CA2479786A1 - Quinoline derivatives and their use as 5-ht6 ligands - Google Patents

Quinoline derivatives and their use as 5-ht6 ligands Download PDF

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CA2479786A1
CA2479786A1 CA002479786A CA2479786A CA2479786A1 CA 2479786 A1 CA2479786 A1 CA 2479786A1 CA 002479786 A CA002479786 A CA 002479786A CA 2479786 A CA2479786 A CA 2479786A CA 2479786 A1 CA2479786 A1 CA 2479786A1
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piperazin
quinoline
compound
formula
methyl
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CA2479786C (en
Inventor
Mahmood Ahmed
Christopher Norbert Johnson
Martin C. Jones
Gregor James Macdonald
Stephen Frederick Moss
Mervyn Thompson
Charles Edward Wade
David Witty
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Sio Gene Therapies Inc
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Priority claimed from GB0207289A external-priority patent/GB0207289D0/en
Priority claimed from GB0225678A external-priority patent/GB0225678D0/en
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Abstract

The present invention relates to quinoline compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 independently represent hydrogen or C1-6 alkyl or R1 is linked to R2 to form a group (CH2) 2, (CH2)3 or (CH2)4; R3, R4 and R5 independently represent hydrogen, halogen, cyano, -CF3, -CF3O, C1-6 alkyl, C1-6 alkoxy, C1-6 alkanoyl or a group - CONR6R7; m represents an integer from 1 to 4, such that when m is an integer greater than 1, two R2 groups may instead be linked to form a group CH2, (CH2)2 or (CH2)3; n represents an integer from 1 to 3; p represents 1 or 2; A represents a group -Ar1 or -Ar2Ar3; Ar1, Ar2 and Ar3 independently represent and aryl group or a heteroaryl group, both of which may be optionally substituted by one or more substituents having pharmacological activity, to processes for their preparation, to compositions containing them and to thei r use in the treatment of CNS and other disorders.

Claims (30)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R1 and R2 independently represent hydrogen or C1-6 alkyl or R1 is linked to R2 to form a group (CH2)2, (CH2)3 or (CH2)4;
R3, R4 and R5 independently represent hydrogen, halogen, cyano, -CF3, -CF3O, alkyl, C1-6 alkoxy, C1-6 alkanoyl or a group -CONR6R7;
R6 and R7 independently represent hydrogen or C1-6 alkyl or together may be fused to form a 5- to 7- membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom;
m represents an integer from 1 to 4, such that when m is an integer greater than 1, two R2 groups may instead be linked to form a group CH2, (CH2)2 or (CH2)3;
n represents an integer from 1 to 3;
p represents 1 or 2;
A represents a group Ar1 or - Ar2Ar3;
Ar1, Ar2 and Ar3 independently represent an aryl group or a heteroaryl group, both of which may be optionally substituted by one or more substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl, trifluoromethanesulfonyloxy, pentafluoroethyl, C1-6 alkoxy, arylC1-6 alkoxy, C1-6 alkylthio, C1-6 alkoxyC1-6 alkyl, C3-7 cycloalkylC1-6 alkoxy, C1-6 alkanoyl, C1-6 alkoxycarbonyl, C1-6 alkylsulfonyl, alkylsulfinyl, C1-6 alkylsulfonyloxy, C1-6 alkylsulfonylC1-6 alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC1-6 alkyl, C1-6 alkylsulfonamido, C1-6 alkylamido, C1-6 alkylsulfonamidoC1-6 alkyl, C1-6 alkylamidoC1-6 alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC1-6 alkyl, arylcarboxamidoC1-6 alkyl, aroyl, aroylC1-6 alkyl, arylC1-6 alkanoyl, or a group CONR8R9 or SO2NR8R9, wherein R8 and R9 independently represent hydrogen or C1-alkyl or together may be fused to form a 5- to 7- membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom;
or solvates thereof.
2. A compound of formula (I) as defined in claim 1 wherein R1 represents hydrogen, methyl, ethyl, isopropyl, isobutyl or 2,2-dimethylpropyl.
3. A compound of formula (I) as defined in claim 2 wherein R1 represents hydrogen.
4. A compound of formula (I) as defined in any one of claims 1 to 3 wherein R2 represents hydrogen, methyl or is linked to R1 to form a (CH2)3 group.
5. A compound of formula (I) as defined in claim 4 wherein R2 represents hydrogen.
6. A compound of formula (I) as defined in any one of claims 1 to 5 wherein R3 represents hydrogen, methyl or halogen.
7. A compound of formula (I) as defined in claim 6 wherein R3 represents hydrogen.
8. A compound of formula (I) as defined in any one of claims 1 to 7 wherein R4 and R5 independently represent hydrogen or methyl.
9. A compound of formula (I) as defined in claim 8 wherein R4 and R5 both represent hydrogen.
10. A compound of formula (I) as defined in any one of claims 1 to 9 wherein n represents 1.
11. A compound of formula (I) as defined in any one of claims 1 to 10 wherein m and p independently represent 1 or 2.
12. A compound of formula (I) as defined in claim 11 wherein m and p both represent 1.
13. A compound of formula (I) as defined in any one of claims 1 to 12 wherein A
represents a group -Ar1.
14. A compound of formula (I) as defined in claim 13 wherein Ar1 represents phenyl optionally substituted with halogen, C1-6 alkyl, C1-6 alkoxy, trifluoromethyl or trifluoromethoxy.
15. A compound of formula (I) as defined in claim 13 or claim 14 wherein Ar1 represents unsubstituted phenyl.
16. A compound of formula (I) according to claim 1 which is 8-(4-Methyl-piperazin-1-yl)-3-phenylsulfonylquinoline;
3-(2-Chloro)phenylsulfonyl-8-piperazin-1-yl-quinoline;
3-(3-Chloro)phenylsulfonyl-8-piperazin-1-yl-quinoline;
3-(2-Fluoro)phenylsulfonyl-8-piperazin-1-yl-quinoline;
3-(4-Chloro)phenylsulfonyl-8-piperazin-1-yl-quinoline;
3-(3-Fluoro)phenylsulfonyl-8-piperazin-1-yl-quinoline;
3-(4-Bromo-2-trifluoromethoxy)phenylsulfonyl-8-piperazin-1-yl-quinoline;
8-Piperazin-1-yl-3-(3-trifluoromethyl)phenylsulfonylquinoline;
7-Chloro-3-phenylsulfonyl-8-piperazin-1-yl-quinoline;
6-Methyl-3-phenylsulfonyl-8-piperazin-1-yl-quinoline;
(R)-8-(3-Methyl)piperazin-1-yl-3-phenylsulfonylquinoline;
(S)-8-(3-Methyl)piperazin-1-yl-3-phenylsulfonylquinoline;
8-Homopiperazin-1-yl-3-phenylsulfonylquinoline;
8-((S)-2-Methyl-piperazin-1-yl)-3-phenylsulfonyl-quinoline;
8-(4-Ethyl-piperazin-1-yl)-3-phenylsulfonylquinoline;
8-Piperazin-1-yl-3-(toluene-2-sulfonyl)-quinoline;
3-(2-Methoxy-benzenesulfonyl)-8-piperazin-1-yl-quinoline;
8-Piperazin-1-yl-3-(toluene-4-sulfonyl)-quinoline;
3-(4-Fluoro-benzenesulfonyl)-8-piperazin-1-yl-quinoline;
3-(2-Trifluoromethyl-benzenesulfonyl)-8-piperazin-1-yl-quinoline;
8-(4-Methyl-piperazin-1-yl)-3-(toluene-2-sulfonyl)-quinoline;
3-(2-Methoxy-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-quinoline;
8-(4-Methyl-piperazin-1-yl)-3-(toluene-4-sulfonyl)-quinoline;
3-(4-Fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-quinoline;
3-(3-Fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-quinoline;
3-(2-Fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-quinoline;
3-(4-Chloro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-quinoline;
3-(3-Chloro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-quinoline;
3-(2-Trifluoromethyl-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-quinoline;
8-((S)-3-Methyl-piperazin-1-yl)-3-(toluene-2-sulfonyl)-quinoline;
3-(2-Methoxy-benzenesulfonyl)-8-((S)-3-methyl-piperazin-1-yl)-quinoline;
8-((S)-3-Methyl-piperazin-1-yl)-3-(toluene-4-sulfonyl)-quinoline;
3-(4-Fluoro-benzenesulfonyl)-8-((S)-3-methyl-piperazin-1-yl)-quinoline;
3-(3-Fluoro-benzenesulfonyl)-8-((S)-3-methyl-piperazin-1-yl)-quinoline;
3-(2-Fluoro-benzenesulfonyl)-8-((S)-3-methyl-piperazin-1-yl)-quinoline;
3-(4-Chloro-benzenesulfonyl)-8-((S)-3-methyl-piperazin-1-yl)-quinoline;
3-(3-Chloro-benzenesulfonyl)-8-((S)-3-methyl-piperazin-1-yl)-quinoline;
3-(3-Trifluoromethyl-benzenesulfonyl)-8-((S)-3-methyl-piperazin-1-yl)-quinoline;
3-Benzenesulfonyl-8-((R)-2-methyl-piperazin-1-yl)-quinoline;
3-Benzenesulfonyl-8-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-quinoline racemate;
3-Benzenesulfonyl-8-(3,3-dimethyl-piperazin-1-yl)-quinoline;
3-Benzenesulfonyl-8-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-quinoline racemate;

3-Benzenesulfonyl-8-(4-isopropyl-piperazin-1-yl)-quinoline;
3-Benzenesulfonyl-8-(4-isobutyl-piperazin-1-yl)-quinoline;
3-Benzenesulfonyl-8-[4-(2,2-dimethyl-propyl)-piperazin-1-yl]-quinoline;
3-Benzenesulfonyl-8-((R)-3,4-dimethyl-piperazin-1-yl)-quinoline;
3-Benzenesulfonyl-8-((S)-3,4-dimethyl-piperazin-1-yl)-quinoline;
3-Phenylsulfonyl 8-({1S, 4S) 2,5-diazabicycloheptan-2-yl) quinoline;
or a pharmaceutically acceptable salt thereof.
17. A compound of formula (I) according to claim 1 which is 3-phenylsulfonyl-8-piperazin-1-yl-quinoline or a pharmaceutically acceptable salt thereof.
18. A compound of formula (I) according to claim 17 which is the free base of phenylsulfonyl-8-piperazin-1-yl-quinoline.
19. A compound of formula (I) according to claim 18 which is 3-phenylsulfonyl-piperazin-1-yl-quinoline (Form I).
20. A compound of formula (I) according to claim 18 which is 3-phenylsulfonyl-piperazin-1-yl-quinoline (Form II).
21. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, which comprises:
(a) reacting a compound of formula (II) wherein R1a is as defined for R1 in claim 1 or an N-protecting group, R2, R3, R4, R5, m, n and p are as defined in claim 1 and L1 is a leaving group;
with a compound of formula A-SO2H, (or A-SH followed by a subsequent oxidation step) wherein A is as defined above and thereafter as necessary removing an R1a N-protecting group; or (b) reacting a compound of formula (IV) with a compound of formula (V) wherein R1a, R2, R3, R4, R5, A, m, n and p are as defined in claim 1, and L2 represents a suitable leaving group, and thereafter as necessary removing an R1a N-protecting group;
or (c) reacting a compound of formula (VI) With a compound of formula (VII) wherein R1a, R2, R3, R4, R5, m, n, p and A are as defined in claim 1 and L3 represents a suitable leaving group, and thereafter as necessary removing an R1a N-protecting group;
or (d) deprotecting a compound of formula (I) which is protected; and thereafter optionally (e) interconversion to other compounds of formula (I) and/or forming a pharmaceutically acceptable salt and/or solvate.
22. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier or excipient.
23. A compound according to any one of claims 1 to 20 for use in therapy.
24. A compound according to any one of claims 1 to 20 for use in the treatment of depression, anxiety, Alzheimers disease, age related cognitive decline, ADHD, obesity, mild cognitive impairment, schizophrenia, cognitive deficits in schizophrenia and stroke.
25. The use of a compound of formula (I) as defined in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of depression, anxiety, Alzheimers disease, age related cognitive decline, ADHD, obesity, mild cognitive impairment, schizophrenia, cognitive deficits in schizophrenia and stroke.
26. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 20 for use in the treatment of depression, anxiety, Alzheimers disease, age related cognitive decline, ADHD, obesity, mild cognitive impairment, schizophrenia, cognitive deficits in schizophrenia and stroke.
27. A method of treating depression, anxiety, Alzheimers disease, age related cognitive decline, ADHD, obesity, mild cognitive impairment, schizophrenia, cognitive deficits in schizophrenia and stroke which comprises administering a safe and therapeutically effective amount to a patient in need thereof of a compound of formula (I) as defined in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.
28. A method of promoting neuronal growth within the central nervous system of a mammal which comprises the step of administering a compound of formula (I) as defined in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.
29. Use of a compound of formula (I) as defined in any one of claims 1 to 20 in the manufacture of a medicament for promoting neuronal growth within the central nervous system of a mammal
30. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 20 for use in promoting neuronal growth within the central nervous system of a mammal.
CA2479786A 2002-03-27 2003-03-25 Quinoline derivatives and their use as 5-ht6 ligands Expired - Fee Related CA2479786C (en)

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Application Number Priority Date Filing Date Title
GB0207289A GB0207289D0 (en) 2002-03-27 2002-03-27 Novel compounds
GB0207289.0 2002-03-27
GB0225678.2 2002-11-04
GB0225678A GB0225678D0 (en) 2002-11-04 2002-11-04 Novel compounds
PCT/EP2003/003197 WO2003080580A2 (en) 2002-03-27 2003-03-25 Quinoline derivatives and their use as 5-ht6 ligands

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CA2479786A1 true CA2479786A1 (en) 2003-10-02
CA2479786C CA2479786C (en) 2011-11-29

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