US 6,583,156 B1Granted

4-Quinolinemethanol derivatives as purine receptor antagonists (1)

AssigneeVernalis Research Limited

InventorsRoger John Gillespie, Joanne Lerpiniere, Suneel Gaur, David Reginald Adoms, Lars Jacob Stray Knutsen, Simon Edward Ward

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Abstract

Use a compound of formula (I) wherein: R1 is hydrogen or alkyl; R2 and R3 are independently selected from hydrogen, alkyl, aryl and heterocyclyle or together may form a ring or R1 and R2 or R3 together may form an oxygen-containing, optionally fused ring pharmaceutically acceptable salts or prodrugs thereof, with the proviso that where R1 and R4 to R9 are hydrogen, R2 or R3 is not 3-methoxy-4-benzyloxyphenyl or 2-dimethylaminoethoxymethyl, in the manufacture of a medicament for the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A2A receptors, may be beneficial. Said disorders are neurodegenerative disorders or movement disorders selected from Parkinson's disease or progressive supernuclear palsy, Huntington's disease, multiple system atrophy, corticobasal degeneration, Wilson's disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity, Alzheimer's disease or other disorders of the basal ganglia which result in dyskinesias.

Claims26

Dependent claims

A method of treating or preventing movement disorders, comprising administering to a subject in need thereof an effective amount of a compound of formula I:

wherein:
R1 is hydrogen or alkyl;
R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered unbridged saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from the group consisting of O, S and N, or together form a 3, 4, 5, 6 or 7 membered saturated or partially-unsaturated carbocyclic ring or a 3, 4, 5, 6, 7 or 8 membered saturated or partially unsaturated heterocyclic ring containing one or more heteroatoms selected from the group consisting of O, S and N;
or R1 and R2 or R3 together form a 3, 4, 5, 6, 7 or 8 membered oxygen-containing saturated or partially unsaturated heterocyclic ring optionally containing one or more additional heteroatoms selected from the group consisting of O, S and N;
or R1 and R2 and R3 together form a 4, 5, 6, 7 or 8 membered oxygen-containing partially unsaturated or aromatic heterocyclic ring optionally containing one or more additional heteroatoms selected from the group consisting of O, S and N in which R2 and R3 together form a double bond;
wherein said carbocyclic ring or said heterocyclic ring when partially unsaturated or aromatic may be fused to an aryl ring;
and
R4, R5, R6, R7, R8 and R9 are independently selected from the group consisting of hydrogen, alkyl;
aryll 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from the group consisting of O, S, and N;
hydroxy;
halogen, nitro, cyano, alkoxy, aryloxy, COR10, OCOR10, CO2R10, SR10, SOR10, SO2R10, SO2NR10R11, CONR10R11, CONR10NR11R12, OCONR10R11, NR10R11, NR10COR11, NR10CONR11R12, NR10CO2R11, NR10SO2R11, CR10NOR11, NR10CONR11NR12R13, NR10NR11CO2R12, NR10NR11CONR12R13, NR10NR11COR12, NR10NR11SO2R12, SO2NR10NR11R12, NR10SO2NR11NR12R13 and NR10SO2NR11R12, wherein R10, R11, R12 and R13 are independently selected from the group consisting of hydrogen, alkyl and aryl,
or a pharmaceutically acceptable salt or prodrug thereof;
other than (—)-(11S,2′R)-α-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol, with the proviso that where R1 and R4 to R9 are hydrogen, R2 or R3 is not 3-methoxy-4-benzyloxyphenyl or 2-dimethylaminoethoxymethyl.

10 more elements

A compound of formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R4, R5, R6, R7, R8 and R9 are independently selected from hydrogen, alkyl, aryl, 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, hydroxy, halogen, nitro, cyano, alkoxy, aryloxy, COR10, OCOR10, CO2R10, SR10, SOR10, SO2R10, SO2NR10R11, CONR10R11, CONR10NR11R12, OCONR10R11, NR10R11, NR10COR11, NR10CONR11R12, NR10CO2R11, NR10SO2R11, CR10NOR11, NR10CONR11NR12R13, NR10NR11CO2R12, NR10NR11CONR12R13, NR10NR11COR12, NR10NR11SO2R12, SO2NR10NR11R12, NR10SO2NR11NR12R13 and NR10SO2NR11R12 wherein R10, R11, R12 and R13 are independently selected from hydrogen, alkyl and aryl, and wherein
(i) R1 is hydrogen or alkyl;
R2 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered unbridged saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N;
or R1 and R2 together may form a 3, 4, 5, 6, 7 or 8 membered oxygen-containing saturated or partially unsaturated heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N;
and R3 is a 5 or 6 membered unbridged saturated, partially-unsaturated or aromatic heterocyclic ring containing one or more heteroatoms selected from O and S;
and R4 to R9 are as hereinbefore defined;
or
(ii) R1 is hydrogen or alkyl;
R2 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered unbridged saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N;
or R1 and R2 together may form a 3, 4, 5, 6, 7 or 8 membered oxygen-containing saturated or partially unsaturated heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N;
R3 is a 3, 4, 5, 6 or 7 membered carbocyclic ring;
and R4 to R9 are as hereinbefore defined provided that at least one thereof is a substituent group other than hydrogen;
or
(iii) R1 is hydrogen or alkyl;
R2 and R3 together form a 3, 4, 5 or 7 membered saturated or partially-unsatutrated carbocyclic ring, or a 4, 5, 6 or 7 membered saturated or partially-unsatgurated heterocyclic ring in which the one or more heteroatoms are selected only from O and S, or a 4, 5 or 7 membered saturated or partially unsaturated heterocyclic ring containing one or more heteroatoms selected from N;
and R4 to R9 are as hereinbefore defined;
or
(iv) R1 is C1 to C4 acyclic alkyl;
R2 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered unbridged saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N;
R3;
is aryl or C3 to C7 cycloalky;
and R4 to R9 are as hereinbefore defined;
or
(v) R1 is C1 to C4 acyclic alkyl;
R2 and R3 together form a 3, 4, 5, 6 or 7 membered saturated or partially-unsaturated carboyclic ring or a 3,4, 5, 6, 7 or 8 membered saturated or partially unsaturated heterocyclic ring containing one or more heteratoms selected from O, S and N;
and R4 to R9 are as hereinbefore defined.
wherein said carbocyclic ring or said heterocyclic ring when partially unsaturated or aromatic is optionally fused to an aryl ring, with the proviso that where R1 and R4 to R9 are hydrogen, R2 or R3 is not 3-methoxy-4-benzyloxyphenyl or 2-dimethylaminoethoxymethyl.

25 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/786,471Filed 16 May 2001
Priority: GB 961938244 Sep 1998
Granted: 24 Jun 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 215/38
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61K 31/47
Having six-membered rings with one nitrogen as the only ring hetero atom: quinolines; Isoquinolines
A61K 31/4709
Quinolines; Isoquinolines: non-condensed quinolines and containing further heterocyclic rings
C07D 215/14
With substituted hydrocarbon radicals attached to ring carbon atoms: radicals substituted by oxygen atoms