WO2007108743A2 - Nouvelles quinazolines comme modulateurs 5-ht6 de type ii - Google Patents

Nouvelles quinazolines comme modulateurs 5-ht6 de type ii Download PDF

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Publication number
WO2007108743A2
WO2007108743A2 PCT/SE2007/000253 SE2007000253W WO2007108743A2 WO 2007108743 A2 WO2007108743 A2 WO 2007108743A2 SE 2007000253 W SE2007000253 W SE 2007000253W WO 2007108743 A2 WO2007108743 A2 WO 2007108743A2
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Prior art keywords
alkyl
benzenesulfonamide
piperazin
methyl
ylquinazolin
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PCT/SE2007/000253
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English (en)
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WO2007108743A3 (fr
Inventor
Gunnar Nordvall
Ulrika Yngve
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Astrazeneca Ab
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Publication of WO2007108743A3 publication Critical patent/WO2007108743A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to new compounds, to pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
  • the present invention further relates to processes for the preparation of said compounds and to new intermediates useful in the preparation thereof.
  • Serotonin (5-hydroxy-tryptamine) (5-HT) receptors play an important role in many physiological and pathological functions like anxiety, sleep regulation, aggression, feeding and depression.
  • the 5-HT receptors are distributed throughout the body and can be divided into seven different 5-HT receptor subtypes, i.e. 5-HT1, 5-HT2, 5HT3, 5HT4, 5HT5, 5HT6 and 5-HT7, with different properties.
  • the 5-HT6 receptor is mostly found in the central nervous system (CNS).
  • 5-HT6 antagonists increase levels of glutamate and aspartate in the frontal cortex and dorsal hippocampus as well as acetylcholine in the frontal cortex. These neurochemicals are known to be involved in memory and cognition (Dawson et al., Neuropsychopharmacology., 25(5), p 662-668, 2001) (Gerard et al., Brain Res., 746, p 207-219, 1997) (Riemer et al J Med Chem 46(7), p 1273-1276, 2003).
  • Acetylcholinesterase inhibitors increase the levels of acetylcholine in the CNS and are used in the treatment of cognitive disorders such as Alzheimer's disease, 5-HT6 antagonists may therefore be used in the treatment of cognitive disorders.
  • 5-HT6 antagonist increases the level of dopamine and noradrenaline in the medial prefrontal cortex suggesting a role for 5-HT6 ligands in cognitive aspects of schizophrenia.
  • Several antidepressants and atypical antipsychotics bind to the 5-HT6 receptor and this may be a factor in their profile of activities (Roth et al. , J. Pharm. Exp. Therapeut, 268, 1402-1420, 1994; Sleight et al. ' Exp. Opin. Ther. Patents, 8, 1217-1224, 1998; Kohen et al., J. Neurochem., 66(1), p 47-56, 1996; Sleight et al. Brit. J. Pharmacol, 124, p 556-562, 1998; Bourson et al., Brit. J. Pharmacol, 125, p 1562-1566, 1998).
  • 5-HT6 modulators have described the potential use of 5-HT6 modulators in the treatment of epilepsy.
  • 5-HT6 receptors have also been linked to generalized stress and anxiety states (Yoshioka et al, Life Sciences, 17/18, p 1473-1477, 1998). The use of modulators for this receptor is therefore expected for a wide range of CNS disorders.
  • 5-HT6 receptor modulators may therefore also be useful in the treatment of feeding disorders like anorexia, obesity, bulimia and similar disorders and also type 2 diabetes.
  • the object of the present invention is to provide compounds exhibiting a modulating activity at the 5-hydroxy-tryptamine 6 receptor.
  • the present invention therefore relates to a compound having the formula I
  • Q is selected from C 6- ioarylQ ⁇ _ 6 alkyl, C 5-I iheteroarylCQ -6 alkyl, C 3-7 cycloalkylC 0-6 alkyl,
  • B is CH or N
  • R 1 is selected from hydrogen, hydroxy, halogen, C 1-10 alkyl, C 2-1 oalkenyl, C 2-1 oalkynyl, C 1- 10 alkoxy, N(R 5 ) 2 , C 6-1 oarylC o- 6alkyl, Cs-eheteroarylCo-ealkyl, Ci -6 haloalkyl, R 5 OC 0-6 alkyl, cyano, SR 5 , R 6 SO 2 C 0-6 alkyl, SOR 6 , R 5 CON(R 5 )C 0-6 alkyl, NR 5 SO 2 R 6 , COR 6 , R 5 CO 2 C 0- ealkyl, R 6 OC(O)C 0-6 alkyl, OSO 2 R 6 , (R 5 ) 2 NCOC 0- 6alkyl J SO 2 N(R 5 ) 2 , N(R 5 )CON(R 5 ) 2 ,NO 2 , oxo, C3
  • n 0, 1, 2, 3 or 4;
  • R 2 is selected from hydrogen, C 1-1 OaIlCyI, Ci- ⁇ haloalkyl, C 1-6 cyanoalkyl, (R ⁇ ) 2 NCOC 1- 6 alkyl, R 7 OC 2-6 alkyl and R 7 C(O)N(R 7 )C 1-6 alkyl; or
  • R 1 and R are connected to give a 5 or 6 membered heterocyclic ring
  • R 3 is selected from hydrogen, C 1-10 alkyl, C 1-6 haloalkyl and C ⁇ ealkylCe-ioaryl;
  • R 4 is selected from cyano, halogen, C ⁇ alkoxy, C 1 ⁇ aIkVl, Ci ⁇ haloalkyl, NO 2 and hydroxy;
  • n 0, 1 or 2;
  • R 5 is selected from hydrogen, C ⁇ oalkyl, C 6-lo arylCo- 6 alkyl, C 5 .6heteroarylCo -6 alkyl, C 1- 6 haloalkyl, C 3-7 cycloalkylC 0-6 alkyl and C 3-7 heterocycloalkylCo-6alkyl;
  • R 6 is selected from C 1-1O aIkVl, Ci -6 haloalkyl, C 3-7 cycloalkylCo- 6 alkyl, Ce-ioarylCo-ealkyl, Cs- ⁇ heteroarylCo- ⁇ alkyl and C 3-7 heterocycloalkylCo- 6 alkyl; 0 whereby any aryl, heteroaryl, cycloalkyl or heterocycloalkyl as defined for R 1 , R 5 and R 6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy, C 1-6 haloalkyl, cyano, OR 7 , C 1-6 alkyl, oxo, SR 7 , CON(R 7 ) 2 , N(R 7 )COR 8 , SO 2 R 8 , SOR & , N(R 7 ) 2 and COR 7 ; s R 7 is hydrogen, C ⁇ alkyl or Ci -6 haloalkyl; and R 8 is C
  • One embodiment of the present invention relates to a compound of formula I, wherein o Q is C 6-1 oarylCo- 6 alkyl or C 5-I iheteroarylCo -6 alkyl;
  • B is CH or N
  • R 1 is selected from hydrogen, halogen, Ci -lo alkyl, C 1-10 alkoxy, C ⁇ -ioarylCo-ealkyl, C 1- 6 haloalkyl, cyano, C 3 . 7 cycloalkylC 0-6 alkyl and C 3-7 heterocycloalkylCo -6 alkyl; n is O, 1, 2, 3 or 4; 25 R 2 is selected from hydrogen, Ci -10 alkyl, C 1-6 haloalkyl and R 7 OC 2-6 alkyl; or
  • R 1 and R 2 are connected to give a 5 or 6 membered heterocyclic ring
  • R 3 is hydrogen, C 1-1O aIlCyI or C 1-6 alkylC 6-10 aryl;
  • R 4 is selected from cyano, halogen, C 1-6 alkoxy, C ⁇ alkyl, Ci -6 haloalkyl, NO 2 and hydroxy; m is 0, 1 or 2; 30 R 5 is selected from hydrogen, C 1-10 alkyl, C 6-1 oarylCo- 6 alkyl, C 5 _ 5 heteroarylCo -6 alkyl, C 1- ⁇ haloalkyl, C 3 _ 7 cycloalkylCo -6 alkyl and C3- 7 heterocycloalkylCo- 6 alkyl;
  • R 6 is selected from C 1-1O aIlCyI, C ⁇ haloalkyl, C 3-7 cycloalkylCo -6 alkyl, C 6- ioarylCo -6 alkyl, C 5 . 6 heteroarylCo.
  • any aryl, heteroaryl, cycloalkyl or heterocycloalkyl as defined for R 1 , R 5 and R 6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy, C lr6 haloalkyl, cyano, OR 7 , C 1-6 alkyl, oxo, SR 7 , CON(R 7 ) 2 , N(R 7 )COR 8 , SO 2 R 8 , SOR 8 , N(R 7 ) 2 and COR 7 ;
  • R 7 is hydrogen, C h alky! or C 1-6 haloalkyl
  • R 8 is Ci- ⁇ alkyl or C 1-6 haloalkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
  • Another embodiment of the present invention relates to a compound of formula I, wherein
  • Q is C 6- ioarylCo- 6 alkyl or Cs-nheteroarylCo- ⁇ alkyl;
  • B is CH or N
  • R 1 is selected from hydrogen, halogen, C 1-1O aIlCyI, C 1-10 alkoxy, C 6-1 oarylC 0-6 alkyl, C 1-
  • n 0, 1, 2, 3 or 4;
  • R 2 is selected from hydrogen, C 1-10 alkyl and Ci- ⁇ haloalkyl; or
  • R 1 and R 2 are connected to give a 5 or 6 membered heterocyclic ring
  • R 3 is hydrogen, Cnoalkyl or Ci -6 alkylC 6-1 oaryl
  • R 4 is selected from cyano, halogen, Ci -6 alkoxy, C ⁇ aUcyl and C 1-6 haloalkyl; m is 0, 1 or 2; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
  • Yet another embodiment of the present invention relates to a compound of formula I, wherein Q is C 6-lo arylCo- 6 alkyl or C 5 - 1 iheteroarylCo-ealkyl;
  • B is CH or N
  • R 1 is selected from hydrogen, halogen, C 1-10 alkoxy, C ⁇ -ioarylCo-ealkyl, Ci- ⁇ haloalkyl and cyano; n is 0, 1, 2, 3 or 4; R 2 is selected from hydrogen, C 1-1O aI-CyI and Ci-ghaloalkyl; or
  • R and R are connected to give a 5 or 6 membered heterocyclic ring
  • R 3 is hydrogen, C 1-10 alkyl or Ci- ⁇ alkylC ⁇ -ioaryl
  • R 4 is selected from cyano, halogen, C 1-6 alkoxy, C 1-6 alkyl and Ci- ⁇ haloalkyl
  • m is 0, 1 or 2; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
  • m is 0.
  • B is N.
  • B is CH.
  • Q is C ⁇ -ioarylCo-ealkyl.
  • C 6- i 0 aryl is phenyl or Ci O aryl.
  • said C 10 aryl is naphtyl.
  • R 2 is hydrogen or methyl.
  • Q is tetrahydroisoquinoline
  • the present invention also relates to compounds selected from the group consisting of: iV-[2-(4-methylpiperazin-l-yl)quinazolin-4-yl]benzenesulfonamide;
  • C m-n or "C m-n group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • alkyl used alone or as a suffix or prefix, refers to a saturated monovalent straight or branched chain hydrocarbon radical comprising from 1 to about 10 carbon atoms.
  • alkyls include, but are not limited to, C 1-6 alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l - butyl, 3 -methyl- 1 -butyl, 2-methy 1-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3- methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2- pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl
  • 'C 0 ' means a bond or does not exist.
  • arylCoalkyl is equivalent with “aryl”
  • C 2 alkylOC 0 alkyl is equivalent with “C 2 alkylO”.
  • alkenyl refers to an unsaturated carbon chain group having one or more double carbon-carbon bonds and includes both straight and branched chain alkenyl groups.
  • Example on alkenyl groups includes, but is not limited to, vinyl, allyl, propenyl, butenyl, pentenyl, or hexenyl, and a butenyl group may for example be buten-2-yl, buten-3-yl or buten-4-yl.
  • alkynyl refers to an unsaturated carbon chain alkyl group having one or more triple carbon-carbon bonds and includes both straight and branched chain alkynyl groups.
  • Example on alkynyl groups includes, but is not limited to, etynyl, propargyl, pentynyl or hexynyl and a butynyl group may for example be butyn-3-yl or butyn-4-yl.
  • cycloalkyl refers to an optionally substituted, partially or completely saturated cyclic hydrocarbon ring system.
  • C 3-7 cycloalkyl may be, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclopentenyl.
  • alkoxy refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical.
  • alkoxy may include, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy or propargyloxy.
  • amine or “amino” refers to radicals of the general formula -NRR', wherein R and R' are selected independently from hydrogen or a hydrocarbon radical.
  • heterocycloalkyl denotes a non-aromatic, partially or completely saturated hydrocarbon group, which contains one ring and at least one heteroatom.
  • heterocycle include, but are not limited to pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, morpholinyl, oxazolyl, 2-oxazolidonyl or tetrahydrofuranyl.
  • aryl refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system with at least one unsaturated aromatic ring.
  • examples of “aryl” may be, but are not limited to phenyl, naphthyl or tetralinyl.
  • heteroaryl refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system with at least one unsaturated ring and containing at least one heteroatom selected independently from N, O or S.
  • heteroaryl may be, but are not limited to pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, benzofuryl, indolyl, isoindolyl, benzimidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazolyl, quinazolinyl isotiazolyl, isoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl or quinolinyl.
  • a Csheteroaryl refers to a 5 membered aromatic ring system containing at least one heteroatom.
  • arylalkyl and “heteroarylalkyl” refer to a substituent that is attached via the alkyl group to an aryl or heteroaryl group.
  • haloalkyl means an alkyl group as defined above, which is substituted with halo as defined above.
  • the term “Ci. 6 haloalkyl” may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl orbromopropyl.
  • the term “Ci. ⁇ haloalkylO” may include, but is not limited to fluoromethoxy, difiuoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.
  • the present invention relates to the compounds of formula I as hereinbefore defined as well as to the salts, solvates or solvated salts thereof.
  • Salts for use in pharmaceutical formulations will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I.
  • a suitable pharmaceutically acceptable salt of the compounds of the invention is, for example, an acid-addition salt, for example a salt with an inorganic or organic acid.
  • a suitable pharmaceutically acceptable salt of the compounds of the invention is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base.
  • Other pharmaceutically acceptable salts and methods of preparing these salts may be found in, for example, Remington's Pharmaceutical Sciences (18 th Edition, Mack Publishing Co.).
  • Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z-isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomeric and geometric isomers.
  • the invention also relates to any and all tautomeric forms of the compounds of formula I.
  • a compound A may be reacted with a compound B, wherein R 1 , R 2 , Q and n are as defined above, in a solvent such as DMSO, DMF, dioxane, propanol, pentanol or THF or mixtures thereof, in the presence of a base such as potassium carbonate, sodium carbonate or sodium hydride to form a compound C, wherein R 1 , R 2 , Q and n are as defined above.
  • the reaction may be performed at temperatures between RT and the reflux temperature of the solvent, for reaction times between 10 minutes and 24 h.
  • reaction mixture containing a compound C, wherein R 1 , R 2 , Q and n are as defined above, may be used in the next step or a compound C, wherein R 1 , R 2 , Q, and n are as defined above, may be isolated by evaporation of the solvent, extraction, precipitation or by column chromatography.
  • a compound C wherein R 1 , R 2 , Q and n are as defined above, may be reacted with a compound D, wherein R 3 is as defined above to form a compound I, wherein R 1 , R 3 , Q and n are as defined above and wherein R 2 is hydrogen for a compound Ia and R 2 is C 1-10 alkyl, C 1-6 haloalkyl or R 7 OC 2-6 alkyl for a compound Ib.
  • the reaction may be performed in a solvent such as DMF, DMSO, z-pentanol, THF or dioxane or mixtures thereof, optionally in the presence of a base such as triethylamine, DIPEA or potassium carbonate.
  • the reaction may be performed at temperatures between room temperature and the reflux temperature of the solvent.
  • the product may be isolated by extraction, precipitation or by column chromatography.
  • a compound G, wherein R 1 , Q and n are as defined above may be reacted with a compound D, wherein R 3 is as defined above, to form a compound Ic, wherein R 1 , R 3 , Q and n are as defined above.
  • the reaction may be performed in a solvent such as DMF, DMSO, 2-pentanol, THF or dioxane or mixtures thereof, optionally in the presence of a base such as triethylamine, DIPEA or potassium carbonate.
  • the reaction may be performed at temperatures between room temperature and the reflux temperature of the solvent.
  • the product may be isolated by extraction, precipitation or by column chromatography. Step 3
  • a compound Ia wherein R 2 is hydrogen and R 1 , R 3 , Q, and n are as defined above, may be transformed into a compound Ib, wherein R 2 is C 1-1O aIkVl, Ci- ⁇ haloalkyl or R 7 OC 2- 6alkyl and R 1 , R 3 , Q, and n are as defined above, by reacting compound Ib with a compound R 2 Z wherein Z is a good leaving group such as for example bromine or iodine and R 2 is C 1- ! oalkyl, C 1-6 haloalkyl or R 7 OC 2-6 alkyl.
  • the reaction may be performed in the presence of a base such as potassium carbonate or sodium hydride in a solvent such as DMF or DMSO.
  • a base such as potassium carbonate or sodium hydride
  • the reaction may be performed at temperatures between RT and the reflux temperature of the solvent for reaction times between 1 and 48 h.
  • the product may be isolated by extraction, precipitation or by column chromatography.
  • a compound B wherein R 1 , R 2 , Q and n are as defined above, may be prepared from a compound E, wherein R 1 , Q and n are as defined above, by reacting said compound with a compound Y, wherein R 2 is as defined above, in a solvent such as methanol, ethanol, dioxane, dichloromethane or mixtures thereof in the presence of a base such as triethylamine, DIPEA or an excess of compound Y.
  • the reaction may be performed at temperatures between —10° and the reflux temperature of the solvent, preferably at 0°C and RT for reaction times between 1 minute to 2 h.
  • a base such as triethylamine or DIPEA may be added to the reaction mixture to liberate the free base of compound Y.
  • the product may be isolated by extraction, precipitation or by column chromatography.
  • Step 5 A compound F, wherein R 1 , Q and n are as defined above, may be deprotonated using a strong base such as n-butyl lithium in a solvent such as THF at temperatures between - 80°C and 0°C. The mixture may be allowed to attain temperatures between -10 0 C and RT and then a compound A may be added and the reaction may proceed at temperatures between RT and the reflux temperature of the solvent.
  • a compound G may either be isolated by for example evaporation of the solvent, extraction or column chromatography or the reaction mixture containing G may be used directly in the next reaction step.
  • a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound of formula I, or salts, solvates or solvated salts thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
  • the composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration e.g. as an ointment, patch or cream, for rectal administration, e.g. as a suppository, or for inhalation.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • a sterile solution e.g. as an ointment, patch or cream
  • rectal administration e.g. as a suppository, or for inhalation.
  • compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical acceptable diluents and/or inert carriers.
  • Suitable daily doses of the compounds of formula I in the treatment of a mammal, including man, are approximately 0.01 to 250 mg/kg bodyweight at peroral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration.
  • the typical daily dose of the active ingredient varies within a wide range and will depend on various factors such as the relevant indication, severity of the illness being treated, the route of administration, the age, weight and sex of the patient and the particular compound being used, and may be determined by a physician.
  • the compounds according to the present invention are useful in therapy.
  • the compounds may be used to produce an inhibitory effect of 5-HT6 receptors in mammals, including man.
  • the compounds of the present invention are expected to be suitable for the treatment of disorders relating to or affected by the 5-HT6 receptor including cognitive, personality, behaviour, psychiatric and neurodegenerative disorders.
  • Such disorder may be selected from the group comprising of Alzheimer's disease anxiety, depression, convulsive disorders such as epilepsy, personality disorders, obsessive compulsive disorders, migraine, cognitive disorders such as memory dysfunction, sleep disorders, feeding disorders such as anorexia, obesity, bulimia, panic attacks, withdrawal from drug abuse, schizophrenia, attention deficit hyperactive disorder (ADHD), attention deficit disorder (ADD), dementia, memory loss, disorders associated with spinal trauma and/or head injury, stroke, diabetes type 2, binge disorders, bipolar disorders, psychoses, Parkinson's disease, Huntington's disease, neurodegenerative disorders characterized by impaired neuronal growth, and pain.
  • ADHD attention deficit hyperactive disorder
  • ADD attention deficit disorder
  • dementia memory loss
  • disorders associated with spinal trauma and/or head injury stroke
  • diabetes type 2 binge disorders
  • bipolar disorders bipolar disorders
  • psychoses Parkinson's disease
  • Huntington's disease neurodegenerative disorders characterized by impaired neuronal growth, and pain.
  • gastro-intestinal disorders such as gastro-esophageal reflux disease (GERD) and irritable bowel syndrome (IBS).
  • GFD gastro-esophageal reflux disease
  • IBS irritable bowel syndrome
  • the compounds may also be used for treatment of tolerance to 5-HT6 activators.
  • One embodiment of the invention relates to a compound the present invention as hereinbefore defined, for use in therapy.
  • Another embodiment of the invention relates to a compound the present invention as hereinbefore defined, for use in treatment of 5-HT6 mediated disorders.
  • a further embodiment of the invention relates to a compound the present invention as hereinbefore defined, for use in treatment of Alzheimer's disease.
  • Another embodiment of the invention relates to a compound the present invention as hereinbefore defined, for use in treatment of cognitive impairment associated with schizophrenia.
  • Yet a further embodiment of the invention relates to a compound the present invention as hereinbefore defined, for use in treatment of obesity.
  • One embodiment of the invention relates to a compound the present invention as hereinbefore defined, for use in Parkinson's disease.
  • Another embodiment of the invention relates to the use of a compound the present invention as hereinbefore defined, in the manufacture of a medicament for treatment of 5- HT6 mediated disorders, Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity and/or Parkinson's disease, and any other disorder mentioned above.
  • a further embodiment of the invention relates to a method of treatment of 5-HT6 mediated disorders, Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity and/or Parkinson's disease, and any other disorder mentioned above, comprising administering to a mammal, including man in need of such treatment, a therapeutically effective amount of a compound the present invention, as hereinbefore defined.
  • Yet another embodiment of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound the present invention as hereinbefore defined, for use in treatment of 5-HT6 mediated disorders, Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity and/or Parkinson's disease, and any other disorder mentioned above.
  • One embodiment of the invention relates to an agent for the prevention or treatment of 5- HT6 mediated disorders, Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity and/or Parkinson's disease, and any other disorder mentioned above, which comprises as active ingredient a compound the present invention as hereinbefore defined.
  • the term “therapy” and “treatment” includes prevention and prophylaxis, unless there are specific indications to the contrary.
  • the terms “treat” /'therapeutic” and “therapeutically” should be construed accordingly.
  • inhibitor and “antagonist” mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the agonist.
  • the compounds according to the present invention are modulators of the 5-HT6 receptors, and may be inhibitors, as well as agonists, inverse-agonists or partial-agonist.
  • disorder means any condition and disease associated with 5-HT6 receptor activity.
  • the compounds of formula I, or salts, solvates or solvated salts thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of modulators of 5-HT6 related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutics agents.
  • G1379A Micro Vacuum Degasser, G1312A Binary Pump, G1367A Well plate auto-sampler, G1316A Thermostatted Column Compartment and G1315B Diode
  • TLC thin layer chromatography
  • Merck TLC-plates Silica gel 60 F 254
  • Flash chromatography was preformed on a Combi Flash ® CompanionTM using RediSepTM normal-phase flash columns or on o Merck Silica gel 60 (0.040-0.063 mm).
  • Typical solvents used for flash chromatography were mixtures of chloroform/methanol, toluene/ethyl acetate and ethyl acetate/hexanes;
  • Mass spectra were recorded on a Waters LCMS consisting of an Alliance 2795 (LC), Waters PDA 2996, ELS detector (Sedex 75) and a ZQ single quadrupole mass spectrometer.
  • the mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode.
  • the capillary voltage was 3 kV and cone voltage was 30 V.
  • the mass spectrometer was scanned between m/z 100-700 with a scan time of 0.3s.
  • the Diode Array Detector was scanned from 200-
  • the APPI repeller and the APCI corona were set to 0.86 kV and 0.80 ⁇ A, respectively.
  • the desolvation 5 temperature (300 0 C), desolvation gas (400 L/Hr) and cone gas (5 L/Hr) were constant for both APCI and APPI mode;
  • melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the Formula I were determined after crystallisation from an appropriate organic solvent or solvent mixture;
  • Example 1 iV-[2-(4-Methylpiperazin-l-yl)quinazolin-4-yl]benzenesulfonamide 2,4-Dichloroquinazoline (200 mg, 1.0 mmol) and benzenesulfonamide (157 mg, 1.0 mmol) were dissolved in DMF (anhydrous, 3 ml) ' .
  • Sodium hydride 29 mg, 1.2 mmol was added and the mixture was heated at 85°C under nitrogen atmosphere for 6 h. The mixture was cooled, poured onto ice water and extracted with dichloromethane (x3), dried (MgSO 4 ) and concentrated.
  • Example 8 3-Bromo-iV-methy ⁇ -iV-(2-piperazin-l-ylquinazolin-4-yl)benzenesulfonamide o
  • the title compound was prepared using the method described in Example 6. Yield 14 %.
  • Example 16 iV-(2-Fluoroethyl)-2-(l-naphthyl)-iV-(2-piperazin-l-ylquinazolin-4- yl)ethanesulfonamide 0
  • the title compound was prepared according to the method in example 13 with the difference that the reaction sequence was performed at RT instead of at 80°C. Yield 7%.
  • the title compound was prepared according to the method in example 13 with the difference that the first step of the reaction sequence was performed at RT instead of at 80°C. Yield 7%.
  • Example 19 is 2-(4-Chlorophenyl)-iV-(2-fluoroethyl)-iV-(2-piperazin-l-ylquinazolin-4- yl)ethanesulfonamide
  • N-(2-Chloroquinazolin-4-yl)-iV-methyl-3,4-dihydroisoquinoIme-2(lH)-sulfonainide (80 mg, 0.21 mmol) was dissolved in DMSO (1 ml) and piperazine (37 mg, 0.42 mmol) was added. The mixture was heated at 9O 0 C for 2 h. Water (0.5 ml) was added and the mixture was purified by preparative ⁇ PLC to give the acetate of the title compound as a solid (49 mg, 48%).
  • Examples 39-59 were prepared using the method described in Example 34.
  • Example 61 2-(4-Methylpiperazin-l-yl)-4-[(phenylsulfonyl)methyl]quinazoline
  • the title compound was prepared according to the method in Example 60 to give a solid (10%).
  • Example 63 4- ⁇ [(4-Chlorophenyl)sulfonyl]methyl ⁇ -2-piperazin-l-ylquinazoline s
  • the title compound was prepared according to the method in Example 60 to give solid (8 mg, 3%)Yield (%): 3 (solid).
  • Striatal tissue from adult rats (Sprague-Dawley, 320-370 g, B & K Sweden) were dissected out, weighed and homogenized in buffer containing 50 mM Tris-HCl, 4 mM MgC12, 1 mM EDTA, 10 ⁇ M pargyline and protease inhibitor (Complete, Roche Diagnostics) pH 7.4 using an Ultra-Turrax T8 (IKA Labortechnik, Germany).
  • the tissue homogenate was centrifuged at 48 000xg for 10 min and the pellet was resuspended and recentrifuged as above.
  • the final membranes were diluted in buffer to a concentration of 60 mg original wet weight (w.w.) per ml and stored in aliquots at -70°C.
  • Radioligand binding assays Saturation binding studies were carried out in duplicate with 1-3 mg w.w. per tube in 0.5 ml buffer (50 mM Tris, 4 mM MgC12, 100 mM NaCl, 1 mM EDTA, 5 mM ascorbate and 10 ⁇ M pargyline at pH 7.4), 0.2 nM [ 125 I]SB258585 and unlabelled SB258585 to give a final concentration range of 0.23- 20 nM (12 cone). Non-specific binding was determined in the presence of 10 ⁇ M methiothepin. In the competition experiments 0.8-2 mg w.w.
  • Typical IC50 values as measured in the assays described above are 1 ⁇ M or less.
  • the IC 5 O is below 500 nM.
  • the IC 50 is below 50 nM.
  • the IC 50 is below 10 nM.

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Abstract

La présente invention concerne de nouveaux composés répondant à la formule I, Q, B, R1, R2, R3, R4, m et n étant tels qu'ils ont été définis dans la revendication 1, ou des sels, solvates ou sels solvatés de ces composés. La présente invention concerne également des procédés de préparation et de nouveaux intermédiaires utilisés pour préparer les composés, ainsi que des formulations pharmaceutiques contenant lesdits composés et l'utilisation desdits composés en thérapie.
PCT/SE2007/000253 2006-03-17 2007-03-15 Nouvelles quinazolines comme modulateurs 5-ht6 de type ii WO2007108743A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9840482B2 (en) 2014-04-19 2017-12-12 Sunshine Lake Pharma Co., Ltd. Sulfonamide derivatives and pharmaceutical applications thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1020445A1 (fr) * 1997-10-02 2000-07-19 Eisai Co., Ltd. Derives de pyridine condenses
WO2001032646A2 (fr) * 1999-11-05 2001-05-10 Smithkline Beecham P.L.C. Nouveaux composes
WO2002100822A1 (fr) * 2001-06-11 2002-12-19 Biovitrum Ab Composants de sulfonamide substitues, procede d'utilisation de ceux-ci comme medicaments dans le traitement de troubles cns, de l'obesite et du diabete de type ii
WO2005021530A1 (fr) * 2003-08-29 2005-03-10 Glaxo Group Limited Derives de 8- (1-piperazinyl)- quinoleine et leur utilisation pour le traitement de troubles du systeme nerveux central

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1020445A1 (fr) * 1997-10-02 2000-07-19 Eisai Co., Ltd. Derives de pyridine condenses
WO2001032646A2 (fr) * 1999-11-05 2001-05-10 Smithkline Beecham P.L.C. Nouveaux composes
WO2002100822A1 (fr) * 2001-06-11 2002-12-19 Biovitrum Ab Composants de sulfonamide substitues, procede d'utilisation de ceux-ci comme medicaments dans le traitement de troubles cns, de l'obesite et du diabete de type ii
WO2005021530A1 (fr) * 2003-08-29 2005-03-10 Glaxo Group Limited Derives de 8- (1-piperazinyl)- quinoleine et leur utilisation pour le traitement de troubles du systeme nerveux central

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9840482B2 (en) 2014-04-19 2017-12-12 Sunshine Lake Pharma Co., Ltd. Sulfonamide derivatives and pharmaceutical applications thereof

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