WO2005035521A1 - Quinoleines substituees, utilisees comme modulateurs de la mch - Google Patents

Quinoleines substituees, utilisees comme modulateurs de la mch 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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English (en)
Inventor
Hazel Joan Dyke
Susan Mary Cramp
Stephen Paul Wren
Christopher Gregory Newton
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Argenta Discovery Ltd.
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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/fr

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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

L'invention concerne des quinoléines de formule (I), utilisées comme médiateurs de la MCH et pour le traitement de l'obésité.
PCT/GB2004/004304 2003-10-09 2004-10-11 Quinoleines substituees, utilisees comme modulateurs de la mch WO2005035521A1 (fr)

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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
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US7514457B2 (en) 2005-05-31 2009-04-07 Pfizer Inc. Substituted aryloxymethyl bicyclicmethyl acetamide compounds
WO2012007500A2 (fr) 2010-07-15 2012-01-19 Bayer Cropscience Ag Nouveaux composés hétérocycliques servant d'agents de lutte contre les nuisibles
US9233951B2 (en) 2010-07-15 2016-01-12 Bayer Intellectual Property Gmbh Heterocyclic compounds as pesticides
US9827248B2 (en) 2013-02-15 2017-11-28 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9353122B2 (en) 2013-02-15 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
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US9861634B2 (en) 2013-02-20 2018-01-09 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10285991B2 (en) 2013-02-20 2019-05-14 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
US10758539B2 (en) 2013-02-20 2020-09-01 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9353123B2 (en) 2013-02-20 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10975090B2 (en) 2013-11-01 2021-04-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10160765B2 (en) 2013-11-01 2018-12-25 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US11713323B2 (en) 2013-11-01 2023-08-01 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
US10618906B2 (en) 2013-11-01 2020-04-14 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds 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
US11220486B2 (en) 2014-10-14 2022-01-11 La Jolla Institute Of Allergy & Immunology Inhibitors of low molecular weight protein tyrosine phosphatase and uses thereof
US10626094B2 (en) * 2014-10-14 2020-04-21 Sanford Burnham Prebys Medical Discovery Institute Inhibitors of low molecular weight protein tyrosine phosphatase 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
US10766907B2 (en) 2016-09-08 2020-09-08 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
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