2)mCH2—COOH, OH, NH, and (C1-C5)alkyl which is optionally substituted with one or more halogens, one or two hydroxyl groups or methoxy;
R4 is independently selected from hydrogen and fluoro;
R5 is selected from hydrogen, halogen, (C1-C3)alkyl, (C1-C3)alkyloxy, (C1-C3)alkylthio, (C2-C4)alkenyl, (C2-C4)alkynyl, and NR6R7;
R6 and R7 are independently selected from hydrogen,(C1-C6)alkyl, (C3-C7)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl,(C1-C6)alkylcarbonyl,(C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl;
wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C3)alkyloxy, phenyl, halo, carboxy, and NR8R9;
and wherein R6 and R7 may form a 5- to 7-membered cycle;
and wherein phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C3)alkyloxy, halogen, (C1-C3)alkyl, carboxy, NR8R9, cyano, trifluormethyl and nitro;
R8 and R9 are independently selected from among hydrogen and (C1-C3)alkyl;
n and m are independently 0, 1 or 2, or
a salt thereof,
and wherein, optionally, the GPR agonist of formula I is as defined in claim 2.

14 more elements

Dependencies are inferred from the claim text.

Facts

Application

13/775,433Filed 25 Feb 2013

Priority

EP 11180467.07 Sep 2011

Published

20 Jun 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification23 codes

C07D 209/42
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon…
A61K 31/405
Indoles, e.g. pindolol: indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…

Abstract

Claims14

Dependent claims

-7. (canceled)

(a) identifying a compound that modulates GPR17 biological activity by
(i) contacting a compound with a GPR17, or a functional GPR17 fragment in the presence of a suitable amount of a GPR17 agonist of formula I
or a salt thereof,
(ii) measuring the biological activity of said GPR17 or said functional GPR17 fragment after addition of said compound, and
(iii) comparing the biological activity measured in step (ii) with the biological activity of said GPR17 or said functional fragment thereof in the presence of said GPR 17 agonist of formula I without the addition of said compound to identify whether the compound is one that modulates GPR17 activity,
wherein in formula I
R1 and R2 are independently selected from the group comprising hydrogen, halogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR6R7, carboxy, carbamoyl, (C1-C8)alkyl, (C1-C8) all yloxy, (C1-C8)alkylthio, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkloxy, (C3-C8)cycloalkylamino, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, trifluoromethyl, (C1-C8)alkylcarbonyl, (C1-C8) alkylaminocarbonyl, di(C1-C8)alkylaminocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl(C1-C8)alkyl, heteroaryl(C1-C8)alkyl, aryl(C1-C8)alkyloxy, heteroaryl(C1-C8)alkyloxy, aryl(C1-C8)alkylcarbonyl, heteroaryl(C1-C8)alkylcarbonyl, aryl(C1-C8)alkyloxycarbonyl, heteroaryl(C1-C8)alkyloxycarbonyl, (C1-C8)alkyloxycarbonyl, (C1-C8)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, sulfonylamino, (C1-C8)alkylaminosulfonyl, di(C1-C8)alkylaminosulfonyl, arylsulfonylamino, heteroarylsulfonylamino and (C1-C8)alkylsulfonylamino;
wherein each alkyl, alkenyl alkynyl or cycloalkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C5)alkyloxy, (C1-C3)alkyloxy(C1-C3)alkyloxy, halogen, and NR6R7;
and wherein each aryl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C5)alkyloxy, halogen, (C1-C5)alkyl, (C3-C8)cycloalkyl, carboxy, NR6R7, cyano, trifluormethyl and nitro;
R3 is selected from hydrogen, a group —(CH2)mCH2—COOH, OH, NH, and (C1-C5)alkyl which is optionally substituted with one or more halogens, one or two hydroxyl groups or (C1-C3)alkoxy;
R4 is selected from hydrogen and fluoro;
R5 is selected from hydrogen, halogen, (C1-C3)alkyl, (C1-C3)alkyloxy, (C1-C3)alkylthio, (C2-C4)alkenvl, (C2-C4)alkynyl, and NR6R7;
R6 and R7 are independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl;
wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C3)alkyloxy, phenyl, halo, carboxy, and NR8R9;
and wherein R6 and R7 may form a 5- to 7-membered cycle;
and wherein phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C3)alkyloxy, halogen, (C1-C3)alkyl, carboxy, NR8R9, cyano, trifluormethyl and nitro;
R8 and R9 are independently selected from among hydrogen and (C1-C3)alkyl;
n and m are independently 0, 1 or 2;
and
(b) administering said GPR17 modulating compound to the patient, optionally together with one or more pharmaceutically acceptable excipients.

17 more elements

A screening assay for the identification of GPR 17 modulators among a multitude of compounds, said screening assay comprising

(a) cells or membrane fractions expressing GPR17 or a functional GPR17 fragment and
(b) a suitable amount of a GPR17 agonist of formula I
wherein in formula I
R1 and R2 are independently selected from the group comprising hydrogen, halogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR6R7, carboxy, carbamoyl, (C1-C8)alkyl, (C1-C8) alkyloxy, (C1-C8)alkylthio, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyloxy, (C3-C8)cycloalkylamino, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, trifluoromethyl, (C1-C8)alkylcarbonyl, (C1-C8) alkylaminocarbonyl, di(C1-C8)alkylaminocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl(C1-C8)alkyl, heteroaryl(C1-C8)alkyl, aryl(C1-C8)alkyloxy, heteroaryl(C1-C8)alkyloxy, aryl(C1-C8)alkylcarbonyl, heteroaryl(C1-C8)alkylcarbonyl, aryl(C1-C8)alkyloxycarbonyl, heteroaryl(C1-C8)alkyloxycarbonyl, (C1-C8)alkyloxycarbonyl, (C1-C8)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, sulfonylamino, (C1-C8)alkylaminosulfonyl, di(C1-C8)alkylaminosulfonyl, arylsulfonylamino, heteroarylsulfonylamino and (C1-C8)alkylsulfonylamino;
wherein each alkyl, alkenyl, alkynyl or cycloalkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C5)alkyloxy, (C1-C3)alkyloxy(C1-C3)alkyloxy, halogen, and NR6R7;
and wherein each aryl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C5)alkyloxy, halogen, (C1-C5)alkyl, (C3-C8)cycloalkyl, carboxy, NR6R7, cyano, trifluormethyl and nitro;
R3 is selected from hydrogen, a group —(CH2)mCH2—COOH, OH, NH, and (C1-C5)alkyl which is optionally substituted with one or more halogens, one or two hydroxyl groups or methoxy;
R4 is independently selected from hydrogen and fluoro;
R5 is selected from hydrogen, halogen, (C1-C3)alkyl, (C1-C3)alkyloxy, (C1-C3)alkylthio, (C2-C4)alkenyl, (C2-C4)alkynyl, and NR6R7;
R6 and R7 are independently selected from hydrogen,(C1-C6)alkyl, (C3-C7)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl,(C1-C6)alkylcarbonyl,(C1-C6)alkoxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl;
wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C3)alkyloxy, phenyl, halo, carboxy, and NR8R9;
and wherein R6 and R7 may form a 5- to 7-membered cycle;
and wherein phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C3)alkyloxy, halogen, (C1-C3)alkyl, carboxy, NR8R9, cyano, trifluormethyl and nitro;
R8 and R9 are independently selected from among hydrogen and (C1-C3)alkyl;
n and m are independently 0, 1 or 2, or
a salt thereof,
and wherein, optionally, the GPR agonist of formula I is as defined in claim 2.

14 more elements

Dependencies are inferred from the claim text.

GPR 17 Agonists and Screening Assay

Life of this patent

Abstract

Claims14

GPR 17 Agonists and Screening Assay

Life of this patent

Abstract

Claims14