WO2005035521A1 - Substituted quinolines as mcr modulators - Google Patents

Substituted quinolines as mcr modulators Download PDF

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Publication number
WO2005035521A1
WO2005035521A1 PCT/GB2004/004304 GB2004004304W WO2005035521A1 WO 2005035521 A1 WO2005035521 A1 WO 2005035521A1 GB 2004004304 W GB2004004304 W GB 2004004304W WO 2005035521 A1 WO2005035521 A1 WO 2005035521A1
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Prior art keywords
acetamide
methyl
heteroaryl
quinolin
alkyl
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PCT/GB2004/004304
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French (fr)
Inventor
Hazel Joan Dyke
Susan Mary Cramp
Stephen Paul Wren
Christopher Gregory Newton
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Argenta Discovery Ltd.
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Publication date
Priority claimed from GB0323690A external-priority patent/GB0323690D0/en
Priority claimed from GB0400460A external-priority patent/GB0400460D0/en
Application filed by Argenta Discovery Ltd. filed Critical Argenta Discovery Ltd.
Publication of WO2005035521A1 publication Critical patent/WO2005035521A1/en

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • BMI Body mass index
  • BMI>30 body mass index
  • a BMI above 30 kg/m 2 significantly increases the risk of diabetes, hypertension, dyslipidemias and cardiovascular disease, gallstones, osteoarthritis and certain forms of cancer and reduces life expectancy. In the vast majority of obese individuals, the cause of the excess adiposity is not immediately apparent.
  • MCH Melanin-concentrating hormone
  • MCH has also been shown to be involved in stress induced or CRF-stimulatedACTH release (Kawauchi. ef al., ⁇ /aftvre,1983305, 321-323).
  • CRF-stimulatedACTH release Kawauchi. ef al., ⁇ /aftvre,1983305, 321-323.
  • two genes encoding MCH have been identified that are expressed in the brain. (Brecton, et al., Mol. Brain Res. 1993, 18, 297 - 310).
  • MCH has been localized primarily to neuronal cell bodies of the hypothalamus which are implicated in the control of food intake, including perikayra of the lateral hypothalamus and zona inertia. (Knigge, et al.,. Peptides, 1996, 17, 1063 -1073).
  • MCH mRNA is up-regulated in fasted mice and rats, in the ob/ob mouse and in mice with targeted disruption in the gene for neuropeptide Y (NPY).
  • NPY neuropeptide Y
  • Injection of MCH intracelebroventricularly (ICV) stimulates food intake and MCH antagonizes the hypophagic effects seen with ⁇ melanocyte-stimulating hormone ( ⁇ MSH).
  • ⁇ MSH ⁇ melanocyte-stimulating hormone
  • MCH deficient mice are lean, hypophagic and have increased metabolic rate. (Shimada, et al., Nature 1998, 396, 670 - 673). MCH action is not limited to modulation of food intake as effects on the hypothalamic-pituitary-axis have been reported. (Nahon, Critical Rev. in Neurobiol. 1994, 8, 221 - 262). MCH may be involved in the body's response to stress as MCH can modulate the stress-induced release of CRF from the hypothalamus and ACTH from the pituitary. In addition, MCH neuronal systems may be involved in reproductive or maternal function.
  • MCH transcripts and MCH peptide were found within germ cells in testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes (Hervieu et al., 1996).
  • MCH injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et ai, 1996).
  • MCH stimulated luteinizing hormone (LH) release while anti-MCH antiserum inhibited LH release (Gonzalez et al., 1997).
  • MCH The zona incerta, which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge (MacKenzie et al., 1984). Therefore modulators of MCH receptors may be useful in the prevention and treatment of reproductive function. MCH has been reported to influence release of pituitary hormones including ACTH and oxytocin.
  • modulators of MCH receptors may be useful in the prevention and treatment of obesity, Cushing's disease, sexual function, appetite and eating disorders, obesity, diabetes, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, gall stones, osteoarthritis, certain cancers, AIDS wasting, cachexia,, frailty (particularly in the elderly), binge eating disorders including bulimia, anorexia, kidney function, diuresis, reproductive function and sexual function.
  • Two receptor subtypes have been identified in humans, MCH-1 R and
  • MCH-2R Both receptors, as well as the gene for the MCH peptide, have been mapped to regions previously reported to contain a susceptibility gene for psychiatric disorders.
  • MCH-1 R was mapped to chromosome 22q13.2 (Kolakowski et al. 1996).
  • the possibility of linkage for schizophrenia susceptibility locus in this area was suggested by independent studies from 2 groups (Pulver et al. 1994; Coon et al. 1994).
  • MCH-2R MCH receptor
  • Cao et al,. (1997) were the first to report evidence of a schizophrenia susceptibility locus in that area. This initial report was confirmed and extended by other reports (Martinez et al. 1999; Kaufmann et al. 1998; Levinson et al. 2000). Schizophrenia has been recognised as a disorder with profound deficits in information-processing and attentional abnormalities.
  • One of the few possible paradigms available to assess these types of deficits in information processing is sensory gating, a filtering process which can be demonstrated by using a paired auditory stimulus. Miller et al.
  • the MCH cell group occupies a rather constant location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called "extrapyramidal" motor circuits. These involve substantial striato-and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to subthalamic nucleus, substantia nigra, and mid-brain centres (Bittencourt et al., 1992). In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with appropriate and coordinated motor activity.
  • modulators of MCH receptor function may be useful in the treatment and prevention of movement disorders, such as Parkinson's disease, Parkinson-like syndromes and Huntingdon's Chorea in which extrapyramidal circuits are known to be involved.
  • Human genetic linkage studies have located authentic hMCH loci on chromosome 12 (12q23-24) and the variant hMCH loci on chromosome 5 (5q 12- 13) (Pedeutour et al., 1994). Locus 12q23-24 coincides with a locus to which autosomal dominant cerebellar ataxia type II (SCA2) has been mapped (Auburger et al., 1992; Twells ef al., 1992).
  • SCA2 autosomal dominant cerebellar ataxia type II
  • This disease comprises neurodegenerative disorders, including an olivopontocerebellar atrophy.
  • Futhermore the gene for Darier's disease, has been mapped to locus 12q23-24 (Craddock ef al., 1993).
  • Darier's disease is characterized by abnormalities in keratinocyte adhesion and mental illnesses in some families.
  • the MCH gene may represent a good candidate for SCA2 or Darier's disease.
  • modulators of MCH receptors may be useful in the treatment of mental disorders including manic depression, depression, schizophrenia, mood disorders, delirium, dementia, severe mental retardation, anxiety, stress, cognitive disorders, and dyskinesias including Parkinson's disease, Tourette's syndrome, Huntington's disease, cerebellar ataxia, and seizures.
  • the gene responsible for chronic or acute forms of spinal muscular atrophies has been assigned to chromosome 5q12-13 using genetic linkage analyses (Melki ef al., 1990; Westbrook ef al., 1992).
  • modulators of MCH receptors may be useful in treating muscular dystrophy and dyskinesias, including Parkinson's disease, Tourette's syndrome, Huntington's disease, cerebellar ataxia, seizures, locomotor disorders, attention deficit disorder (ADD) and substance abuse disorders. Still further, modulators of MCH receptor binding may also be useful in treating epilepsy. In the PTZ seizure model, injection of MCH prior to seizure induction prevented seizure activity in both rats and guinea pigs, suggesting that MCH-containing neurons may participate in the neural circuitry underlying PTZ- induced seizure (Knigge and Wagner, 1997). MCH has also been observed to affect behavioural correlates of cognitive functions.
  • MCH treatment hastened extinction of the passive avoidance responses in rats (McBride ef al., 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage and/or retention.
  • a role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers.
  • MCH receptor modulators may be useful as antinociceptives or as analgesics, particularly for the treatment of neuropathic pain.
  • MCH may participate in the regulation of fluid intake. ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and kaliuretic changes in response to increased plasma volume (Parkes, 1996).
  • MCH may be an important peptide involved in the central control of fluid homeostasis in mammals. Therefore, modulators of MCH receptors may be useful in kidney function and diuresis.
  • modulators of MCH receptors may be useful in kidney function and diuresis.
  • Several antagonists of MCH-1 R have been reported (Carpenter and Hertzog, Expert Opin. Ther. Patents, 2002, 12, 1639-1646; Collins and Kym, Curr. Opin. Invest. Drugs, 2003, 4, 386-394; Takekawa etal., Eur. J. Pharmacol., 2002, 438, 129-135; Borowsky et al., Nature Medicine, 2002, 8, 825-830).
  • the compounds of the present invention are modulators of the MCH-1 R receptor and are useful in the treatment, prevention and suppression of diseases mediated by the MCH-1 R receptor.
  • the invention is concerned with the use if these novel compounds to selectively antagonize the MCH-1 R receptor.
  • compounds of the present invention are useful for the treatment or prevention of obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, gall stones, osteoarthritis, certain cancers, AIDS wasting, cachexia, frailty (particularly in the elderly), binge eating disorders including bulimina, anorexia, mental disorders including manic depression, depression, schizophrenia, mood disorders, delirium, dementia, severe mental retardation, anxiety, stress, cognitive disorders, sexual function, reproductive function, kidney function, diuresis, locomotor disorders, attention deficit disorder (ADD), substance abuse disorders and dyskinesias including Parkinson's disease, Parkinson-like syndromes, Tourette's syndrome, Huntington's disease, epilepsy, improving memory function, and spinal muscular atrophy.
  • This invention provides compounds of formula (1 )
  • R1 represents optionally substituted aryl, heteroaryl, aryl-fused-cycloalkyl, heteroaryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl-fused- heterocycloalkyl;
  • R2 represents H, halogen, alkyl, haloalkyl, cyano;
  • R3 represents H, alkyl, R6 or alkyl-R6;
  • R6 represents halogen, CN, CF 3 , CONR7R8, SO 2 NR7R8, OR9, NR7R8, NR7COR10, NR7SO 2 R10, NR7CONR7R8;
  • R7 and R8 which may be the same or different, each independently represent H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalky
  • R1 preferably represents an optionally substituted heteroaryl group attached to the quinoline via a carbon atom. Suitable representative heteroaryl groups include pyridyl, furanyl, imidazolyl and pyrazolyl. In an alternative embodiment, R1 represents an optionally substituted heteroaryl group attached to the quinoline via a nitrogen atom.
  • a suitable representative heteroaryl group is imidazolyl.
  • R2 represents H.
  • R3 represents alkyl or haloalkyl, especially alkyl, particularly methyl.
  • R4 represents H.
  • the L-R5 substituent is attached to the 6 position of the quinoline.
  • R5 preferably represents a phenyl group substituted in the para position by a suitable substituent.
  • Suitable substituents include haloalkyl, especially trifluoromethyl.
  • L represents -(CH 2 ) n N(R11 )CO(CH 2 ) m O(CH 2 ) p -, in which n and p preferably represent 0 and m preferably represents 1.
  • L represents -(CH 2 ) n N(R11 )CO(CH 2 ) m - in which n represents 0 and m represents 2.
  • R11 preferably represents H.
  • L is attached as written, i.e. the left hand end is attached to the quinoline ring.
  • the compounds of the present invention may be useful in treating the following conditions: obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, gall stones, osteoarthritis, certain cancers, AIDS wasting, cachexia, frailty (particularly in the elderly), binge eating disorders including bulimina, anorexia, mental disorders including manic depression, depression, schizophrenia, mood disorders, delirium, dementia, severe metal retardation, anxiety, stress, cognitive disorders, sexual function, reproductive function, kidney function, diuresis, locomotor disorders, attention deficit disorder (ADD), substance abuse disorders and dyskinesias including Parkinson's disease, Parkinson-like syndromes, Tourette's syndrome, Huntingdon's disease, epilepsy, improving memory function, and spinal muscular atrophy.
  • ADD attention deficit disorder
  • the present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions.
  • the invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient.
  • the invention is further concerned with processes for preparing the compounds of this invention. DESCRIPTION OF THE INVENTION
  • Acyl means a -CO-alkyl group in which the alkyl group is as described herein.
  • Exemplary acyl groups include -COCH 3 and -COCH(CH 3 ) 2 .
  • Acylamino means a -NR-acyl group in which R and acyl are as described herein.
  • exemplary acylamino groups include -NHCOCH 3 and -N(CH 3 )COCH 3 .
  • Alkoxy and alkyloxy means an -O-alkyl group in which alkyl is as defined below.
  • Exemplary alkoxy groups include methoxy and ethoxy.
  • Alkoxycarbonyl means a -COO-alkyl group in which alkyl is as defined below.
  • Exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
  • Alkyl as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, preferably 1 to 6, carbon atoms, in the chain.
  • exemplary alkyl groups include methyl, ethyl, 1-propyl and 2-propyl.
  • Alkylamino means a -NH-alkyl group in which alkyl is as defined above.
  • Exemplary alkylamino groups include methylamino and ethylamino.
  • Alkylsufinyl means a -SO-alkyl group in which alkyl is as defined above.
  • alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl.
  • Alkylsufonyl means a -SO 2 -alkyl group in which alkyl is as defined above.
  • Exemplary alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl.
  • Alkylthio means a -S-alkyl group in which alkyl is as defined above.
  • Exemplary alkylthio groups include methylthio and ethylthio.
  • Aminacyl means a -CO-NRR group in which R is as herein described.
  • aminoacyl groups include -CONH 2 and -CONHCH 3 .
  • Aminoalkyl means an alkyl-NH 2 group in which alkyl is as previously described.
  • Exemplary aminoalkyl groups include -CH 2 NH 2 .
  • Aminosulfonyl means a -SO 2 -NRR group in which R is as herein described.
  • Exemplary aminosulfonyl groups include -SO 2 NH 2 and -SO 2 NHCH 3 .
  • Aryl as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, such as phenyl or naphthyl, and in one embodiment preferably phenyl.
  • the aryl group may be substituted by one or more substituent groups.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C1-4 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthlenemethyl.
  • Arylalkyloxy means an aryl-alkyloxy- group in which the aryl and alkyloxy moieties are as previously described. Preferred arylalkyloxy groups contain a C1-4 alkyl moiety. Exemplary arylalkyl groups include benzyloxy.
  • Aryl-fused-cycloalkyl means a monocyclic aryl ring, such as phenyl, fused to a cycloalkyl group, in which the aryl and cycloalkyl are as described herein. Exemplary aryl-fused-cycloalkyl groups include tetrahydronaphthyl and indanyl.
  • the aryl and cycloalkyl rings may each be substitued by one or more substituent groups.
  • the aryl-fused-cycloalkyl group may be attached to the remainder of the compound of formula (1 ) by any available carbon atom.
  • Aryl-fused-heterocycloalkyl means a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl are as described herein.
  • Exemplary aryl-fused-heterocycloalkyl groups include tetrahydroquinolinyl, indolinyl, benzodioxinyl, benxodioxolyl, dihydrobenzofuranyl and isoindolonyl.
  • the aryl and heterocycloalkyl rings may each be sustitued by one or more substituent groups.
  • the aryl-fused-heterocycloalkyl group may be attached to the remainder of the compound of formula (1 ) by any available carbon or nitrogen atom.
  • Aryloxy means an -O-aryl group in which aryl is described above.
  • Exemplary aryloxy groups include phenoxy.
  • Cyclic amine means an optionally substituted 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen, and which may optionally contain an additional heteroatom selected from O, S or NR (where R is as described herein).
  • Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine and N- methylpiperazine.
  • the cyclic amine group may be substituted by one or more substituent groups.
  • Cycloalkyl means an optionally substituted saturated monocyclic or bicyclic ring system of from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the cycloalkyl group may be substituted by one or more substituent groups.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described.
  • Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • Dialkylamino means a -N(alkyl) 2 group in which alkyl is as defined above.
  • dialkylamino groups include dimethylamino and diethylamino.
  • Halo or “halogen” means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
  • Haloalkoxy means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms.
  • Exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy.
  • Haloalkyl means an alkyl group which is substituted by one or more halo atoms.
  • Exemplary haloalkyl groups include trifluoromethyl.
  • Heteroaryl as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, in which one or more of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups.
  • the heteroaryl group may be substituted by one or more substituent groups.
  • the heteroaryl group may be attached to the remainder of the compound of formula (1 ) by any available carbon or nitrogen atom.
  • Heteroarylalkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
  • Heteroarylalkyloxy means a heteroaryl-alkyloxy- group in which the heteroaryl and alkyloxy moieties are as previously described. Preferred heteroarylalkyloxy groups contain a lower alkyl moiety.
  • heteroarylalkyloxy groups include pyridylmethyloxy.
  • Heteroaryloxy means a heteroaryloxy- group in which the heteroaryl is as previously described.
  • exemplary heteroaryloxy groups include pyridyloxy.
  • Heteroaryl-fused-cycloalkyl means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a cycloalkyl group, in which heteroaryl and cycloalkyl are as previously described.
  • Exemplary heteroaryl-fused-cycloalkyl groups include tetrahydroquinolinyl and tetrahydrobenzofuranyl.
  • the heteroaryl and cycloalkyl rings may each be sustitued by one or more substituent groups.
  • heteroaryl-fused-cycloalkyl group may be attached to the remainder of the compound of formula (1 ) by any available carbon or nitrogen atom.
  • Heteroaryl-fused-heterocycloalkyl means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a heterocycloalkyl group, in which heteroaryl and heterocycloalkyl are as previously described.
  • Exemplary heteroaryl-fused- heterocycloalkyl groups include dihydrodioxinopyridinyl, dihydropyrrolopyridinyl, dihydrofuranopyhdinyl and dioxolopyridinyl.
  • heteroaryl and heterocycloalkyl rings may each be substitued by one or more substituents groups.
  • the heteroaryl-fused-heterocycloalkyl group may be attached to the remainder of the compound of formula (1 ) by any available carbon or nitrogen atom.
  • Heterocycloalkyl means: (i) an optionally substituted cycloalkyl group of from 4 to 8 ring members which contains one or more heteroatoms selected from
  • heterocycloalkyl group may be substituted by one or more substituent groups.
  • the heterocycloalkyl group may be attached to the remainder of the compound of formula (1 ) by any available carbon or nitrogen atom.
  • Heterocycloalkylalkyl means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 4 carbon atoms in the chain, i.e.
  • R means hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heteroaryl or aryl.
  • Sulfonyl means a -SO 2 -alkyl group in which alkyl is as described herein. Exemplary sulfonyl groups include methanesulfonyl.
  • “Sulfonylamino” means a -NR-sulfonyl group in which R and sulfonyl are as described herein. Exemplary sulfonylamino groups include -NHSO 2 CH 3 .
  • “Prodrug” means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of formula (1 ). For example an ester prodrug of a compound of formula (1 ) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of formula (I) containing a hydroxy group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule [Examples of ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 18:379 (1987)]. "Saturated” pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.
  • cyclic groups referred to above namely, aryl, heteroaryl, cycloalkyl, aryl-fused-cycloalkyl, heteroaryl-fused-cycloalkyl, heterocycloalkyl, aryl-fused- heterocycloalkyl, heteroaryl-fused-heterocycloalkyl and cyclic amine may be substituted by one or more substituent groups.
  • Suitable optional substituent groups include acyl (e.g. -COCH 3 ), alkoxy (e,g, -OCH 3 ), alkoxycarbonyl (e.g. -CO 2 CH 3 ), alkylamino (e.g.
  • alkylsulfinyl e.g. -SOCH 3
  • alkylsulfonyl e.g. -SO 2 CH 3
  • alkylthio e.g. -SCH 3
  • -NH 2 aminoalkyl (e.g. -CH 2 NH 2 ), arylalkyl (e.g. -CH 2 Ph or -CH 2 -CH 2 -Ph), cyano, dialkylamino (e.g. -N(CH 3 ) 2 ), halo, haloalkoxy (e.g. -OCF 3 or -OCHF 2 ), haloalkyl (e.g.
  • alkyl e.g. -CH 3 or -CH 2 CH 3
  • -OH, -CHO, -NO 2 aryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl, aminoacyl (e.g. -CONH 2 , -CONHCH 3 ), aminosulfonyl (e.g. -SO 2 NH 2 , -SO 2 NHCH 3 ), acylamino (e.g.
  • Components of formula (1 ) may contain one or more asymmetric centres and can thus occur as racemates and racemic mixtures, single enantiomers, disastereomeric mixtures and individual disastereomers. The present invention is meant to comprehend all such isomeric forms of the compound of Formula (1 ).
  • Some of the compound described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
  • Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto enol tautomers.
  • the individual tautomers as well as mixtures thereof are encompassed with compounds of formula (1 ).
  • Compounds of the formula (1 ) may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventionial means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.
  • any enantiomer of a compound of the general formula (1 ) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • the term 'pharmaceutically acceptable salts' refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts derived derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ /, ⁇ /'-dibenzylethylenediamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylipiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • salts may be prepared from the pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, latic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulphuric, tartaric, p-toluenesulfonicacid, and the like.
  • references to the compounds of Formula (1 ) are meant to also include the pharmaceutically acceptable salts.
  • Compounds of this invention are antagonists of the MCH receptor and as such are useful for the prevention and treatment of disorders or diseases associated with the MCH receptor. Accordingly, another aspect of the present invention provides a method for the treatment (including prevention, alleviation, amelioriation or suppression) of diseases or disorders or symptoms medicated by MCH receptor binding and subsequent cell activation, which comprises administering to a mammal an effective amount of a compound of Formula (1 ).
  • Such diseases, disorders, conditions or symptoms are for example, obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, gall stones, osteroarthritis, certain cancers, AIDS wasting, cachexia, frailty (particularly in the elderly), binge eating disorders including bulimia, anorexia, mental disorders including manic depression, depression, schizophrenia, mood disorders, delirium, dementia, severe mental retardation, anxiety, stress, cognitive disorders, sexual function, reproductive function, kidney function, diuresis, locomotor disorders, attention deficit disorder (ADD), substance abuse disorders and dyskinesias including Parkinson's disease, Parkinson like syndromes, Tourette's syndrome, Huntington's disease, epilepsy, improving memory function, and spinal muscular atrophy.
  • ADD attention deficit disorder
  • prophylactic or therapeutic dose of a compound of Formula (1 ) will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula (1 ) and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • a suitable dosage range is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of Formula (1 ) per kg of body weight per day and for cytoprotective use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1mg to about 10 mg) of a compound of Formula (1 ) per kg of body weight per day.
  • a suitable dosage range is, e.g. from about 0.01 mg to about 10Omg of a compound of Formula (1 ) per day, preferably from about 0.1 mg to about 10mg per day.
  • compositions are preferably provided in the form of tablets containing from 0.01 to 1 ,000mg, preferably 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0 or 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of Formula (1 ) and a pharmaceutically acceptable carrier.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula (1 ), additional active ingredient(s), and pharmaceutically acceptable excipients. Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention.
  • compositions of the present invention comprise a compound of Formula (1 ) as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non- toxic bases or acids including inorganic bases or acids and organic bases or acids.
  • MDI metered dose inhalation
  • suitable propellants such as fluorocarbons or hydrocarbons
  • DPI dry powder inhalation
  • Suitable topical formulations of a compound of formula (1 ) include transdermal devices, aerosols, creams, ointments, lotions, dusting powders and the like.
  • the compounds of Formula (1 ) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such, as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • the compounds of Formula (1 ) may also be administered by controlled release means and/or delivery devices such as those described in U.S Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non- aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from about 1 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 1 to about 500 mg of the active ingredient.
  • Benzalkonium chloride 1.0 Water for injection to a total volume of 1 mL
  • Compounds of Formula (1 ) may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula (1 ) are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (1 ). When a compound of Formula (1 ) is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula (1 ) is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula (1 ).
  • a compound of the present invention may be used in conjunction with other anorectic agents.
  • the present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anorectic agent, such that together they give effective relief.
  • Suitable anorectic agents for use in combination with a compound of the present invention include, but are not limited to, aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropoin, diphemethoxidine, ⁇ /-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramore, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine,
  • a particularly suitable class of anorectic agent is the halogenated amphetamine derivatives, including chorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine, and pharmaceutically acceptable salts thereof.
  • Particularly preferred halogenated amphetamine derivatives of use in combination with a compound of the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof. It will be appreciated that for the treatment or prevention of obesity, the compounds of the present invention may also be used in combination with a selective serotonin reuptake inhibitor (SSRI).
  • SSRI selective serotonin reuptake inhibitor
  • the present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of SSRI, such that together they give effective relief.
  • Suitable selective serotonin reuptake inhibitors of use in combination with a compound of the present invention include fluxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof.
  • the present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of growth hormone secretagogues such as those disclosed and specifically described in US patent 5,536,716; melanacortin agonists such as Melantan II; ⁇ -3 agonists such as those disclosed and specifically described in patent publications WO94/18161 , WO95/29159, WO97/46556, WO98/04526 and WO98/32753; 5HT-2 agonists; orexin antagonists; melanin concentrating hormone antagonists; galanin antagonists; CCK agonists; GPL-1 agonists; corticotropin - releasing hormone agonists; NPY - 5 antagonists; CB1 modulators, such as N-( 1 -piperidinyl)-5-(4-chlorophenyl)-1 - (2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide
  • WO98/43636 WO98/31227, WO98/41519, WO98/37061 , WO00/10967, WO00/10968, WO97/29079, WO99/02499 and WO08.43635, and EPO Application No. EP - 658546; WO99/02499 and WO98/43635, and EPO Application No. EP - 658546; and Y1 antagonists, such that together they give effective relief.
  • “obesity” refers to a condition whereby a mammal has a body mass index (BMI), which is calculated as weight per height squared (kg/m 2 ), of at least 25.9.
  • BMI body mass index
  • the compounds of the present invention may also be used in combination with the histamine receptor - 3 (H3) modulators, CB1 cannabinoid receptor antagonists or inverse agonists, and/or phosphodiesterase - 3B (PDE3B) inhibitors.
  • H3 histamine receptor - 3
  • PDE3B phosphodiesterase - 3B
  • “Treatment” (of obesity) refers to reducing the BMI of the mammal to less than about 25.9 and maintaining that weight for at least 6 months. The treatment suitably results in a reduction in food or calorie intake by the mammal.
  • Prevention refers to preventing obesity from occurring if the treatment is administered prior to the onset of the obese condition. Moreover, if treatment is commenced in already obese subjects, such treatment is expected to prevent, or to prevent the progression of, the medical sequelae of obesity, such as, e.g., arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglceridemia and cholelithiasis. Excessive weight is a contributing factor to different diseases including hypertension, diabetes, dyslipidemias, cardiovascular disease, gallstones, osteoarthritis and certain forms of cancers.
  • Weight reduction can be achieved by antagonizing MCH-1 R receptor activity to obtain, for example, one or more of the following effects: reducing appetite, increasing metabolic rate, reducing fat intake or reducing carbohydrate craving.
  • Other compounds that may be combined with a compound of Formula (1 ), either administered separately or in the same pharmaceutical compositions, for the treatment of diabetes and other sequelae or existing weight include but are not limited to: (a) insulin sensitizers including (i) PPAR ⁇ agonists such as the glitazones (e.g.
  • neuropeptide Y5 such as those disclosed in WO 97/19682, WO 97/20820, WO 97/20821 , WO 97/20822 and WO 97/20823; (i) PPAR ⁇ agonists such as described in WO 97/36579 by Glaxo; (j) PPARg agonists as described in WO97/10813; (k) Serotonin reuptake inhibitors such as fluxetine and sertraline; (I) Growth hormone secretagogues such as MK - 0677. It will be appreciated that for the treatment or prevention of stress, a compound of the present invention may be used in conjunction with other anti-stress agents, such as anti-anxiety agents.
  • Suitable classes of anti-anxiety agents include benzodiazepines and 5-HT 1A agonists or antagonists, especially 5-HT 1A partial agonists, and corticotropin releasing factor (CRF) antagonists.
  • Suitable benzodiazepines include: alprazolam, chloridazepoxide , clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxzepam and prazepam, and pharmaceutically acceptable salts thereof.
  • Suitable 5-HT 1A receptor agonists or antagonists include, in particular the 5-HT 1A receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
  • Suitable CRF antagonists include the 4-tetrahydropyridylpyrimidine derivatives disclosed in US 6, 187,781 ; the aryloxy and arylthio-fused pyrimidine and pyrimidine derivatives disclosed in US 6,124,300; the arylamino-fused pyrimidine derivatives disclosed in US 6,107,300; the pyrazole and pyrazolopyrimidine derivatives disclosed in US 5,705,656, US 5,712,303, US 5,968,944, US 5,958,948, US 6,103,900 and US 6,005,109; the tetrahydropteridine derivatives disclosed in US 6,083,948; the benzoperimidine carboxylic acid derivatives disclosed in US 5,861 ,398; the substituted 4- phenylaminothiazol derivatives disclosed in US 5,880,135; the cyclic CRF analogs disclosed in US 5,493,006, US 5,663,292 and US 5,874,227; and the compounds disclosed in US 5,063,245, US 5,
  • the term "substance abuse disorder” includes substance dependence or abuse with or without physiological dependence.
  • the substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, ***e, hallucinogens, inhalants, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all the above.
  • the term "substance abuse disorders” includes drug withdrawal disorders such as alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; ***e withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances. It will be appreciated that reference to treatment of nicotine withdrawal includes the treatment of symptoms associated with smoking cessation. Other "substance abuse disorders” include substance-induced anxiety disorder with onset during withdrawal; substance-induced mood disorder with onset during withdrawal; and substance-induced sleep disorder with onset during withdrawal.
  • compositions for modulating the perception of pain comprising a non-toxic therapeutically effective amount of the compound of Formula (1 ) as defined above and one or more ingredients such as another pain reliever including acetaminophen or phenacetin, or a cyclooxygenase-2 (COX-2) inhibitor; a potentiator including caffeine; a prostaglandin including misoprostol, enprostil, rioprostil, ornoprostol or rosaprostol; a sedating or non-sedating antihistamine.
  • another pain reliever including acetaminophen or phenacetin, or a cyclooxygenase-2 (COX-2) inhibitor
  • COX-2 cyclooxygenase-2
  • cyclooxygenase-2 selective inhibitos examples include rofecoxib (VIOXX®, see U.S Patent No. 5,474,995), etoricoxib (ARCOXIATM see U.S. Patent No 5,861 ,419), celecoxib (CELEBREX®, see U.S. Patent No. 5,466,823), valdecoxib (see U.S. No. 6,633,272), parecoxib (see U.S. No.
  • cyclooxygenase-2 inhibitors compounds are disclosed in U.S. Patent No. 6,020,343.
  • the invention encompasses a method of treating pain comprising: administration to a patient in need of such treatment a non-toxic therapeutically effective amount of the compound of Formula (1 ), optionally co- administered with one or more of such ingredients as listed immediately above.
  • Suitable antipsychotic agents of use in combination with a compound of the present invention for the treatment of schizophrenia include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic agent.
  • Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, aceophenazine, fluphenazine, perphenazine and trifluoperazine.
  • Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
  • dibenzazepines include clozapine and olanzapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other antipsychotic agents included loxapine, sulphiride and risperidone.
  • the antipsychotic agents whn used in combination with a CB1 receptor modulator may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine, hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • a pharmaceutically acceptable salt for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine, hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochlor
  • Perhenazine, chlorprothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • Other classes of antipsychotic agent of use in combination with a compound of the present invention include dopamine receptor antagonists, especially D2, D3 and D4 dopamine receptor antagonists, and muscarinic M1 receptor agonists.
  • An example of a D3 dopamine receptor antagonist is the compound PNU-99194A.
  • An example of a D4 dopamine receptor antagonist is
  • muscarinic M1 receptor agonist is xanomeline.
  • 5-HT 2A receptor antagonists examples of which include
  • SDAs serotonin dopamine antagonists
  • olanzapine and ziperasidone examples of which include olanzapine and ziperasidone. It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other anti- depressant or anti-anxiety agents.
  • Suitable classes of anti-depressant agents include norepineph ne reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotrophin releasing factor (CRF) antagonists, ⁇ -adrenoreceptor antagonists, neurokinin-1 antagonists and atypical anti-depressants.
  • Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics.
  • Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof.
  • Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protripyline, and pharmaceutically acceptable salts thereof.
  • Suitable selective serotonin reuptake inhibitors include those described supra.
  • Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selediline, and pharmaceutically acceptable salts thereof.
  • Suitable reversible inhibitors of monoamine oxidase include: moclobemide, and pharmaceutically acceptable salts thereof.
  • Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venlafaxine, and pharmaceutically acceptable salts thereof.
  • Suitable CRF antagonists include those described hereinabove Suitable atypical anti-depressants include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof.
  • the neurokinin-1 receptor antagonist may be peptidal or non-peptidal in nature, however, the use of a non-peptidal neurokinin-1 receptor antagonist is preferred.
  • the neurokinin-1 receptor antagonist is a CNS-penetrant neurokinin-1 receptor antagonist.
  • the neurokinin-1 receptor antagonist is a long acting neurokinin-1 receptor antagonist.
  • neurokinin-1 receptor antagonists of use in the present invention are those compounds which are orally active and long acting.
  • Neurokinin-1 receptor antagonists of use in the present invention are fully described, for example, in U.S. Patent Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699; European Patent Publiction Nos.
  • Suitable classes of anti-anxiety agents include benzodiazepines and 5- HT 1A agonists or antagonists, especially 5-HT 1A partial agonists, and corticotropin releasing factor (CRF) antagonists.
  • Suitable benzodiaepines include those previously described herein.
  • Suitable 5-HT 1A receptor agonists or antagonists include, in particular, those described supra.
  • the compounds of the present invention may be used in combination with butyrophenones.
  • the compounds of the present invention may be used in combination with levodopa, carbidopa/levodopa, amantadine, bromocryptine and other ergot alkaloids, anticholinergic medications such as benztrophine, trihexyphenidyl, antihistamines such as dephenhydramine and orphenadrine, mild sedatives, tricyclic antidepressants such as amitriptiline and others described supra, and propanolol.
  • anticholinergic medications such as benztrophine, trihexyphenidyl, antihistamines such as dephenhydramine and orphenadrine, mild sedatives, tricyclic antidepressants such as amitriptiline and others described supra, and propanolol.
  • the compounds of the present invention may be used in combination with phenothiazine, chlorpromazine, and butyrophenone neuroleptics such as haloperidol or reserpine.
  • the compounds of the present invention may be used together with anticonvulsants such as penytoin, phenobarbital, primidone, carbamazepine, trimethadione, clonazepam, valproate and ethosuximide
  • the second ingredient to be combined with a compound of Formula (1 ) can be type V cyclic-GMP-specific phosphodiesterase (PDE-V) inhibitor, such as sildenafil and IC-351 or a pharmaceutical acceptable salt thereof; an alpha-adrenergic receptor antagonist, such as phentolamine and yohimbine or a pharmaceutically acceptable salt therefore; or a dopamine receptor
  • PDE-V type V cyclic-GMP-specific phosphodiesterase
  • “Male sexual dysfunction” includes impotence, loss of libido, and erectile dysfunction.
  • Esrectile dysfunction is a disorder involving the failure of a male mammal to achieve erection, ejaculation, or both. Symptoms of erectile dysfunction include an inability to achieve or maintain an erection, ejactulatory failure, premature ejaculation, or inability to achieve an orgasm.
  • An increase in erectile dysfunction and sexual dysfunction can have numerous underlying causes, including but not limited to (1 ) ageing, (2) and underlying physical dysfunction, such as trauma, surgery and peripheral vascular disease, and (3) side-effects resulting from drug treatment, depression, and other CNS disorders.
  • Female sexual dysfunction can be seen as resulting from multiple components including dysfunction in desire, sexual arousal, sexual receptivity, and orgasm related to disturbances in the clitoris, vagina, periurethral glans, and other trigger points of sexual function.
  • anatomic and functional modification of such trigger points may diminish the orgasmic potential in breast cancer and gynecologic cancer patients.
  • Treatment of female sexual dysfunction with a MC- 4 receptor agonist can result in improved blood flow, improved lubrication, improved sensation, facilitation of reaching orgasm, reduction in the refractory period between orgasms, and improvements in arousal and desire.
  • male sexual dysfunction also incorporates sexual pain, premature labor, and dysmenorrhea.
  • the compounds of the present invention may be employed in combination with a compound selected from a type V cyclic-GMP-specific phosphodiesterase (PDE-V) inhibitor, such as sildenafil and IC-351 or a pharmaceutically acceptable salt thereof; an alpha-adrenergic receptor antagonist, a such as phentolamine and yohimbine or a pharmaceutically acceptable salt thereof; or a dopamine receptor agonist, such as apomorphine or a pharmaceutically acceptable salt thereof.
  • PDE-V cyclic-GMP-specific phosphodiesterase
  • MCH-1 R antagonist compounds can be provided in kit. Such a kit typically contains as active compound in dosage forms for administration.
  • a dosage form contains a sufficient amount of active compound such that a beneficial effect can be obtained when administered to a patient during regular intervals, such as 1 to 6 times a day, during the course of 1 or more days.
  • a kit contains instructions indicating the use of the dosage form for weight reduction (e.g. , to treat obesity or overweight) or stress reduction, and the amount of dosage form to be taken over a specified time period.
  • the method of treatment of this invention comprises a method of treating melanin concentrating hormone receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the MCH receptor in preference to the other G-protein coupled receptors.
  • the present invention comprises a method of treating MCR-1 R receptor subtype mediated diseases by administering a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the MCH-1 R receptor.
  • the weight ratio of the compound of the Formula (1 ) to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula (1 ) is combined with a ⁇ -3 agonist the weight ratio of the compound of the Formula (1 ) to the ⁇ -3 agonist will generally range from about 1000:1 to about 1 :1000, preferable about 200:1 to about 1 :200.
  • Combinations of a compound of the Formula (1 ) and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compounds of Formula (1 ) of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The Examples further illustrate details for the preparation of the compounds of the present invention.
  • the instant compounds may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above.
  • the free amine bases corresponding to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide, and extraction of the liberated amine free base into an organic solvent followed by evaporation.
  • the amine free base isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent followed by addition of the appropriate acid and subsequent evaporation, precipitation, or crystallization. It may be necessary to protect reactive functional groups (e.g.
  • a 2-haloquinoline may be reacted with an aryl or heteroaryl boronic acid or boronate ester in the presence of a palladium catalyst such as [1 ,1 -b/s(diphenylphosphino) ferrocenejdichloropalladium (II) and in the presence of a suitable base, such as cesium carbonate, in a suitable solvent, such as 1,4-dioxane, at an appropriate temperature, such as elevated temperature. It may be advantageous to conduct the reaction in a microwave.
  • a palladium catalyst such as [1 ,1 -b/s(diphenylphosphino) ferrocenejdichloropalladium (II)
  • a suitable base such as cesium carbonate
  • a suitable solvent such as 1,4-dioxane
  • a 2-haloquinoline may be reacted with an appropriate tin compound, for example a th-n-butylstannyl analogue, in the presence of a palladium catalyst, such as dichlorob/s-(triphenylphosphine) palladium and triphenylphosphine, in an appropriate solvent, such as xylene, at a suitable temperature, such as the reflux temperature of the solvent.
  • a palladium catalyst such as dichlorob/s-(triphenylphosphine) palladium and triphenylphosphine
  • solvent such as xylene
  • Compounds of formula (2) in which L contains an amide can be obtained by reaction of an aminoquinoline of formula (3) with an appropriate carboxylic acid using any suitable standard conditions known to those skilled in the art.
  • the reaction can be conducted using an activating agent such as O-(7-azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'- tetramethyluronium hexafluorophosphate in the presence of a base such as N,N- diisopropylamine in a suitable solvent such as dichloromethane, dimethylformamide, or a mixture of the two.
  • an activating agent such as O-(7-azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'- tetramethyluronium hexafluorophosphate
  • a base such as N,N- diisopropylamine
  • a suitable solvent such as dichloromethane, dimethylformamide, or a mixture of
  • the carboxylic acid may be converted into a reactive intermediate such as an acid chloride or mixed anhydride and this can be reacted with the aminoquinoline (3) in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane.
  • a suitable base such as triethylamine
  • a suitable solvent such as dichloromethane
  • the reactive intermediate may be used in situ without isolation, or it may be isolated and then treated with the aminoquinoline (3).
  • compounds of formula (2) in which L contains a sulphonamide may be prepared by reaction of an aminoquinoline of formula (3) with a sulphonyl chloride in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane.
  • Compounds of formula (2) in which L contains a urea may be prepared by reaction of an aminoquinoline of formula (3) with an appropriate isocyanate in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane.
  • a suitable base such as triethylamine
  • a suitable solvent such as dichloromethane.
  • Compounds of formula (2) in which L contains an -N(R11 )(CH 2 )- group can be prepared from aminoquinolines of formula (3) an appropriate aldehyde under reactive amination conditions. Suitable conditions include the use of a reducing agent, such as triacetoxyborohydride, in a suitable solvent such as 1 ,2-dichloroethane.
  • Aminoquinolines of formula (3) can be prepared by reduction of nitroquinolines of formula (4).
  • the reduction may be carried out using any suitable conditions known to those skilled in the art, for example by using a metal such as iron or tin in the presence of an acid, such as hydrochloric acid, in a suitable solvent, such as ethanol, at an appropriate temperature, such as the reflux temperature of the solvent.
  • Nitroquinolines of formula (4) can be obtained from quinolines of formula (5) by nitration, which can be carried out using any suitable conditions such as the use of fuming nitric acid and concentrated sulphuric acid at reduced temperature.
  • a nitroquinoline of formula (4) may be converted in a nitroquinoline of formula (6) using an appropriate metal catalysed biaryl bond formation as discussed previously in relation to the preparation of a compound of formula (1 ) from a compound of formula (2). Subsequent reduction of the nitroquinoline of formula (6) would provide an aminoquinoline of formula (7), which could then be converted into a compound of formula (1 ).
  • n 0
  • n 0
  • the reaction can be conducted using an activating agent such as O-(7-azabenzotriazol-1-yl)- ⁇ /, ⁇ /, ⁇ /' / ⁇ /'-tetramethyluronium hexafluorophosphate in the presence of a base such as ⁇ /, ⁇ /-diisopropylamine in a suitable solvent such as dichloromethane, dimethylformamide, or a mixture of the two.
  • the carboxylic acid may be converted into a reactive intermediate such as an acid chloride or mixed anhydride and this can be reacted with the amine in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane.
  • the reactive intermediate may be used in situ without isolation, or it may be isolated and then treated with the amine.
  • a quinolinecarboxylic acid of formula (8) may be prepared from a haloquinoline of formula (9) (in which X represents chlorine, bromine or iodine) using a metal catalysed carbonylation reaction, such as a palladium catalysed reaction.
  • the reaction may be carried out using carbon monoxide
  • a haloquinoline of formula (9) may be prepared from a quinoline of (10) using standard conditions of aromatic halogenation.
  • a quinoline of formula (10) may be treated with a halogenating agent such as chlorine, N- chlorosuccinimide, bromine or idodine
  • a quinoline of formula (10) may be prepared from a quinoline of formula (5) using any suitable biaryl bond forming method, such as those described earlier.
  • Compounds of formula (1 ) - (10) may be prepared using any suitable procedures known to those skilled in the art, including appropriate functional group inter-conversion. It will be appreciated that such functional group inter- conversions may be carried out at any suitable stage during the synthesis.
  • primary amine (-NH 2 ) groups may be alkylated using a reductive alkylation process employing an aldehyde or a ketone and a borohydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, for example 1 ,2-dichloroethane, or an alcohol such as ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
  • a halogenated hydrocarbon for example 1 ,2-dichloroethane
  • alcohol such as ethanol
  • Secondary amine (-NH-) groups may be similarly alkylated employing an aldehyde.
  • primary amine or secondary amine groups may be converted into amide groups (-NHCOR' or -NRCOR') by acylation.
  • Acylation may be achieved by reaction with an appropriate acid chloride in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, or by reaction with an appropriate carboxylic acid in the presence of a suitable coupling agent such HATU (O-(7-azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'- tetramethyluronium hexafluorophosphate) in a suitable solvent such as dichloromethane.
  • a suitable coupling agent such as HATU (O-(7-azabenzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'- tetramethyluronium hexafluorophosphate) in a suitable solvent such as dichloromethane.
  • amine groups may be converted into sulphonamide groups (-NHSO 2 R' or -NR"SO 2 R') groups by reaction with an appropriate sulphonyl chloride in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dichloromethane.
  • Primary or secondary amine groups can be converted into urea groups (-NHCONR'R" or -NRCONR'R”) by reaction with an appropriate isocyanate in the presence of a suitable base such as triethylamine, in a suitable solvent, such as dichloromethane.
  • An amine (-NH 2 ) may be obtained by reduction of a nitro (-NO 2 ) group, for example by catalytic hydrogenation, using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethyl acetate or an alcohol e.g. methanol.
  • a metal catalyst for example palladium on a support such as carbon in a solvent such as ethyl acetate or an alcohol e.g. methanol.
  • the transformation may be carried out by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
  • amine (-CH 2 NH 2 ) groups may be obtained by reduction of nithles (-CN), for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, or Raney nickel, in a solvent such as an ether e.g. a cyclic ether such as tetrahydrofuran, at a temperature from -78°C to the reflux temperature of the solvent.
  • a metal catalyst for example palladium on a support such as carbon, or Raney nickel
  • Aldehyde groups (-CHO) may be converted to amine groups (-CH 2 NR'R")) by reductive amination employing an amine and a borohydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, for example dichloromethane, or an alcohol such as ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
  • Aldehyde groups may be obtained by reduction of ester groups (such as
  • aldehyde groups may be obtained by the oxidation of alcohol groups using any suitable oxidising agent known to those skilled in the art.
  • Ester groups (-CO 2 R') may be converted into the corresponding acid group (-CO 2 H) by acid- or base-catalused hydrolysis, depending on the nature of R.
  • acid-catalysed hydrolysis can be achieved for example by treatment with an organic acid such as tnfluoroacetic acid in an aqueous solvent, or by treatment with an inorganic acid such as hydrochloric acid in an aqueous solvent.
  • Carboxylic acid groups (-CO 2 H) may be converted into amides (-CONHR' or -CONR'R") by reaction with an appropriate amine in the presence of a suitable coupling agent, such as HATU, in a suitable solvent such as dichloromethane.
  • a suitable coupling agent such as HATU
  • carboxylic acids may be homologated by one carbon
  • -OH groups may be generated from the corresponding ester (e.g. -CO 2 R'), or aldehyde (-CHO) by reduction, using for example a complex metal hydride such as lithium aluminium hydride in diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol.
  • a complex metal hydride such as lithium aluminium hydride in diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol.
  • an alcohol may be prepared by reduction of the corresponding acid (-CO 2 H), using for example lithium aluminium hydride in a solvent such as tetrahydrofuran, or by using borane in a solvent such as tetrahydrofuran.
  • Alcohol groups may be converted into leaving groups, such as halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. t fluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxy group using conditions known to those skilled in the art.
  • halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. t fluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxy group using conditions known to those skilled in the art.
  • an alcohol may be reacted with thionyl chloride in a halogenated hydrocarbon (e.g. dichloromethane) to yield the corresponding chloride.
  • a base e.g. triethyl
  • alcohol or phenol groups may be converted to ether groups by, coupling a phenol with an alcohol in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl, or dimethylazodicarboxylate.
  • a phosphine e.g. triphenylphosphine
  • an activator such as diethyl-, diisopropyl, or dimethylazodicarboxylate.
  • ether groups may be prepared by deprotonation of an alcohol, using a suitable base e.g. sodium hydride followed by subsequent addition of an alkylating agent, such as an alkyl halide.
  • Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange by treatment with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran, and then quenched with an electrophile to introduce a desired substituent.
  • a base for example a lithium base such as n-butyl or t-butyl lithium
  • a solvent such as tetrahydrofuran
  • an electrophile to introduce a desired substituent.
  • a formyl group may be introduced by using ⁇ /, ⁇ /-dimethylformamide as the electrophile.
  • Aromatic halogen substituents may alternatively be subjected to metal (e.g.
  • pyridine-N-oxide may be prepared by oxidation of compounds of formula (I) in which R1 is the corresponding non- oxidised heteroaryl. It will be appreciated by those skilled in the art that the functional group interconversions described above may be carried out at any suitable stage of the synthesis.
  • the following Examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein. 1 H NMR spectra were recorded at ambient temperature using a Varian Unity Inova (400MHz) spectrometer with a triple resonance 5mm probe. Chemical shifts are expressed in ppm relative to tetramethylsilane.
  • the initial solvent system was 95% water containing 0.1 % formic acid (solvent A) and 5% acetonitrile containing 0.1 % formic acid (solvent B) for the first minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes.
  • the final solvent system was held constant for a further 2 minutes.
  • Method B Experiments performed on a Micromass Platform LC spectrometer with positive and negative ion electrospray and ELS/Diode array detection using a Phenomenex Luna C18(2) 30 x 4.6mm column and a 2 ml/minute flow rate.
  • the solvent system was 95% solvent A and 5% solvent B for the first 0.50 minutes followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 0.50 minutes Microwave experiments were carried out using a Personal Chemistry
  • Smith SynthesizerTM which uses a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperatures from 40- 250°C can be achieved, and pressures of up to 20 bar can be reached. Two types of vial are available for this processor, 0.5-2.0ml and 2.0-5.0ml.
  • Example 1 N-[4-Methyl-2-(4-pyridyl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide
  • the resultant mixture was stirred and heated at 100°C in the microwave for 12 minutes. Further 4-pyridylboronic acid (28mg), [1,1-bis(diphenylphosphino) ferrocenejdichloropalladium (II), complex with dichloromethane (1 : 1 ) (13mg) and aqueous cesium carbonate solution (2M, 228 ⁇ l) were added and the mixture was stirred and heated in the microwave at 100°C for 12 minutes. The resultant mixture was partitioned between dichloromethane and water and the organic phase was washed with aqueous sodium chloride solution, dried (MgSO 4 ) and filtered.
  • Example 6 N-[4-Methyl-2-(3,4-methylenedioxyphenyl)quinolin-6-yl] 2-(4- trifluoromethyl-phenoxy)acetamide
  • the resultant mixture was heated in the microwave at 150°C for 20 minutes.
  • the mixture was filtered and the filtrate was diluted with dichloromethane, washed with water, dried (MgSO 4 ) and filtered.
  • the filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of dichloromethane and ether (99:1) increasing to a ratio of 99:3 to give N-[4-methyl-2-(3,4- methylenedioxyphenyl)quinolin-6-yl]2-(4-trifluoromethylphenoxy)acetamideas a brown solid (27mg).
  • Example 10 N-[4-Methyl-2-(2-pyridyl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide
  • N-(2-chloro-4-methylquinolin-6-yl) 2-(4- trifluoromethylphenoxy)-acetamide (intermediate 4, 100mg)
  • dichlorob/s- (triphenylphosphine) palladium (II) (11.3mg)
  • triphenyl phosphine (7.29mg) in xylene was degassed and purged with nitrogen then treated with 2-(tri-n- butylstannyl)pyridine (128mg). The mixture was stirred and heated at 130°C overnight.
  • Example 12 N-[4-Methyl-2-(imidazol-4(5)-yl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide A solution of tnfluoroacetic acid in water (19:1, 1.7ml) was added to a solution of N-[4-methyl-2-(1-tritylimidazol-4-yl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide (intermediate 5, 51.3mg) in dichloromethane
  • Example 13 N-[4-Methyl-2-(1-oxypyrid-3-yl)quinoline-6-yl] 2-(4- trifluoromethylphenoxy)acetamide 3-Chloroperoxybenzoic acid ( ⁇ 60%, 92mg) was added to a solution of N- [4-methyl-2-(3-pyridyl)quinolin-6-yl] 2-(4-trifluoromethylphenoxy)acetamide (example 11 , 70mg) in dichloromethane. The resultant mixture was stirred at room temperature for 4h. The suspension was washed with water, saturated aqueous sodium bicarbonate solution, water, dried (MgSO 4 ) and filtered.
  • Example 14 N-[4-Methyl-2-(3-furyl)quinolin-6-yl] 2-(4-methoxyphenoxy)acetamide
  • O-(7-Aza enzotriazol-1 -yl)- ⁇ /, ⁇ /, ⁇ /', ⁇ /'-tetramethyluronium hexafluorophosphate (340mg) and ⁇ /, ⁇ /-diisopropylethylamine (0.4ml) were added to a solution of 2-(3-furyl)-4-methylquinolin-6-ylamine (intermediate 6, 75mg) and 4-methoxyphenoxyacetic acid (81.2mg) in dimethylformamide. The mixture was stirred at room temperature overnight.
  • MCH-1 R (Euroscreen s.a.) were incubated with 25 ⁇ g of wheat germ agglutinin SPA beads (Amersham Biosciences UK Ltd) and 0.4nM 125 l-[Phe 13 , Tyr 19 ]-MCH (Amersham Biosciences UK Ltd) in a final volume of 100 ⁇ l of binding buffer (25mM HEPES, 10mM NaCI, 5mM MgCI 2 , 1 mM CaCI 2 , 0.1 % BSA) containing 5mM phosphoramidonfor 1 hour at room temperature.
  • binding buffer 25mM HEPES, 10mM NaCI, 5mM MgCI 2 , 1 mM CaCI 2 , 0.1 % BSA
  • Non-specific binding was determined in the presence of 1 ⁇ M (Phe 13 , Tyr 9 )-MCH (Bachem (UK) Ltd).
  • Bound 125 l-[Phe 13 , Tyr 19 ]-MCH was detected using a MicroBeta TRILUX liquid scintillation counter (Perkin Elmer).
  • Compound IC 50 was determined using a 6- point dose response curve in duplicate with a semi-log compound dilution series. IC 50 calculations were performed using Excel and XL fit (Microsoft).
  • Ca 2+ Mobilization Assay Stable CHO-K1 cells expressing the MCH-1 R were seeded (35,000 cells per well with a plating volume of 50 ⁇ l) into collagen-coated 96-well plates 24 hours prior to the assay.
  • the cells were then loaded with a fluorescence- imaging plate reader (FLIPR) calcium kit dye (Calcium 3 kit, Molecular Devices Ltd) containing 5mM final concentration of probenecid and incubated at 37°C for 1 hour in a 5% CO 2 atmosphere.
  • FLIPR fluorescence- imaging plate reader
  • the fluorescence emission caused by intracellular calcium mobilization elicited by the agonist, (Phe 13 , Tyr 19 )-MCH, of the expressed receptor was determined with a FLEXstation benchtop scanning and integrated fluid transfer workstation (Molecular Devices Ltd).
  • FLEXstation benchtop scanning and integrated fluid transfer workstation Molecular Devices Ltd.
  • compounds were pre-incubated at varying concentrations with the loaded cells for 15 minutes at 37°C, 5% CO 2 , prior to the addition of the agonist at its EC 80 .
  • the fractional response values for each well were calculated as peak minus basal response. Results were calculated as the mean of triplicate wells using Excel and XL fit (Mi

Abstract

Quinolines of formula (I) are useful as MCH mediators, and in the therapy of obesity.

Description

SUBSTITUTED QUINO INES AS MCR MODULATORS
FIELD OF THE INVENTION This invention relates to quinolines and their therapeutic use. BACKGROUND OF THE INVENTION Obesity, defined as excess adiposity for a given body size, results from a chronic imbalance between energy intake and energy expenditure. Body mass index (BMI, kg/m2) is an accepted clinical estimate of being overweight (BMI 25 to 30) and of obesity (BMI>30). A BMI above 30 kg/m2 significantly increases the risk of diabetes, hypertension, dyslipidemias and cardiovascular disease, gallstones, osteoarthritis and certain forms of cancer and reduces life expectancy. In the vast majority of obese individuals, the cause of the excess adiposity is not immediately apparent. A currently accepted working hypothesis is that obesity is the result of maladaptation of the innate metabolic response to environmental challenges such as unlimited availability of low cost/energy dense foods and sedentariness (Hill et al., Science, 1998, 280, 1371 ). The study of energy intake in free living humans has met with only limited success and definitive experimental evidence that hyperphagia causes most forms of human obesity is lacking. Following the discovery of leptin, the interest in the neurohormonal regulation of food intake has regained momentum. However, while much knowledge has been gained on the regulation of food intake in rodents and other animal species, the understanding of the neurophysiology of feeding behaviour in humans remains extremely limited. Neuropeptides present in the hypothalamus play a major role in mediating the control of body weight.(Flier, et al., Cell, 1998 92, 437 - 440). Melanin-concentrating hormone (MCH) is a cyclic 19 amino acid neuropeptide synthesized as part of a larger pre-prohormone prercusor in the hypothalamus which also encodes neuropeptides NEI and NGE. (Nahon, el al., Mol. Endocrinol. 1990, 4, 632 - 637). MCH was first identified in salmon pituitary, and in fish MCH affects melanin aggregation thus affecting skin pigmentation. In trout and in eels MCH has also been shown to be involved in stress induced or CRF-stimulatedACTH release (Kawauchi. ef al., Λ/aftvre,1983305, 321-323). In humans two genes encoding MCH have been identified that are expressed in the brain. (Brecton, et al., Mol. Brain Res. 1993, 18, 297 - 310). In mammals MCH has been localized primarily to neuronal cell bodies of the hypothalamus which are implicated in the control of food intake, including perikayra of the lateral hypothalamus and zona inertia. (Knigge, et al.,. Peptides, 1996, 17, 1063 -1073). Pharmacological and genetic evidence suggest that the primary mode of MCH action is to promote feeding (orexigenic). MCH mRNA is up-regulated in fasted mice and rats, in the ob/ob mouse and in mice with targeted disruption in the gene for neuropeptide Y (NPY). (Qu, et al., Nature, 1996, 380, 243 - 247, and Erickson, et al., Nature 1996, 381, 415 - 418). Injection of MCH intracelebroventricularly (ICV) stimulates food intake and MCH antagonizes the hypophagic effects seen with α melanocyte-stimulating hormone (αMSH). (Qu, et al., Nature, 1996, 380, 243 - 247). MCH deficient mice are lean, hypophagic and have increased metabolic rate. (Shimada, et al., Nature 1998, 396, 670 - 673). MCH action is not limited to modulation of food intake as effects on the hypothalamic-pituitary-axis have been reported. (Nahon, Critical Rev. in Neurobiol. 1994, 8, 221 - 262). MCH may be involved in the body's response to stress as MCH can modulate the stress-induced release of CRF from the hypothalamus and ACTH from the pituitary. In addition, MCH neuronal systems may be involved in reproductive or maternal function. MCH transcripts and MCH peptide were found within germ cells in testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes (Hervieu et al., 1996). MCH injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et ai, 1996). In ovariectomized rats primed with estradiol, MCH stimulated luteinizing hormone (LH) release while anti-MCH antiserum inhibited LH release (Gonzalez et al., 1997). The zona incerta, which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge (MacKenzie et al., 1984). Therefore modulators of MCH receptors may be useful in the prevention and treatment of reproductive function. MCH has been reported to influence release of pituitary hormones including ACTH and oxytocin. Therefore, modulators of MCH receptors may be useful in the prevention and treatment of obesity, Cushing's disease, sexual function, appetite and eating disorders, obesity, diabetes, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, gall stones, osteoarthritis, certain cancers, AIDS wasting, cachexia,, frailty (particularly in the elderly), binge eating disorders including bulimia, anorexia, kidney function, diuresis, reproductive function and sexual function. Two receptor subtypes have been identified in humans, MCH-1 R and
MCH-2R. Both receptors, as well as the gene for the MCH peptide, have been mapped to regions previously reported to contain a susceptibility gene for psychiatric disorders. In particular, MCH-1 R was mapped to chromosome 22q13.2 (Kolakowski et al. 1996). The possibility of linkage for schizophrenia susceptibility locus in this area was suggested by independent studies from 2 groups (Pulver et al. 1994; Coon et al. 1994). In addition, a more recent study (Stoeber et al. 2000) of samples from patients with periodic catatonia, a clinical subtype of unsystematic schizophrenia, suggested possible linkage of the region around 22q13. Human genetics implicates these loci not only for schizophrenia but also for bipolar disorder. The second MCH receptor (MCH-2R) has been mapped to chromosome 6q16.2-16.3 (Sailer et al., 2001 ). Cao et al,. (1997) were the first to report evidence of a schizophrenia susceptibility locus in that area. This initial report was confirmed and extended by other reports (Martinez et al. 1999; Kaufmann et al. 1998; Levinson et al. 2000). Schizophrenia has been recognised as a disorder with profound deficits in information-processing and attentional abnormalities. One of the few possible paradigms available to assess these types of deficits in information processing is sensory gating, a filtering process which can be demonstrated by using a paired auditory stimulus. Miller et al. (1993) examined the effects of ICV administered MCH on the decrease in amplitude of the second of two tone-evoked CNS potentials that can be measured when pairs of identical tones are presented 500ms apart. They found that MCH application decreases sensory gating in this paradigm. Based on pathogenesis and pathophysiology (reviewed in Lewis and Libermann, 2000) several brain areas have been implicated in schizophrenia, all of which show high expression for MCH receptors: thalamus, midbrain, nucleus accumbens, temporo-limbic, and prefrontal cortices. These studies and findings support the use of MCH receptor modulators in the treatment and prevention of schizophrenia. Kelsoe ef al. (2001 ) recently reported on a genome survey indicating a possible susceptibility locus for bipolar disorder identified on 22q.The MCH gene which encodes the MCH pro-peptide was mapped to chromosome 12q23.1. This area has been identified by Morissette ef al. (1999) in a genome wide scan for susceptibility loci for bipolar disorder in families in the Province of Quebec. In addition, Ewald ef al. (1998) showed significant linkage to chromosome 12q23.1 (maximum lod score 3.37) in Danish families suffering from bipolar affective disorder. In addition, Presse et al. (1997) have shown that lithium, the "gold standard" and most appropriate initial treatment for the depressive phase of bipolar disorder, can alter MCH mRNA levels in NGF-treated PC12 cells by increasing mRNA stability. These studies and findings support the use of MCH receptor modulators in the treatment and prevention of bipolar disorder and depression. Philippe and colleagues (1999) performed a genome-wide screen for a autism susceptibility gene and found suggestive linkage for the region of chromosome 6q16.1-16.3 (maximum lod score 2.23). This finding supports the use of MCH receptor modulators in the treatment of autism. In all species studied to date, a major portion of the neurons of the MCH cell group occupies a rather constant location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called "extrapyramidal" motor circuits. These involve substantial striato-and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to subthalamic nucleus, substantia nigra, and mid-brain centres (Bittencourt et al., 1992). In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with appropriate and coordinated motor activity. Thus, modulators of MCH receptor function may be useful in the treatment and prevention of movement disorders, such as Parkinson's disease, Parkinson-like syndromes and Huntingdon's Chorea in which extrapyramidal circuits are known to be involved. Human genetic linkage studies have located authentic hMCH loci on chromosome 12 (12q23-24) and the variant hMCH loci on chromosome 5 (5q 12- 13) (Pedeutour et al., 1994). Locus 12q23-24 coincides with a locus to which autosomal dominant cerebellar ataxia type II (SCA2) has been mapped (Auburger et al., 1992; Twells ef al., 1992). This disease comprises neurodegenerative disorders, including an olivopontocerebellar atrophy. Futhermore, the gene for Darier's disease, has been mapped to locus 12q23-24 (Craddock ef al., 1993). Darier's disease is characterized by abnormalities in keratinocyte adhesion and mental illnesses in some families. In view of the functional and neuroanatomical patterns of the MCH neural system in the rat and human brains, the MCH gene may represent a good candidate for SCA2 or Darier's disease. Therefore, modulators of MCH receptors may be useful in the treatment of mental disorders including manic depression, depression, schizophrenia, mood disorders, delirium, dementia, severe mental retardation, anxiety, stress, cognitive disorders, and dyskinesias including Parkinson's disease, Tourette's syndrome, Huntington's disease, cerebellar ataxia, and seizures. Further, the gene responsible for chronic or acute forms of spinal muscular atrophies has been assigned to chromosome 5q12-13 using genetic linkage analyses (Melki ef al., 1990; Westbrook ef al., 1992). Therefore, modulators of MCH receptors may be useful in treating muscular dystrophy and dyskinesias, including Parkinson's disease, Tourette's syndrome, Huntington's disease, cerebellar ataxia, seizures, locomotor disorders, attention deficit disorder (ADD) and substance abuse disorders. Still further, modulators of MCH receptor binding may also be useful in treating epilepsy. In the PTZ seizure model, injection of MCH prior to seizure induction prevented seizure activity in both rats and guinea pigs, suggesting that MCH-containing neurons may participate in the neural circuitry underlying PTZ- induced seizure (Knigge and Wagner, 1997). MCH has also been observed to affect behavioural correlates of cognitive functions. MCH treatment hastened extinction of the passive avoidance responses in rats (McBride ef al., 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage and/or retention. A role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers. MCH receptor modulators may be useful as antinociceptives or as analgesics, particularly for the treatment of neuropathic pain. Finally, MCH may participate in the regulation of fluid intake. ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and kaliuretic changes in response to increased plasma volume (Parkes, 1996). Together with anatomical data reporting the presence of MCH in fluid regulatory areas of the brain, the results indicate that MCH may be an important peptide involved in the central control of fluid homeostasis in mammals. Therefore, modulators of MCH receptors may be useful in kidney function and diuresis. Several antagonists of MCH-1 R have been reported (Carpenter and Hertzog, Expert Opin. Ther. Patents, 2002, 12, 1639-1646; Collins and Kym, Curr. Opin. Invest. Drugs, 2003, 4, 386-394; Takekawa etal., Eur. J. Pharmacol., 2002, 438, 129-135; Borowsky et al., Nature Medicine, 2002, 8, 825-830). SUMMARY OF THE INVENTION It is an object of the current invention to provide novel antagonists of the MCH-1 R receptor. The compounds of the present invention are modulators of the MCH-1 R receptor and are useful in the treatment, prevention and suppression of diseases mediated by the MCH-1 R receptor. The invention is concerned with the use if these novel compounds to selectively antagonize the MCH-1 R receptor. As such, compounds of the present invention are useful for the treatment or prevention of obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, gall stones, osteoarthritis, certain cancers, AIDS wasting, cachexia, frailty (particularly in the elderly), binge eating disorders including bulimina, anorexia, mental disorders including manic depression, depression, schizophrenia, mood disorders, delirium, dementia, severe mental retardation, anxiety, stress, cognitive disorders, sexual function, reproductive function, kidney function, diuresis, locomotor disorders, attention deficit disorder (ADD), substance abuse disorders and dyskinesias including Parkinson's disease, Parkinson-like syndromes, Tourette's syndrome, Huntington's disease, epilepsy, improving memory function, and spinal muscular atrophy. This invention provides compounds of formula (1 )
Figure imgf000008_0001
(1 ) R1 represents optionally substituted aryl, heteroaryl, aryl-fused-cycloalkyl, heteroaryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl-fused- heterocycloalkyl; R2 represents H, halogen, alkyl, haloalkyl, cyano; R3 represents H, alkyl, R6 or alkyl-R6; R6 represents halogen, CN, CF3, CONR7R8, SO2NR7R8, OR9, NR7R8, NR7COR10, NR7SO2R10, NR7CONR7R8; R7 and R8, which may be the same or different, each independently represent H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; R9 represents H, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; R10 represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl; R4 represents H, halogen, cyano, alkyl, haloalkyl, OR9, NR7R8; R5 represents optionally substituted aryl, heteroaryl, aryl-fused-cycloalkyl heteroaryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl-fused heterocycloalkyl; L represents -(CH2)nCON(R11)(CH2)m-, -(CH2)nSO2N(R11)(CH2)m- -(CH2)nCON(R11)(CH2)rO-, -(C H2)nS O2N ( R 11 )(C H2)rO- -(CH2)nCON(R11)(CH2)rS-, -( C H2)nS O2N( R 11 )(C H2)rS- -(CH2)nCON(R11)(CH2)rN(R11)-, -(CH2)nSO2N(R11 )(CH2)rN(R11 )- -(CH2)nN(R11 )CO(CH2)m-, -( C H2 )n N ( R 11 ) S O2( C H2)m- -(CH2)nN(R11 )CO(CH2)mO(CH2)p-, -(CH2)nN(R11 )SO2(CH2)mO(CH2)p- -(CH2)nN(R11)CO(CH2)mS(CH2)p-, -(CH2)nN(R11 )SO2(CH2)mS(CH2)p- -(CH2)nN(R11 )CO(CH2)mN(R11 )(CH2)p-, -(CH2)nN(R11 )SO2(CH2)mN(R11 )(CH2)p- -(CH2)nO(CH2)m-, -(CH2)nS(CH2)m-, -(CH2)nN(R11)(CH2)m-, -(CH2)nCO(CH2)m- -(CH2)nSO2(CH2)m-, -(CH2)q-, -(CH2)nCO(CH2)mO(CH2)p- -(CH2)nSO2(CH2)mO(CH2)p-, -(CH2)nCO(CH2)mS(CH2)p- -(CH2)nSO2(CH2)mS(CH2)p-, -(CH2)nCO(CH2)mN(R11 )(CH2)p- -(CH2)nSO2(CH2)mN(R11 )(CH2)p-, -(CH2)n-cycloalkyl-(CH2)m-, -(CH2)n- heterocycloalkyl-(CH2)m, -(CH2)n-aryl-(CH2)m-, -(CH2)n-heteroaryl-(CH2)m- in each case, the linker may be attached either way round, i.e. the left hand end as drawn may be attached to the quinoline and the right hand end to R5, or vice versa; R11 represents H or alkyl; n, m and p each independently represent 0, 1 or 2; q represents 0, 1 , 2, 3, 4 or 5; r represents 2 or 3; and corresponding N-oxides, pharmaceutically acceptable salts, solvates and prodrugs of such compounds. In one embodiment, R1 preferably represents an optionally substituted heteroaryl group attached to the quinoline via a carbon atom. Suitable representative heteroaryl groups include pyridyl, furanyl, imidazolyl and pyrazolyl. In an alternative embodiment, R1 represents an optionally substituted heteroaryl group attached to the quinoline via a nitrogen atom. A suitable representative heteroaryl group is imidazolyl. In the same or another embodiment, R2 represents H. In the same or another embodiment, R3 represents alkyl or haloalkyl, especially alkyl, particularly methyl. In the same or another embodiment, R4 represents H. In the same or another embodiment, the L-R5 substituent is attached to the 6 position of the quinoline. R5 preferably represents a phenyl group substituted in the para position by a suitable substituent. Suitable substituents include haloalkyl, especially trifluoromethyl. In the same or another embodiment, L represents -(CH2)nN(R11 )CO(CH2)mO(CH2)p-, in which n and p preferably represent 0 and m preferably represents 1. In an alternative embodiment, L represents -(CH2)nN(R11 )CO(CH2)m- in which n represents 0 and m represents 2. In both embodiments, R11 preferably represents H. In both embodiments, L is attached as written, i.e. the left hand end is attached to the quinoline ring. As MCH-1 R antagonists, the compounds of the present invention may be useful in treating the following conditions: obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, gall stones, osteoarthritis, certain cancers, AIDS wasting, cachexia, frailty (particularly in the elderly), binge eating disorders including bulimina, anorexia, mental disorders including manic depression, depression, schizophrenia, mood disorders, delirium, dementia, severe metal retardation, anxiety, stress, cognitive disorders, sexual function, reproductive function, kidney function, diuresis, locomotor disorders, attention deficit disorder (ADD), substance abuse disorders and dyskinesias including Parkinson's disease, Parkinson-like syndromes, Tourette's syndrome, Huntingdon's disease, epilepsy, improving memory function, and spinal muscular atrophy. The present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions. The invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient. The invention is further concerned with processes for preparing the compounds of this invention. DESCRIPTION OF THE INVENTION For purposes of the present invention, the following chemical terms as used above, and throughout the description of the invention, and unless otherwise indicated, shall be understood to have the following meanings: "Acyl" means a -CO-alkyl group in which the alkyl group is as described herein. Exemplary acyl groups include -COCH3 and -COCH(CH3)2. "Acylamino" means a -NR-acyl group in which R and acyl are as described herein. Exemplary acylamino groups include -NHCOCH3 and -N(CH3)COCH3. "Alkoxy" and "alkyloxy" means an -O-alkyl group in which alkyl is as defined below. Exemplary alkoxy groups include methoxy and ethoxy. "Alkoxycarbonyl" means a -COO-alkyl group in which alkyl is as defined below. Exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. "Alkyl" as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, preferably 1 to 6, carbon atoms, in the chain. Exemplary alkyl groups include methyl, ethyl, 1-propyl and 2-propyl. "Alkylamino" means a -NH-alkyl group in which alkyl is as defined above. Exemplary alkylamino groups include methylamino and ethylamino. "Alkylsufinyl" means a -SO-alkyl group in which alkyl is as defined above. Exemplary alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl. "Alkylsufonyl" means a -SO2-alkyl group in which alkyl is as defined above. Exemplary alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl. "Alkylthio" means a -S-alkyl group in which alkyl is as defined above. Exemplary alkylthio groups include methylthio and ethylthio. "Aminoacyl" means a -CO-NRR group in which R is as herein described. Exemplary aminoacyl groups include -CONH2 and -CONHCH3. "Aminoalkyl" means an alkyl-NH2 group in which alkyl is as previously described. Exemplary aminoalkyl groups include -CH2NH2. "Aminosulfonyl" means a -SO2-NRR group in which R is as herein described. Exemplary aminosulfonyl groups include -SO2NH2 and -SO2NHCH3. "Aryl" as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, such as phenyl or naphthyl, and in one embodiment preferably phenyl. The aryl group may be substituted by one or more substituent groups. "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C1-4 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthlenemethyl. "Arylalkyloxy" means an aryl-alkyloxy- group in which the aryl and alkyloxy moieties are as previously described. Preferred arylalkyloxy groups contain a C1-4 alkyl moiety. Exemplary arylalkyl groups include benzyloxy. "Aryl-fused-cycloalkyl" means a monocyclic aryl ring, such as phenyl, fused to a cycloalkyl group, in which the aryl and cycloalkyl are as described herein. Exemplary aryl-fused-cycloalkyl groups include tetrahydronaphthyl and indanyl. The aryl and cycloalkyl rings may each be substitued by one or more substituent groups. The aryl-fused-cycloalkyl group may be attached to the remainder of the compound of formula (1 ) by any available carbon atom. "Aryl-fused-heterocycloalkyl" means a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl are as described herein. Exemplary aryl-fused-heterocycloalkyl groups include tetrahydroquinolinyl, indolinyl, benzodioxinyl, benxodioxolyl, dihydrobenzofuranyl and isoindolonyl. The aryl and heterocycloalkyl rings may each be sustitued by one or more substituent groups. The aryl-fused-heterocycloalkyl group may be attached to the remainder of the compound of formula (1 ) by any available carbon or nitrogen atom. "Aryloxy" means an -O-aryl group in which aryl is described above. Exemplary aryloxy groups include phenoxy. "Cyclic amine" means an optionally substituted 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen, and which may optionally contain an additional heteroatom selected from O, S or NR (where R is as described herein). Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine and N- methylpiperazine. The cyclic amine group may be substituted by one or more substituent groups. "Cycloalkyl" means an optionally substituted saturated monocyclic or bicyclic ring system of from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group may be substituted by one or more substituent groups. "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. "Dialkylamino" means a -N(alkyl)2 group in which alkyl is as defined above. Exemplary dialkylamino groups include dimethylamino and diethylamino. "Halo" or "halogen" means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro. "Haloalkoxy" means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms. Exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy. "Haloalkyl" means an alkyl group which is substituted by one or more halo atoms. Exemplary haloalkyl groups include trifluoromethyl. "Heteroaryl" as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, in which one or more of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups. The heteroaryl group may be substituted by one or more substituent groups. The heteroaryl group may be attached to the remainder of the compound of formula (1 ) by any available carbon or nitrogen atom. "Heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. "Heteroarylalkyloxy" means a heteroaryl-alkyloxy- group in which the heteroaryl and alkyloxy moieties are as previously described. Preferred heteroarylalkyloxy groups contain a lower alkyl moiety. Exemplary heteroarylalkyloxy groups include pyridylmethyloxy. "Heteroaryloxy" means a heteroaryloxy- group in which the heteroaryl is as previously described. Exemplary heteroaryloxy groups include pyridyloxy. "Heteroaryl-fused-cycloalkyl" means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a cycloalkyl group, in which heteroaryl and cycloalkyl are as previously described. Exemplary heteroaryl-fused-cycloalkyl groups include tetrahydroquinolinyl and tetrahydrobenzofuranyl. The heteroaryl and cycloalkyl rings may each be sustitued by one or more substituent groups.
The heteroaryl-fused-cycloalkyl group may be attached to the remainder of the compound of formula (1 ) by any available carbon or nitrogen atom. "Heteroaryl-fused-heterocycloalkyl" means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a heterocycloalkyl group, in which heteroaryl and heterocycloalkyl are as previously described. Exemplary heteroaryl-fused- heterocycloalkyl groups include dihydrodioxinopyridinyl, dihydropyrrolopyridinyl, dihydrofuranopyhdinyl and dioxolopyridinyl. The heteroaryl and heterocycloalkyl rings may each be substitued by one or more substituents groups. The heteroaryl-fused-heterocycloalkyl group may be attached to the remainder of the compound of formula (1 ) by any available carbon or nitrogen atom. "Heterocycloalkyl" means: (i) an optionally substituted cycloalkyl group of from 4 to 8 ring members which contains one or more heteroatoms selected from
O, S or NR; (ii) a cycloalkyl group of from 4 to 8 ring members which contains
CONR and CONRCO (examples of such groups include succinimidyl and 2- oxopyrrolidinyl). The heterocycloalkyl group may be substituted by one or more substituent groups. The heterocycloalkyl group may be attached to the remainder of the compound of formula (1 ) by any available carbon or nitrogen atom. "Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described. "Lower alkyl" as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 4 carbon atoms in the chain, i.e. methyl, ethyl, propyl (n-propyl or i-propyl) or butyl (n- butyl, i-butyl or t-butyl). "R" means hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heteroaryl or aryl. "Sulfonyl" means a -SO2-alkyl group in which alkyl is as described herein. Exemplary sulfonyl groups include methanesulfonyl. "Sulfonylamino" means a -NR-sulfonyl group in which R and sulfonyl are as described herein. Exemplary sulfonylamino groups include -NHSO2CH3. "Prodrug" means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of formula (1 ). For example an ester prodrug of a compound of formula (1 ) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- β-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. As another example an ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule [Examples of ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 18:379 (1987)]. "Saturated" pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds. The cyclic groups referred to above, namely, aryl, heteroaryl, cycloalkyl, aryl-fused-cycloalkyl, heteroaryl-fused-cycloalkyl, heterocycloalkyl, aryl-fused- heterocycloalkyl, heteroaryl-fused-heterocycloalkyl and cyclic amine may be substituted by one or more substituent groups. Suitable optional substituent groups include acyl (e.g. -COCH3), alkoxy (e,g, -OCH3), alkoxycarbonyl (e.g. -CO2CH3), alkylamino (e.g. -NHCH3), alkylsulfinyl (e.g. -SOCH3), alkylsulfonyl (e.g. -SO2CH3), alkylthio (e.g. -SCH3), -NH2, aminoalkyl (e.g. -CH2NH2), arylalkyl (e.g. -CH2Ph or -CH2-CH2-Ph), cyano, dialkylamino (e.g. -N(CH3)2), halo, haloalkoxy (e.g. -OCF3 or -OCHF2), haloalkyl (e.g. -CF3), alkyl (e.g. -CH3 or -CH2CH3), -OH, -CHO, -NO2, aryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl, aminoacyl (e.g. -CONH2, -CONHCH3), aminosulfonyl (e.g. -SO2NH2, -SO2NHCH3), acylamino (e.g. -NHCOCH3), sulfonylamino (e.g. -NHSO2CH3), heteroarylalkyl, cyclicamine (e.g. morpholine), aryloxy, heteroaryloxy, arylalkyloxy (e.g. benzyloxy) and heteroarylalkyloxy. Components of formula (1 ) may contain one or more asymmetric centres and can thus occur as racemates and racemic mixtures, single enantiomers, disastereomeric mixtures and individual disastereomers. The present invention is meant to comprehend all such isomeric forms of the compound of Formula (1 ). Some of the compound described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of formula (1 ). Compounds of the formula (1 ) may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventionial means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column. Alternatively, any enantiomer of a compound of the general formula (1 ) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration. The term 'pharmaceutically acceptable salts' refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, Λ/, Λ/'-dibenzylethylenediamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylipiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from the pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, latic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulphuric, tartaric, p-toluenesulfonicacid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulphuric, and tartaric acids. It will be understood that, as used in herein, references to the compounds of Formula (1 ) are meant to also include the pharmaceutically acceptable salts. Compounds of this invention are antagonists of the MCH receptor and as such are useful for the prevention and treatment of disorders or diseases associated with the MCH receptor. Accordingly, another aspect of the present invention provides a method for the treatment (including prevention, alleviation, amelioriation or suppression) of diseases or disorders or symptoms medicated by MCH receptor binding and subsequent cell activation, which comprises administering to a mammal an effective amount of a compound of Formula (1 ). Such diseases, disorders, conditions or symptoms are for example, obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, gall stones, osteroarthritis, certain cancers, AIDS wasting, cachexia, frailty (particularly in the elderly), binge eating disorders including bulimia, anorexia, mental disorders including manic depression, depression, schizophrenia, mood disorders, delirium, dementia, severe mental retardation, anxiety, stress, cognitive disorders, sexual function, reproductive function, kidney function, diuresis, locomotor disorders, attention deficit disorder (ADD), substance abuse disorders and dyskinesias including Parkinson's disease, Parkinson like syndromes, Tourette's syndrome, Huntington's disease, epilepsy, improving memory function, and spinal muscular atrophy. The utilities of the present compounds in these diseases or disorders may be demonstrated in animal disease models that have been reported in the literature. The following are examples of such animal disease models: a) suppression of food intake and resultant weight loss in rats (Life Sciences, 1998, 63, 113-117); b) reduction of sweet food intake in marmosets (Behavioural Pharm, 1998, 9, 179-181 ); c) the reduction of sucrose and ethanol intake in mice (Psychopharm. 1997, 132, 104 - 106); d) increased motor activity and place conditioning in rats (Psychopharm. 1998, 135, 324-332; Psychopharmacol. 2000, 151 : 25-30); e) spontaneous locomotor activity in mice (J. Pharm. Exp. Ther. 1996, 277, 586 - 594). The magnitude of prophylactic or therapeutic dose of a compound of Formula (1 ) will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula (1 ) and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases. For use where a composition for the intravenous administration is employed, a suitable dosage range is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of Formula (1 ) per kg of body weight per day and for cytoprotective use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1mg to about 10 mg) of a compound of Formula (1 ) per kg of body weight per day. In the cases where an oral composition is employed, a suitable dosage range is, e.g. from about 0.01 mg to about 10Omg of a compound of Formula (1 ) per day, preferably from about 0.1 mg to about 10mg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from 0.01 to 1 ,000mg, preferably 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0 or 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of Formula (1 ) and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula (1 ), additional active ingredient(s), and pharmaceutically acceptable excipients. Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. The pharmaceutical compositions of the present invention comprise a compound of Formula (1 ) as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non- toxic bases or acids including inorganic bases or acids and organic bases or acids. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers. The compounds may also be delivered as powders which may be formulated and the power composition may be inhaled with the aid of insufflation powder inhaler device. The preferred delivery systems for inhalation are metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula (1 ) in suitable propellants, such as fluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol, which can be formulated as a dry powder of a compound of Formula (1 ) with or without additional excipients. Suitable topical formulations of a compound of formula (1 ) include transdermal devices, aerosols, creams, ointments, lotions, dusting powders and the like. In practical use, the compounds of Formula (1 ) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such, as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. In addition to the common dosage forms set out above, the compounds of Formula (1 ) may also be administered by controlled release means and/or delivery devices such as those described in U.S Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719. Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non- aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 1 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 1 to about 500 mg of the active ingredient. The following are examples of representative pharmaceutical dosage forms for the compounds of Formula (1 ):
Injectable Suspension (I.M.) mg/mL Compound of Formula (1 ) 10 Methylcellulose 5.0
Tween 80 0.5 Benzyl alcohol 9.0
Benzalkonium chloride 1.0 Water for injection to a total volume of 1 mL
Tablet mg/tablet Compound of Formula (1 ) 25
Microcrystalline Cellulose 415
Povidone 14.0
Pregelatinized Starch 43.5
Magnesium Stearate 2.5 500
Capsule mg/capsule
Compond of Formula (1 ) 25 Lactose Powder 573.5
Magnesium Stearate 1.5 600
Aerosol Per canister
Compound of Formula (1 ) 24mg
Lecithin, NF Liq. Cone. 1.2mg
Trichlorofluoromethane, NF 4.025g
Dichlorodifluoromethane, NF 12.15g
Compounds of Formula (1 ) may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula (1 ) are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (1 ). When a compound of Formula (1 ) is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula (1 ) is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula (1 ). It will be appreciated that for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents. The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anorectic agent, such that together they give effective relief. Suitable anorectic agents for use in combination with a compound of the present invention include, but are not limited to, aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropoin, diphemethoxidine, Λ/-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramore, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine, and pharmaceutically acceptable salts thereof. A particularly suitable class of anorectic agent is the halogenated amphetamine derivatives, including chorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine, and pharmaceutically acceptable salts thereof. Particularly preferred halogenated amphetamine derivatives of use in combination with a compound of the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof. It will be appreciated that for the treatment or prevention of obesity, the compounds of the present invention may also be used in combination with a selective serotonin reuptake inhibitor (SSRI). The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of SSRI, such that together they give effective relief. Suitable selective serotonin reuptake inhibitors of use in combination with a compound of the present invention include fluxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof. The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of growth hormone secretagogues such as those disclosed and specifically described in US patent 5,536,716; melanacortin agonists such as Melantan II; β-3 agonists such as those disclosed and specifically described in patent publications WO94/18161 , WO95/29159, WO97/46556, WO98/04526 and WO98/32753; 5HT-2 agonists; orexin antagonists; melanin concentrating hormone antagonists; galanin antagonists; CCK agonists; GPL-1 agonists; corticotropin - releasing hormone agonists; NPY - 5 antagonists; CB1 modulators, such as N-( 1 -piperidinyl)-5-(4-chlorophenyl)-1 - (2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A), and those described in US Patents US 5,624,941 and US 6,028,084, PCT Application Nos. WO98/43636, WO98/31227, WO98/41519, WO98/37061 , WO00/10967, WO00/10968, WO97/29079, WO99/02499 and WO08.43635, and EPO Application No. EP - 658546; WO99/02499 and WO98/43635, and EPO Application No. EP - 658546; and Y1 antagonists, such that together they give effective relief. As used herein "obesity" refers to a condition whereby a mammal has a body mass index (BMI), which is calculated as weight per height squared (kg/m2), of at least 25.9. Conventionally, those persons with normal weight have a BMI of 19.9 to less than 25.9. It will be appreciated that for treatment or prevention of obesity, the compounds of the present invention may also be used in combination with the histamine receptor - 3 (H3) modulators, CB1 cannabinoid receptor antagonists or inverse agonists, and/or phosphodiesterase - 3B (PDE3B) inhibitors. The obesity described herein may be due to any cause, whether genetic or environmental. Examples of disorders that may result in obesity or be the cause of obesity include overeating and bulimia, polycystic ovarian disease, craniopharynagioma, the Prader-Willi Syndrome, Frohlich's syndrome, Type II diabetes, GH - deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat free mass, e.g. children with acute lymphoblastic leukaemia. "Treatment" (of obesity) refers to reducing the BMI of the mammal to less than about 25.9 and maintaining that weight for at least 6 months. The treatment suitably results in a reduction in food or calorie intake by the mammal. "Prevention" (of obesity) refers to preventing obesity from occurring if the treatment is administered prior to the onset of the obese condition. Moreover, if treatment is commenced in already obese subjects, such treatment is expected to prevent, or to prevent the progression of, the medical sequelae of obesity, such as, e.g., arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglceridemia and cholelithiasis. Excessive weight is a contributing factor to different diseases including hypertension, diabetes, dyslipidemias, cardiovascular disease, gallstones, osteoarthritis and certain forms of cancers. Bringing about weight loss can be used, for example, to reduce the likelihood of such diseases and as part of a treatment for such diseases. Weight reduction can be achieved by antagonizing MCH-1 R receptor activity to obtain, for example, one or more of the following effects: reducing appetite, increasing metabolic rate, reducing fat intake or reducing carbohydrate craving. Other compounds that may be combined with a compound of Formula (1 ), either administered separately or in the same pharmaceutical compositions, for the treatment of diabetes and other sequelae or existing weight include but are not limited to: (a) insulin sensitizers including (i) PPARγ agonists such as the glitazones (e.g. troglitazone, piolitazone, englitazone, MMC-555, BRL49653and the like), and compounds disclosed in WO97/27857, 97/38137 and 97/27847; (ii) biguanides such as metfirmin and phenformin; (b) Insulin or insulin mimetics; (c) Sulfonylureas, such as tolbutamide and glipizide; (d) α - glucosidase inhibitors (such as acarbose), (e) Cholesterol lowering agents such as (i) HMG - CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastain, and other statins), (ii) sequestrants (chloestyramine, colestipol and dialkylaminoalkl derivatives or a cross - linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) proliferator-activator receptor α agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (v) inhibitors of cholesterol absorption for example beta-sitosterol and (acyl CoA: cholesterol acyltransferase) inhibitors for example melinamide, (vi) probucol, (vii) vitamin E, and (viii) thyromimetics; (f) PPARδ agonists, such as those disclosed in WO97/28149; (g) Antiobesity compounds, such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, or β-3 adrenergic receptor agonists; (h) Feeding behaviour modifying agents, such as neuropeptide Y antagonists (e.g. neuropeptide Y5) such as those disclosed in WO 97/19682, WO 97/20820, WO 97/20821 , WO 97/20822 and WO 97/20823; (i) PPARα agonists such as described in WO 97/36579 by Glaxo; (j) PPARg agonists as described in WO97/10813; (k) Serotonin reuptake inhibitors such as fluxetine and sertraline; (I) Growth hormone secretagogues such as MK - 0677. It will be appreciated that for the treatment or prevention of stress, a compound of the present invention may be used in conjunction with other anti-stress agents, such as anti-anxiety agents. Suitable classes of anti-anxiety agents include benzodiazepines and 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. Suitable benzodiazepines include: alprazolam, chloridazepoxide , clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxzepam and prazepam, and pharmaceutically acceptable salts thereof. Suitable 5-HT1A receptor agonists or antagonists include, in particular the 5-HT1A receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof. Suitable CRF antagonists include the 4-tetrahydropyridylpyrimidine derivatives disclosed in US 6, 187,781 ; the aryloxy and arylthio-fused pyrimidine and pyrimidine derivatives disclosed in US 6,124,300; the arylamino-fused pyrimidine derivatives disclosed in US 6,107,300; the pyrazole and pyrazolopyrimidine derivatives disclosed in US 5,705,656, US 5,712,303, US 5,968,944, US 5,958,948, US 6,103,900 and US 6,005,109; the tetrahydropteridine derivatives disclosed in US 6,083,948; the benzoperimidine carboxylic acid derivatives disclosed in US 5,861 ,398; the substituted 4- phenylaminothiazol derivatives disclosed in US 5,880,135; the cyclic CRF analogs disclosed in US 5,493,006, US 5,663,292 and US 5,874,227; and the compounds disclosed in US 5,063,245, US 5,245,009, US 5,510,458 and US 5, 109, 111 ; as well as compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO 94/13661 , WO 94/13676 and WO 94/13677. As used herein, the term "substance abuse disorder" includes substance dependence or abuse with or without physiological dependence. The substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, ***e, hallucinogens, inhalants, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all the above. In particular, the term "substance abuse disorders" includes drug withdrawal disorders such as alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; ***e withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances. It will be appreciated that reference to treatment of nicotine withdrawal includes the treatment of symptoms associated with smoking cessation. Other "substance abuse disorders" include substance-induced anxiety disorder with onset during withdrawal; substance-induced mood disorder with onset during withdrawal; and substance-induced sleep disorder with onset during withdrawal. Similarly, compounds of Formula (1 ), will be useful as a partial or complete substitute for conventional pain relievers in preparations wherein they are presently co-administered with other agents or ingredients. Thus in further aspects, the invention encompasses pharmaceutical compositions for modulating the perception of pain comprising a non-toxic therapeutically effective amount of the compound of Formula (1 ) as defined above and one or more ingredients such as another pain reliever including acetaminophen or phenacetin, or a cyclooxygenase-2 (COX-2) inhibitor; a potentiator including caffeine; a prostaglandin including misoprostol, enprostil, rioprostil, ornoprostol or rosaprostol; a sedating or non-sedating antihistamine. Examples of cyclooxygenase-2 selective inhibitos include rofecoxib (VIOXX®, see U.S Patent No. 5,474,995), etoricoxib (ARCOXIA™ see U.S. Patent No 5,861 ,419), celecoxib (CELEBREX®, see U.S. Patent No. 5,466,823), valdecoxib (see U.S. No. 6,633,272), parecoxib (see U.S. No. 5,932,598), COX-189 (Novartis), BMS347070 (Bristol Myers Squibb), tiracoxib (JTE522, Japan Tobacco), ABT963 (Abbott), CS502 (Sankyo) and GW406381 (GlaxoSmithKline). Other examples of cyclooxygenase-2 inhibitors compounds are disclosed in U.S. Patent No. 6,020,343. In addition the invention encompasses a method of treating pain comprising: administration to a patient in need of such treatment a non-toxic therapeutically effective amount of the compound of Formula (1 ), optionally co- administered with one or more of such ingredients as listed immediately above. Suitable antipsychotic agents of use in combination with a compound of the present invention for the treatment of schizophrenia include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, aceophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. Suitable examples of dibenzazepines include clozapine and olanzapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other antipsychotic agents includ loxapine, sulphiride and risperidone. It will be appreciated that the antipsychotic agents whn used in combination with a CB1 receptor modulator may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine, hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perhenazine, chlorprothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form. Other classes of antipsychotic agent of use in combination with a compound of the present invention include dopamine receptor antagonists, especially D2, D3 and D4 dopamine receptor antagonists, and muscarinic M1 receptor agonists. An example of a D3 dopamine receptor antagonist is the compound PNU-99194A. An example of a D4 dopamine receptor antagonist is
PNU-101387. An example of a muscarinic M1 receptor agonist is xanomeline. Another class of antipsychotic agent of use in combination with CB1 receptor modulator is the 5-HT2A receptor antagonists, examples of which include
MDL100907 and fananserin. Also of use in combination with a compound of the present invention are the serotonin dopamine antagonists (SDAs) which are believed to combine 5-HT2A and dopamine receptor antagonist activity, examples of which include olanzapine and ziperasidone. It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other anti- depressant or anti-anxiety agents. Suitable classes of anti-depressant agents include norepineph ne reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotrophin releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, neurokinin-1 antagonists and atypical anti-depressants. Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof. Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protripyline, and pharmaceutically acceptable salts thereof.
Suitable selective serotonin reuptake inhibitors include those described supra. Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selediline, and pharmaceutically acceptable salts thereof. Suitable reversible inhibitors of monoamine oxidase include: moclobemide, and pharmaceutically acceptable salts thereof. Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venlafaxine, and pharmaceutically acceptable salts thereof. Suitable CRF antagonists include those described hereinabove Suitable atypical anti-depressants include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof. The neurokinin-1 receptor antagonist may be peptidal or non-peptidal in nature, however, the use of a non-peptidal neurokinin-1 receptor antagonist is preferred. In a preferred embodiment, the neurokinin-1 receptor antagonist is a CNS-penetrant neurokinin-1 receptor antagonist. In addition, for convenience the use of an orally active neurokinin-1 receptor antagonist is preferred. To facilitate dosing, it is also preferred that the neurokinin-1 receptor antagonist is a long acting neurokinin-1 receptor antagonist. An especially preferred class of neurokinin-1 receptor antagonist of use in the present invention are those compounds which are orally active and long acting. Neurokinin-1 receptor antagonists of use in the present invention are fully described, for example, in U.S. Patent Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699; European Patent Publiction Nos. EPO 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430 771 , 0 436 334, 0 443 132, 0 482 539, 0498 069, 0499 313, 0 512 901 , 0 512 902, 0 514 273, 0 514274, 0 514 275, 0 514 276, 0 515 681 , 0 517 589, 0 520 555, 0 522 808, 0 528495, 0 532 456, 0 553280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913, 0 590 152, 0 599 538, 0610 793, 0634404, 0686 629, 0693489, 0694535, 0699655, 0699674, 0 707 006, 0 708 101 , 0 709 375, 0 709 376, 0 714 891 , 0 723 959, 0 733 632 and 0 776 893; PCT International Patent Publication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151 , 92/15585, 92/17449, 92/20661 , 92/20676, 92/21677, 92/22569, 93/00330, 93/00331 , 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/141 13, 93/18023, 93/19064, 93/21155, 93/21181 , 93/23380, 93/24465, 94/00440, 94/01402, 94/02461 , 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311 , 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181 , 9605193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661 , 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671 , 97/17362, 97/18206, 97/19084, 97/19942, 97/21702, and 97/49710; and in British Patent Publication Nos. 2 266 529, 2 268 931 , 2 269 170, 2 269 590, 2 271 774, 2 294 144, 2 293 168, 2 293 169, and 2 302 689. Suitable classes of anti-anxiety agents include benzodiazepines and 5- HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. Suitable benzodiaepines include those previously described herein. Suitable 5-HT1A receptor agonists or antagonists include, in particular, those described supra. For the treatment of autism, the compounds of the present invention may be used in combination with butyrophenones. For the treatment of Parkinson's disease and Parkinson-like syndromes, the compounds of the present invention may be used in combination with levodopa, carbidopa/levodopa, amantadine, bromocryptine and other ergot alkaloids, anticholinergic medications such as benztrophine, trihexyphenidyl, antihistamines such as dephenhydramine and orphenadrine, mild sedatives, tricyclic antidepressants such as amitriptiline and others described supra, and propanolol. For the treatment of Huntingdon's Chorea, the compounds of the present invention may be used in combination with phenothiazine, chlorpromazine, and butyrophenone neuroleptics such as haloperidol or reserpine. For the treatment of epilepsy, the compounds of the present invention may be used together with anticonvulsants such as penytoin, phenobarbital, primidone, carbamazepine, trimethadione, clonazepam, valproate and ethosuximide In one embodiment of a combination for the treatment of male or female sexual dysfunctions, the second ingredient to be combined with a compound of Formula (1 ) can be type V cyclic-GMP-specific phosphodiesterase (PDE-V) inhibitor, such as sildenafil and IC-351 or a pharmaceutical acceptable salt thereof; an alpha-adrenergic receptor antagonist, such as phentolamine and yohimbine or a pharmaceutically acceptable salt therefore; or a dopamine receptor agonist, such as apomorphine or a pharmaceutically acceptable salt thereof. "Male sexual dysfunction" includes impotence, loss of libido, and erectile dysfunction. "Erectile dysfunction" is a disorder involving the failure of a male mammal to achieve erection, ejaculation, or both. Symptoms of erectile dysfunction include an inability to achieve or maintain an erection, ejactulatory failure, premature ejaculation, or inability to achieve an orgasm. An increase in erectile dysfunction and sexual dysfunction can have numerous underlying causes, including but not limited to (1 ) ageing, (2) and underlying physical dysfunction, such as trauma, surgery and peripheral vascular disease, and (3) side-effects resulting from drug treatment, depression, and other CNS disorders. "Female sexual dysfunction" can be seen as resulting from multiple components including dysfunction in desire, sexual arousal, sexual receptivity, and orgasm related to disturbances in the clitoris, vagina, periurethral glans, and other trigger points of sexual function. In particular, anatomic and functional modification of such trigger points may diminish the orgasmic potential in breast cancer and gynecologic cancer patients. Treatment of female sexual dysfunction with a MC- 4 receptor agonist can result in improved blood flow, improved lubrication, improved sensation, facilitation of reaching orgasm, reduction in the refractory period between orgasms, and improvements in arousal and desire. In a broader sense, "female sexual dysfunction" also incorporates sexual pain, premature labor, and dysmenorrhea. For the treatment of male and female sexual dysfunction, the compounds of the present invention may be employed in combination with a compound selected from a type V cyclic-GMP-specific phosphodiesterase (PDE-V) inhibitor, such as sildenafil and IC-351 or a pharmaceutically acceptable salt thereof; an alpha-adrenergic receptor antagonist, a such as phentolamine and yohimbine or a pharmaceutically acceptable salt thereof; or a dopamine receptor agonist, such as apomorphine or a pharmaceutically acceptable salt thereof. MCH-1 R antagonist compounds can be provided in kit. Such a kit typically contains as active compound in dosage forms for administration. A dosage form contains a sufficient amount of active compound such that a beneficial effect can be obtained when administered to a patient during regular intervals, such as 1 to 6 times a day, during the course of 1 or more days. Preferable, a kit contains instructions indicating the use of the dosage form for weight reduction (e.g. , to treat obesity or overweight) or stress reduction, and the amount of dosage form to be taken over a specified time period. The method of treatment of this invention comprises a method of treating melanin concentrating hormone receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the MCH receptor in preference to the other G-protein coupled receptors. In particular, the present invention comprises a method of treating MCR-1 R receptor subtype mediated diseases by administering a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the MCH-1 R receptor. The weight ratio of the compound of the Formula (1 ) to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula (1 ) is combined with a β-3 agonist the weight ratio of the compound of the Formula (1 ) to the β-3 agonist will generally range from about 1000:1 to about 1 :1000, preferable about 200:1 to about 1 :200. Combinations of a compound of the Formula (1 ) and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. The compounds of Formula (1 ) of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The Examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The instant compounds may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above. The free amine bases corresponding to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide, and extraction of the liberated amine free base into an organic solvent followed by evaporation. The amine free base isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent followed by addition of the appropriate acid and subsequent evaporation, precipitation, or crystallization. It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of formula (1 ) to avoid their unwanted participation in a reaction leading to the formation of compounds of formula (1 ). Conventional protecting groups, for example those described by T. W. Greene and P. G. M. Wuts in "Protective groups in organic chemistry" John Wiley and Sons, 1999, may be used. In the reaction schemes provided below, all definitions of R1 to R11 are to be understood to include such protected functional groups. Compounds of formula (1 ) may be conveniently prepared from compounds of formula (2) (in which X represents chlorine, bromine or iodine) by using a metal-mediated coupling reaction with an appropriate aryl or heteroaryl derivative. For example, a 2-haloquinoline may be reacted with an aryl or heteroaryl boronic acid or boronate ester in the presence of a palladium catalyst such as [1 ,1 -b/s(diphenylphosphino) ferrocenejdichloropalladium (II) and in the presence of a suitable base, such as cesium carbonate, in a suitable solvent, such as 1,4-dioxane, at an appropriate temperature, such as elevated temperature. It may be advantageous to conduct the reaction in a microwave. Alternatively, a 2-haloquinoline may be reacted with an appropriate tin compound, for example a th-n-butylstannyl analogue, in the presence of a palladium catalyst, such as dichlorob/s-(triphenylphosphine) palladium and triphenylphosphine, in an appropriate solvent, such as xylene, at a suitable temperature, such as the reflux temperature of the solvent. It will be appreciated by those skilled in the art there are many ways to form a bond between the quinoline and an aryl or heteroaryl group. A list of examples of biaryl bond forming reactions which could be used is provided by Fu et al. J. Am. Chem. Soc.2001 , 123, pages 2719-2724 and by Lemaire ef al. Chem. Rev.2002, 102, pages 1359-1469.
Figure imgf000036_0001
(1) (2)
Compounds of formula (2) in which L represents (CH2)nN(R11 )CO(CH2)m-,(CH2)nN(R11 )SO2(CH2)m-, -(CH2)nN(R1 1 )CO(CH2)mO(CH2)p-, -(CH2)nN(R1 1 )SO2(CH2)mO(CH2)p-, -(CH2)nN(R1 1 )CO(CH2)mS(CH2)p-, -(CH2)nN(R1 1 )SO2(CH2)mS(CH2)p-, -(CH2)nN(R11 )CO(CH2)mN(R11 )(CH2)p-, -(CH2)nN(R11 )SO2(CH2)mN(R11 )(CH2)p-, or -(CH2)nN(R11 )(CH2)m- and n represents 0 can be readily prepared from an aminoquinoline of formula (3). Compounds of formula (2) in which L contains an amide can be obtained by reaction of an aminoquinoline of formula (3) with an appropriate carboxylic acid using any suitable standard conditions known to those skilled in the art. For example, the reaction can be conducted using an activating agent such as O-(7-azabenzotriazol-1 -yl)-Λ/,Λ/,Λ/',Λ/'- tetramethyluronium hexafluorophosphate in the presence of a base such as N,N- diisopropylamine in a suitable solvent such as dichloromethane, dimethylformamide, or a mixture of the two. Alternatively, the carboxylic acid may be converted into a reactive intermediate such as an acid chloride or mixed anhydride and this can be reacted with the aminoquinoline (3) in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane. The reactive intermediate may be used in situ without isolation, or it may be isolated and then treated with the aminoquinoline (3). Similarly, compounds of formula (2) in which L contains a sulphonamide may be prepared by reaction of an aminoquinoline of formula (3) with a sulphonyl chloride in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane. Compounds of formula (2) in which L contains a urea may be prepared by reaction of an aminoquinoline of formula (3) with an appropriate isocyanate in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane. Compounds of formula (2) in which L contains an -N(R11 )(CH2)- group can be prepared from aminoquinolines of formula (3) an appropriate aldehyde under reactive amination conditions. Suitable conditions include the use of a reducing agent, such as triacetoxyborohydride, in a suitable solvent such as 1 ,2-dichloroethane.
Figure imgf000038_0001
(2) (3)
Aminoquinolines of formula (3) can be prepared by reduction of nitroquinolines of formula (4). The reduction may be carried out using any suitable conditions known to those skilled in the art, for example by using a metal such as iron or tin in the presence of an acid, such as hydrochloric acid, in a suitable solvent, such as ethanol, at an appropriate temperature, such as the reflux temperature of the solvent.
Figure imgf000038_0002
(3) (4) Nitroquinolines of formula (4) can be obtained from quinolines of formula (5) by nitration, which can be carried out using any suitable conditions such as the use of fuming nitric acid and concentrated sulphuric acid at reduced temperature.
Figure imgf000038_0003
(4) (5) Quinolines of formula (5) may be prepared using any standard methods known to those skilled in the art, or may be commercially available. Standard methods for the formation of quinolines are described in standard texts such as Advances in Heterocyclic Chemistry (Ed. Katritzky), The Chemistry of Heterocyclic Compounds (Ed. Weissberger and Taylor), Comprehensive Heterocyclic Chemistry (Pub. Pergamon Press), Comprehensive Heterocyclic Chemistry II (Pub. Pergamon Press) and Heterocyclic Compounds (Ed. Jones, Pub. Wiley). It will be appreciated by those skilled in the art that the reactions described above may be conducted in a different order. For example, a nitroquinoline of formula (4) may be converted in a nitroquinoline of formula (6) using an appropriate metal catalysed biaryl bond formation as discussed previously in relation to the preparation of a compound of formula (1 ) from a compound of formula (2). Subsequent reduction of the nitroquinoline of formula (6) would provide an aminoquinoline of formula (7), which could then be converted into a compound of formula (1 ).
Figure imgf000039_0001
(4) (6) (7) Compounds of formula (1 ) in which L represents
-(CH2)nCON(R11 )(CH2)m-, -(CH2)nCON(R11 )(CH2)rO-, -(CH2)nCON(R11 )(CH2)rS- or -(CH2)nCON(R11 )(CH2)rN(R11 )- in which n represents 0 could be prepared from a quinolinecarboxylic acid of formula (8) by reaction with an appropriate amine using any suitable standard conditions known to those skilled in the art. For example, the reaction can be conducted using an activating agent such as O-(7-azabenzotriazol-1-yl)-Λ/,Λ/,Λ/'/Λ/'-tetramethyluronium hexafluorophosphate in the presence of a base such as Λ/,Λ/-diisopropylamine in a suitable solvent such as dichloromethane, dimethylformamide, or a mixture of the two. Alternatively, the carboxylic acid may be converted into a reactive intermediate such as an acid chloride or mixed anhydride and this can be reacted with the amine in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane. The reactive intermediate may be used in situ without isolation, or it may be isolated and then treated with the amine.
Figure imgf000040_0001
(1 ) (8)
A quinolinecarboxylic acid of formula (8) may be prepared from a haloquinoline of formula (9) (in which X represents chlorine, bromine or iodine) using a metal catalysed carbonylation reaction, such as a palladium catalysed reaction. The reaction may be carried out using carbon monoxide
Figure imgf000040_0002
(8) (9)
A haloquinoline of formula (9) may be prepared from a quinoline of (10) using standard conditions of aromatic halogenation. For example, a quinoline of formula (10) may be treated with a halogenating agent such as chlorine, N- chlorosuccinimide, bromine or idodine
Figure imgf000041_0001
(9) (10) A quinoline of formula (10) may be prepared from a quinoline of formula (5) using any suitable biaryl bond forming method, such as those described earlier.
Figure imgf000041_0002
(10) (5) Compounds of formula (1 ) - (10) may be prepared using any suitable procedures known to those skilled in the art, including appropriate functional group inter-conversion. It will be appreciated that such functional group inter- conversions may be carried out at any suitable stage during the synthesis. For example primary amine (-NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde or a ketone and a borohydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, for example 1 ,2-dichloroethane, or an alcohol such as ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature. Secondary amine (-NH-) groups may be similarly alkylated employing an aldehyde. In a further example, primary amine or secondary amine groups may be converted into amide groups (-NHCOR' or -NRCOR') by acylation. Acylation may be achieved by reaction with an appropriate acid chloride in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, or by reaction with an appropriate carboxylic acid in the presence of a suitable coupling agent such HATU (O-(7-azabenzotriazol-1 -yl)-Λ/,Λ/,Λ/',Λ/'- tetramethyluronium hexafluorophosphate) in a suitable solvent such as dichloromethane. Similarly, amine groups may be converted into sulphonamide groups (-NHSO2R' or -NR"SO2R') groups by reaction with an appropriate sulphonyl chloride in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dichloromethane. Primary or secondary amine groups can be converted into urea groups (-NHCONR'R" or -NRCONR'R") by reaction with an appropriate isocyanate in the presence of a suitable base such as triethylamine, in a suitable solvent, such as dichloromethane. An amine (-NH2) may be obtained by reduction of a nitro (-NO2) group, for example by catalytic hydrogenation, using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethyl acetate or an alcohol e.g. methanol. Alternatively, the transformation may be carried out by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid. In a further example, amine (-CH2NH2) groups may be obtained by reduction of nithles (-CN), for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, or Raney nickel, in a solvent such as an ether e.g. a cyclic ether such as tetrahydrofuran, at a temperature from -78°C to the reflux temperature of the solvent. In a further example, amine (-NH2) groups may be obtained from carboxylic acid groups (-CO2H) by conversion to the corresponding acyl azide (-CONj), Curtius rearrangement and hydrolysis of the resultant isocyanate (- N=C=O). Aldehyde groups (-CHO) may be converted to amine groups (-CH2NR'R")) by reductive amination employing an amine and a borohydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, for example dichloromethane, or an alcohol such as ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature. In a further example, aldehyde groups may be converted into alkenyl groups (-CH=CHR') by the use of a Wittig or Wadsworth-Emmons reaction using an appropriate phosphorane or phosphonate under standard conditions known to those skilled in the art. Aldehyde groups may be obtained by reduction of ester groups (such as
-CO2Et) or nithles (-CN) using diisobutylaluminium hydride in a suitable solvent such as toluene. Alternatively, aldehyde groups may be obtained by the oxidation of alcohol groups using any suitable oxidising agent known to those skilled in the art. Ester groups (-CO2R') may be converted into the corresponding acid group (-CO2H) by acid- or base-catalused hydrolysis, depending on the nature of R. If R is t-butyl, acid-catalysed hydrolysis can be achieved for example by treatment with an organic acid such as tnfluoroacetic acid in an aqueous solvent, or by treatment with an inorganic acid such as hydrochloric acid in an aqueous solvent. Carboxylic acid groups (-CO2H) may be converted into amides (-CONHR' or -CONR'R") by reaction with an appropriate amine in the presence of a suitable coupling agent, such as HATU, in a suitable solvent such as dichloromethane. In a further example, carboxylic acids may be homologated by one carbon
(i.e -CO2H to -CH2CO2H) by conversion to the corresponding acid chloride (-
COCI) followed by Arndt-Eistert synthesis. In a further example, -OH groups may be generated from the corresponding ester (e.g. -CO2R'), or aldehyde (-CHO) by reduction, using for example a complex metal hydride such as lithium aluminium hydride in diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol. Alternatively, an alcohol may be prepared by reduction of the corresponding acid (-CO2H), using for example lithium aluminium hydride in a solvent such as tetrahydrofuran, or by using borane in a solvent such as tetrahydrofuran. Alcohol groups may be converted into leaving groups, such as halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. t fluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxy group using conditions known to those skilled in the art. For example, an alcohol may be reacted with thionyl chloride in a halogenated hydrocarbon (e.g. dichloromethane) to yield the corresponding chloride. A base (e.g. triethylamine) may also be used in the reaction. In another example, alcohol or phenol groups may be converted to ether groups by, coupling a phenol with an alcohol in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl, or dimethylazodicarboxylate. Alternatively ether groups may be prepared by deprotonation of an alcohol, using a suitable base e.g. sodium hydride followed by subsequent addition of an alkylating agent, such as an alkyl halide. Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange by treatment with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran, and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using Λ/,Λ/-dimethylformamide as the electrophile. Aromatic halogen substituents may alternatively be subjected to metal (e.g. palladium or copper) catalysed reactions, to introduce, for example, acid, ester, cyano, amide, aryl, heteraryl, alkenyl, alkynyl, thio- or amino substituents. Suitable procedures which may be employed include those described by Heck, Suzuki, Stille, Buchwald or Hartwig. Aromatic halogen substituents may also undergo nucleophilic displacement following reaction with an appropriate nucleophile such as an amine or an alcohol. Advantageously, such a reaction may be carried out at elevated temperature in the presence of microwave irradiation. As another example, compounds of formula (I) in which R1 is heteroaryl containing an N-oxide group (e.g. pyridine-N-oxide) may be prepared by oxidation of compounds of formula (I) in which R1 is the corresponding non- oxidised heteroaryl. It will be appreciated by those skilled in the art that the functional group interconversions described above may be carried out at any suitable stage of the synthesis. The following Examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein. 1H NMR spectra were recorded at ambient temperature using a Varian Unity Inova (400MHz) spectrometer with a triple resonance 5mm probe. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations have been used: br = broad signal, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, m = multiplet. High Pressure Liquid Chromatography - Mass Spectrometry (LCMS) experiments to determine retention times and associated mass ions were performed using one of the following methods. Method A: Experiments performed on a Micromass Platform LCT spectrometer with positive ion electrospray and single wavelength UV 254nm detection using a Higgins Clipeus C18 5μm 100 x 3.0mm column and a 2 ml/minute flow rate. The initial solvent system was 95% water containing 0.1 % formic acid (solvent A) and 5% acetonitrile containing 0.1 % formic acid (solvent B) for the first minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes. The final solvent system was held constant for a further 2 minutes. Method B: Experiments performed on a Micromass Platform LC spectrometer with positive and negative ion electrospray and ELS/Diode array detection using a Phenomenex Luna C18(2) 30 x 4.6mm column and a 2 ml/minute flow rate. The solvent system was 95% solvent A and 5% solvent B for the first 0.50 minutes followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 0.50 minutes Microwave experiments were carried out using a Personal Chemistry
Smith Synthesizer™, which uses a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperatures from 40- 250°C can be achieved, and pressures of up to 20 bar can be reached. Two types of vial are available for this processor, 0.5-2.0ml and 2.0-5.0ml.
Intermediate 1 2-Hydroxy-4-methyl-6-nitroquinoline Fuming nitric acid (13.5ml) was added slowly to a cooled solution of 2- hydroxy-4-methylquinoline (10.0g) in concentrated sulphuric acid, while maintaining the temperature below 0°C. The mixture was stirred at 0 to -5°C for 4h then poured onto crushed ice. The resultant solid was collected by filtration, washed with water and air dried to give 2-hydroxy-4-methyl-6-nitroquinoline as a yellow solid (14.4g). 1H NMR (DMSO-d6) δ 12.15 (br s, 1 H) 8.5 (d, 1 H) 8.35 (dd, 1 H) 7.4 (d, 1 H) 6.55 (s, 1 H) 2.5 (s, 3H)
Intermediate 2 2-Chloro-4-methyl-6-nitroquinoline A mixture of 2-hydroxy-4-methyl-6-nitroquinoline (intermediate 1 , 1.0g) and phosphorus oxychloride was stirred and heated at reflux for 4h. The mixture was allowed to cool to room temperature and poured carefully into a mixture of ice and water. The resultant solid was collected by filtration, washed with water and air dried to give 2-chloro-4-methyl-6-nitroquinoline as a white solid (899mg). 1H NMR (DMSO-d6) δ 8.95 (d, 1 H) 8.5 (dd, 1 H) 8.15 (d, 1 H) 7.75 (s, 1 H) 2.85 (s, 3H)
Intermediate 3 2-Chloro-4-methylquinolin-6-ylamine Concentrated hydrochloric acid (5.0ml) was added to a stirred mixture of 2-chloro-4-methyl-6-nitroquinoline (intermediate 2, 10.Og) and iron dust (10.03g) in ethanol. The resultant mixture was stirred and heated at reflux for 90mins. After cooling to room temperature further concentrated hydrochloric acid (5.0ml) was added and the mixture was then stirred and heated at reflux for 3h. The mixture was allowed to cool to room temperature and left to stand overnight. It was filtered through celite and the filtrate was evaporated to dryness. The residue was partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic phase was dried (MgSO4), filtered and evaporated to dryness to give 2-chloro-4-methylquinolin-6-ylamine as a tan coloured solid (7.2g). 1H NMR (DMSO-d6) δ 7.6 (d, 1H) 7.25 (s, 1H) 7.15 (dd, 1H) 6.9 (d, 1H) 5.75 (s,2H) 2.5 (s,3H)
Intermediate 4 N-(2-Chloro-4-methylquinolin-6-yl) 2-(4-trifluoromethylphenoxy)acetamide O-(7-Azabenzotriazol-1 -yl)-/V,Λ/,V',Λ/'-tetramethyluronium hexafluorophosphate (5.12g) and Λ/,Λ/-diisopropylethylamine (5.4ml) were added to a solution of 2-chloro-4-methylquinolin-6-ylamine (intermediate 3, 1.99g) and
4-trifluoromethylphenoxy acetic acid (2.5g) in a 1 :1 mixture of dichloromethane and dimethylformamide. The reaction mixture was stirred at room temperature for 5 days then partitioned between dichloromethane and water. The organic layer was washed with water, dried (MgSO4), filtered and evaporated to dryness. The residue was triturated with ether and the solid was purified by chromatography on silica eluting with a mixture of diethyl ether and cyclohexane (4:1) to give N-(2-chloro-4-methylquinolin-6-yl) 2-(4- trifluoromethylphenoxy)acetamide as a white solid (2.0g). 1H NMR (DMSO-d6) δ 10.6 (br s, 1 H) 8.5 (d, 1 H) 7.95 (dd, 1 H) 7.9 (d, 1 H) 7.7 (d, 2H) 7.5 (s, 1H) 7.2 (d, 2H) 5.9 (s, 2H) 2.65 (s, 3H)
Intermediate 5 N-[4-Methyl-2-(1-tritylimidazol-4-yl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)-acetamide A mixture of N-(2-chloro-4-methylquinolin-6-yl) 2-(4- trifluoromethylphenoxy)acetamide (intermediate 4, 120mg), 4-(tributylstannyl)-1 - tritylimidazole (Synthesis, 1998, 829) (200mg) and tetrakis(triphenylphosphine) palladium (17.5mg) in a mixture of toluene and tetrahydrofuran (6:1) was stirred and heated at 100°C for 42h. After cooling to room temperature a saturated aqueous solution of potassium fluoride was added. The mixture was stirred for 10 minutes then extracted with dichloromethane. The organic phase was washed with water, dried (Na2SO4), filtered and evaporated to dryness. The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (1:9 increasing to 3:7) to give N-[4-methyl-2-(1- thtylimidazol-4-yl)quinolin-6-yl] 2-(4-trifluoromethylphenoxy)acetamide (51 mg). LCMS (method B) retention time 3.79 min, (M+H+) 669
Intermediate 6 2-(3-Furyl)-4-methylquinoline-6-ylamine A mixture of 2-chloro-4-methyl-6-nitroquinoline (intermediate 2, 100mg), 3-furanboronic acid (75mg), [1 ,1 -bis(diphenylphosphino) ferrocenejdichloropalladium (II), complex with dichloromethane (1:1) (74mg) and aqueous cesium carbonate solution (2M, 0.7ml) in dimethylformamide was stirred and heated in the microwave at 130°C for 30 minutes. The solvent was removed by evaporation and the residue was diluted with dichloromethane and filtered through celite. The filtrate was washed with water, dried (MgSO4), filtered and evaporated to dryness to give 2-(3-furyl)-4-methylquinoline-6- ylamine as a brown solid (127mg). 1H NMR (DMSO-d6)δ 8.35 (s, 1H) 7.75 (s, 1H) 7.7 (d, 1H) 7.55 (s, 1H) 7.1
(dd, 1 H) 7.05 (d, 1 H) 6.9 (d, 1 H) 5.6 (br s, 2H) 2.5 (s, 3H)
Example 1 N-[4-Methyl-2-(4-pyridyl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide A mixture of N-(2-chloro-4-methylquinolin-6-yl) 2-(4-trifluoromethyl- phenoxy)-acetamide (intermediate 4, 60mg), 4-pyridylboronic acid (28mg), [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (13mg) and aqueous cesium carbonate solution (2M, 228ml) in 1 ,4-dioxane was degassed and purged with argon. The resultant mixture was stirred and heated at 100°C in the microwave for 12 minutes. Further 4-pyridylboronic acid (28mg), [1,1-bis(diphenylphosphino) ferrocenejdichloropalladium (II), complex with dichloromethane (1 : 1 ) (13mg) and aqueous cesium carbonate solution (2M, 228μl) were added and the mixture was stirred and heated in the microwave at 100°C for 12 minutes. The resultant mixture was partitioned between dichloromethane and water and the organic phase was washed with aqueous sodium chloride solution, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with dichloromethane then increasing amounts of methanol to a ratio of dichloromethane to methanol of 19:1 to give N-[4- methyl-2-(4-pyridyl)quinolin-6-yl] 2-(4-trifluoromethylphenoxy)acetamide as an off-white solid (11mg). LCMS (method A) retention time 7.53 min, (M+H+) 438 1H NMR (DMSO-d6) δ 10.6 (br s, 1 H) 8.75 (d, 2H) 8.55 (d, 1 H) 8.2 (d, 2H) 8.15 (s, 1 H) 8.1 (d, 1 H) 8.0 (dd, 1 H) 7.7 (d, 2H) 7.25 (d, 2H) 5.95 (s, 2H) 2.75 (s, 3H) By proceeding in a similar manner the following compounds were prepared from the appropriate starting materials:
Example 2 N-[4-Methyl-2-(3-nitrophenyl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide LCMS (method A) retention time 11.69 min, (M+H+) 482 1HNMR(DMSO-d6)δ10.6(brs, 1H)9.1 (d, 1H)8.7(d, 1H)8.5(d, 1H)8.3 (dd, 1 H) 8.2 (s, 1 H) 8.1 (d, 1 H) 8.0 (dd, 1 H) 7.85 (t, 1 H) 7.7 (d, 2H) 7.25 (d, 2H) 4.95 (s, 2H) 2.75 (s, 3H) From intermediate 4 and 3-nitrophenylboronic acid
Example 3 N-[2-(4-Dimethylaminophenyl)-4-methylquinolin-6-yl]2-(4-trifluoromethyl- phenoxy)acetamide LCMS (method A) retention time 7.84 min, (M+H+) 480 1H NMR (DMSO-d6) δ 10.45 (brslH) 8.4 (s,1H) 8.1 (d, 2H)7.95 (d, 1H)
7.9 (s, 1 H) 7.85 (d, 1 H) 7.7 (d, 2H) 6.8 (d, 2H) 5.9 (s, 2H) 3.0 (s, 6H) 2.65 (s, 3H) From intermediate 4 and 4-dimethylaminophenylboronic acid
Example 4 N-[4-Methyl-2-(2-thienyl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide LCMS (method A) retention time 11.38 min, (M+H+) 443 1H NMR (DMSO-d6) δ 10.5 (br s, 1 H) 8.45 (s, 1 H) 8.0 (s, 1 H) 7.9 (m, 3H) 7.7 (d, 2H) 7.65 (m, 1H) 7.25 (m, 3H)4.9 (s, 2H) 2.7 (s, 3H) From intermediate 4 and thiophene-2-boronic acid
Example 5 N-{4-Methyl-2-[4-(N-methylcarboxamido)phenyl]quinolin-6-yl} 2-(4- trifluoromethylphenoxy)acetamide LCMS (method A) retention time 8.33 min, (M+H+) 494 1H NMR (DMSO-d6)δ 10.6 (brs, 1H)8.55(q, 1H)8.5(s, 1H)8.3(d, 2H)
8.1 (s, 1H) 8.05 (d, 1H) 8.0 (d, 2H) 7.95 (d, 1H) 7.7 (d 2H) 7.25 (d, 2H) 5.9 (s, 2H) 2.85 (d, 3H) 2.7 (s, 3H) From intermediate 4 and 4-(N-methylcarboxamido)phenylboronic acid
Example 6 N-[4-Methyl-2-(3,4-methylenedioxyphenyl)quinolin-6-yl] 2-(4- trifluoromethyl-phenoxy)acetamide A mixture of N-(2-chloro-4-methylquinolin-6-yl) 2-(4- trifluoromethylphenoxy)-acetamide (intermediate 4, 20mg), 3,4- methylenedioxyphenylboronic acid (16.8mg), palladium acetate (1.16mg), 2- biphenyl-dicyclohexylphosphine (4.53mg), aqueous cesium carbonate solution (2M, 100μl) in dimethoxyethane (700μl), ethanol (60μl) and water (120μl) was degassed and purged with nitrogen. The resultant mixture was heated in the microwave at 150°C for 20 minutes. The mixture was filtered and the filtrate was diluted with dichloromethane, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of dichloromethane and ether (99:1) increasing to a ratio of 99:3 to give N-[4-methyl-2-(3,4- methylenedioxyphenyl)quinolin-6-yl]2-(4-trifluoromethylphenoxy)acetamideas a brown solid (27mg). LCMS (method A) retention time 9.01 min, (M+H+) 481 1H NMR (DMSO-d6) δ 10.5 (br s, 1 H) 8.45 (s, 1 H) 8.0 (m, 2H) 7.9 (d, 1 H) 7.8 (s, 1 H) 7.8 (d, 1 H) 7.7 (d, 2H) 7.25 (d, 2H) 7.05 (d, 1 H) 6.1 (s, 2H) 5.9 (s, 2H) 2.65 (s, 3H) By proceeding in a similar manner the following compounds were prepared from the appropriate starting materials:
Example 7 N-[4-Methyl-2-(4-methylsulphonylphenyl)quinolin-6-yl]2-(4-trifluoromethyl- phenoxy)acetamide LCMS (method A) retention time 9.99 min, (M+H+) 515 1H NMR (DMSO-d6) δ 10.6 (br s, 1H) 8.5 (m, 3H) 8.15 (s, 1H) 8.1 (m, 3H) 8.0 (dd, 1H) 7.7 (d, 2H) 7.25 (d, 2H) 4.95 (s, 2H) 3.3 (s, 3H) 2.75 (s, 3H) From intermediate 4 and 4-methylsulphonylphenylboronic acid
Example 8 N-[2-(3-Furyl)-4-methylquinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide LCMS (method A) retention time 8.54 min, (M+H+) 427 1H NMR (DMSO-d6) δ 10.6 (br s, 1 H) 8.5 (s, 1 H) 8.4 (s, 1 H) 7.95 (m, 2H) 7.85 (m, 1H) 7.75 (s, 1H) 7.7 (d, 2H) 7.25 (d, 2H) 7.15 (s, 1H) 4.95 (s, 2H) 2.65 (s, 3H) From intermediate 4 and furan-3-boronic acid
Example 9 N-[4-Methyl-2-(2-pyrrolyl)quinolin-6-yl] 2 - ( 4 - tπ'fluoromethylphenoxy)acetamide LCMS (method A) retention time 7.46 min, (M+H+) 426 1H NMR (DMSO-d6) δ 11.9 (brs 1H) 10.6 (br s, 1H) 8.45 (s, 1H) 8.05 (m,
2H) 7.9 (br s, 1 H) 7.7 (d, 2H) 7.25 (d, 2H) 7.2 (m, 2H) 6.3 (br s, 1 H) 4.9 (s, 2H)
2.7 (s, 3H) From intermediate 4 and 1-(fet-butoxycarbonyl)pyrrole-2-boronic acid
Example 10 N-[4-Methyl-2-(2-pyridyl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide A mixture of N-(2-chloro-4-methylquinolin-6-yl) 2-(4- trifluoromethylphenoxy)-acetamide (intermediate 4, 100mg), dichlorob/s- (triphenylphosphine) palladium (II) (11.3mg) and triphenyl phosphine (7.29mg) in xylene was degassed and purged with nitrogen then treated with 2-(tri-n- butylstannyl)pyridine (128mg). The mixture was stirred and heated at 130°C overnight. Further dichloro/5/'s-(triphenylphosphine) palladium (II) (13.5mg), triphenylphosphine ((8.7mg) and 2-(tri-n-butylstannyl)pyridine (128mg) was added and the mixture was stirred and heated at 130°C for 7h. The mixture was cooled to room temperature and a saturated aqueous solution of ammonium chloride was added. The resultant mixture was extracted with dichloromethane and the organic phase was washed with water, dried (Na2SO4), filtered and evaporated to dryness. The residue was purified by preparative thin layer chromatography using Fluka aluminium backed thin layer chromatography plates and eluting with a mixture of cyclohexane and dichloromethane (3:1). Extraction of the silica with a mixture of dichloromethane and methanol (10:1) gave N-[4- methyl-2-(2-pyridyl)quinolin-6-yl] 2-(4-trifluoromethylphenoxy)acetamide as a brown solid (10mg). LCMS (method A) retention time 8.69 min, (M+H+) 438 1H NMR (DMSO-d6) δ 10.6 (br s 1H) 8.75 (d, 1H)8.6 (d, 1H) 8.55 s, 1H) 8.45 (s, 1 H) 8.1 (d, 1 H) 8.0 (m„ 2H) 7.7 (d, 2H) 7.5 (m, 1 H) 7.25 (d, 2H)4.95 (s, 2H) 2.7 (s, 3H) Example 11 N-[4-Methyl-2-(3-pyridyl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide A mixture of N-(2-chloro-4-methylquinolin-6-yl) 2-(4- thfluoromethylphenoxy)acetamide (intermediate 4, 60mg), 3-pyridylboronicacid 1 , 3 - p r o p a n e d i o I cycl ic ester (25mg), [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1 :1 ) (12mg) and cesium carbonate (198mg) in 1 ,4-dioxane was degassed and purged with argon. The resultant mixture was stirred and heated at reflux for 6h. It was allowed to cool to room temperature and evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water, dried (MgSO4), filtered and evaporated to dryness. The residue was purified by chromatography on silica eluting with a mixture of dichloromethane and methanol (49: 1 increasing to 19: 1 ) to give N-[4-methyl-2-(3-pyridyl)quinolin-6-yl] 2-(4-trifluoromethylphenoxy)acetamide as a brown solid (34mg). LCMS (method A) retention time 8.14 min, (M+H+) 438. 1H NMR (DMSO-d6) δ 10.55 (br s 1 H) 9.45 (s, 1 H) 8.7 (dd, 1 H) 8.6 (dd, 1H) 8.5 (d, 1H) 8.1 (s, 1H) 8.05 (d, 1H) 7.95 (dd, 1H) 7.7 (d, 2H) 7.55 (m, 1H) 7.25 (d, 2H) 4.95 (s, 2H) 2.75 (s, 3H)
Example 12 N-[4-Methyl-2-(imidazol-4(5)-yl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide A solution of tnfluoroacetic acid in water (19:1, 1.7ml) was added to a solution of N-[4-methyl-2-(1-tritylimidazol-4-yl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide (intermediate 5, 51.3mg) in dichloromethane
(1.7ml) at 0°C. The mixture was stirred for 1 h then evaporated to dryness. The residue was purified by reverse phase HPLC using acetonitrile and water (1:9 increasing to 4:1) to give N-[4-methyl-2-(imidazol-4(5)-yl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide as a pale brown solid (10mg). LCMS (method A) retention time 6.36 min, (M+H+) 427 1H NMR (DMSO-d6) δ 12.9-12.3 (br s 1 H) 10.55-10.4 (br s, 1 H) 8.4 (s, 1 H) 8.05-7.75 (m, 5H) 7.7 (d, 2H) 7.2 (d, 2H) 4.9 (s, 2H)2.65 (s, 3H)
Example 13 N-[4-Methyl-2-(1-oxypyrid-3-yl)quinoline-6-yl] 2-(4- trifluoromethylphenoxy)acetamide 3-Chloroperoxybenzoic acid (~60%, 92mg) was added to a solution of N- [4-methyl-2-(3-pyridyl)quinolin-6-yl] 2-(4-trifluoromethylphenoxy)acetamide (example 11 , 70mg) in dichloromethane. The resultant mixture was stirred at room temperature for 4h. The suspension was washed with water, saturated aqueous sodium bicarbonate solution, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and dichloromethane (1:49 increasing to 1:19) to give N-[4-methyl-2-(1-oxypyrid-3- yl)quinoline-6-yl] 2-(4-trifluoromethylphenoxy)acetamide as an off-white solid (35mg). LCMS (method A) retention time 8.38 min, (M+H+) 454 1H NMR (DMSO-d6) δ 10.6 (s, 1H) 9.05 (s, 1H) 8.55 (d, 1H) 8.3 (dd,1H) 8.15 (dd, 1H) 8.1 (s, 1H)8.05(d, 1H)7.95(dd, 1H) 7.7 (d, 2H) 7.6 (dd, 1H)7.2 (d, 2H) 4.95 (s,2H) 2.7 (s,3H)
Example 14 N-[4-Methyl-2-(3-furyl)quinolin-6-yl] 2-(4-methoxyphenoxy)acetamide O-(7-Aza enzotriazol-1 -yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate (340mg) and Λ/,Λ/-diisopropylethylamine (0.4ml) were added to a solution of 2-(3-furyl)-4-methylquinolin-6-ylamine (intermediate 6, 75mg) and 4-methoxyphenoxyacetic acid (81.2mg) in dimethylformamide. The mixture was stirred at room temperature overnight. The solvent was removed by evaporation and the residue was partitioned between water and dichloromethane. The organic phase was washed with water, dried (MgSO4), filtered and the filtrate was evaporated to dryness. The residue was triturated with diethyl ether and the solid was collected by filtration and dried in vacuo to give N-[4-methyl-2-(3-furyl)quinolin-6-yl] 2-(4-methoxyphenoxy)acetamide as a light brown solid (17mg) LCMS (method A) retention time 7.01 min, (M+H+) 389 1H NMR (DMSO-d6) δ 10.7 (br s, 1 H) 8.5 (s, 1 H) 8.45 (s, 1 H) 7.95 (dd, 2H) 7.8 (s, 1 H) 7.75 (s, 1 H) 7.15 (s, 1 H) 7.0 (d, 2H) 6.9 (d, 2H) 4.7 (s, 2H) 3.7 (s, 3H)
2.65 (s, 3H) By proceeding in a similar manner the following compound was prepared from the appropriate starting materials:
Example 15 N-[4-Methyl-2-(3-furyl)quinolin-6-yl] 2-(4-chlorophenoxy)acetamide LCMS (method A) retention time 7.95 min, (M+H+) 393, 395 1H NMR (DMSO-d6) δ 10.5 (br s, 1 H) 8.65 (br s, 1 H) 8.5 (s, 1 H) 8.1 (s, 2H) 7.95 (br s, 1 H) 7.9 (s, 1 H) 7.4 (d, 2H) 7.25 (br s, 1 H) 7.05 (d, 2H)4.8 (s, 2H)2.7 (s, 3H) From intermediate 6 and 4-chlorophenoxyacetic acid
The following assays may be used. MCH-1 R SPA Chinese hamster ovary (CHO) cell membranes (5μg) overexpressing the
MCH-1 R (Euroscreen s.a.) were incubated with 25μg of wheat germ agglutinin SPA beads (Amersham Biosciences UK Ltd) and 0.4nM 125l-[Phe13, Tyr19]-MCH (Amersham Biosciences UK Ltd) in a final volume of 100μl of binding buffer (25mM HEPES, 10mM NaCI, 5mM MgCI2, 1 mM CaCI2, 0.1 % BSA) containing 5mM phosphoramidonfor 1 hour at room temperature. Non-specific binding was determined in the presence of 1 μM (Phe13, Tyr 9)-MCH (Bachem (UK) Ltd). Bound 125l-[Phe13, Tyr19]-MCH was detected using a MicroBeta TRILUX liquid scintillation counter (Perkin Elmer). Compound IC50 was determined using a 6- point dose response curve in duplicate with a semi-log compound dilution series. IC50 calculations were performed using Excel and XL fit (Microsoft). Ca2+ Mobilization Assay Stable CHO-K1 cells expressing the MCH-1 R were seeded (35,000 cells per well with a plating volume of 50μl) into collagen-coated 96-well plates 24 hours prior to the assay. The cells were then loaded with a fluorescence- imaging plate reader (FLIPR) calcium kit dye (Calcium 3 kit, Molecular Devices Ltd) containing 5mM final concentration of probenecid and incubated at 37°C for 1 hour in a 5% CO2 atmosphere. The fluorescence emission caused by intracellular calcium mobilization elicited by the agonist, (Phe13, Tyr19)-MCH, of the expressed receptor was determined with a FLEXstation benchtop scanning and integrated fluid transfer workstation (Molecular Devices Ltd). To detect antagonists and determine compound IC50, compounds were pre-incubated at varying concentrations with the loaded cells for 15 minutes at 37°C, 5% CO2, prior to the addition of the agonist at its EC80. The fractional response values for each well were calculated as peak minus basal response. Results were calculated as the mean of triplicate wells using Excel and XL fit (Microsoft). Compounds of formula (1 ) exhibit useful activity in the assays described above.

Claims

1. A compound of structural formula (1 ):
Figure imgf000057_0001
(1) wherein R1 represents optionally substituted aryl, heteroaryl, aryl-fused- cycloalkyl, heteroaryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl or heteroaryl- fused-heterocycloalkyl; R2 represents H, halogen, alkyl, haloalkyl or cyano; R3 represents H, alkyl, R6 or alkyl-R6; R6 represents halogen, CN, CF3, CONR7R8, SO2NR7R8, OR9, NR7R8, NR7COR10, NR7SO2R10 or NR7CONR7R8; R7 and R8, which may be the same or different, each independently represent H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R9 represents H, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R10 represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R4 represents H, halogen, cyano, alkyl, haloalkyl, OR9 or NR7R8; R5 represents optionally substituted aryl, heteroaryl, aryl-fused-cycloalkyl, heteroaryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl or heteroaryl-fused- heterocycloalkyl; L represents -(CH2)nCON(R11)(CH2)m-, -(CH2)nSO2N(R11)(CH2)m-, -(CH2)nCON(R11)(CH2)rO-, -( C H2)nSO2N ( R 11 )( C H2)rO-, -(CH2)nCON(R11 )(CH2)rS-, -( C H2)nSO2N ( R 11 )(C H2)rS- -(CH2)nCON(R11)(CH2)rN(R11)-, -(CH2)nSO2N(R11 )(CH2)rN(R11 )- -(CH2)nN(R11 )CO(CH2)m-, -( C H2)n N ( R 11 ) S O2( C H2 )m- -(CH2)nN(R11)CO(CH2)mO(CH2)p-, -(CH2)nN(R11)SO2(CH2)mO(CH2)p- -(CH2)nN(R11)CO(CH2)mS(CH2)p-, -(CH2)nN(R11)SO2(CH2)mS(CH2)p- -(CH2)nN(R11 )CO(CH2)mN(R11 )(CH2)p- -(CH2)nN(R11 )SO2(CH2)mN(R11 )(CH2)p- -(CH2)nO(CH2)m-, -(CH2)nS(CH2)m-, -(CH2)nN(R11)(CH2)m-, -(CH2)nCO(CH2)m- -(CH2)nSO2(CH2)m-, -(CH2)q-, -(CH2)nCO(CH2)mO(CH2)p- -(CH2)nSO2(CH2)mO(CH2)p-, -(CH2)nCO(CH2)mS(CH2)p- -(CH2)nSO2(CH2)mS(CH2)p-, -(CH2)nCO(CH2)mN(R11 )(CH2)p- -(CH2)nSO2(CH2)mN(R11 )(CH2)p-, -(CH2)n-cycloalkyl-(CH2)m-, -(CH2)n- heterocycloalkyl-(CH2)m, -(CH2)n-aryl-(CH2)m- or -(CH2)n-heteroaryl-(CH2)m-, and in each case, the linker may be attached either way round, i.e. the left hand end as drawn may be attached to the quinoline and the right hand end to R5, or vice versa; R11 represents H or alkyl; n, m and p each independently represent 0, 1 or 2; q represents 0, 1 , 2, 3, 4 or 5; r represents 2 or 3; and corresponding N-oxides, pharmaceutically acceptable salts, solvates and prodrugs thereof.
2. A compound according to claim 1 , wherein R1 is an optionally substituted heteroaryl group attached to the quinoline ring via a carbon or nitrogen atom.
3. A compound according to claim 2, wherein the heteroaryl group is pyridyl, furanyl, imidazolyl or pyrazolyl.
4. A compound according to any preceding claim, wherein R2 is H.
5. A compound according to any preceding claim, wherein R3 is alkyl or heteroalkyl.
6. A compound according to any preceding claim, wherein R4 is H.
7. A compound according to any preceding claim, wherein L-R5 is attached to the 6-position of the quinoline ring.
8. A compound according to any preceding claim, wherein R5 is para- substituted phenyl.
9. A compound according to any preceding claim, wherein L is *-(CH2)nN(R11)CO(CH2)mO(CH2)p- or *-(CH2)nN(R11)CO(CH2)m- and * is attached to the quinoline ring.
10. A compound according to claim 1 , selected from: N-[4-methyl-2-(4-pyridyl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide N-[4-methyl-2-(3-nitrophenyl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide N-[2-(4-dimethylaminophenyl)-4-methylquinolin-6-yl 2-(4-thfluoromethyl- phenoxy)acetamide N-[4-methyl-2-(2-thienyl)quinolin-6-yl] 2-(4- trifluoromethylphenoxy)acetamide N-{4-methyl-2-[4-(N-methylcarboxamido)phenyl]quinolin-6-yl} 2-(4- thfluoromethylphenoxy)acetamide N-[4-methyl-2-(3,4-methylenedioxyphenyl)quinolin-6-yl] 2-(4- trifluoromethyl-phenoxy)acetamide N-[4-methyl-2-(4-methylsulphonylphenyl)quinolin-6-yl] 2-(4- trifluoromethyl-phenoxy)acetamide N-[2-(3-furyl)-4-methylquinolin-6-yl] 2-(4-trifluoromethyl- phenoxy)acetamide N-[4-methyl-2-(2-pyrrolyl)quinolin-6-yl] 2-(4-trifluoromethyl- phenoxy)acetamide N-[4-methyl-2-(2-pyridyl)quinolin-6-yl] 2-(4-trifluoromethyl- phenoxy)acetamide N-[4-methyl-2-(3-pyridyl)quinolin-6-yl] 2-(4-trifluoromethyl- phenoxy)acetamide N-[4-methyl-2-(imidazol-4(5)-yl)quinolin-6-yl] 2-(4-trifluoromethyl- phenoxy)acetamide N-[4-methyl-2-(1-oxypyrid-3-yl)quinoline-6-yl] 2-(4-trifluoromethyl- phenoxy)acetamide N-[4-methyl-2-(3-furyl)quinolin-6-yl]2-(4-methoxyphenoxy)acetamideand N-[4-methyl-2-(3-furyl)quinolin-6-yl] 2-(4-chlorophenoxy)acetamide.
11. A compound according to any preceding claim, for use in therapy.
12. A pharmaceutical composition comprising a compound according to any preceding claim and an acceptable carrier or diluent.
13. The use of a compound according to any of claims 1 to 9, for the manufacture of a medicament for use in the treatment, prevention or suppression of a disease mediated by the MCH receptor.
14. Use according to claim 13, wherein the disease is selected from: obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, gall stones, osteoarthritis, certain cancers, AIDS wasting, cachexia, frailty (particularly in the elderly), binge eating disorders including bulimina, anorexia, mental disorders including manic depression, depression, schizophrenia, mood disorders, delirium, dementia, severe mental retardation, anxiety, stress, cognitive disorders, sexual function, reproductive function, kidney function, diuresis, locomotor disorders, attention deficit disorder (ADD), substance abuse disorders and dyskinesias including Parkinson's disease, Parkinson-like syndromes, Tourette's syndrome, Huntingdon's disease, epilepsy, improving memory function, and spinal muscular atrophy.
15. Use according to claim 14, wherein the disease is obesity.
16. Use according to claim 15, wherein the compound is for use in combination with an anorectic agent or a selective serotonin reuptake inhibitor.
17. Use according to claim 15 or claim 16, wherein the compound is to be administered in an amount of 0.01 to 100 mg per kg of a patient.
18. Use according to claim 13, wherein the disease is a condition selected from schizophrenia, anxiety, bipolar disorder and depression.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7514457B2 (en) 2005-05-31 2009-04-07 Pfizer Inc. Substituted aryloxymethyl bicyclicmethyl acetamide compounds
WO2012007500A2 (en) 2010-07-15 2012-01-19 Bayer Cropscience Ag New heterocyclic compounds as pesticides
US9353123B2 (en) 2013-02-20 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9353122B2 (en) 2013-02-15 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
US20170247340A1 (en) * 2014-10-14 2017-08-31 La Jolla Institute Of Allergy & Immunology Inhibitors of Low Molecular Weight Protein Tyrosine Phosphatase and Uses Thereof
US9790232B2 (en) 2013-11-01 2017-10-17 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US9890173B2 (en) 2013-11-01 2018-02-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10253036B2 (en) 2016-09-08 2019-04-09 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10336767B2 (en) 2016-09-08 2019-07-02 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10766907B2 (en) 2016-09-08 2020-09-08 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11066420B2 (en) 2017-05-01 2021-07-20 Sanford Burnham Prebys Medical Discovery Institute Inhibitors of low molecular weight protein tyrosine phosphatase (LMPTP) and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6376670B1 (en) * 1997-06-19 2002-04-23 Sepracor Inc. Quinoline-indole antimicrobial agents, uses and compositions related thereto
WO2003045313A2 (en) * 2001-11-27 2003-06-05 Merck & Co. Inc. 2-aminoquinoline compounds
WO2003045920A1 (en) * 2001-11-27 2003-06-05 Merck & Co., Inc. 4-aminoquinoline compounds
WO2003066604A2 (en) * 2002-02-05 2003-08-14 Novo Nordisk A/S Novel aryl- and heteroarylpiperazines
WO2004052370A2 (en) * 2002-12-11 2004-06-24 7Tm Pharma A/S Quinoline compounds for use in mch receptor related disorders

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6376670B1 (en) * 1997-06-19 2002-04-23 Sepracor Inc. Quinoline-indole antimicrobial agents, uses and compositions related thereto
WO2003045313A2 (en) * 2001-11-27 2003-06-05 Merck & Co. Inc. 2-aminoquinoline compounds
WO2003045920A1 (en) * 2001-11-27 2003-06-05 Merck & Co., Inc. 4-aminoquinoline compounds
WO2003066604A2 (en) * 2002-02-05 2003-08-14 Novo Nordisk A/S Novel aryl- and heteroarylpiperazines
WO2004052370A2 (en) * 2002-12-11 2004-06-24 7Tm Pharma A/S Quinoline compounds for use in mch receptor related disorders

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KENDE A S ET AL: "A NEW AND EFFICIENT TOTAL SYNTHESIS OF STREPTONIGRIN", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, vol. 103, no. 5, 1981, pages 1271 - 1273, XP002054102, ISSN: 0002-7863 *
KENDE A S ET AL: "An unusual rearrangement during pyridine synthesis. Anomalous condensation of a .beta.-keto enamine with a tetronic acid", TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 25, no. 23, 1984, pages 2423 - 2426, XP002286194, ISSN: 0040-4039 *

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