WO2008009125A1 - Tetrahydro-5h-pyrido[2,3-d]azepines as 5-ht2c ligands - Google Patents

Tetrahydro-5h-pyrido[2,3-d]azepines as 5-ht2c ligands Download PDF

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Publication number
WO2008009125A1
WO2008009125A1 PCT/CA2007/001286 CA2007001286W WO2008009125A1 WO 2008009125 A1 WO2008009125 A1 WO 2008009125A1 CA 2007001286 W CA2007001286 W CA 2007001286W WO 2008009125 A1 WO2008009125 A1 WO 2008009125A1
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Prior art keywords
tetrahydro
pyrido
alkyl
azepine
compound
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PCT/CA2007/001286
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French (fr)
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WO2008009125A9 (en
Inventor
Guangri Sun
Abdelmalik Slassi
Methvin Isaac
Tan Quach
Tao Xin
Zhi He
Guy Higgins
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Cascade Therapeutics Inc.
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Priority to US12/309,446 priority Critical patent/US20090312306A1/en
Priority to JP2009519768A priority patent/JP2009543812A/en
Priority to AU2007276631A priority patent/AU2007276631A1/en
Priority to CA 2692440 priority patent/CA2692440A1/en
Priority to EP07784957A priority patent/EP2094695A4/en
Publication of WO2008009125A1 publication Critical patent/WO2008009125A1/en
Publication of WO2008009125A9 publication Critical patent/WO2008009125A9/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This invention relates to compounds which act at the 5-HT 2c receptor and to the use of such compounds in the treatment of diseases.
  • 5-Hydroxytryptami ⁇ e 5-HT or serotonin
  • PNS and CNS peripheral and central nervous system
  • the diverse effects of this neurotransmitter are related to the extensive projections of serotonergic neurons throughout the brain and the large number of distinct serotonin receptor subtypes. At least 14 distinct serotonin receptor subtypes are expressed in the mammalian CNS The contribution of these receptors to the action of serotonin has been difficult to ascertain owing to the paucity of selective pharmacological agents.
  • the 5-HT 2 subfamily of serotonin receptors is composed of three subtypes; namely the 5-HT2 a .
  • 5-HT2& and 5-HT 2c receptors All the members of this subfamily couple to the activation of the inositol phosphate and diacyl glycerol pathway via the G-protei ⁇ .Gqm
  • MAP-kinase mitogen activated protein kinase
  • the limited access to selective pharmacological tools amongst the 5-HT 2 subfamily of serotonin receptors has led to the use of gene targeting techniques to generate mouse lines that selectively lack functional receptor genes. This strategy has been applied to the study of 5-HT 2 t receptor function.
  • the S-HT ⁇ c receptor is expressed in many brain regions including the limbic system, extrapyramidal motor pathways, hypothalamus, thalamus and monoaminergic cell groups.
  • 5-HT 2c receptors have been implicated in the regulation of food intake and anxiety
  • the n ⁇ n-selective 5-HT 2C receptor agonist, m- chlorophenylpiperazine 1 (mCPP) produces hypophagic and anxiogenic effects that were attenuated by 5-HT 2c receptor antagonists
  • mCPP m- chlorophenylpiperazine 1
  • the propensity of a 5-HT 20 receptor agonist to regulate food intake suggests a crrtical role for this receptor subtype in controlling obesity ⁇ Vickers, S.; Clifton, P.; Dourish, C; Tecott, L. Psychopharma ⁇ logy (Berlin) 1999, 143, 309; Nilsso ⁇ , B. J. Med Chem. 2006, 49, 4023 ).
  • BMI body mass index
  • BMl body weight
  • m 2 height squared
  • Overweight is defined as a BMI in the range 25-30 kg/m 2
  • obesity is a BMI greater than 30 kg/m 2 .
  • body fat content is also be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively.
  • Schizophrenia affects approximately 5 million people.
  • the most prevalent treatments for schizophrenia are currently the 'atypical' antipsychotics, which combine dopamine (Dj) and serotonin (5-HT 2 A) receptor antagonism.
  • Dj dopamine
  • 5-HT 2 A serotonin
  • these compounds do not appear to adequately treat all the symptoms of schizophrenia and are accompanied by problematic stde effects, such as weight gain (Allison, D. B , et. al , Am J Psychiatry, 156: 1686-1696, 1999; Masand, P S., Exp. Opin. Pharmacother. 1.377-389, 2000; Whitaker, R M Spectrum Life Sciences Decision Resources. 2.1-9, 2000).
  • Atypical antipsychotics also bind with high affinity to S-HT 2C receptors and function as 5-HT2c receptor antagonists or inverse agonists.
  • Weight gam is a problematic side effect associated with atypical antipsychotics such as clozapine and olanzapine, and it has been suggested that 5-HT 20 antagonism is responsible for the increased weight gain.
  • stimulation of the 5- H ⁇ 2C receptor is known to result in decreased food intake and body weight (Walsh et. al., Psychopharmacology 124: 57-73, 1996; Cowen, P J , et al., Human Psychopharmacology I ⁇ : 385-391, 1995; Rosenzweig-Lipson, S . et al . ASPET abstract, 2000 ⁇
  • 5-HT 2C receptor agonism or partial agonism as a treatment for schizophrenia.
  • 5-HT 2 c antagonists increase synaptic levels of dopamine and may be effective in animal models of Parkinson's disease (Di Matteo, V., et al., Neuropharmacology 37: 265-272, 1998; Fox, S. H., et. al., Expenm ⁇ ntal Neurology 151 35-49, 1998).
  • 5-HT 2C agonists do not decrease dopamine levels in the striatum, the brain region most closely associated with extrapyramidal side effects.
  • a recent study demonstrates that 5-HT 2C agonists decrease f ⁇ g in the ventral tegmental area (VTA), but not in the substantia nigra.
  • VTA ventral tegmental area
  • 5-HT2C agonists have limbic selectivity, and will be less likely to produce extrapyramidal side effects associated with typical antipsychotics.
  • 5-HT2C receptors might also be involved in modulation of the rewarding properties of food, which is linked to increased mesolimbic dopamine levels in the nucleus accumbens of the brain in response to food ingestion.
  • a number of studies have suggested that food and drug rewards may share some common neural substrates, specifically the nucleus accumbens (Saper, C. B.; Chou, T. C; Efmquist, J. K. The need to feed: homeostatic and hedonic control of eating. Neuron 2002, 36, 199-211).
  • 5-HTac receptor agonists may decrease dopamine levels in the nucleus accumbens and that reward-related behaviors (e.g., cocaine or nicotine self- admtnistration in rats) may be reduced by 5-HT 2 C receptor activation
  • reward-related behaviors e.g., cocaine or nicotine self- admtnistration in rats
  • 5-HT 2 C receptor activation the possibility that 5-HT 2 c receptor agonists may reduce the rewarding properties of food should also be considered (Higgins, G. A.; Fletcher, P. J. Serotonin and drug reward" focus on 5-HT 2 Q receptors. Eur. J. Pharmacol. 2003, 480, 151-162).
  • Epilepsy a brain disorder manifested by recurrent seizures, refers to a complicated constellation of more than 40 distinct disorders.
  • the seizure a sudden massive neuronal discharge, can be either partial or complete, depending on the area of brain involved or whether or not consciousness is impaired. Normally there is a balance between excitation and inhibition in the brain. When this balance is disrupted by increased excitation or decreased inhibition, a seizure may result.
  • the neuronal discharges may stimulate muscles innervated by the nerves involved, resulting in involuntary muscle contractions, or convulsions (Lee, G. V ; Jones, E. J. Epilepsy.
  • a sodium ion channel is a structure in the cell membrane that is selectively permeable to sodium ions and is opened by changes in voltage across the cell membrane
  • Other drugs affect calcium ion channels.
  • the third category of drugs affects some aspect of inhibitory synapses that are activated by the neurotransmitter ⁇ -aminobutyric acid (GABA).
  • GABA neurotransmitter ⁇ -aminobutyric acid
  • mice bearing a targeted disruption of the 5-HT 2 c receptor genes exhibit an epilepsy syndrome associated with sporadic spontaneous seizures that occasionally result in death.
  • mice lacking the ⁇ -HT ⁇ c receptors were significantly more seizure susceptible than wild-type controls.
  • Results indicate that mutants have lower focal seizure thresholds, increased focal seizure excitability, and facilitated propagation within the forebrain seizure system. Mutants also exhibit lower generalized seizure threshold for the expression of both generalized clonic and generalized tonic seizures.
  • the 5-HT receptor antagonist mesulergine (2 or 4 mg/kg), administered prior to electroshock testing, recapitulated the mutant phenotype in wild-type mice.
  • these data strongly implicate a role for serotonin and the 5-HT 2C receptors in the modulation of neuronal network excitability and seizure propagation throughout the CNS (Appelgate, C. D , Tecott, L. H. Global increases in seizure susceptibility in mice lacking 5-HT2C receptors; a behavioral analysis. Exp. Neurol. 1998, 154, 522-530, Hetsler, L. K ; Chu. H. M.; Tecott, L. H. Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice. Ann. N.
  • mCPP 5-HT 2 C preferring agonist
  • the selective 5-HT zc receptor antagonist, SB 242084 do not induce pro-convulsant effects in rats, which are characteristic of mutant mice lacking the 5-HT 2C receptor.
  • AD Alzheimer's disease
  • APP amyloid precursor protein
  • APP amyloid precursor protein
  • SSRIs Selective serotonin reuptake inhibitors
  • 5HT serotonin
  • OCD obsessive compulsive disorder
  • SSRIs have become standard therapy for neuropsychiatry disorders such as obsessive compulsive disorder (OCD), depression, and panic anxiety.
  • OCD obsessive compulsive disorder
  • 5HT 2 c receptor-mediated functions There is accumulating evidence for the involvement of 5HT 2 c receptor-mediated functions in the therapeutic efficacy of SSRIs (PalvimSki, E. -P ; Roth, B. L.; Majasuo, H ; Laakso, A , Kuoppamaki, M.; Syvalahti, E.; Hietala, J.
  • R 1 to R 3 and R 5 to R 12 are independently selected from H, halo, hydroxy, cyano, nitro, alkyl, alkoxy, CH 2 OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cya ⁇ oalkyl, alkenyl, alkyny), cycloalkyl, cycloalkenyl, heterocydoalky), heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cydoalkyl, O- heterocycloalkyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, aJkylene-O- heterocycloalkyl, alkylene-O-alkyle ⁇ e-cycloalkyl, alkyle ⁇ e-O-alkyle ⁇ e- heterocycloalkyl.
  • S-alkyl ⁇ S ⁇ O)-alkyl, S(O) 2 -alkyl, S-cycloalkyl, S(O)-cycloalkyl, S(0) z -cycloalkyl, S-heterocycloalkyl, S ⁇ O)-heterocycloalkyl, S(O) 2 - heterocycloalkyl, O-aryl, O-heteroaryl, N(H)alky
  • R 4 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylene- O-alkyl, alkylene-O-cycloalkyl, alkylene-O-alkylene-cycloalkyl;
  • any cyclic group is substituted with one or more R 13 , R 13 being selected from F, Cl 1 Br, I, CN, nitro, hydroxy, oxo, d -6 -alkyl, Od-e-alkyl, Ci- 5 -alkylhalo or OC 1- ⁇ -alkylhal ⁇ .
  • R 4 is selected from H, alkyl, cycloalkyl, or cycloatkenyl.
  • R A is selected from H or alkyl.
  • R 9 to R 1z are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.
  • R 9 to R 12 are independently selected from H, afkyl or cycloalkyf.
  • the compound is a pharmaceutically-acceptabfe salt, optical isomer, or combination thereof.
  • the pharmaceutically-acceptable salt comprises an acid addition salt or a basic addition salt.
  • the acid addition salt is formed from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acid metal salt, monocarboxylic acids, dicarboxylic acids, or tricarboxylic acids.
  • the compound of Formula I comprises a compound of Formula IA:
  • R 2 and R 5 are independently selected from H 1 alky!, alkyle ⁇ e-O-alkyl, C(O)Oalkyl, C(O)N(H)alkyl, haloalkyl, halogen or CH 2 OH; and
  • R 3 and R 6 are each H; or R 2 and R 3 and/or R 5 and R 6 , together with the carbon atom to which they are attached form a cycloalkyl group;
  • R 2 and R 5 are independently selected from CH 2 F, CHF 2 , or CF 3 .
  • the compound of Formula I comprises a compound of Formula IB:
  • R 14 to R 16 are independently selected from from H, halo, hydroxy, cyano, nitr ⁇ , alkyl, alkoxy, CH 2 OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alky ⁇ yl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O-heterocycloalkyl, alkylene-O-alkyl, alkylene-0-cyc/oalky
  • S- heterocycloalkyl S(0)-heterocycloalkyl, S(0) 2 -heterocycloalkyl, O-aryl, O- heteroaryl, N(H)alkyl, N(alkyl)aJkyl.
  • R 1 is selected from H or halo; R 2 and R 3 are independently selected from H or alkyl; R 14 and R 15 are independently selected from H, halo, or alkyf; and R 1 ⁇ is selected from H or alkyl.
  • the halo is bromo, chloro, or fluoro.
  • Z is CR 14 R 15 , wherein R 14 is H or fluoro and R 15 is fluoro.
  • R 1 is H and Z is CR 14 R 15 , wherein R 14 is H and R 15 is fluoro.
  • the compound of Formula I comprises a compound of Formula IC:
  • R 14 to R 1 ⁇ are independently selected from from H 1 halo, hydroxy, cyano, ⁇ itro, alKyl, alkoxy, CH 2 OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloafkenyl, aryl, heter ⁇ aryl, alkylaryl, alkylheteroaryl, 0-cycloalkyl, O-heterocycloalkyI, alkylene-O-alkyl, alkyte ⁇ e-O-cycloalkyl, atkylene-O-heterocycioalkyl, alkylene- O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloafkyl, S-alkyl, S(O)- alkyl, S(
  • R 1 is selected from H or halo; R 2 and R 3 are independently selected from H or alky); R 14 and R 15 are independently selected from H, halo, or alkyl; and R 1 ⁇ is selected from H or alkyl.
  • the halo is bromo, chloro, or fluoro.
  • Z is O.
  • the compound of Formula ⁇ comprises a compound of Formula II:
  • R , R , R 7 and R B are as defined hereinabove.
  • the compound of Formula J comprises a compound of Formula III:
  • R 1 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined hereinabove.
  • the compound of Formula I comprises a compound of Formula IV:
  • R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are as defined herei ⁇ above.
  • R 1 is selected from H, alkyl or halo
  • R 2 , R 3 and R 8 are independently selected from H or alkyl
  • R* is selected from H or alkyl
  • R 7 is selected from H, alkyl, alkoxy, CHzOH, alke ⁇ yl, cydoalkyl, heterocydoalkyl, aryl, or heteroaryl.
  • N N-dimBthyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine; N,N-dimethyJ-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aze ⁇ i ⁇ e-2-carboxamide;
  • IM,N-dimethyl-6,7,8 1 9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine, N-ethyl-N , 9-d ⁇ methyl-6,7,8, 9-tetrahydro-5H-pyrid o[2 , 3-d]azepin-2-amine; and/or
  • a compound according to any one of the compounds noted above wherein the compound has an EC50 for a human 5-H ⁇ 2 C receptor selected from less than 1000 nM, less than 500 nM, less than 300 nM, or less than 100 nM.
  • composition comprising at least one of the compounds noted above and at least one pharmaceutically acceptable carrier and/or excipient.
  • a method for treating a 5-H ⁇ 2C receptor- mediated disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound or composition noted above, in a further aspect, the mammal is a human.
  • the disorder is selected from obesity, schizophrenia, epilepsy, depression, panic anxiety, alcoholism or obsessive compulsive disorder, a depressive disorder, an anxiety disorder, including panic attack, agoraphobia, and specific or social phobia, bipolar disorder, post-traumatic stress, an eating disorder, obesity, a gastro-intesti ⁇ al disorder, alcoholism, drug addiction, schizophrenia, a psychotic disorder, a sleep disorder, including sleep apnea, migraine, sexual dysfunction, a central nervous system disorder, including trauma, stroke and spinal cord injury, a cardio-vascular disorder, diabetes insipidus, obsessive compulsive disorder, premenstrual tension, chronic fatigue syndrome, age- related memory disorder, personality disorder and raised intracranial pressure.
  • the disorder is selected from obesity, schizophrenia, epilepsy, a depressive disorder, panic attack, alcoholism, drug addiction or obsessive compulsive disorder.
  • the compound is administered orally and/or parenterally.
  • the compound is administered intravenously and/or intraperitoneally.
  • the mammal is a human.
  • the disorder is selected from obesity, schizophrenia, epilepsy, depression, panic anxiety, alcoholism or obsessive compulsive disorder, a depressive disorder, an anxiety disorder, including panic attack, agoraphobia, and specific or social phobia, bipolar disorder, post-traumatic stress, an eating disorder, obesity, a gastro-intestinal disorder, alcoholism, drug addiction, schizophrenia, a psychotic disorder, a sleep disorder, including sleep apnea, migraine, sexual dysfunction, a central nervous system disorder, including trauma, stroke and spinal cord injury, a cardio-vascular disorder, diabetes insipidus, obsessive compulsive disorder, premenstrual tension, chronic fatigue syndrome, age-related memory disorder, personality disorder and raised intracranial pressure.
  • the disorder is selected from obesity, schizophrenia, epilepsy, a depressive disorder, panic attack, alcoholism, drug addiction or obsessive compulsive disorder.
  • the compound is administrable orally and/or parenterally. In yet another aspect, the compound is administrable intravenously and/or intraperitoneally.
  • a method for decreasing food intake in a mammal comprising administering to the mammal a therapeutically effective amount of a compound or composition as noted above.
  • a method of controlling weight gain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound or composition as noted above.
  • Figure 1 shows graphically the effect of two exemplary compounds of the invention at vanous doses (mg/ml, X-axis), administered i ⁇ traperitoneally (open bars) or orally (solid bars) on mouse locomotion expressed as % change control (Y axis)
  • Figure 2 shows graphicalfy the effect of two exemplary compounds of the invention at various doses (mg/ml) or vehicle administered intraperitoneal ⁇ (X-axis) on rat food consumption (Y-axis). Hatched bars show pretreatment with S-HT 26 antagonist SB242084 before compound administration.
  • the compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E. L. Eliel and S. H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.
  • alkyl as used herein means a straight- or bra ⁇ ched-chai ⁇ hydrocarbon radical; in one aspect, having from one to eight carbon atoms, and includes, for example, and without being limited thereto, methyl, ethyl, propyl, isopropyl, t-butyl and the like.
  • alkyl encompasses substituted alkyl.
  • Substituted alkyl includes, for example, and without being limited thereto, haloalkyl, hydroxyalkyl, cyanoalkyl, and the like. This is applied to any of the groups mentioned herein. Groups such as “alkenyl”, “alkynyl", “aryl”, etc. encompass substituted “alkenyl", “alky ⁇ yl", “aryf”, etc.
  • alkenyl as used herein means a straight- or branched-chain alkenyl radical; in one aspect, having from two to eight carbon atoms, and includes, for example, and without being limited thereto, ethenyl, 1-propenyl, 1-butenyl and the like.
  • alkenyl encompasses radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • alky ⁇ yl as used herein means a straight- or branched-chain alkynyl radical; in one aspect, having from two to eight carbon atoms, and includes, for example, and without being limited thereto, 1-propy ⁇ yl (propargyl), 1- buty ⁇ yl and the like.
  • cycloalkyl as used herein means a carbocyclic system (which may be unsaturated) containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused.
  • the ring(s) may have from three to seven carbon atoms, and includes, for example, and without being limited thereto, cyclopropyl, cyclohexyl, cyclohexenyi and the like.
  • heterocycloalkyl as used herein means a heterocyclic system (which may be unsaturated) having at least one heteroatom selected from N 1 S and/or O and containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused.
  • the ring(s) may have a three- to seven-membered cyclic group and includes, for example, and without being limited thereto, piperidinyl, pjperazinyl, pyrrolidi ⁇ yl, tetrahydrofuranyl and the like.
  • alkoxy as used herein means a straight- or branched-chair* alkoxy radical; in one aspect, having from one to eight carbon atoms and includes, for example, and without being limited thereto, methoxy, ethoxy, propyloxy, isopropyloxy, /-butoxy and the like.
  • haio means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms.
  • alkylene as used herein means a difunctional branched or unbranched saturated hydrocarbon radical; in one aspect, having one to eight carbon atoms, and includes, for example, and without being limited thereto, methylene, ethylene, n-propylene, n-butylene and the like.
  • alkenyle ⁇ e as used herein means a difunctional branched or unbranched hydrocarbon radical; in one aspect, having two to eight carbon atoms, and having at least one double bond, and includes, for example, and without being limited thereto, ethenylene, n-propenyle ⁇ e, n-buteny!ene and the like.
  • alkynylene as used herein means a difunctional branched or unbranched hydrocarbon radical; in one aspect, having two to eight carbon atoms, and having at least one triple bond, and includes, for example, and without being limited thereto, ethynylene, ⁇ -propynylene, n-buty ⁇ ylene and the like.
  • aryl alone or in combination, as used herein means a carbocyclic aromatic system containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl is one, two or three rings
  • the aryl has five to twelve ring atoms.
  • aryf encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, bipnenyl, phenanthryl, a ⁇ thryl or acenaphthyl
  • the "aryl” group may have 1 to 4 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylami ⁇ o and the like.
  • heteroaryl alone or in combination, as used herein means an aromatic system having at least one heteroatom selected from N, S and/or O and containing one or more nngs wherein such rings may be attached together in a pendent manner or may be fused.
  • heteroaryl is one, two or three rings. In one aspect, the heteroaryl has five to twelve ring atoms.
  • heteroaryl encompasses heteroaromatic radicafs such as pyridyl, mdolyl, furyl, be ⁇ zofuryl, thienyl, benzothienyl, quinolyl, oxazolyl and the like.
  • the "heteroaryl” group may have 1 to 4 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
  • substituents and substitution patterns on the compounds of the invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, as long as a stable structure results.
  • pharmaceutically acceptable salt means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients.
  • a “pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates
  • Illustrative inorganic acids which form suitable salts include, but are not limited thereto, hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic adds which form suitable salts include the mono-, di- and tricarboxylic acids.
  • lllustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malo ⁇ ic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phe ⁇ oxybenzoic, p-toluenesulf ⁇ nic acid and other sulfonic acids such as metha ⁇ esulfonic acid and 2-hydroxyethanesulfo ⁇ ic acid.
  • Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form.
  • the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection criteria for the appropriate salt will be known to one skilled in the art,
  • Other non-pharmaceutically acceptable salts e.g oxalates may be used for example in the isolaiioii uf of Formula 1 for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • a "pharmaceutically acceptable basic addition salt” is any non-toxic organic or inorganic base addition salt of the acid compounds represented by Formula I or any of its intermediates
  • Illustrative inorganic bases which form suitable salts include, but are not limited thereto, lithium, sodium, potassium, calcium, magnesium or barium hydroxides.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoli ⁇ e or ammonia. The selection of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the molecule is not hydrolyzed.
  • Solvate means a compound of Formula I or the pharmaceutically acceptable salt of a compound of Formula t wherein molecules of a suitable solvent are incorporated in a crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered as the solvate. Examples of suitable solvents, but are not limited thereto, are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate
  • stereoisomers is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space, ft includes mirror image isomers (ena ⁇ tiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).
  • treat or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
  • terapéuticaally effective amount means an amount of the compound which is effective in treating the named disorder or condition.
  • pharmaceutically acceptable carrier means a non-toxic solvent dispersant, excipient, adjuvant or other material which rs mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient
  • a pharmaceutical composition i.e., a dosage form capable of administration to the patient
  • a pharmaceutically acceptable oil typically used for parenteral administration.
  • a “5-HT 2C receptor-mediated disorder”, as used herein, is a disorder in which there is believed to be involvement of the pathway controlled by the S-HT ⁇ c receptor and which is ameliorated by treatment with an agonist of the 5-HTzc receptor.
  • ⁇ -HT ⁇ c receptor-mediated disorders include a depressive disorder, an anxiety disorder, including panic attack, agoraphobia, and specific or social phobia, bipolar disorder, post-traumatic stress, an eating disorder, obesity, a gastro-intestinal disorder, alcoholism, drug addiction, schizophrenia, a psychotic disorder, a sleep disorder, including sleep apnea, migraine, sexual dysfunction, a central nervous system disorder, including trauma, stroke and spinal cord injury, a cardio-vascular disorder, diabetes insipidus, obsessive compulsive disorder, premenstrual tension, chronic fatigue syndrome, age- related memory disorder, personality disorder and raised intracranial pressure.
  • R 1 to R 12 are defined heremabove.
  • R 2 , R 3 . R 5 , R ⁇ , R 9 , R 10 , R 11 and R 13 are H (Formula II. below).
  • a further embodiment of the invention provides compounds where R 2 , R 3 , R 8 , R 10 , R 11 and RTM are H (Formula III, below).
  • Yet another embodiment of the invention provides compounds where R 5 and R B , R 9 , R 10 , R 11 and R 12 are H (Formula IV, below).
  • a further embodiment of the invention provides compounds of Formula I where R 5 , R 6 , R 9 , R 10 , R 11 and R 12 are H and R 7 is a 6-membered heterocyclic ring ⁇ see Formula IB, below).
  • R 14 to R 1B are independently selected from from H 1 halo, hydroxy, cyano, nitro, alkyl, alkoxy, CHbOH 1 haloalkyl, O-haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alky ⁇ yl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalke ⁇ yl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O-heterocycloalkyl, a!kylene-O-alkyl, alkylene-0-cycloalky), alkyfene-O-heterocycloalkyl, alkylene- O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocyctoalkyf, S-alkyl, S(O)- alkyl, S(O) 2 -alkyl, S-
  • a further embodiment of the invention provides compounds of Formula I where R 5 .
  • R e , R 9 , R 10 , R 11 and R 12 are H and R 7 is a 7-membered heterocyclic ring (see Formula IC, below)
  • R 14 to R 19 are Independently selected from from H, halo, hydroxy, cya ⁇ o, nitro, alkyl, alkoxy, CH 2 OH, haloalkyl, O-haloalkyl, hydroxyaJkyl, cyanoalkyl, alkenyl, alkynyl, cydoalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O-heterocycloalkyl, alkylene-O-alkyl, alkyle ⁇ e-O-cycloalkyl, alkylene-O-heterocydoalkyl, alkylene- O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloalkyl, S-alkyl, S(O)- alkyl, S(O) 2 -
  • the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture.
  • the present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I.
  • the optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate or chemical or enzymatic resolution methodology, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.
  • salts of the compounds of Formula I are also salts of the compounds of Formula I.
  • pharmaceutically acceptable salts of compounds of the present invention are obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCI or acetic acid, to afford a salt with a physiologically acceptable anion.
  • alkali metal such as sodium, potassium, or lithium
  • alkaline earth metal such as a calcium
  • quaternary ammonium salts can be prepared by the addition of alkylating agents, for example, to neutral amines.
  • the compound of Formula I may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate.
  • R * can be alkyl or cycloalkyl and (a) comprises heat and base assisted cyclization of a compound of Formula A to provide a compound of Formula B and (b) comprises reduction of the carbo ⁇ yl of the amide of the compound of Formula B.
  • (a) comprises heating in DMF and (b) comprises reduction with LiAIH 4 ZAlCl 3 .
  • R' can be alkyl or cycloalkyl and (a) comprises heat and base assisted cydization of a compound of Formula AA to provide a compound of Formula BB and (b) comprises reduction of the carbonyl of the amide of the compound of Formula B.
  • (a) comprises heating in DMF and (b) comprises reduction with LiAIH 4 ZAlCIs
  • compounds of Formula I wherein R 11 and R 12 are H, may be prepared via reduction of a carbonyl of the following amide:
  • Reduction can occur, for example, using UAIH 4 /AICI 3 .
  • Compounds of Formula I, wherein R and R j10 are H and R and R are not H 1 may be prepared via reduction of a carbo ⁇ yl group of a similar amide except that the carbonyl is now C7 instead of C2, and C2 is substituted with R 11 and R 1Z .
  • compounds of Formula I wherein R ⁇ , R 10 , R 11 and R 12 are H 1 may be prepared via reduction of the carbonyl groups of the following amide:
  • R' can be alkyl or cycloalkyl.
  • the resultant Formula I can be converted to a salt addition of an acid, for example.
  • R' can be alkyl or cycloalkyl.
  • the resultant Formula I can be converted to a salt addition of an add, for example.
  • (a) comprises cyclization of the compound of Formula D, whereby R' can be alky! or cycloalkyl.
  • R' can be alky! or cycloalkyl.
  • base can be used to initiate cyclization.
  • (a) comprises cyclization of the compound of Formula DD, whereby R' can be alkyl or cycloalkyl.
  • R' can be alkyl or cycloalkyl.
  • base can be used to initiate cyclization.
  • the compounds of Formula II where R* is H or alkyl, R 7 and R 8 are H and R 1 is methoxy may be prepared according to Scheme 1 , below, from nitrile intermediate V by alkylation with benzylamine, followed by hydrolysis of the nitrile function to afford the amino ester VII. Microwave- assisted cyclization to azepinone VIII and reduction with UAIH4/AICI3 gave the benzyl-protected azepine IX. Subsequent hydroge ⁇ olysis of the protecting group provided the compound of Formula II.
  • the intermediate V was prepared from 2-(2-chloroethyl)-3-(chloromethy ) )-6-rnethoxypyridine [Feng, S.; He, X.; Yu, G.; Yu, X.; Bai, D. Org. Prep. Proced. Int. 2004, 36 (2); 129-134] via mono-cyanatio ⁇ and the Finkelstien chloro-iodo exchange.
  • Compounds of Formula Il can also be obtained from diester XVIII by reduction first to the diol XIX. Activation of the diol (eg mesylation or halide formation) and cyclization with amines give Il (Scheme 2).
  • compounds of Formula IV can also be obtained from the intermediate XXXIII [Feng, S.; He, X.; Yu, G.; Yu, X.; BaI 1 D. Ocg Prep. Proced lnt 2004, 36 (2); 129-134] by simple alkylation to give XXXIV which is then transformed to the desired compounds in a manner similar to that shown in Scheme 1 (see Scheme 5).
  • R 5 or R 6 Methyl is shown) to introduce functionality onto the azeprne ring
  • a reducing agent e g LiAIH 4
  • diol intermediate E Treatment of the diester D with a reducing agent (e g LiAIH 4 ) provides diol intermediate E.
  • a reducing agent e g LiAIH 4
  • mesyl chloride Treatment of diol E with mesyl chloride gives the chloro-mesylate F which on mild cyanation with NaCN in DMSO gives the cyano-mesylate G.
  • Selective cyano reduction e.g. with alane generated in situ from AICb and LiAIhU
  • cyclization gives the pyridyl-fused azepine intermediate H.
  • Trifiatio ⁇ of J to the versatile intermediate K followed by coupling with the various amines give the Boc-protected precusor L of the compounds of Formula III.
  • Treatment of L with HCI gives M, the HCI salts of the compounds of this invention.
  • Acid addition salts of the compounds of Formula I are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric add.
  • Other non-pharmaceuticafly acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • base addition salts such as sodium, potassium and ammonium salts
  • solvates and hydrates of compounds of the invention are also included within the scope of the invention.
  • the compounds of the invention have an EC 50 value for the human 5-HT zc receptor less than 1000 nM, or less than 50OnM, or less than 300 nM, or less than 100 nM.
  • the compounds of the invention are therefore of interest for the treatment of 5-HT 2c receptor-mediated disorders, including a depressive disorder, an anxiety disorder, including panic attack, agoraphobia, and specific or social phobia, bipolar disorder, post-traumatic stress, an eating disorder, obesity, a gastro-intestinal disorder, alcoholism, drug addiction, schizophrenia, a psychotic disorder, a sleep disorder, including sleep apnea, migraine, sexual dysfunction, a central nervous system disorder, including trauma, stroke and spinal cord injury, a cardio-vascular disorder, diabetes insipidus, obsessive compulsive disorder, premenstrual tension, chronic fatigue syndrome, age- related memory disorder, personality disorder and raised intracranial pressure
  • the compounds of the invention are, for instance, administered orally, sublingually, rectally, nasally, vaginally, topically (including the use of a patch or other transdermal delivery device), by pulmonary route by use of an aerosol, or parenterally, including, for example, intramuscularly, subcutaneously, intraarterially, intravenously or intrathecally. Administration can be by means of a pump for periodic or continuous delivery.
  • the compounds of the invention are administered alone, or are combined with a pharmaceutically-acceptable carrier or excipient according to standard pharmaceutical practice.
  • the compounds of the invention are used in the form of tablets, capsules, lozenges, chewing gum, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like, tn the case of tablets, carriers that are used include lactose, sodium citrate and salts of phosphoric acid.
  • disintegrants such as starch, and lubricating agents such as magnesium stearate and talc, are commonly used in tablets
  • useful diluents are lactose and high molecular weight polyethylene glycols
  • certain sweetening and/or flavoring agents are added
  • ste ⁇ ie solutions of the compounds of the invention are usually prepared, and the phis of the solutions are suitably adjusted and buffered.
  • the total concentration of solutes should be controlled to render the preparation isotonic.
  • ointments or droppable liquids may be delivered by ocular delivery systems known to the art such as applicators or eye droppers.
  • compositions can include mucomimetjcs such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or be ⁇ zylchromium chloride, and the usual quantities of diluents and/or carriers.
  • mucomimetjcs such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol
  • preservatives such as sorbic acid, EDTA or be ⁇ zylchromium chloride
  • diluents and/or carriers will be selected to be appropriate to allow the formation of an aerosol.
  • Suppository forms of the compounds of the invention are useful for vaginal, urethral and rectal administrations.
  • Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature.
  • the substances commonly used to create such vehicles include theobroma oil, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weight and fatty acid esters of polyethylene glycol. See, Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.
  • Analogous gels or creams can be used for vaginal, urethral and recta) administrations.
  • Examples of pharmaceutically acceptable acid addition salts for use in the present invention include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, p-toluenesulphonic and arylsulphonic acids, for example
  • Examples of pharmaceutically acceptable base addition salts for use in the present invention include those derived from non-toxic metals such as sodium or potassium, ammonium salts and organoamino salts such as triethylamine salts. Numerous appropriate such salts will be known to those of ordinary skill.
  • the physician or other health care professional can select the appropriate dose and treatment regimen based on the subject's weight, age, and physical condition. Dosages will generally be selected to maintain a serum level of compounds of the invention between about 0.01 ⁇ g/cc and about 1000 ⁇ g/cc, preferably between about 0.1 ⁇ g/cc and about 100 ⁇ g/cc.
  • an alternative measure of preferred amount is from about 0.001 mg/kg to about 10 mg/kg (alternatively, from about 0.01 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg), will be administered.
  • an alternative measure of preferred administration amount is from about 0.001 mg/kg to about 10 mg/kg (from about 0.1 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg).
  • an alternative measure of preferred administration amount is from about 0.1 mg/kg to about 10 mg/kg, more preferably from about 0.1 mg/kg to about 1 mg/kg.
  • reaction mixture was concentrated to dry and the residue was redissolved in tetrahyrofuran (100 mL).
  • the reaction mixture was diluted with diethyl ether and quenched with 5M sodium hydroxide carefully at 0 0 C. the mixture was dried with magnesium sulfate, filtered.
  • reaction mixture was filtered through Celite ® , concentrated and purified on silica gel using dichloromethane:2M NH 3 in methanol (10:0 to 9.2:0.8) to give the product (2 mg).
  • the product was treated with hydrochloric acid in diethyl ether to give the hydrochloric acid salt (2 salt equivalents).
  • the reaction mixture was stirred at 0 0 C for an hour and a half Water (200 mL) and saturated sodium carbonate (10 mL) were used to quench the reaction.
  • the reaction mixture was extracted with ethyl acetate, dried with sodium sulfate, concentrated by Rotavapor.
  • the residue was mixed with diisoprapylethylamine (3 36 g, 26 mmol) in acetonit ⁇ le (45 ml) and stirred at 30 ⁇ C for 24 hours, concentrated again, saturated sodium carbonate (15mL) was added
  • the mixture was extracted with ethyl acetate, dried, purified by chromatography to give the title compound (1.25g, 52 7%)
  • Example 14.1 The title compound from Example 14.1 (5.72 g, 17. 54 mmol) was suspended in dichloromethane (90 mL) under a nitrogen atmosphere and cooled to 0 °C. Diisopropylethyamine (7.93 g, 61.39 mmol) was added to the suspension with stirring. In a separate flask, di-tert-butyl dicarbonate (8.04 g, 36.83 mmol) was dissolved in dichloromethane (50 mL) under a nitrogen atmosphere. This solution was added slowly to the main reaction vessel via cannula. The reaction was stirred at r.t. for 2 hours.
  • the salt was mixed with di ⁇ sopropylethyamine (2.5 mL) and di-tert-butyl dicarbonate (570 mg, 2.5 mmol) in dichloromethane (20 mL) and water (10 mL) at 0 0 C and stirred for two hours.
  • the organic layer was separated and dried, concentrated to give tert-butyl 9-ethyl-2-hydroxy-5,6,8,9-tetrahydro-7H- pyrido[2,3-d]azepine-7-carboxylate.
  • This intermediate was mixed with diisopropylethyaimine (1 mL) and triflic anhydride (420 ⁇ L, 2.5 mmol)) in dichloromethane at -50 0 C and stirred overnight.
  • Example 21.11 2-(M ⁇ thvl-phen ⁇ l-ami ⁇ o)-5,6,8,9-tetrahydro-pyridor2,3- d]azepi ⁇ e-7-carboxy1ic acid tert-butyl ester
  • Example 21.17 tert-Butyl 2-tert-b ⁇ tyl-5,6,8,9-t ⁇ trahydro-7H-pyrido[2,3- d]azepine-7-carboxyfat ⁇
  • Ted-butyl lithium (1 93 mL, 3.28 mmol) was added to a suspension of copper cyanide (0 158 g, 1.77 mmol) in tetrahydrofuran (4.0 mL) under nitrogen at - 40 0 C.
  • a solution of the title compound from Example 17.1 (0 200 g, 0.505 mmol) in tetrahydrofuran (2.0 mL) was added slowly to the reaction mixture The reaction was stirred at -40 0 C for 24 hours and then warmed to r t over 6 hours The reaction mixture was quenched with saturated ammonium chloride (20 mL) and diluted with ethyl acetate.
  • Example 21.78 Tert-butvl 3-chloro-2-piperidin-1-yl 5,6,8,9-tetrahydro-7H- pyrido[2, 3-d]azepi ⁇ e-7 ⁇ carboxylate
  • Example 21.84 OR)- and (9S)-tert-butyl 9-methyl-2-pipendin-1-yl-5,6,8,9- tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxy)ate
  • Example 21.86 OR)- and (9S)-2-(4-fluoropipe ⁇ d ⁇ n-1-yl)-9-methy
  • Example 22.1 6,7,8,9-Tetrahydro-5H-pyridoP,3-d]azepine-2-carbonitrile
  • dichloromethane 1 mL
  • tr ⁇ fluoroacetic acid 0.5 mL
  • the reaction mixture was stirred at 0° C for 2 hours.
  • the reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous sodium carbonate.
  • the organic layer was dried over sodium sulfate and concentrated to give the product.
  • the product was treated with hydrochloric acid in diethyl ether to give the hydrochloric acid salt (2 salt equivalents, 5 mg).
  • Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo and in vivo assays that are well known in the art, including the assays described in the fo/lowing examples.
  • Gq coupled 5-HT 2 receptors stimulates phospholipase C activity and leads to formation of inositol trisphosphate (IP3) and the subsequent release of calcium from intracellular stores.
  • Functional activity of Gq coupled receptors can be quantified in a FLIPR assay by measuring intracellular calcium levels with calcium sensitive dyes (using a fluorescence imaging plate reader, FLIPR) and in a Phosphatidyl Inositol Hydrolysis Assay (IP accumulation assay) which measures IPs derived from IP3. Both assays provide robust functional readouts of receptor activation.
  • Stable cell lines expressing human 5-HT2A, 5-HT2B and 5HT- 2C (both INI and VSV isoforms) receptors were created in an MHEK cell background (an HEK293-based cell background which also expresses the Macrophage Scavenger Receptor 1, to increase the adherence of cells to tissue culture plates).
  • Recombinant cell lines were cultured in Growth Medium (High glucose DMEM (Hyclone) with 10% dialyzed fetal bovine serum (Hyclone), and L-glutamme (Gibco; 0.8mM for 5HT2A and 2C, 2.0 mM for 5HT2B), and grown under selection with 200 ⁇ g/ml Zeocin (I ⁇ vitrogen), and either 200 ⁇ g/ml Hygromyci ⁇ B (Invitrogen for 5HT2A and 5HT2C) or 500 ug/ml Geneticin (Invitrogen for 5HT2B)
  • FLIPR assay methodology Cells that recombinant ⁇ expressed the 5HT2 receptors were enzymatically dissociated with Trypsin/EDTA 0 25 % (Hyclone) 24 hours p ⁇ or to testing, and seeded at 60,000 cells per well in 100 ⁇ l Growth Medium in black sided, clear bottom 96 well plates (Greiner, BioExpress) at 37 Q C and 5% CO2.
  • Antagonist activity was measured after pre-incubatio ⁇ of cells with compound for 30 minutes at room temperature, followed by the online addition of agonrst (5-HT, EC80) in the FLFPR. Antagonist activity was determined by normalizing the response to the maximal 5-HT response in the absence of test compound.
  • Phosphatidyl Inositol Hydrolysis Assay 24 hours prior to testing, cells were plated in poly-D-Lysine-coated 96 well plates (VWR) at 100,000 cells/ well in 200 ⁇ l culture medium containing 10 ⁇ Ci/ml of [ 3 HJ-myo-lnositol (Perki ⁇ Elmer ⁇ CeIi monolayers were washed twice with HBSS (HEPES Buffered Saline solution: 20 mM HEPES, 146mM NaCl, 4 2mM KCl, 0.5mM MgCI 2 , 0.1% Glucose, pH 7.4) The cell monolayers were pre-incubated for 5 minutes at 37°C in 100 ⁇ l/well HBSS containing 1OmM LiCI Compounds were tested for agonist activity in duplicate at concentrations ranging from 3nM to 30 ⁇ M.
  • VWR poly-D-Lysine-coated 96 well plates
  • the Filter Plate was then placed in a vacuum manifold and a gentle vacuum was applied Total phosphatidyl inositols were eluted with 800 ⁇ l 3OmM ammonium formate, and the eluate was discarded Total inositol phosphates were eluted with 600 ⁇ l (2X 300 ⁇ l) 70OmM ammonium formate / 10OmM formic acid and collected in a clean 2ml, 96 well, polypropylene, round bottom Uniplate.
  • Animals and housing Male, Sprague-Dawley rats or CD-1 mice were used for all studies. All animals were allowed ad-lib access to food and water except during experiment. Animals were housed within an animal vivarium maintained under a 12h light:dark cycle (lights on: 07.0Oh), and all experiments were conducted in the animals' light phase. For all experiments, animals were habituated to the vivarium for a minimum of 72h before experimentation The experimental procedures used in the present investigation were conducted under the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) and the Canadian Council on Animal Care (CCAC) guidelines.
  • AALAC Association for Assessment and Accreditation of Laboratory Animal Care
  • CCAC Canadian Council on Animal Care
  • Mouse hypolocomotio ⁇ assay Selective 5-HT2C receptor agonists have been reported to produce hypolocomotion in rodent species by a relatively well defined CNS mechanism. A mouse locomotor assay was therefore used to screen compounds. Mafe, CD-1 mice were administered test compound 15min before placement in a chamber where locomotor activity was measured through photocell beam breaks. Test compounds were administered either by the oral or intraperitoneal route.
  • Deprivation-induced feeding in the rat Male Sprague-Dawley rats (Charles River, St. Constant, Quebec, Canada) of approximate weight 180-20Og were pair housed on arrival in the animaf facility (lights on 7:00-19:00h) After a 7 day acclimitisat ⁇ on period where the animals received ad-libitum access to standard rodent lab chow (Harla ⁇ Teklad rodent maintenance diet, 2014; Harlan Teklad, Madison, Wl) 1 the animals were trained to receive a daily ration of lab chow in distinct chambers over a 2h period.
  • standard rodent lab chow Harla ⁇ Teklad rodent maintenance diet, 2014; Harlan Teklad, Madison, Wl
  • test compound or vehicle as control
  • test compound or vehicle was administered 10 to 1 S minutes before the beginning of the 2 hr. food access period, and food intake over that period was measured as during the training period.
  • Test compound or vehicle was administered on Tuesdays and Fridays, with drug free (washout) days in between Typically the animals received 3 doses of test compound and vehicle in a counterbalanced sequence
  • mice Male Sprague-Dawley rats (Charles River, St Constant, Quebec. Canada) of approximate weight 180-20Og are pair housed on arrival in the animal facility (lights on 7 00-19 0Oh). After a 7 day acclimitisation period where the animals receive ad-hbitum access to standard rodent lab chow (HarJan Teklad rodent maintenance diet, 2014; Harlan Teklad, Madison, Wl) 1 the animals are trained to receive single 45mg food pellets under a fixed time interval of 60s over a 2h pe ⁇ od within an operant chamber equipped with a water bottle Thus during the 2h session, the rats can earn a maximum of 120 pellets The total volume of water consumed by rats dunng this 2h penod is recorded Daily food allowance is supplemented by a 45m ⁇ n access period sometime between 15' 00-18 OOh
  • the rats may be dosed orally or parentally with vehicle or test compound.
  • Test compound or vehicfe is administered on Tuesdays and Fridays with drug free (washout) days in between Typically the animals will receive 3 closes of test compound and vehicle in a counterbalanced sequence.
  • mice Male, CD-1 mice (Charles River, St. Constant, Quebec, Canada) of approximate body weight 20-3Og are housed in groups of four on arrival at the facility. Food (Harlan Teklad rodent maintenance diet, 2014; Harlan Teklad, Madison, Wl) and water are available ad-libitum After a minimum 3 day acclimatization period the animals would be tested in a s c pentylenetetrazol assay - which is considered both a model of primary generalized convulsive seizures and non-convulsive absence (petit rnal) seizures (Upton, N (1994) Mechanisms of action of new antiepileptic drugs, rational design and serendipitous findings Trends Pharmacol. Sci 15: 456-463)
  • the experiment is conducted within a single day with animals receiving a single pretreatment, Le independent groups design. Following drug or vehicle control treatment by either oral, or parenteral route, the animals would receive pentylenetetrazol (85mg/kg mice) administered by the subcutaneous route.
  • pentylenetetrazol 85mg/kg mice
  • the dose of pentylenetetrazol is selected as it is of sufficient intensity to induce a clonic seizure in the majority of animals, i e a CD97 dose.
  • the animals are restrained by hand to deliver the chemical convulsa ⁇ t, following which the animals are released and transferred to a test cage to permit observation of the subsequent seizure throughout its course
  • the animal would receive a single pentylenetetrazol injection and would be terminated on reaching endpoint, i.e clonic seizure If an animal displays no seizure activity after 60min it is considered protected and the experiment completed as endpoint reached
  • a parallel tests of motor function using the rotorod would be undertaken to establish a therapeutic index (Tl), e g ratio between the ED50 dose required to block seizures, compared to ED50 dose required to disrupt motor function in same species
  • Tl therapeutic index
  • the rotorod test consists of placing the animal on a rotating treadmill (a rod) traveling at a constant speed of 16r p.m.
  • the dependant measure is the time that the animal remains on the rod before falling. Up to three separate measures may be taken to get a meaningful measure ⁇ f performance.
  • a modification to the above procedure is to pretreat mice with either vehicle or a selective 5-HT 2 c receptor antagonist, 6-chloro-5-methyl-N-(2-(2- methylpyridin-3-yl-oxy)pyridine-5-yl)am ⁇ nocarbonyl)-2,3-dihydro ⁇ ndole (1 mg/kg in 8% HPCD, 25mM citric acid in saline) p ⁇ or to the oral or parental dose of test compound,
  • Antagonism of increased locomotion produced by the psychostimulant amphetamine in rodents is a feature of many drugs with antipsychotic property in man As such reversal of amphetamine hyperlocomotion is a widely used preclinical test to detect novel drugs for the treatment of schizophrenia
  • the animals After a predetermined pe ⁇ od, the animals would be dosed with either saline vehicle or d-amphetamine (0.5mg/kg) by the intraperitoneal route and returned to the test chamber for 2h. While in the test chamber, the animal's activity will be monitored automatically by infrared sensors and/or manually by an experimenter for expression of 'normal' behaviors such as sniffing, grooming, rearing, and 'abnormal' behaviors such as 'circling' At the completion of such test, the animals will be returned to their holding cages.
  • saline vehicle or d-amphetamine 0.5mg/kg
  • a modification to the above procedure is to pretreat rats with either vehicle or a selective 5-HT2C receptor antagonist, 6-chloro-5-methyl-N-(2-(2- methylpynd ⁇ n-3-yl-oxy)pyridine-&-yl)am ⁇ nocarbonyl)-2,3-dihydroindole (1 mg/kg in 8% HPCD, 25mM citric acid in saline) prior to the oral or parental dose of test compound.
  • Table 1 shows the 6-HT 2C agonist potency of compounds in accordance with the invention, determined by FLIPR assay described above.
  • Figure 1 shows the effect of two exemplary compounds of the invention on mouse locomotion after either oral or intraperitoneal injection.
  • Figure 2 shows the dose-related reduction in food intake in rats treated intraperitoneal ⁇ with two exemplary compounds of the invention.
  • Pre-treatme ⁇ t of rats with the selective S-HT ⁇ c antagonist SB 242084 blocked the effect of the agonist compounds, as shown by the hatched bars.

Abstract

Compounds according to Formula (I); wherein the radical R7 preferably represents a hetereocycle of 6 or 7 members and R4, R9-12 all preferably represent hydrogen atoms. These compounds and their pharmaceutical acceptable salts are used in pharmaceutical compositions and are useful for treating serotonin 5HT2C receptor mediated diseases. Processes to make such derivatives are as well disclosed therein.

Description

Tβtrahvdro-5H-pyridorz.3-dlazepiπes as 5-HTW Uqartds
Field of the Invention
This invention relates to compounds which act at the 5-HT2c receptor and to the use of such compounds in the treatment of diseases.
Background of the Invention
5-Hydroxytryptamiπe (5-HT or serotonin), a key neurotransmitter of the peripheral and central nervous system (PNS and CNS), has been implicated in a variety of sensory, motor and behavioral processes. The diverse effects of this neurotransmitter are related to the extensive projections of serotonergic neurons throughout the brain and the large number of distinct serotonin receptor subtypes. At least 14 distinct serotonin receptor subtypes are expressed in the mammalian CNS The contribution of these receptors to the action of serotonin has been difficult to ascertain owing to the paucity of selective pharmacological agents.
The 5-HT2 subfamily of serotonin receptors is composed of three subtypes; namely the 5-HT2a. 5-HT2& and 5-HT2c receptors All the members of this subfamily couple to the activation of the inositol phosphate and diacyl glycerol pathway via the G-proteiπ.Gqm Recently, other second messenger systems have been shown to be regulated by 5-HT2 stimulation including mitogen activated protein kinase (MAP-kinase). The limited access to selective pharmacological tools amongst the 5-HT2 subfamily of serotonin receptors has led to the use of gene targeting techniques to generate mouse lines that selectively lack functional receptor genes. This strategy has been applied to the study of 5-HT2t receptor function. The S-HT≥c receptor is expressed in many brain regions including the limbic system, extrapyramidal motor pathways, hypothalamus, thalamus and monoaminergic cell groups. 5-HT2c receptors have been implicated in the regulation of food intake and anxiety For example, the nαn-selective 5-HT2C receptor agonist, m- chlorophenylpiperazine 1 (mCPP) produces hypophagic and anxiogenic effects that were attenuated by 5-HT2c receptor antagonists The propensity of a 5-HT20 receptor agonist to regulate food intake suggests a crrtical role for this receptor subtype in controlling obesity {Vickers, S.; Clifton, P.; Dourish, C; Tecott, L. Psychopharma∞logy (Berlin) 1999, 143, 309; Nilssoπ, B. J. Med Chem. 2006, 49, 4023 ).
It has been widely recognized that obesity is a disease process influenced by environmental factors in which the traditional weight loss methods of dieting and exercise need to be supplemented by therapeutic products (S. Parker, 'Obesity: Trends and Treatments", Scrip Reports, PJB Publications Ltd, 1969).
Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI)1 which is calculated by dividing body weight (kg) by height squared (m2). Thus, the units of BMl are kg/m2 and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m2, and obesity as a BMI greater than 30 kg/m2. There are problems with this definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this, obesity can also be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively. As the BMF increases there is an increased risk of death from a variety of causes that in independent of other risk factors. The most common diseases with obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.
in addition to its growing role in the regulation of food intake and hence obesity, the 5-HT2c receptor has been implicated in the treatment of
Schizophrenia. Schizophrenia affects approximately 5 million people. The most prevalent treatments for schizophrenia are currently the 'atypical' antipsychotics, which combine dopamine (Dj) and serotonin (5-HT2A) receptor antagonism. Despite the reported improvements in efficacy and side-effect liability of atypical antipsychotics relative to typical antipsychotics, these compounds do not appear to adequately treat all the symptoms of schizophrenia and are accompanied by problematic stde effects, such as weight gain (Allison, D. B , et. al , Am J Psychiatry, 156: 1686-1696, 1999; Masand, P S., Exp. Opin. Pharmacother. 1.377-389, 2000; Whitaker, RM Spectrum Life Sciences Decision Resources. 2.1-9, 2000).
Atypical antipsychotics also bind with high affinity to S-HT2C receptors and function as 5-HT2c receptor antagonists or inverse agonists. Weight gam is a problematic side effect associated with atypical antipsychotics such as clozapine and olanzapine, and it has been suggested that 5-HT20 antagonism is responsible for the increased weight gain. Conversely, stimulation of the 5- HΪ2C receptor is known to result in decreased food intake and body weight (Walsh et. al., Psychopharmacology 124: 57-73, 1996; Cowen, P J , et al., Human Psychopharmacology Iβ: 385-391, 1995; Rosenzweig-Lipson, S . et al . ASPET abstract, 2000}
Several lines of evidence support a role for 5-HT2C receptor agonism or partial agonism as a treatment for schizophrenia. Studies suggest that 5-HT2c antagonists increase synaptic levels of dopamine and may be effective in animal models of Parkinson's disease (Di Matteo, V., et al., Neuropharmacology 37: 265-272, 1998; Fox, S. H., et. al., Expenmβntal Neurology 151 35-49, 1998). Since the positive symptoms of schizophrenia are associated with increased levels of dopamine, compounds with actions opposite to those of S-HT∞ antagonists, such as 5-HTzc agonists and partial agonists, should reduce levels of synaptic dopamine Recent studies have demonstrated that 5-HT2C agonists decrease levels of dopamine in the prefrontal cortex and nucleus accumbeπs (Millan, M. J., et. al., Neuropharmacology ST. 953-955, 1998; Di Matteo, V , et. al., Neuropharmacology 38 1195-1205, 1999; Di Giovanni, G., et. al , Synapse 35 53-61, 2000), brain regions that are thought to mediate critical antipsychotic effects of drugs like clozapine. However, 5-HT2C agonists do not decrease dopamine levels in the striatum, the brain region most closely associated with extrapyramidal side effects. In addition, a recent study demonstrates that 5-HT2C agonists decrease fϊππg in the ventral tegmental area (VTA), but not in the substantia nigra. The differential effects of 5-HT2C agonists in the mesolimbic pathway relative to the nigrostriatal pathway suggest that 5-HT2C agonists have limbic selectivity, and will be less likely to produce extrapyramidal side effects associated with typical antipsychotics.
Additionally, 5-HT2C receptors might also be involved in modulation of the rewarding properties of food, which is linked to increased mesolimbic dopamine levels in the nucleus accumbens of the brain in response to food ingestion. A number of studies have suggested that food and drug rewards may share some common neural substrates, specifically the nucleus accumbens (Saper, C. B.; Chou, T. C; Efmquist, J. K. The need to feed: homeostatic and hedonic control of eating. Neuron 2002, 36, 199-211). Given that 5-HTac receptor agonists may decrease dopamine levels in the nucleus accumbens and that reward-related behaviors (e.g., cocaine or nicotine self- admtnistration in rats) may be reduced by 5-HT2C receptor activation, the possibility that 5-HT2c receptor agonists may reduce the rewarding properties of food should also be considered (Higgins, G. A.; Fletcher, P. J. Serotonin and drug reward" focus on 5-HT2Q receptors. Eur. J. Pharmacol. 2003, 480, 151-162).
Another therapeutic area where the use of a 5-HT2C receptor agonist is considered of value is in the treatment of epilepsy Epilepsy, a brain disorder manifested by recurrent seizures, refers to a complicated constellation of more than 40 distinct disorders. The seizure, a sudden massive neuronal discharge, can be either partial or complete, depending on the area of brain involved or whether or not consciousness is impaired. Normally there is a balance between excitation and inhibition in the brain. When this balance is disrupted by increased excitation or decreased inhibition, a seizure may result. The neuronal discharges may stimulate muscles innervated by the nerves involved, resulting in involuntary muscle contractions, or convulsions (Lee, G. V ; Jones, E. J. Epilepsy. Neurobiology of Diseases 2000, 7, 549- 551). There are currently several drugs in clinical use to inhibit seizures, which fall into three different categories in terms of their target (Cosford, N. D. P.; McDonald, I. A.; Schweiger, E. J. Recent Progress in Antiepileptic Drug Research. Annu. Rep. Mθd. Chem. 1998, 33, 61-70). Most common are the drugs that affect the flow of sodium into the cell via voltage-gated sodium ion channels. A sodium ion channel is a structure in the cell membrane that is selectively permeable to sodium ions and is opened by changes in voltage across the cell membrane Other drugs affect calcium ion channels. The third category of drugs affects some aspect of inhibitory synapses that are activated by the neurotransmitter γ-aminobutyric acid (GABA). Despite the availability of these drugs, a large proportion of patients continue to have seizures. Furthermore, among those in whom seizures are effectively inhibited, substantial numbers experienced persistent and undesirable effects from these drugs. In light of this, the current goal of researchers is to identify new classes of anti-seizure drugs that act on novel molecular targets and by novel mechanisms that may permit effective treatment of large numbers of individuals unsatisfactorily treated at present. The recently cloned 5-HT2c receptor has revealed a novel molecular target that provides just this opportunity for the development of novel antiepileptic drugs
There is growing evidence that serotonergic neurotransmission modulates a wide variety of experimentally-induced seizures and Involved in the enhanced seizure susceptibility observed in some genetically prone rodents Przegalinski, E., Baran, L.; Siwanowicz, J. role of 5-hydroxytryptamine receptor subtypes in the 1-[3-{trifluoromethyl)phenyl] piperazine-induced increase in threshold for maximal electroconvulsions in mice Epilepsia, 1994, 35, 889-894; Wada, Y.; Shiraishi, J.; Nakamura, M.; Koshmo, Y. Role of serotonin receptor subtypes in the development of amygdaloid kindling in rats. Brain Res , 1997, 747, 338-342). Studies have shown that mice bearing a targeted disruption of the 5-HT2c receptor genes exhibit an epilepsy syndrome associated with sporadic spontaneous seizures that occasionally result in death. In all epifeptc paradigms, mice lacking the δ-HTϊc receptors were significantly more seizure susceptible than wild-type controls. Results indicate that mutants have lower focal seizure thresholds, increased focal seizure excitability, and facilitated propagation within the forebrain seizure system. Mutants also exhibit lower generalized seizure threshold for the expression of both generalized clonic and generalized tonic seizures. Importantly, the 5-HT receptor antagonist, mesulergine (2 or 4 mg/kg), administered prior to electroshock testing, recapitulated the mutant phenotype in wild-type mice. Together, these data strongly implicate a role for serotonin and the 5-HT2C receptors in the modulation of neuronal network excitability and seizure propagation throughout the CNS (Appelgate, C. D , Tecott, L. H. Global increases in seizure susceptibility in mice lacking 5-HT2C receptors; a behavioral analysis. Exp. Neurol. 1998, 154, 522-530, Hetsler, L. K ; Chu. H. M.; Tecott, L. H. Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice. Ann. N. Y. Acad. Sci. 1998, 861, 74-78; Rueter, L E.; Tecott, L. H ; Blier, P. In vivo electrophysiological examination of 5-HT responses in 5-HT2C receptor mutant mice. Naunyn-Schmiedβberg's Arch. Pharmacol, 2000, 361, 484-491) Furthermore, agents that elevate extracellular serotonin {5-HT) levels, such as 5-hydroxytryptophan and 5-HT reuptake blockers, inhibit both limbic and generalized seizures Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically and electrically evoked convulsion (Loscher, W ; Genetic animal models of epilepsy as a unique resource for the evaluation of anticonvulsant drugs. A review. Methods Find Exp. Clin. Pharmacol., 1984, 6, 531-547, Prendiville, S ; Gale, K. Anticonvulsant effect of fluoxetine on focally evoked limbic motor seizures in rats. Epilepsia, 1993, 34, 381-384; Yan, Q. S ; Jobe, P. C; Cheong, J. H.; Ko, K. H.; Daily, J. W Role of serotonin in the anticonvulsant effect of fluoxetine in genetically epilepsy-prone rats. NaunynSchmiedβberg's Arch. Pharmacol , 1994, 350, 149-152)
Reduction in seizure activity has been observed for the 5-HT2C receptor agonists mCPP and TFMPP when microinjected bilaterally into the rat substantia nigra. This indicates that the 5-HT2C receptors in the substantia nigra may contribute to seizure regulation (Gobert, A.; Rivet, J.; Lejeune, F., et a/ Serotonin (2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 2000, 36, 205- 221, Hutsoπ, P. H., Barton, C. L; Jay, M., et al. Activation of mesolimbic dopamine function by phencyclidine is enhanced by 5-HT2c/2B receptor antagonists: neurochemical and behavioural studies. Neuropharmacology 2000, 39, 2318-2328). Among the clinically effective anticonvulsants such as carbamazepine, dose-related anticonvulsant effects correlate with increased extracellular serotonin further implicating the role of serotonin and hence the 5-HT2C receptor agonist in epileptic seizures. Nevertheless, cross talk between the δ-HTzc and γ-amino butyric acid (GABA) receptors in the mediation of the observed anticonvulsant activity should not be overlooked (Huidobro-Toro, J. P.; Valenzuela, C. F.; Harris, R. A Modulation of GABAA receptor function by G protein-coupled 5-HT2C receptors Neuropharmacology 1996, 35, 1355-1363).
Despite the fact that a large number of 5-HT receptors with different anatomical localization and function have been identified, there are only few studies investigating the role of 5-HT receptor subtypes in the modulation of seizure activity and the results are sometimes controversial depending on the experimental epilepsy model used (Jakuε, R.; Graf, M.; Juhasz, G.; Geber, K.; Evay, G.; Halasz, P ; Bagdy, G. 5-HTzc receptors inhibit and 5-HTIA receptors activate the generation of spike-wave discharges in a genetic rat model of absence epilepsy. Exp. Neurol. 2003, 184, 964-972). In order to further delineate the role of the &-HT2C receptors in seizure generation, the effects of the 5-HT2C preferring agonist, mCPP, were evaluated in a genetic absence epilepsy mode!. mCPP weakly elevated seizure threshold in mice {but not in rats) electroshock test, however appreciable protection against pentylenetetrazol-induced myoclonic and/or tonic seizures in mice and rats were observed. This protection against pentylenetetrazol-induced myoclonic and/or tonic seizures in mice and rats was inhibited by the 5-HT2C/2B receptor antagonist, SB 206533. The fact that the 5-HT2B agonist, BW-723C86, had no effect on animal seizure models supports the view that the 5-HT2C receptor mediated the mCPP-induced anticonvulsant effects (Upton, N ; Middlemiss, D ; Dlαckburn, T., αi α/. studies on tne roie Oftj-M fib and "5"-"RTzB" receptors in regulating generalized seizure threshold in rodents. Eur. J. Pharmacol. 1998, 359, 33-40). The selective 5-HTzc receptor antagonist, SB 242084 do not induce pro-convulsant effects in rats, which are characteristic of mutant mice lacking the 5-HT2C receptor. This failure to exhibit pro-convulsant properties in rats in contrast to the reported characteristics of mutant mice lacking 5-HΪ2C receptors might be accounted for by species differences (Di Matteo, V.; Di Giovanni, G,; Eposito, E. SB-242084: A Selective 5-HT2C Antagonist. CNS Drug Rev. 2000, 6, 195-205). Curiously, given the link between transferrin and the 5-HT2c receptor, it would be of interest to study whether other transport proteins synthesized in the choroid plexus, in particular transthyretin (formerly called prealbumin), also are modulated by 5-HT2C receptors. While speculative, this may be relevant for research on Alzheimer's disease (AD) because independent studies have indicated that both 5-HTzc receptor agonism and transthyretin may reduce the amyloidogenic cleavage of the amyloid precursor protein (APP), a cleavage that produces neurotoxic /S-amyloid protein, the principal proteinaceous component of brain amyloid plaques characteristic of AD (Arjona, A. A.; Pooler, A. M.; Lee, R. K.; Wurtman, R. J. Effect of a 5-HT2c serotonin agonist, dexnorfeπfluramine, on amyloid precursor protein metabolism in guinea pigs. Brain Res. 2002, 951, 135-140; Stein, T. D.; Anders, N. J.; DeCarli, C; Chan, S. L; Mattson, M. P.; Johnson, J. A. Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPsw mice resulting in tau phosphorylation and loss of hippocampal neurons: support for the amyloid hypothsis. J. Neumsci. 2004, 24, 7707- 7717).
In recent years, several case reports of the efficacy of psilocybin in the treatment of obsessive-compulsive disorder (OCD) have been published (Delgado, P. L; Moreno, F. A. J. Psychoactive Drugs 1998, 30, 359). As a result, an FDA-approved clinical triaJ for patients suffering from OCD is now underway (Sard, H.; Kumaran, G.; Morency, C; Roth, B, L; Toth, B.; He, P.; Shuster, L. Bioorg. Med. Cham. Lett. 2005, 15, 4555). The hallucinogenic activity of psilocybin and psifocin is believed to be largely due to activation of 5-HT2A receptors, while the anti-OCD activity is associated with agonist activity at 5-HT2C Thus, it is believed that a selective 5-HT2C agonist would have considerable potential for treatment of OCD (Roth, B L; Shapiro, D Expert Opin. Ther. Targets 2001 , 5, 685)
Selective serotonin reuptake inhibitors (SSRIs) increase extracellular levels of serotonin (5HT) and thereby nonselective^ cause stimulation of all postsynaptic 5HT receptor subtypes SSRIs have become standard therapy for neuropsychiatry disorders such as obsessive compulsive disorder (OCD), depression, and panic anxiety. There is accumulating evidence for the involvement of 5HT2c receptor-mediated functions in the therapeutic efficacy of SSRIs (PalvimSki, E. -P ; Roth, B. L.; Majasuo, H ; Laakso, A , Kuoppamaki, M.; Syvalahti, E.; Hietala, J. Interactions of selective serotonin reuptake inhibitors with the serotonin 5HT2C receptor, Psychopharmacology 1996, 126, 234-240; Jenck, F : Moreau, J -L.; Mutel, V , Martin, J. R ; Haefely, W. E. Evidence for a role of 5HTic receptors in the antiserotonergic properties of some antidepressant drugs. Eur J. Pharmacol 1993, 231, 223- 229). The increased 5HT synaptic content resulting from the reuptake inhibition also allows 5HT to act on the other 5HT receptor subtypes, possibly explaining some of the side effects associated with SSRI treatment. Selective 5HT2C receptor agonists, therefore, may represent a direct means to produce the beneficial therapeutic effects of SSRIs without concomitant side effects.
Although these studies implicated the 5-HT2c receptors in the modulation of feeding (obesity), schizophrenia, epilepsy, OCD and other related disorders, elucidation of the functional roles of these receptors has been hindered by a limited availability of selective agents In addition, such paucity of selective agents can be attributed to the fact that the 5-HT2C receptors share substantial sequence homology with the 5-HT2, and 5-HT2b receptor.
Summary of the Invention
In one aspect, there is provided a compound of Formula I:
Figure imgf000011_0001
wherein:
R1 to R3 and R5 to R12 are independently selected from H, halo, hydroxy, cyano, nitro, alkyl, alkoxy, CH2OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cyaπoalkyl, alkenyl, alkyny), cycloalkyl, cycloalkenyl, heterocydoalky), heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cydoalkyl, O- heterocycloalkyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, aJkylene-O- heterocycloalkyl, alkylene-O-alkyleπe-cycloalkyl, alkyleπe-O-alkyleπe- heterocycloalkyl. S-alkylτ S{O)-alkyl, S(O)2-alkyl, S-cycloalkyl, S(O)-cycloalkyl, S(0)z-cycloalkyl, S-heterocycloalkyl, S{O)-heterocycloalkyl, S(O)2- heterocycloalkyl, O-aryl, O-heteroaryl, N(H)alky|, N(alkyl)alkyl, N(H)^r/!, N{alkyl)-aryl, N(H)-heteroaryl, N(alkyl)-heteroaryl, alkylene-O-aryl, alkyleπe-O- heteroaryl, alkylene-O-alkylene-aryl, alkyleπe-O-aikylene-heteroaryl, S-aryl, S- heteroaryl, S(O)-aryl, S(O)-heteroaryl, S(O)2-aryl, S(O)3-heteroaryl, C(O}alkyl, OC(O)alkyl, C(O)Oalkyl, C(O)N(H)alkyl, C(O)N(alkyi)alkyl, S(O)2N(H)alkyl or S(O)2N(alkyl)alkyl; R2 and R3, R5 and R6, R9 and R10, and/or R11 and R12, together with the carbon atom to which they are attached, form a cycloalkyl group; and
R4 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylene- O-alkyl, alkylene-O-cycloalkyl, alkylene-O-alkylene-cycloalkyl;
and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof. in another aspect, any cyclic group is substituted with one or more R13, R13 being selected from F, Cl1 Br, I, CN, nitro, hydroxy, oxo, d-6-alkyl, Od-e-alkyl, Ci-5-alkylhalo or OC1-β-alkylhalθ.
In a further aspect, R4 is selected from H, alkyl, cycloalkyl, or cycloatkenyl.
In yet a further aspect, RA is selected from H or alkyl.
In a further aspect, R9 to R1z are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.
In yet a further aspect, R9 to R12 are independently selected from H, afkyl or cycloalkyf.
In a further aspect the compound is a pharmaceutically-acceptabfe salt, optical isomer, or combination thereof.
In a further aspect, the pharmaceutically-acceptable salt comprises an acid addition salt or a basic addition salt.
In a further aspect, the acid addition salt is formed from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acid metal salt, monocarboxylic acids, dicarboxylic acids, or tricarboxylic acids.
In yet a further aspect, the compound of Formula I comprises a compound of Formula IA:
Figure imgf000013_0001
IA wherein:
R2 and R5 are independently selected from H1 alky!, alkyleπe-O-alkyl, C(O)Oalkyl, C(O)N(H)alkyl, haloalkyl, halogen or CH2OH; and
R3 and R6 are each H; or R2 and R3 and/or R5 and R6, together with the carbon atom to which they are attached form a cycloalkyl group;
and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
In a further aspect. R2 and R5 are independently selected from CH2F, CHF2, or CF3.
In a further aspect, the compound of Formula I comprises a compound of Formula IB:
Figure imgf000013_0002
IB wherein : 2 is selected from CR14R15, O, NR16, C=O, S-O. SO2 or S; and
R14 to R16 are independently selected from from H, halo, hydroxy, cyano, nitrσ, alkyl, alkoxy, CH2OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alkyπyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O-heterocycloalkyl, alkylene-O-alkyl, alkylene-0-cyc/oalky|, alkylene-O-heterocycloalkyl, alkyleπe- O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloalkyl, S-alkyl, S(O)- alkyl, S(O)2-alkyl, S-cycloalkyl, S(0)-cydoalkyl, S(0)2-cycloalkyl. S- heterocycloalkyl, S(0)-heterocycloalkyl, S(0)2-heterocycloalkyl, O-aryl, O- heteroaryl, N(H)alkyl, N(alkyl)aJkyl. N(H)-aryl, N(alkyl)-aryl, N(H)-heteroaryl, N(a)kyl)-heteroaryl, alkylene-O-aryl, alkylene-O-heteroaryl, alkylene-O- alkylene-aryl, alkyleπe-O-alkylene-heteroaryf, S-aryl, S-heteroaryl, S(O)-aryϊ, S(O)-heteroaryl, S{O)2-aryl, S(O>2-rιeteroaryl, C(O)alkyl, OC(O)alkyl, C(O)Oalkyl, C(O)N(H)alkyl, C(O)N(alkyl)alkyl, S(O)2N(H)alkyl or S(O)2N(alkyl)alkyl;
and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof. In a further aspect, R1 is selected from H or halo; R2 and R3 are independently selected from H or alkyl; R14 and R15 are independently selected from H, halo, or alkyf; and R1β is selected from H or alkyl. In a further aspect, the halo is bromo, chloro, or fluoro. In a further aspect, Z is CR14R15, wherein R14 is H or fluoro and R15 is fluoro. In a further aspect, R1 is H and Z is CR14R15, wherein R14 is H and R15 is fluoro.
In a further aspect, the compound of Formula I comprises a compound of Formula IC:
Figure imgf000015_0001
wherein :
2 is selected from CR14R15, O, NR16, C=O, S=O1 SO2 or S; and
R14 to R1β are independently selected from from H1 halo, hydroxy, cyano, πitro, alKyl, alkoxy, CH2OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloafkenyl, aryl, heterαaryl, alkylaryl, alkylheteroaryl, 0-cycloalkyl, O-heterocycloalkyI, alkylene-O-alkyl, alkyteπe-O-cycloalkyl, atkylene-O-heterocycioalkyl, alkylene- O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloafkyl, S-alkyl, S(O)- alkyl, S(Q)2~alkyl, S-cycloalkyl, S(O)-cyc!oalkyl, S(O)2-cycloalkyl, S- heterocycloalkyl, S<0)-heterocycloalkyl, S(0)2-heterocycloalky|, O-aryl, O- heteroaryl, N(H)alkyl, N(alkyl)alky|, N(H)-aryl, N(alkyl)-ary|, N(H)-heteroaryl, N(alkyl)-heteroary(, alkylene-O-aryl, alkylene-O-heteroaryl, alkylene-O- alkyiene-aryl, alkylene-O-alkylene-heteroaryl, S-aryl, S-heteroaryl, S(O)-aryI, S{O)-heteroary|, S(O)2-aryl, S(0)2-heteroaryl, C(O)alkyl, OC(O)alkyl, C(0)Oalkyl, C(O)N(H)alkyl, C(O)N(alkyl)alkyl. S(O)2N(H)alkyi or S(O)?N(alkyl)alkyl;
and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof. In a further aspect, R1 is selected from H or halo; R2 and R3 are independently selected from H or alky); R14 and R15 are independently selected from H, halo, or alkyl; and R1βis selected from H or alkyl. In a further aspect, the halo is bromo, chloro, or fluoro. In a further aspect, Z is O. In a further aspect, the compound of Formula \ comprises a compound of Formula II:
Figure imgf000016_0001
R , R , R7 and RB are as defined hereinabove.
In a further aspect, the compound of Formula J comprises a compound of Formula III:
Figure imgf000016_0002
R1, R4, R5, R6, R7 and R8 are as defined hereinabove.
In a further aspect, the compound of Formula I comprises a compound of Formula IV:
Figure imgf000017_0001
IV
R1, R2, R3, R4, R7 and R8 are as defined hereiπabove.
In a further aspect, R1 is selected from H, alkyl or halo; R2, R3 and R8 are independently selected from H or alkyl; R* is selected from H or alkyl; and R7 is selected from H, alkyl, alkoxy, CHzOH, alkeπyl, cydoalkyl, heterocydoalkyl, aryl, or heteroaryl.
In a further aspect, there is provided a compound selected from:
(9R)-2-(4,4-difluoropiperidin-1-yl)-9-methyl-6,7,8,9-tetrahydro-5H- pyrido[2, 3d]azepine;
(9R)-2-{4-fluoropiperidin-1-yl)-9-methyl-6,7,8,9-tetrahydro-5H-pyrido{2,3- djazepine; (9R)-9-methyl-2-(1 ^-oxazepan-^ylJ-θ./.Θ.S-tetrahydro-SH-pyridoIS.a- d]azepine;
{9R)-9-methyl-2-morpholin-4-yl-6,7,8,9-te{rahydro-5H-pyrido[2,3-d]azepine;
(ΘRVΘ^ethyl^piperidin-i-yl-ej.β.θ-tetrahydro-SH-pyrido^S-dlazepine,
(9R)-N-ethyl-N,9-dlmetnyl-6,7,8r9-tetrahydro-5H-pyrido[2,3-d]azepiπ-2-amine; (9S)-2-(4I4-difluoropiperidin-1-yl)-9-methyl-6,7.a,9-tetrahydro-5H-pyrido[2l3- d]azepine;
(9S)-2-(4-fluoropiperidin-1-yl)-9-methyl-6,7,8l9-tetrahydro-5H-pyrido[2,3- djazepine;
(9S)'9-methyl-2-(1,4-oxazepan-4-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3- d]azepine
(9S)-9-methyl-2-morpholin-4-yl-6,718,9-tetrahydro-5H-pyrido[2,3-d]azepine,
(9S)-9-methyl-2-piperidm-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; (9S)-N-ethyl-N,9-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
2-(1,4-djazepan-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-(1,4-oxazepan-4-yl)-6>7l8τ9-tetrahydrθ'5H-pyrido[2,3-d]azepine;
2-(1-oxidothiornoφholin-4-y|)-6,7,8,9-tetrahydro-5H-pyrido[2l3-d]azepine; 2-(3-thieπyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-(4,4-difluoroazepan-1-yl)-6)7,8,9-tetrahydro-5H'Pyrido{2t3-d]azepine;
2-(4,4-difluoroazepan-1-yl)-9-fnethy/-6,7,8,9-tetrahydro-5H-pyrido[2,3- djazepine;
2-(4,4-difluoropjperidin-1-yl)-6,7,8,9'tetrahydro-5H-pyrido[2,3-d]azepine; 2-(4,4-difluoropiperidin-1-yl)-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3- d]azepine;
2-(4-fluoropiperrdin-1-yl)-6l7,8Iθ-tetrahydro-5H-pyrido[2,3-d]azepine;
2-(4-fluoropiperidin-1-yl)-9-methyl-6,7,8,9-tetrahydro-5H-pyrido{2.3-d]azepine;
2-(4-methylpiperazin-1-yt)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine: 2-(8-a2abicyclo[3.2.1]oct-8-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-(trifluoromethyl)-6l7,8,9-tetrahydro5H-pyrido[2,3-d]azepine;
2,9-dimethy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-[methyl(6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino]ethaπol;
2-azepan-1-yl-6,7,8,9-tetrahydiO-5H-pyπdo[2,3-d]a2:epiπe; 2-azepan-1-yl-9-isopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepiπe;
2-azepan-1-yl-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-cyclopropyl-6,7,8,9-tetrahydro-5H-pyridol2,3-dJazepine;
2-cyclopropyl-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3'd]azepine;
2-isopropenyl-6, 7,8, 9-tetrahydro-5H-pyrido[2, 3-d]azepine; 2-isopropeπy]-9-methyl-6,7,819-tetrahydro-5H-pyrido[2,3-d]azepine;
2-isopropyl-6,7,8,9-tetrahydro-5H-pyπdo{2,3-d]azepine;
2-isopropyl-9-methyl-6r7,8,9-tetrahydro-5H-pyrido[2l3-d]azepine;
2-methoxy-6p7,8,9-tetrahydro-5H-pyridof2,3-d]azepine;
2-methoxy-9-methy[-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; 2-methyl-6,7,8,9-tetrahydro-5H-pyridot2,3-d]azepine;
2-morpholiπ-4-yl-6,7,8,9'tetrahydro-5H-pyrido[2,3-d]azepine;
2-piperazin-1-yl-6,7,8,9-tetrahydro-5H-pyridot2,3-d]azepine;
2-piperrdin-1-yl-6,7,8p9-tetrahydro-5H-pyridof2,3-d]azepine;
2-pyrrolidiπ-1-yl-6,7t8l9-tetrahydro-5H-pyrido[2,3-dlazepine; 2-tert-butyl-6,7,8.9-tefrahydro-5H-pyrido[2,3-cl]azepiπe;
2-thiomorpholin-4-yl-6,7,8,9-tetrahydro-5H-pyridof2,3-d]azepine;
2-vinyl-6, 7, 8, 9-tetra hydro-5H-pyrido[2, 3-d]azepine;
3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; 3-bromo-2-moφholin-4-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
3-bromo-2-piperidin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2l3-d]azepiπe;
3-bromo-N-ethyl-N-methyl-6,7.8.9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
3-chlDro-2-{1,4-oxazepan-4-yl)-6l7.8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
3-chloro-2-(4,4'difluoropiperidiπ*1-yl)-6,7,8l9-tetrahydro-5H-pyrido[2,3- djazepine;
3-chloro-2-(4-fluoropiperidiπ-1-yl)-6,7,8,9-tetrahydro-5H-pyricJot2l3-d]azepine;
S-chloro^-morpholin^-yl-ej.δ.θ-tetrahydro-SH-pyridoβ.S-dlazepine;
3-chlαro-2-piperidin-1-yl-6,7,8,9-tetrahydro-5H-pyridot2.3-d]azepine; ej.S.B-tetrahydrO'δH-pyrido^^-dJazepine^-carbaldehyde; e.T.O^^etrai'iycliu^SH^ytitJotZ.j-ajazepine^-cartjonitrile;
9-ethyl-2-moφholin-4-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
9-ethyl-2-pipeπdin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
9-isopropyl-2-morpholin-4-yl-6.7,8,9-tetrahydro-5H-pyrido[2,3-d]azepinβ;
9-isopropyl-2-piperidin-1-y[-6,7,8,9-tetrahydro-5H-pyιido[2,3-d]azepine; 9-methyl-2-(1,4-oxazepan-4-yl)-6,7,8.9-tetrahydro-5H-pyrido[2,3-d]azepine;
9-methyl-2-moφholin-4-yl-6,7,819-tetrahydro-5H-pyrido[2,3-d]azepine;
9-methyl-2-piperidin-1-yl-j6l7,8,9-tetrahydro-5H-pyrido[2,3-d]azepϊne; ethyl 4-(6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepiπ-2-yl)piperazine-1- carboxylate; N,9-diethyl-N-methyl-617,8,9'tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
N,N,9-trimethyl-6,7,8,9-tetrahydra-5H-pyrido[2,3-d]azepiπ-2-anniπe;
N.N-diallyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amiπe;
N.N-diethyt-ej.δ.θ-tetrahydro-SH-pyridoI∑.S-dJazepin^-amine;
N>N-dimBthyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine; N,N-dimethyJ-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azeρiπe-2-carboxamide;
N'beπzyl-N-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
N-ethyl-N,9-dimethyl-6,7,8,9'tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
N-ethyi-N-methyI-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
N-isopropyl-N-methyl-6,7p8p9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine; N-methyl-6,7,8,9-tetrahydro-5H'pyrido[2,3-d]arepin~2-amine; N-methyl'N-(6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-y{)acetamide; 2-Phenyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; 6,7,8,9-Tetrahydro-5H-pyrido[2τ3-d]azepine-2-carboπitrile; 2-Chloro-6,7,8,9-tetrahydro-5H-pyridot213-d]azepine,
[2-(6-Methoχy-3-methyl-pyridin-2-yl)-ethyl]-methy|-amιne; and/or 7,8,9-Tetrahydro-5H-pyrido[2,3-d]azepin-2-ol;
and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof
In a further aspect, there is provided a compound selected from:
(9R)-2-(4,4-difluoropιperidin-1-yl)-9-methyl-6,7,8,9-tetrahydro-5H~ pyrido[2,3d]azeρine; {9R)-2'(4-fluoropiperidin-1-yl)-9-methyl-6,7,a,9-tetrahydro-5H-pyπdo[2,3- d)azepine;
(ΘRJ-S-methyl^^i.Φoxazepan-^-yO-ej.S.Θ-tetrahydro-SH-pyπdo^.S- d]azepine;
(9R)-9-methyl-2-morpholin-4-yl-6,7,8,9-tetrahydro-5H-pyridot2,3-d]azepine; (9R)-9-methyl-2-piperidln-1-yt-6,7,8,9-tetranydro-5H-pyrjdo[2,3-d]azepine;
(ΘRJ-N-ethyl-N.Q-dimethyl-ej.β.θ-tetrahydro-SH-pyridop.S-dlazepin-a-amine,
(9S)-2-(4l4-difli-Oropiperidin-1-yl)-9-methyl-6l7,8r9-tetrahydro-5H-pyrido[2l3- djazepine;
(9S)-2-(4-fluoropiperidjn-1-yF)-9-methyl-θ,7,8,9-tetrahydro-5H-pyrido[2,3- d]azepine;
(9S)-9-methyl-2-(1,4-oxazepan-4-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3- d]azepιπe
(gSj-g-methyl^-morpholin-A-yl-ej.β.θ-tetrahydro-δH-pyrido^.S-dJazepine;
<9S)-9-methyl-2-piperidin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; (gSJ-N-ethyl-N.Θ-dimethyl-e^^.g-tetrahydro-SH-pyridop.S-dlazepin^-amine;
2-(1r4-diazepan-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-dJazepine,
2-(1,4-oxazepaπ-4-yl)-6,7,8,9-tetrahydro-5H-pyπdo[2,3-d]azepine;
2-(4,4-difluoroazepan-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepiπe;
2-(4,4-difluoropiperidiπ-1-yl)-6,7,8,9-tefrahydro-5H-pyπdo[2,3-d]azepine; 2-<4-fluoropιperidιn-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine,
2-azepan- 1 -yi-6, 7, 8,9-tetrahydro~5H-pyrido[2, 3-dJazepme;
2-azepaπ-1-yl-9-methyl-6,7t8,9-tetrahydrσ-5H-pyrιdo[2,3-d]azepine;
2-cyclopropyl-9-rnethyl-6,7,8,9-tetrahydro-5H-pyrido(2,3-d]azepine; 2-isopropenyl-6,7,8,9-tetrahydro-5H-pyπdo[2.3-dlazepine,
2-ιsopropeny l-9-methyi-6, 7, 8, 9-tetrahy dro-5H-pyrido[2 , 3-d]azepιne;
2-ιsopropyl-6t7,8,9-tetrahydro-5H-pyπdo[2,3-d]azepine.
2-ιsopropyl-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepιne;
2-morpholin-4-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepιπe; 2-pιperidιn-1-yl-6,7,8,9-tetrahydro-5H-pyndo[2,3-d]azepιπe;
2-tert-butyl-6,7,8,9-tetrahydro-5H-pyπdo[2,3-d]azepiπe;
2-thiomorpholin-4-yl-6,7,8,9-tetrahydro-5H-pyπdo{2,3-d]azepine,
3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine,
3-chloro-2-(1 l4-oxazepan-4-yl)-6,7,8,9-tetrahydro-5H-pyπdo[2,3-d]azepine; S-chloro^^.Φdifluoropiperidiπ-i-yO-βJ^.Θ-tetrahydro-SHφyridop.S- djazepine;
3-chloro-2-(4-fluoropιperidin-1-yl)-6,7,8I9-tetrahydfθ-5H-pyrido[2,3-d]azepjπe;
S-chloro^-morpholin^-yt-ej.S.O-tetrahydro-SH-pyridop^-dJazepine,
3-chlαro-2-pιperidin-1-yt-6,7,8,9-tetrahydro-5H-pyπdo[2,3-d]azepιne; θ-isopropyl^-piperidm-i-yNβJ.δ.θ-tetrahydro-SH-pyπdoP.S-dJazepine;
9-methyl-2-morpholιn-4-yl-6,7,8,9-tetrahydro-5H-pyrido{2,3-d]azBpine; θ-methyl^-pipendin-i-yl-ε.T.δ.D-tetrahydro-δH-pyridop^-djazepine;
N.N-diethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-dJazepin-2-amine,
IM,N-dimethyl-6,7,819-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine, N-ethyl-N , 9-dιmethyl-6,7,8, 9-tetrahydro-5H-pyrid o[2 , 3-d]azepin-2-amine; and/or
N-ethyI-^N-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
and/or a pharmaceuticalty-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
In yet another aspect, there is provided a compound according to any one of the compounds noted above, wherein the compound has an EC50 for a human 5-HΪ2C receptor selected from less than 1000 nM, less than 500 nM, less than 300 nM, or less than 100 nM.
In another aspect, there is provided a Boc-protected precusor of the compound according to any one of the compounds noted above, or mixtures thereof
In another aspect, there is provided a pharmaceutical composition comprising at least one of the compounds noted above and at least one pharmaceutically acceptable carrier and/or excipient.
In a further aspect, there is provided a method for making the compound of Formula I, wherein R11 and R12 are H, the method comprising:
Figure imgf000022_0001
reacting a compound of Formula A under conditions (a), wherein said (a) comprises heat and base assisted cyclizatton of the compound of Formula A to provide an amide of Formula B; and reducing the carboπyl of the amide of Formula B1 whereby R' is alkyl or cycloalkyl In a further aspect, there is provided a method for making the compound of Formula I, wherein R9 and R10 are H, the method comprising:
Figure imgf000023_0001
BB reacting a compound of Formula AA under conditions (a), wherein said (a) comprises heat and base assisted cyclization of the compound of Formula AA to provide an amide of Formula BB; and reducing the carbonyl of the amide of Formula BB, whereby R' is alky] or cycloalkyl.
In a further aspect, there is provided a method for making the compound of Formula I, wherein R11 and R1Z are H, the method comprising: reducing a carbonyl of an amide:
Figure imgf000023_0002
In a further aspect, there is provided a method for making the compound of Formula I, wherein R9 and R10 are H1 the method comprising, reducing a carbonyl of an amide:
Figure imgf000024_0001
In a further aspect, there is provided a method for making the compound of Formula I, wherein RB, R10, R11 and R1Z are H, the method comprising: reducing carbonyl groups of an amide:
Figure imgf000024_0002
In a yet further aspect, there is provided a method for making the compound of Formula I, wherein R11 and R12 are H, the method comprising:
Figure imgf000024_0003
reacting a compound of Formula C under conditions (a), wherein said (a) comprises selective cyaπo reduction followed by cyclization of the compound of Formula C to provide Formula I1 whereby R' is alkyl or cycloalkyl.
In a yet further aspect, there is provided a method for making the compound of Formula I, wherein R9 and R10 are H, the method comprising:
Figure imgf000025_0001
cc
reacting a compound of Formula CC under conditions (a), wherein said (a) comprises selective cyano reduction followed by cyclization of the compound of Formula CC to provide Formula I1 whereby R' is alkyl or cycloalkyl.
In a yet further aspect, there is provided a method for making the compound of Formula I, wherein the method comprises:
Figure imgf000025_0002
reacting a compound of Formula D under conditions (a), wherein said (a) comprises cyclization of the compound of Formula D to provide Formula I1 whereby R' is alkyl or cycloalkyl. In a yet further aspect, there is provided a method for making the compound of Formula I, wherein the method comprises:
Figure imgf000026_0001
reacting a compound of Formula DD under conditions (a), wherein sard (a) comprises cyclization of the compound of Formula DD to provide Formula I, whereby R' is alkyl or cycloalky).
In another aspect, there is provided a method for treating a 5-HΪ2C receptor- mediated disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or composition noted above, in a further aspect, the mammal is a human. In another aspect, the disorder is selected from obesity, schizophrenia, epilepsy, depression, panic anxiety, alcoholism or obsessive compulsive disorder, a depressive disorder, an anxiety disorder, including panic attack, agoraphobia, and specific or social phobia, bipolar disorder, post-traumatic stress, an eating disorder, obesity, a gastro-intestiπal disorder, alcoholism, drug addiction, schizophrenia, a psychotic disorder, a sleep disorder, including sleep apnea, migraine, sexual dysfunction, a central nervous system disorder, including trauma, stroke and spinal cord injury, a cardio-vascular disorder, diabetes insipidus, obsessive compulsive disorder, premenstrual tension, chronic fatigue syndrome, age- related memory disorder, personality disorder and raised intracranial pressure. In a further aspect, the disorder is selected from obesity, schizophrenia, epilepsy, a depressive disorder, panic attack, alcoholism, drug addiction or obsessive compulsive disorder. In stilf a further aspect, the compound is administered orally and/or parenterally. In yet another aspect, the compound is administered intravenously and/or intraperitoneally In yet a further aspect, there is provided the use of the compound or composition noted above for the manufacture of a medicament for treatment of a 5-HT2c receptor-mediated disease in a mammal. In yet a further aspect, there is provided the use of the compound or composition noted above to treat a 5-HT2c receptor-mediated disease in a mammal. In a further aspect, the mammal is a human. In another aspect, the disorder is selected from obesity, schizophrenia, epilepsy, depression, panic anxiety, alcoholism or obsessive compulsive disorder, a depressive disorder, an anxiety disorder, including panic attack, agoraphobia, and specific or social phobia, bipolar disorder, post-traumatic stress, an eating disorder, obesity, a gastro-intestinal disorder, alcoholism, drug addiction, schizophrenia, a psychotic disorder, a sleep disorder, including sleep apnea, migraine, sexual dysfunction, a central nervous system disorder, including trauma, stroke and spinal cord injury, a cardio-vascular disorder, diabetes insipidus, obsessive compulsive disorder, premenstrual tension, chronic fatigue syndrome, age-related memory disorder, personality disorder and raised intracranial pressure. In a further aspect, the disorder is selected from obesity, schizophrenia, epilepsy, a depressive disorder, panic attack, alcoholism, drug addiction or obsessive compulsive disorder. In still a further aspect, the compound is administrable orally and/or parenterally. In yet another aspect, the compound is administrable intravenously and/or intraperitoneally.
In another aspect, there is provided a method for decreasing food intake in a mammal comprising administering to the mammal a therapeutically effective amount of a compound or composition as noted above.
In another aspect, there is provided a method of controlling weight gain in a mammal comprising administering to the mammal a therapeutically effective amount of a compound or composition as noted above.
The novel features of the present invention will become apparent to those of skill in the art upon examination of the following detailed description of the invention. It should be understood, however, that the detailed description of the invention and the specific examples presented, while indicating certain embodiments of the present invention, are provided for illustration purposes only because various changes and modifications within the spirit and scope of the invention will become apparent to those of skill in the art from the detailed description of the invention and claims that follow.
Brief Description of the Drawings
Certain embodiments of the invention are described, reference being made to the accompanying drawings, wherein:
Figure 1 shows graphically the effect of two exemplary compounds of the invention at vanous doses (mg/ml, X-axis), administered iπtraperitoneally (open bars) or orally (solid bars) on mouse locomotion expressed as % change control (Y axis)
Figure 2 shows graphicalfy the effect of two exemplary compounds of the invention at various doses (mg/ml) or vehicle administered intraperitoneal^ (X-axis) on rat food consumption (Y-axis). Hatched bars show pretreatment with S-HT26 antagonist SB242084 before compound administration.
Definitions
Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A1 B, C, D, E1 F, and H1 Pergamon Press, Oxford, 1979, which is incorporated by references herein for its exemplary chemical structure names and rules on naming chemical structures Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 5.09/September 2001 , Advanced Chemistry Development, lnc , Toronto, Canada.
The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E. L. Eliel and S. H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.
Generally, reference to a certain element such as hydrogen or H is meant to, if appropriate, include all isotopes of that element.
The following terms are meant to encompass uπsubstituted and/or substituted.
The term "aikyl" as used herein means a straight- or braπched-chaiπ hydrocarbon radical; in one aspect, having from one to eight carbon atoms, and includes, for example, and without being limited thereto, methyl, ethyl, propyl, isopropyl, t-butyl and the like. As noted above, "alkyl" encompasses substituted alkyl. Substituted alkyl includes, for example, and without being limited thereto, haloalkyl, hydroxyalkyl, cyanoalkyl, and the like. This is applied to any of the groups mentioned herein. Groups such as "alkenyl", "alkynyl", "aryl", etc. encompass substituted "alkenyl", "alkyπyl", "aryf", etc.
The term "alkenyl" as used herein means a straight- or branched-chain alkenyl radical; in one aspect, having from two to eight carbon atoms, and includes, for example, and without being limited thereto, ethenyl, 1-propenyl, 1-butenyl and the like. The term "alkenyl" encompasses radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.
The term "alkyπyl" as used herein means a straight- or branched-chain alkynyl radical; in one aspect, having from two to eight carbon atoms, and includes, for example, and without being limited thereto, 1-propyπyl (propargyl), 1- butyπyl and the like.
The term "cycloalkyl" as used herein means a carbocyclic system (which may be unsaturated) containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. In one aspect, the ring(s) may have from three to seven carbon atoms, and includes, for example, and without being limited thereto, cyclopropyl, cyclohexyl, cyclohexenyi and the like.
The term "heterocycloalkyl" as used herein means a heterocyclic system (which may be unsaturated) having at least one heteroatom selected from N1 S and/or O and containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. In one aspect, the ring(s) may have a three- to seven-membered cyclic group and includes, for example, and without being limited thereto, piperidinyl, pjperazinyl, pyrrolidiπyl, tetrahydrofuranyl and the like.
The term "alkoxy" as used herein means a straight- or branched-chair* alkoxy radical; in one aspect, having from one to eight carbon atoms and includes, for example, and without being limited thereto, methoxy, ethoxy, propyloxy, isopropyloxy, /-butoxy and the like.
The term "haio" as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms.
The term "alkylene" as used herein means a difunctional branched or unbranched saturated hydrocarbon radical; in one aspect, having one to eight carbon atoms, and includes, for example, and without being limited thereto, methylene, ethylene, n-propylene, n-butylene and the like.
The term "alkenyleπe" as used herein means a difunctional branched or unbranched hydrocarbon radical; in one aspect, having two to eight carbon atoms, and having at least one double bond, and includes, for example, and without being limited thereto, ethenylene, n-propenyleπe, n-buteny!ene and the like.
The term "alkynylene" as used herein means a difunctional branched or unbranched hydrocarbon radical; in one aspect, having two to eight carbon atoms, and having at least one triple bond, and includes, for example, and without being limited thereto, ethynylene, π-propynylene, n-butyπylene and the like.
The term "aryl" , alone or in combination, as used herein means a carbocyclic aromatic system containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. In particular embodiments, aryl is one, two or three rings In one aspect, the aryl has five to twelve ring atoms. The term "aryf" encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, bipnenyl, phenanthryl, aπthryl or acenaphthyl The "aryl" group may have 1 to 4 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamiπo and the like.
The term "heteroaryl", alone or in combination, as used herein means an aromatic system having at least one heteroatom selected from N, S and/or O and containing one or more nngs wherein such rings may be attached together in a pendent manner or may be fused. In particular embodiments, heteroaryl is one, two or three rings. In one aspect, the heteroaryl has five to twelve ring atoms. The term "heteroaryl" encompasses heteroaromatic radicafs such as pyridyl, mdolyl, furyl, beπzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl and the like. The "heteroaryl" group may have 1 to 4 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.
It is understood that substituents and substitution patterns on the compounds of the invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, as long as a stable structure results.
The term "pharmaceutically acceptable salt" means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients. A "pharmaceutically acceptable acid addition salt" is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates Illustrative inorganic acids which form suitable salts include, but are not limited thereto, hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic adds which form suitable salts include the mono-, di- and tricarboxylic acids. lllustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, maloπic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- pheπoxybenzoic, p-toluenesulfθnic acid and other sulfonic acids such as methaπesulfonic acid and 2-hydroxyethanesulfoπic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art, Other non-pharmaceutically acceptable salts e.g oxalates may be used for example in the isolaiioii uf
Figure imgf000032_0001
of Formula 1 for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
A "pharmaceutically acceptable basic addition salt" is any non-toxic organic or inorganic base addition salt of the acid compounds represented by Formula I or any of its intermediates Illustrative inorganic bases which form suitable salts include, but are not limited thereto, lithium, sodium, potassium, calcium, magnesium or barium hydroxides. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoliπe or ammonia. The selection of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art "Solvate" means a compound of Formula I or the pharmaceutically acceptable salt of a compound of Formula t wherein molecules of a suitable solvent are incorporated in a crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered as the solvate. Examples of suitable solvents, but are not limited thereto, are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate
The term "stereoisomers" is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space, ft includes mirror image isomers (enaπtiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).
The term "treat" or "treating" means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
The term "therapeutically effective amount" means an amount of the compound which is effective in treating the named disorder or condition.
The term "pharmaceutically acceptable carrier" means a non-toxic solvent dispersant, excipient, adjuvant or other material which rs mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.
A "5-HT2C receptor-mediated disorder", as used herein, is a disorder in which there is believed to be involvement of the pathway controlled by the S-HT∑c receptor and which is ameliorated by treatment with an agonist of the 5-HTzc receptor. δ-HT∑c receptor-mediated disorders include a depressive disorder, an anxiety disorder, including panic attack, agoraphobia, and specific or social phobia, bipolar disorder, post-traumatic stress, an eating disorder, obesity, a gastro-intestinal disorder, alcoholism, drug addiction, schizophrenia, a psychotic disorder, a sleep disorder, including sleep apnea, migraine, sexual dysfunction, a central nervous system disorder, including trauma, stroke and spinal cord injury, a cardio-vascular disorder, diabetes insipidus, obsessive compulsive disorder, premenstrual tension, chronic fatigue syndrome, age- related memory disorder, personality disorder and raised intracranial pressure.
Detailed Description
Compounds of the invention conform generally to Formula I:
Figure imgf000034_0001
I wherein R1 to R12 are defined heremabove.
In an embodiment, there is provided compounds of Formula I where Ra, R10, R11 and R12 are H:
Figure imgf000034_0002
IA Another embodiment of the invention provides compounds of Formula I where R2, R3. R5, Rβ, R9, R10, R11 and R13 are H (Formula II. below). A further embodiment of the invention provides compounds where R2, R3, R8, R10, R11 and R™ are H (Formula III, below). Yet another embodiment of the invention provides compounds where R5 and RB, R9, R10, R11 and R12 are H (Formula IV, below).
Figure imgf000035_0001
Figure imgf000035_0002
IV
A further embodiment of the invention provides compounds of Formula I where R5, R6, R9, R10, R11 and R12 are H and R7 is a 6-membered heterocyclic ring {see Formula IB, below).
Figure imgf000036_0001
IB wherein:
Z is selected from CR14R15, O, NR15, C=O, S=O. SO2 or S; and
R14 to R1B are independently selected from from H1 halo, hydroxy, cyano, nitro, alkyl, alkoxy, CHbOH1 haloalkyl, O-haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alkyπyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkeπyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O-heterocycloalkyl, a!kylene-O-alkyl, alkylene-0-cycloalky), alkyfene-O-heterocycloalkyl, alkylene- O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocyctoalkyf, S-alkyl, S(O)- alkyl, S(O)2-alkyl, S-cycloalkyl, S(O)-cycloalky!, S(O)2-cycloalkyl, S- heterocycloalkyl, S(O)-heterocycloalkyl, S(Oh heterocycloalkyl, O-aryl, O- heteroaryl, N(H)alkyl, N(alkyl)alkyl, N(H)-aryl, N(alkyl)-aryl, N(H)-heteroaryl, N(alkyl)-heteroaryl, alkylene-O-aryl, alkyleπe-O-heteroaryl, alkylene-O- alkylene-aryl, alkylene-O-alkylene-heteroaryl. S-aryl, S-heteroaryl, S(O)-aryl, S(O)-heteroaryl, S(O)2-ary<, S(O)2-heteroaryl, C(O)alkyl, OC(O)alkyl, C(O)Oalkyl, C(O)N(H)alkyl, C(O)N(alkyl)alkyl, S(O)2N(H)alkyl or S(O)2N(alkyl)alkyl.
A further embodiment of the invention provides compounds of Formula I where R5. Re, R9, R10, R11 and R12 are H and R7 is a 7-membered heterocyclic ring (see Formula IC, below)
Figure imgf000037_0001
IC wherein:
Z is selected from CR14R18, O, NR1β, C=O, S=O1 SO2 or S; and
R14 to R19 are Independently selected from from H, halo, hydroxy, cyaπo, nitro, alkyl, alkoxy, CH2OH, haloalkyl, O-haloalkyl, hydroxyaJkyl, cyanoalkyl, alkenyl, alkynyl, cydoalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O-heterocycloalkyl, alkylene-O-alkyl, alkyleπe-O-cycloalkyl, alkylene-O-heterocydoalkyl, alkylene- O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloalkyl, S-alkyl, S(O)- alkyl, S(O)2-alkyl, S-cydoatkyl, S(O)-cydoalkyl, S(0)2-cycloalkylτ S- heterocydoalkyl, S{O)-heterocydoalky|, S{O)2-heterocydoalkyl, O-aryl, O- heteroaryl, N(H)alkyl. N(alkyl)alkyl, N(H)-aryl, N(alkyl)-aryl, N(H)-heteroaryl, N(alkyl)-heteroaryl. alkylene-O-aryl, alkyleneO-heteroaryl, alkylene-O- alkylene-aryl, alkylene-O-alkylene-heteroaryl, S-aryl, S-heteroaryl, S(O)-ary), S(O)-heteroaryl, S(O)2-aryl, S(0)2-heteroaryl, C(O)alkyl, OC(O)alky|, C(O)Oalkyl, C(O)N(H)alkyl, C(O)N(alkyl)alkyl, S{O)2N(H)alkyl or S(O)2N(alkyl)alkyl.
It will be understood by those of skill in the art that when compounds of the present invention contain one or more chiral centers, the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I. The optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate or chemical or enzymatic resolution methodology, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.
It will also be appreciated by those of skill in the art that certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes. The present invention includes any geometrical isomer of a compound of Formula I. It will further be understood that the present invention encompasses tautomers of the compounds of Formula I.
It will also be understood by those of skill in the art that certain compounds of the present invention may exist in solvated, for example hydrated, as well as uπso/vatecf forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of Formula I.
Within the scope of the invention are also salts of the compounds of Formula I. Generally, pharmaceutically acceptable salts of compounds of the present invention are obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCI or acetic acid, to afford a salt with a physiologically acceptable anion. It is also possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol, with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkox/de (such as the ethoxide or methoxϊde), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques. Additionally, quaternary ammonium salts can be prepared by the addition of alkylating agents, for example, to neutral amines.
In one embodiment of the present invention, the compound of Formula I may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate.
Specific examples of the present invention include the following compounds, their pharmaceutically acceptable salts, hydrates, solvates, optical isomers, and combinations thereof:
(9R)-2-(4,4-difluoropιperidin-1-yl)-9-methyl-6,7l8,9-tetrahydro-5H- pyrιdo[2,3d]azepine,
(9R)-2-(4-fluoropjperidin-1-yl)-9-methyl-6,7,8,9-tetrarιyd(O-5H-pyrido[2,3- djazepine;
(ΘRJ-g-methyl^-OAσxazepaπ^-yO-β^.δ.θ-tetrahydro-δH-pyridop.S- d]azepine;
(ΘRj-θ-methyl^-morphofin^-yl-β^.β.θ-tetrahydro-SH-pyridop.S-dJazepine;
(9R)-9-methyl-2-piperidin-1-yl-6,7,β,9-tetrahydro-5H-pyrido[2,3-d)azepine; (9R)-N-ethyl-N,9-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
(9S)-2-(4,4-difluoropiper!din-1-yl)-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3- djazepine;
(9S)-2-(4-flυoropiperidin-1-yl}-9-methy1-6,7,8,9-tetrahydro-5H-pyrιdo[2,3- d]azepine, (9S)-9-methyl-2-(1 ,4-oxazepaιv4-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3- d]azepine
(9S)-9-methyl-2-morpholin-4-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
(9S)-9-methyl-2-pιperidin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
(9S)-N-ethyl-N,9-dιmethyl-6,718,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine, 2-(1 ,4-diazepan-1 -yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepiπe;
Σ^i^oxazepaπ^-yO-e.r.β.θ-tetrahydro-SH-pyiidoP.S-dJazepine;
2-(1-oxidothiomorpholin-4-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-(3-thienyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine,
2.(4,4-difIuoroazepan-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; 2-(4,4-difluoroazepan-1-yl)-9-methyl-6,7)8,9-tetrahydro-5H-pyndo[2,3- djazepine;
2-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-<4,4-difluoropiperidin-1-yl)-9-methyl-6,7,8I9-tetrahydro-5H-pyπdo[2,3- d]azepιne. 2-(4-f]uoropiperidrn-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; a^-fluoropiperidin-i-yJJ-θ-methyl-ej.δ.θ-tetrahydro-SH-pyridoIZ.S-dlazepine;
2-(4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro-5H-pyridof2,3-c(]a2epiπe;
Σ-Cβ-azabicyclofS.Σ.Iloct-S-ylJ-βJ.δ.θ-tetrahydro-SH-pyπdo^.S-dlazepine; 2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-pyridol2,3-d]azepine;
219-dϊmethyl-6(7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-[methyl(6,718.9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino]ethanol;
2-azepan-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-azepan-1-yl-9-isopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; 2-a--epan-1-yl-9-methyl-6,7l8l9-tetrahydro-5H-pyrido[2?3-d]azepine;
2-cyclopropyl-6,7,8.9-tetrahydro-5H'Pyrido[2,3-d]a2epine;
2-cyclopropyl-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-isopropenyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-isopropenyt-9-methyl-6,7,8,9-tetrahydro-5H-pyridot2,3-d]azepme; 2-isopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-isopropyl-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
Σ-methoxy-S^.S.D-tetrahydro-δH-pyrido^.S-dJazepine;
2'methoxy-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; 2-morpholin-4-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3'd]azepine;
2-piperazin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-piperidin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-tert-buty 1-6,7, 8,9-tetrahydro-5H-pyrido[2,3-d]azepine; 2-thiomorpholin-4-yl-617,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-viny[-6,718,9-tetrahydro-5H-pyrido[2l3-d]azepine;
S-bromo^-methoxy-βJ.δ.θ-tefrahydro-SH-pyridoβ.S-dJazepiπe;
3-bromo-2-morpholin-4-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
3-brQmo-2-piperidin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepiπe; 3-bromD-N-ethyl-N-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
3-chloro-2-(1 ,4-oxazepan-4-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
3-chloro-2-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3- d]azepiπe;
3-chloro-2-{4-fluoropϊperidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2.3-dIazeprne; 3-chloro-2-morpholin-4-yl-6,7,8,9-tetrahydro-5H-pyndo[2,3-d]azepine,
3-chloro-2-pιpeπdιn-i-yl-€,71819-tetrahydro-5H-pyrido[2,3-d]azepine,
6,7,8,9-tetrahydro-5H-pyridot2>3-d]azepιne-2-carbaldehyde,
6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepιne-2-carbonitrιle; 9-ethy!-2-moφholιπ-4-yl-6,718τ9-tetrahydro-5H-pyrido(2,3-d]azepine>
9-ethyl-2-piperidin-1-yl-6,7,8l9-tetrahydrθ'5H-pyπdo[2ι3-d]azepιne;
9-isopropyl-2-morpholin-4-yl-6t7,8,9-tetrahydro-5H-pyndo[2,3-d]azepme;
9-isopropyl-2-piperιdin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine,
9-methyl-2-(1,4-oxazepaπ-4-yl)-6I7,8l9-tetrahydro-5H-pyπdo[2,3-d]azepιne; 9-methyl-2-morρholιn-4-yl-6,7,819-tetrahydro-5H-pyrιdo(2,3-d]azepine;
9-methyl-2-pιperιdιn-1-yl-β,7,8,9-tetrahydro-5H-pyrιdo[2,3-d]azepiπe; ethyl 4-{6,7,8,9-tetrahydro-5H-pyπdo[2,3-d]azepin-2-yl)piperazine-1" carboxytate,
N,9-diethyl-N-methyl-6,71819-tetrahydro-5H-pyrido[2,3-d]azepιπ-2-amine, N.N.g-trimethyl-ej.S.Θ-tetrahydro-δH-pyπdo^.S-dlazepin^-amine;
N,N-diallyl-6,7r8,9-tetrahydro-5H-pyπdo{2,3-d]azepin-2-amine;
N,N-diethyl-6,7.8,9-tetrahydro-5H-pyrido[2,3-d]azepιn-2-amine,
N , N-dι methyl-6,7, 8, 9-tetrahydro-5H-pyrido[2, 3-d]azepιπ-2-amiπe;
N,N-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-dIazepιne-2-carboχamide, N-benzyl-N-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amιne;
N-ethyl-N,9-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepιπ-2-amine;
N-ethyl-N-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepιπ-2-amιne;
N-isopropyl-N-methyl-6,7,8,9-tetrahydro-5H-ρyrιdo[2,3-d]azepιn-2-amine;
N-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amιne; N-methyl-N-(6,7,8,9-tetrahydro-5H-ρyrido{2,3-d]azepin-2-yl)acetamide,
2-Phenyl-6,7>8,9-tetrahydro-5H-pyrιdo[213-d]azepine1
6,7,8,9-Tetrahydro-5H-pyrido[2,3-d]azepine-2-carbonftrile;
2-Chloro-6,7,8,9-tetrahydrc>-5H-pyrido[2,3-d]azepine, l2-(6-MethDxy-3-methyl-pyridιπ-2-yl)-ethy)]-methyl-amme; and/or 7,8,9-Tetrahydro-5H-pyrtdo[2,3-d]azepιn-2-ol.
Several methods for preparing compounds of this invention are illustrated in the following, non-limiting, Schemes and Examples Starting materials and the requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures or as illustrated herein.
Compounds of Formula I, wherein R11 and R12 are H1 may be prepared as follows-
Figure imgf000042_0001
β
whereby R* can be alkyl or cycloalkyl and (a) comprises heat and base assisted cyclization of a compound of Formula A to provide a compound of Formula B and (b) comprises reduction of the carboπyl of the amide of the compound of Formula B. For example, (a) comprises heating in DMF and (b) comprises reduction with LiAIH4ZAlCl3.
Compounds of Formula I, wherein R8 and R10 are H, may be prepared as follows:
Figure imgf000043_0001
BB
whereby R' can be alkyl or cycloalkyl and (a) comprises heat and base assisted cydization of a compound of Formula AA to provide a compound of Formula BB and (b) comprises reduction of the carbonyl of the amide of the compound of Formula B. For example, (a) comprises heating in DMF and (b) comprises reduction with LiAIH4ZAlCIs
Generally, compounds of Formula I, wherein R11 and R12 are H, may be prepared via reduction of a carbonyl of the following amide:
Figure imgf000043_0002
Reduction can occur, for example, using UAIH4/AICI3. Compounds of Formula I, wherein R and R j10 are H and R and R are not H1 may be prepared via reduction of a carboπyl group of a similar amide except that the carbonyl is now C7 instead of C2, and C2 is substituted with R11 and R1Z.
Generally, compounds of Formula I, wherein Rβ, R10, R11 and R12 are H1 may be prepared via reduction of the carbonyl groups of the following amide:
Figure imgf000044_0001
Again, reduction can occur, for example, using UAIH4/AICI3.
Compounds of Formula I, wherein R11 and R12 are H1 may be prepared as follows:
Figure imgf000044_0002
whereby (a) comprises selective cyano reduction followed by cyclization of the compound of Formula C. R' can be alkyl or cycloalkyl. For example, cyano reduction using LiAIH4ZAICIs and DIPEA in acetonitrile for cyclization. The resultant Formula I can be converted to a salt addition of an acid, for example.
Compounds of Formula I1 wherein R11 and R12 are H, may be prepared as follows:
Figure imgf000045_0001
CC whereby (a) comprises selective cyaπo reduction followed by cyclization of the compound of Formula CC. R' can be alkyl or cycloalkyl. For example, cyano reduction using UAIH4/AICI3 and DIPEA in acetonitrile for cyclization. The resultant Formula I can be converted to a salt addition of an add, for example.
Compounds of Formula I may also be prepared as follows:
Figure imgf000045_0002
D
whereby (a) comprises cyclization of the compound of Formula D, whereby R' can be alky! or cycloalkyl. For example, base can be used to initiate cyclization.
Compounds of Formula I may also be prepared as follows:
Figure imgf000046_0001
DD
whereby (a) comprises cyclization of the compound of Formula DD, whereby R' can be alkyl or cycloalkyl. For example, base can be used to initiate cyclization.
In specific embodiments, the compounds of Formula II where R* is H or alkyl, R7 and R8 are H and R1 is methoxy may be prepared according to Scheme 1 , below, from nitrile intermediate V by alkylation with benzylamine, followed by hydrolysis of the nitrile function to afford the amino ester VII. Microwave- assisted cyclization to azepinone VIII and reduction with UAIH4/AICI3 gave the benzyl-protected azepine IX. Subsequent hydrogeπolysis of the protecting group provided the compound of Formula II. The intermediate V was prepared from 2-(2-chloroethyl)-3-(chloromethy))-6-rnethoxypyridine [Feng, S.; He, X.; Yu, G.; Yu, X.; Bai, D. Org. Prep. Proced. Int. 2004, 36 (2); 129-134] via mono-cyanatioπ and the Finkelstien chloro-iodo exchange.
Figure imgf000047_0001
Vl VIl ViH
Figure imgf000047_0002
IX Example 13.1
Scheme 1
Alternatively, compounds of Formula Il can also be prepared from the readily accessible 2-substituted-3-iodopyridine Xl [X = Cl, Br or OTf, [Zhang, Y βt at., J. Med. Chβm. 2004, 47, 2453] which is in turn obtained from the 2- Hydroxypyridine X. α-Arylation of esters with Xl under metal-catalyzed coupling conditions [Hartwig et al., J. Med. Chem. 2004, 47, 2453], or simple α-arylation of a dialkylmalonate [Buchwald θt a/, , Org. Lett. 2002. 4. 269] followed by decarboxylation gives XII. Coupling of XII with acrylates (eg. t- butyl acrylate) under standard Heck conditions gives XIIi. Catalytic hydrogenation followed by ester hydrolysis delivers acids XIV (R8 =H). Curtis rearrangement and cyclization afford XVI (M = H1 H). Subsequent reduction then provides compounds of Formula II.
Another alternative to compounds of Formula Il includes the transformation of intermediate Xl, simultaneously or sequentially, into the diester intermediate XVIIl. Cyclization to form the imide XVI (M=O), followed by reduction, provides compounds of Formula II.
Compounds of Formula Il can also be obtained from diester XVIII by reduction first to the diol XIX. Activation of the diol (eg mesylation or halide formation) and cyclization with amines give Il (Scheme 2).
Figure imgf000048_0001
XVJ
Scheme 2
Compounds of Formula III where R4 is H or alkyl and Rs and/or R6 is H or alkyl respectively can be prepared in a manner similar to that shown in Scheme 2 (see Scheme 3). Alternatively, α-alkyations of XII also provide intermediates such as XX, which may then be transformed into compounds of Formula III (Scheme 4).
XIl
Figure imgf000049_0001
Figure imgf000049_0002
XXV
Scheme 3
Figure imgf000049_0003
XXVHI XXX
Figure imgf000049_0004
XXXIt XXXI
Scheme 4
Compounds of Formula IV can be prepared from pyridyl carboxaldehydes such as XXVII (X = Cl, Br, I, OTf) by condensation with πitramethane followed by reduction to the amine XXIX. Protection of the amine (e g. Boc-protection) followed by simple α-arylation of esters as above gives XXXI which, on de- protection and cyclization, affords azepinone XXXII. Reduction with LiAIH4 or other reducing agents such as Red-AI gives the compounds of Formula IV.
Alternatively, compounds of Formula IV can also be obtained from the intermediate XXXIII [Feng, S.; He, X.; Yu, G.; Yu, X.; BaI1 D. Ocg Prep. Proced lnt 2004, 36 (2); 129-134] by simple alkylation to give XXXIV which is then transformed to the desired compounds in a manner similar to that shown in Scheme 1 (see Scheme 5).
Figure imgf000050_0001
XXXIV
Scheme 5
For another synthetic strategy to prepare compounds of Formula III wherein R7 =H and Rβ=H, R5 and R° is H (as in Formula II) and R1 is an amine containing group is outlined in Scheme 6. Condensation of the β-ketodiester B with the acetylinjc amide A gives the functionalized pyridone C which on treatment with Ag∑CC^ and methyl iodide gives the methoxypyridine intermediate D. The intermediate D can be treated wrth a number of alkylating groups (e.g. R5 or R6 =Methyl is shown) to introduce functionality onto the azeprne ring Treatment of the diester D with a reducing agent (e g LiAIH4) provides diol intermediate E. Treatment of diol E with mesyl chloride gives the chloro-mesylate F which on mild cyanation with NaCN in DMSO gives the cyano-mesylate G. Selective cyano reduction (e.g. with alane generated in situ from AICb and LiAIhU) followed by cyclization gives the pyridyl-fused azepine intermediate H. O-Deprotection with HBr in acetic acid to I followed by N- protection with for example (BOC)ΪO affords intermediate J. Trifiatioπ of J to the versatile intermediate K followed by coupling with the various amines give the Boc-protected precusor L of the compounds of Formula III. Treatment of L with HCI gives M, the HCI salts of the compounds of this invention.
Figure imgf000051_0001
Figure imgf000051_0002
Scheme 6
The compounds of Formula Il where R1 = CF3 were prepared according to Scheme 7. The commercially available methyl acid is treated with base to effect methyl-deprotonatioπ. Subsequent reduction with alane provides the common diol intermediate that is further transformed into the compounds of this invention in a manner analogous to Scheme 6.
Figure imgf000052_0001
Scheme 7
Acid addition salts of the compounds of Formula I are most suitably formed from pharmaceutically acceptable acids, and include for example those formed with inorganic acids e.g. hydrochloric, sulphuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric add. Other non-pharmaceuticafly acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the invention are base addition salts (such as sodium, potassium and ammonium salts), solvates and hydrates of compounds of the invention.
The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, well known to one skilled in the art.
Compounds in accordance with the invention have been shown to be potent agonists or partial agonists of the 5-HTzc receptor and have good specificity for the 5-HTzc receptor compared to the 5-HT2A and S-HT26 receptors.
In embodiments of the invention, the compounds of the invention have an EC50 value for the human 5-HTzc receptor less than 1000 nM, or less than 50OnM, or less than 300 nM, or less than 100 nM.
The compounds of the invention are therefore of interest for the treatment of 5-HT2c receptor-mediated disorders, including a depressive disorder, an anxiety disorder, including panic attack, agoraphobia, and specific or social phobia, bipolar disorder, post-traumatic stress, an eating disorder, obesity, a gastro-intestinal disorder, alcoholism, drug addiction, schizophrenia, a psychotic disorder, a sleep disorder, including sleep apnea, migraine, sexual dysfunction, a central nervous system disorder, including trauma, stroke and spinal cord injury, a cardio-vascular disorder, diabetes insipidus, obsessive compulsive disorder, premenstrual tension, chronic fatigue syndrome, age- related memory disorder, personality disorder and raised intracranial pressure
The studies described herein of the effect of compounds of the invention in a feeding assay which Is an accepted in vivo rodent model for studies on overeating and control of food intake confirms the potential of these compounds for treatment of obesity.
Compounds of the invention have also been shown to be effective in inhibiting locomotor activity in a rodent model relevant to treatment of schizophrenia or other psychotic disorders.
For pharmaceutical use, the compounds of the invention are, for instance, administered orally, sublingually, rectally, nasally, vaginally, topically (including the use of a patch or other transdermal delivery device), by pulmonary route by use of an aerosol, or parenterally, including, for example, intramuscularly, subcutaneously,
Figure imgf000053_0001
intraarterially, intravenously or intrathecally. Administration can be by means of a pump for periodic or continuous delivery. The compounds of the invention are administered alone, or are combined with a pharmaceutically-acceptable carrier or excipient according to standard pharmaceutical practice. For the oral mode of administration, the compounds of the invention are used in the form of tablets, capsules, lozenges, chewing gum, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like, tn the case of tablets, carriers that are used include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, and lubricating agents such as magnesium stearate and talc, are commonly used in tablets For oral administration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols If desired, certain sweetening and/or flavoring agents are added For parenteral administration, steπie solutions of the compounds of the invention are usually prepared, and the phis of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids may be delivered by ocular delivery systems known to the art such as applicators or eye droppers. Such compositions can include mucomimetjcs such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or beπzylchromium chloride, and the usual quantities of diluents and/or carriers. For pulmonary administration, diluents and/or carriers will be selected to be appropriate to allow the formation of an aerosol.
Suppository forms of the compounds of the invention are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include theobroma oil, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weight and fatty acid esters of polyethylene glycol. See, Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms. Analogous gels or creams can be used for vaginal, urethral and recta) administrations.
Numerous administration vehicles will be apparent to those of ordinary skill in the art, including without limitation slow release formulations, liposomal formulations and polymeric matrices.
Examples of pharmaceutically acceptable acid addition salts for use in the present invention include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, p-toluenesulphonic and arylsulphonic acids, for example Examples of pharmaceutically acceptable base addition salts for use in the present invention include those derived from non-toxic metals such as sodium or potassium, ammonium salts and organoamino salts such as triethylamine salts. Numerous appropriate such salts will be known to those of ordinary skill.
The physician or other health care professional can select the appropriate dose and treatment regimen based on the subject's weight, age, and physical condition. Dosages will generally be selected to maintain a serum level of compounds of the invention between about 0.01 μg/cc and about 1000 μg/cc, preferably between about 0.1 μg/cc and about 100 μg/cc. For parenteral administration, an alternative measure of preferred amount is from about 0.001 mg/kg to about 10 mg/kg (alternatively, from about 0.01 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg), will be administered. For oral administrations, an alternative measure of preferred administration amount is from about 0.001 mg/kg to about 10 mg/kg (from about 0.1 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg). For administrations in suppository form, an alternative measure of preferred administration amount is from about 0.1 mg/kg to about 10 mg/kg, more preferably from about 0.1 mg/kg to about 1 mg/kg.
When introducing elements disclosed herein, the articles "a", "an", "the", and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "having", "including" are intended to be open-ended and mean that there may be additional elements other than the listed elements
The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific Examples These Examples are described solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation.
Examples: Example 1.1: Propiolamide o
'NH2
Methyl propioate (5 mL, 55 mmol) was added to ammonium hydroxide (15 mL) at -50 to -60" C over 20 minutes. The reaction mixture was stirred at this temperature for 1 hour. The solvent was evaporated and the residue dried under vacuum to give the product (3.7 g, 92 %). 1H NMR (300 MHz, CDCI3): δ (ppm) 6.35 (bs, 1H), 5.97 (bsf 1H), 2.88 <sr 1H).
Example 2.1: Ethyl 2-{2-ethoxy-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3- cartooxylate
Figure imgf000056_0001
Propiolamide (20.0 g, 289.6 mmol), diethyl 3-oxopentanedioate (87.8 g, 434.4 mmol) and sodium carbonate (24.6 g, 231.7 mmol) were mixed in water (800 mL) at 0 0C and then warmed to r.t. over 4 hours. The reaction was allowed to continue tσ stir at r.t. for 3 days. The reaction was neutralized with aqueous hydrochloric acid (5M) at 0 0C with vigorous stirring. A solid precipitate was collected by filtration and washed with diethyl ether/hexanes (2:1) to yield a first batch of the title compound (43g). The filtrate was further extracted with ethyl acetate and the combined organic phases were dried over sodium sulphate and purified by column chromatography (10-80% ethyl acetate/hexanes) to yield another batch of the title compound (7g), in total gave 50 g (68%). 1H NMR (300 MHz, CDCI3): δ(ppm) 13-12 (br S, 1 H)1 8.08 (d, 1H), 6.52 (d, 1H), 4.3 (q, 2H), 4.21 (q, 2H)1 4.13 (s, 2H)1 1.29 (m, 6H).
Example 3.1: Ethyl 2-{2-ethoxy-2-oxoethyl)-6-methoxynicotinate
Figure imgf000057_0001
The title compound from Example 2.1 {20 g, 79.05 mmoi) was stirred with silver carbonate (23.7 g, 105.3 mmol) and iodomethaπe (40.7 g, 286.6 mmol) in chloroform (180 ml_) at 500C overnight The reaction mixture was filtered and the filtrate was concentrated to give the crude title compound (22 g, quantitative). 1H NMR (300 MHz, CDCI3): δ (ppm) 8.21 (d, 1H), 6.69 (d, 1H), 4.32 (q, 2H), 4.17 (m, 4H)1 3.97 (S1 3H), 1.37 (t, 3H)1 1.29 (t, 3H).
Example 3.2: Ethyl 2-(2-ethoxy-1-methyl-2-oxoethyl)-6- methoxynicotinate
Figure imgf000057_0002
To a suspension of sodium tert-butoxide (7.98 g, 82.3 mmol) in tetrahydrofuran (250 ml_) was added a solution of ethyl 2-(2-ethoxy-2- oxoethyl)-6-methoxynicotinate (20.0 g, 74.8 mmol) (the title compound from Example 3.1) in tetrahydrofuran (100 mL) at 0 0C over 15 minutes. After being stirred for 15 minutes, iodomethane (53.1 g, 374 mmol) was added at 0 0C. The reaction was allowed to warm up to r.t. over 2 hours. Acetic acid (1 mL) was added at 0 0C and the mixture was stirred for 30 minutes. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give the title compound (20.16 g, 96%). 1H NMR (300 MHz, CDCl3): δ(ppm) B.16 (d, 1 H)1 6.64 (Cl1 1H), 4.87 (q. 1 H)1 4.33 (m, 2H), 4.13 (m, 2H), 3.94 (3H), 1.54 (d, 3H)1 1.36 (m, 3H), 1.18 (m, 3H).
Example 4.1: 2-(3-Hydroxymethyl-6-methoxy-pyridin-2-yl)-ethanol
Figure imgf000058_0001
To a suspension of lithium aluminum hydride (2.66 g, 70 mmol) in THF (120 mL) at 0D C was added 2-ethoxycarbonylmethyl-6-methoxy-nicotinic acid ethyl ester (5.26 g, 22 mmol). The reaction mixture was stirred at room temperature for 10 minutes and then at reflux for 80 minutes. The reaction mixture was cooled to 0° C and to it was successively added water (3 mL), aqueous sodium hydroxide (15 %, 3 mL) and water (9 mL). The resulting mixture was filtered and concentrated to give the product (3.68 g, 91.3 %). 1H NMR (300 MHz, CDCI3): δ (ppm) 7.57 (d, 1H), 6.63 (d, 1H), 4.63 (s, 2H), 4.07 (t, 2H), 3.92 (s, 3H)1 3.02 (t, 2H).
Using the above general procedure, the following compounds were synthesized:
Figure imgf000058_0002
Example 4.3 2-r3-(hvdroxvmethvl)-6-(trifluoromethvnpvridin-2- yl]θthaπol
Figure imgf000059_0001
To a solution of 2.5 M n-butyl lithium (11.7 mL. 29.25 mmol) in tetrahydrofuran (100ml), diisopropylamine (1.479g, 14.62 mmol) was added at -78 0C. After the mixture was placed in ice bath for 5 min, cooled to -78 0C again. A solution of 2-methyl-6-(trifluoromethyl)nicotinic acid (3.Og, 14.62 mmol) in tetrahydrofuran (50 mL) was added to the reaction mixture via syringe and reaction mixture was stirred at -78 0C for an hour. Then a dry carbon dioxide gas was bubbled to the reaction mixture for 30 min. the reaction mixture was concentrated to dry and the residue was redissolved in tetrahyrofuran (100 mL). A solution of AIH3 in tetrahydrofuran which was prepared from aluminum chloride (2.933g, 22 mmol) in tetrahydrofuran (22mL) reacted with 1M lithium aluminum hydride ( 66ml, 666 mmol) in tetrahydrofuran was added to the reaction mixture slowly at 0 0C and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether and quenched with 5M sodium hydroxide carefully at 0 0C. the mixture was dried with magnesium sulfate, filtered. The cproduct was purified by column chromatography to give the title compound 400mg (12.4 %). 1H NMR (300 MHz, CDCI3): δ(ppm) 7.88 (d, 1H)1 7.54 (d, 1 H), 4,33 (S, 2H), 4.14 (br, 2H), 3.93 (t, 2H), 3.02 (t, 2H).
Example 5.1: 2-(2-Chloro-θthyl)-3-chloromethyl-6-methoxy-pyridiπe
Figure imgf000059_0002
A mixture of 2-(3-hydroxymethyl-6-methoxy-pyridin-2-yl)-ethanol (3.68 g, 20 mmol), thionyl chloride (16 mL) and chloroform (80 mL) was stirred at room temperature overnight and then heated at reflux for 1 hour. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous sodium carbonate containing ice. The organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica gel using hexanes:ethyl acetate (10:0 to 9.5:0.5) to give the product (3.23 g, 73 %). 1H NMR (300 MHz, CDCI3): δ (ppm) 7.52 (d, 1H)1 6.62 (d, 1 H), 4.61 (s, 2H), 4.03 (t, 2H), 3.93 {s, 3H), 3.28 (t, 2H).
Example 6.1: [2-{2-Chloro-ethyl)-6-methoxy-pyridin-3-yl]-acetoπitrile
Figure imgf000060_0001
To a suspension of sodium cyanide (808 mg, 16.5 mmol) in N1N- dimethylformamide (20 mL) was added 2-(2-chtoro-ethyl)-3-ch!oromethyl-6- methoxy-pyridine (2.88 g, 15 mmol). The reaction mixture was stirred at 25° C for 3 hours. To the reaction mixture was added water and ethyl acetate. The organic layer was separated and washed further with water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica gel using heχanes:ethyl acetate (10:0 to 8:2) to give the product {2.4 g, 88 %). 1H NMR (300 MHz, CDCI3): δ {ppm) 7.56 (d, 1H)T 6.67 {d, 1 H), 4.04 (t, 2H), 3.93 (S, 3H), 3.71 (S, 2H), 3.16 (t, 2H).
Example 7.1: [2-{2-lodo-βthyl)-6-methoxy-pyridm-3-yl]-acetonitrile
Figure imgf000060_0002
To the crude mixture of [2-(2-chlorθ'ethyl)-6-methoxy-pyridin-3-yl]-acetonitrile (875 mg, 4.8 mmol), sodium iodide (5.0 g, 33.3 mmol) and acetone {10 mL) was heated at 58° C for 2 days. The reaction mixture was concentrated, diluted with dichloromethane, filtered and concentrated once again to give the product (1.30 g). 1H NMR (300 MHz, CDCI3): δ (ppm) 7.55 (d, 1H), 6.66 (d, 1H), 3.93 (S1 3H), 3.68 (s, 2H)1 3.63 (t, 2H), 3.3 (t, 2H).
Example 8.1 : [2-(2-Bβnzylamino-ethyl)*6-methoxy-pyridiπ-3-yl]- acetonitrile
Figure imgf000061_0001
A solution of [2-(2-iodo-ethyl)-6-methoxy-pyridiπ-3-yl]-acetonitrile (7,9 g, 29 mmol) in butanol (40 mL) was added to a mixture of benzylamine (11 ml_, 0.1 mol) in butanol (80 mL) at 90° C. The reaction mixture was stirred at 100° C for 1 hour. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous sodium carbonate. The organic layer was dried over sodium sulfate, concentrated and purified on silica gel using dichloromethane:2M NH3 in methanol (10:0 to 9.5:0.5) to give the product (5.2 g, 90 % pure). 1H NMR (300 MHz, CDCI3): δ (ppm) 7.54 (d, 1H), 6.62 (d, 1H), 3.86 (m, 5H), 3.66 (s, 2H), 3.13 (t, 2H), 2.91 (t, 2H).
Example 9.1: [2-{2-Beπzylamlno-ethyl)-6-methoxy-pyridin-3-yl]-acetic acid methyl ester
Figure imgf000061_0002
A mixture of [2-(2-benzylamino-ethyl)-6-methoxy-pyridin-3-yl]-acetoπitrile (5.2 g) and a solution of hydrochloric acid in methanol (12 %, 150 mL) was heated at reflux overnight The reaction mixture was cooled to room temperature and sodium bicarbonate was then added. After stirring for 30 minutes, methanol was evaporated. To the residue was added ethyl acetate and water. The aqueous layer was separated and further extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated to give the product (4.85 g). 1H NMR {300 MHz, CDCl3): δ fppm) 7.27 (m, 6H), 6.56 (d, 1H), 3.86 (m, 5H), 3.67 (m, 3H), 3.59 (s, 2H), 3.09 (t, 2H), 2.94 (t, 2H).
Example 10.1: 7-Beπzyl-2-methύxy-5,7,8,9-tetrahydro-pyrido[2,3- d]azepiπ-6-oπe
Figure imgf000062_0001
A mixture of [2-(2-benzylamiπo-ethyl)-6-methoxy-pyridin-3-yl]-acetic acid methyl ester (1.6 g, 5.4 mmol) in N,N-dimethylformamide (18 mL) was heated at 200° C in a microwave for 4 hours. The above reaction was repeated using 3.2 g of substrate. The two reaction mixtures were combined, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, concentrated and purified on silica gel using hexanes:ethyl acetate (9:1 to 1 :1) to give the product (2.0 g, 47 %). 1H NMR (300 MHz, CDCI3): δ (ppm) 7.32 (m, 6H), 6.54 (d, 1H), 4.67 (s, 2H), 3.86 (s, 5H), 3.7 (t, 2H)1 2.99 (t. 2H).
Example 11.1: 7-Benzyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3- d]azepfne
Figure imgf000062_0002
To a suspension of lithium aluminum hydride (1.9 g, 50 mmol) in tetrahydrofuran (60 mL) at -78° C1 was added to aluminum chloride (2.4 g, 18 mmol) followed by a solution of 7-benzyl-2-methoxy-5,7,8,9-tetrahydrα- pyndo[2,3-d]azepin-6-one (1 6 g, 6 mmol) in tetrahydrofuran (40 ml_). The reaction mixture was stirred at room temperature for 2 days. To the reaction mixture at 0° C was slowly and successively added water (2 ml_), aqueous sodium hydroxide (1 N, 2 mL) and water (4 ml_) The resulting mixture was filtered through Celite® and concentrated The above reaction was repeated using 422 mg of substrate. The combined residue was purified on silica gel using dichloromethane:2M NHjin methanol (10:0 to 9.5:0.5} to give the product (1.8 g, 95 %) The product was treated with hydrochloric acid in diethyl ether to give the hydrochloric acid salt (2 salt equivalents). 1H NMR (300 MHz. CDCI3): δ (ppm) 7.31 (m, 6H). 6.48 (d. 1H), 3.9 (s, 3H), 3.65 (S1 2H), 3 07 (m, 2H)1 2.82 (m, 2H), 2.68 (m, 2H), 2.61 (m, 2H).
Example 12.1 : 2-[3-(Chloromethyl)-6-methoxypyridin-2-yl]ethyl methanesulfoπate
Figure imgf000063_0001
The title compound from Example 3 {24.70 g, 134.8 mmol) was dissolved in dichloromethane (500 mL) under a nitrogen atmosphere and cooled to -30 "C Then triethylamine (30.01 g, 296.6 mmol) and methyl sulfoπyl chloride (33.98 g, 296.6 mmol) were added. The reaction was allowed to warm to r.t. and was stirred overnight The reaction mixture was diluted with hexaπes (400 mL) and filtered to remove solids. The filtrate was concentrated and redissolved in ethyl acetate, washing with saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give the title compound as pale yellow oil (36 38 g, 96%). 1H NMR (300 MHz, CDCI3): δ(ppm) 7.51 (d, 1 H), 6.60 (d, 1 H), 4.75 (t, 2H), 4.57 (S1 2H), 3.90 (s, 3H), 3.25 (t, 2H), 2.92 (s, 3H).
Using the above general procedure, the following compounds were synthesized:
1H)1 2.88 (s,
1 H)1
Figure imgf000064_0001
Example 13.1: 2-[3-(Cyanomethyl)-6-metrιoxypyridin-2-yl]ethyl methanesulfonate
Figure imgf000065_0001
The title compound from Example 4 (36.38 g, 130.05 mmol) was dissolved in dimethylformamide (400 mL) and cooled to 0 0C. Sodium cyanide (6 69 g, 135.55 mmol) was added and the reaction mixture was allowed to warm up to r.t. overnight. The reaction mixture was filtered through celite filtering agent. The filtrate was washed with 25% saturated sodium bicarbonate solution and extracted with portions of ethyl acetate. The organic extracts were dried over sodium sulphate, filtered and concentrated. The product was purified by column chromatography (30-50% ethyl acetate in hβxanes) to give the title compound (21.13 g, 60%). 1H NMR (300 MHz, CDCI3): δ(ppm) 7.48 (d, 1H)f 6.57 (d, 1 H), 4.65 (t, 2H), 3.84 (s, 3H), 3.62 (s, 2H), 3.07 (t, 2H)1 2,90 (s, 3H).
Using the above general procedure, the following compounds were synthesized:
(d, 1H), (s,
Figure imgf000065_0002
Figure imgf000066_0003
Example 14.1 : 6,7,8,9-Tetrahydro-5H-pyrldo[2,3-d]azepiπ-2-ol
Figure imgf000066_0001
A mixture of 7-benzyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine {35 mg, 0.14 mrnoDC the compound from Example 11.1). hydrobromic acid in ethanol (1.3 mL) and acetic acid (1.3 mL) was heated at 80° C overnight. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous sodium carbonate. The organic layer was dried over sodium sulfate and concentrated to give the crude amide. The amide was hydrogenated in methanol using palladium (10 % on carbon). The reaction mixture was filtered through Celite®, concentrated and purified on silica gel using dichloromethane:2M NH3 in methanol (10:0 to 9.2:0.8) to give the product (2 mg). The product was treated with hydrochloric acid in diethyl ether to give the hydrochloric acid salt (2 salt equivalents).
Example 15.1: 2-Methoxy-6,7,8,9-tetrahydro-5H-pyrido[2I3-d]azepinβ
Figure imgf000066_0002
Method A
A mixture of 7-benzyl-2-methoxy-6,7,819-tetrahydro-5H-pyrido[2,3-dlazepine (1.05 g, 4.2 mmol).( the compound from Example 11.1). palladium hydroxide (20 % on carbon, 180 mg) and methanol (50 mL) was stirred under hydrogen (36 psi) for 6 hours. The reaction mixture was filtered through Celite® and concentrated to give the product (565 mg). The product was treated with hydrochloric acid in diethyl ether to give the hydrochloric acid salt (2 salt equivalents). 1H NMR {300 MHz, CDCI3) δ (ppm) 7.29 (d, 1 H)1 6 48 (d, 1H), 3 91 (S. 3H), 3.08 (m, 2H). 2.98 (m, 4H)1 2 82 (m, 2H).
Method B
To a mixture of aluminum chloride (1.8 g, 13.3 mmol) and lithium aluminum hydride (1 Og, 26.6 mmol) at -78 0C1 dry diethyl ether (30 ml) was added carefully After being stirred at r.t. for 30 mm, the reaction mixture was cooled down to -780C again. Then a solution of 2-[3-(cyanomethyl)-6- methoxypyridin-2-yl]ethyl methanesulfonate (3.6 g, 13 3 mmoWthe compound from Example 13.1) in tetrahydrofuran (3OmL) was added slowly. The reaction mixture was stirred at 0 0C for an hour and a half Water (200 mL) and saturated sodium carbonate (10 mL) were used to quench the reaction. The reaction mixture was extracted with ethyl acetate, dried with sodium sulfate, concentrated by Rotavapor. The residue was mixed with diisoprapylethylamine (3 36 g, 26 mmol) in acetonitπle (45 ml) and stirred at 30 βC for 24 hours, concentrated again, saturated sodium carbonate (15mL) was added The mixture was extracted with ethyl acetate, dried, purified by chromatography to give the title compound (1.25g, 52 7%)
Using the method B general procedure, the following compounds were synthesized:
Figure imgf000068_0002
Example 16.1: tβrt-Butyl 2-methθxy-5,6,8,9-tβtrahydro-7H-pyrido[2,3- d]azepine-7-carboxylatβ
Figure imgf000068_0001
To a solution of the title compound Example 13.1 (1.07 g, 6 mmol) and diisopropylethylamine(1.5 mL) in dichlromethaπe (30 mL) at -50 0C, di-tert- butyl dicarbonate (1.6 g, 7.2 mmol) was added. The reaction mixture was stirred at room temperature for two hours, then quenched with water and extracted with dichloromethane. The product was purified by column chromatograph with 10 % ethyl acetate in hexanes to give the title compound 1.188g (71 %).
Example 16.2: tert-butyl 3-bromo-2-methoxy-5,6,8,9-tetrahydro-7H- pyrido[2,3-d]azepine-7-carboxylate
Figure imgf000069_0001
tenSButyl 2-methoxy-5,6f8,9-tetrahydπ>7H-pyrido[2,3-d]azepiπe-7--carboxylate (140 mg, 0.5 mmol) was mixed with sodiumn acetate (50 mh, 0.6 mmol) in dichloromethane at 0 0C. Then Bromine (96 mg, 0.6 mmol) was added, the reaction mixture was filtered and concentrated to dry to give the title compound 200mg (112% ) which can be carried on for the next step reaction without further purification. . 1H NMR (300 MHz, CDCI3): δ(ppm) 7.55 (s, 1H)1 3.99 (S, 3H), 3.58 (m, 4H), 3.04 (m, 2H), 2.78 (m. 2H)1 1.49 (s, 9H).
Example 17.1: 6,7,8,9-Tetrahydro-5H-pyrido[2,3-d]azepin-2-ol dihydrobromidβ
Figure imgf000069_0002
A mixture of 2-(6-methoxy-3-methyl-pyridin-2-yl)-ethyl]-methyl-amine (549 mg, 3.3 mmol), hydrobromic acid in ethanol (16 mL) and acetic acid (16 mL) was heated at 88° C for 1 day. The reaction mixture was concentrated and the residue was triturated with hexanes to give the product (879 mg).
Using the method B general procedure, the following compounds were synthesized:
Figure imgf000069_0003
3-bromo-6,7,8,9- Not taken H Br tetrahydro-5H-
Figure imgf000070_0001
Example pyrido[2,3- 17.3 d]azepin-2-ol; hydrobromide
NMR 1H NMR (300 MHz1 CDCI3): δ(ppm) not characterized
Example 18.1: 2»Chloro-6,7.8.9-tetrahydro-5H-pyrido[2,3-d]azepine
Figure imgf000070_0002
A mixture of ej.δ.θ-tetrahydro-SH-pyrido^.S-dlazepin^-ol dihydrobromide (114 mg, 0.38 mmol) and phosphorus oxychloride (1.5 mL) was heated at 120° C for 1 hour. The reaction mixture was concentrated and to the residue was added aqueous sodium carbonate. The resulting mixture was extracted with ethyl acetate and the organic layer concentrated. The residue was purified on silica gel using dichloromethane:2M NH3 in methanol (10:0 to 9.5:0.5) to give the product (3 mg). The product was treated with hydrochloric acid in diethyl ether to give the hydrochloric acid salt (2 salt equivalents). 1H NMR (300 MHz. CDCI3): δ (ppm) 7.36 (d, 1 H), 7.08 (d, 1 H)1 3.15 (m, 2H), 3.01 (m, 3H), 2.89 (m, 2H), 2.62 (m, 1 H).
Example 19.1: tert-Butyl 2-hydroxy-5,6,8,9-tetrahydro-7H-pyrido[2,3- d]azβpiπe-7-carboxylatβ
Figure imgf000071_0001
The title compound from Example 14.1 (5.72 g, 17. 54 mmol) was suspended in dichloromethane (90 mL) under a nitrogen atmosphere and cooled to 0 °C. Diisopropylethyamine (7.93 g, 61.39 mmol) was added to the suspension with stirring. In a separate flask, di-tert-butyl dicarbonate (8.04 g, 36.83 mmol) was dissolved in dichloromethane (50 mL) under a nitrogen atmosphere. This solution was added slowly to the main reaction vessel via cannula. The reaction was stirred at r.t. for 2 hours. The reaction mixture was washed with a 50% saturated solution of ammonium chloride and the aqueous phase was extracted with portions of dichloromethane. The combined organic extracts were washed with brine, dried over manesium sulfate, filtered and concentrated to give the title compound as a plae brown solid (4.64 g, quant.). 1H NMR (300 MHz, CDCI3): δ(ppm) 13.53 (br s, 1H)1 7.25 (d, 1 H), 6.38 (d, 1 H), 3.55 (m, 4H), 2.94 <m, 2H)1 2.68 (m, 2H), 1.46 (s, 9H).
Using the above general procedure, the following compounds were synthesized:
Figure imgf000071_0002
Figure imgf000072_0001
Example 20.1 : tert-Butyl 2-{[(trifIuoromethyl)sulfonyl]oxy}-5,6,8,9- tetrahydro-7H-pyrido[2,3-d]azeplne-7-carboxylate
Figure imgf000072_0002
The title compound from Example 16.1 (4.64 g, 17.54 mmol) was dissolved in dichloromethane (150 mL) and cooled to 0 0C under nitrogen. To this solution was added diisopropylethyalmine (2.83 g, 21.93 mmol) and triflic anhydride (6.19 g, 21.93 g) and the reaction was allowed to warm to r.t. over 2 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic phase was washed with 50% sat. ammonium chloride and bππe. The organic phase was neutralized with sat. sodium bicarbonate and concentrated to give the title compound (1.94 g, 28%). 1H NMR (300 MHz, CDCI3); δ(ppm) 7.59 (d, 1H), 6.94 (d, 1 H), 3.61 (br d, 4H), 3.12 (t, 2H), 2.93 (t, 2H), 1.49 (S1 9H).
Using the above general procedure, the following compounds were synthesized:
Figure imgf000073_0004
Figure imgf000073_0001
11,0, i.PijNEI
Figure imgf000073_0003
Figure imgf000073_0002
Example 20.4: tert-Butyl 9-ethyl-2-{t(trifluoromethyi)sulfonyl]oxy}-5,6,8,9- tetrahydro-7H-pyrido[2,3-d]azepiπe'7-carboxylate
Figure imgf000074_0001
To a solution of 7-benzyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3- djazepine (500mg, 1 86 mmol) in toluene (8mL) at -58 0C, π-BuLJ (1.5 mL of 2.5 M in hexanes, 3.75 mmol) was aaded. After the mixture was stirred at 0 0C for two hours, iodoethane (650 μL, 8 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate, dried and concentrated by Rotavapor. The residue was mixed with 20 % Pd(OH)2 (400 mg) and methanol (30 mL) and stirred under H2 for a week. The reaction mixture was fittered and the filtrate was concentrated again to give 9- ethyl-2-methoxy-6T7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. This compound was mixed with 20 %wt HBr in ethaπol (16 mL) and acetic acid (16 mL) and heated at 90 0C overnight and then concentrated to give 9-ethy 1-6,7,8, 9- tetrahydro-5H-pyrido[2,3-d]azepin-2-ol dihydrobromide salt. The salt was mixed with diϊsopropylethyamine (2.5 mL) and di-tert-butyl dicarbonate (570 mg, 2.5 mmol) in dichloromethane (20 mL) and water (10 mL) at 0 0C and stirred for two hours. The organic layer was separated and dried, concentrated to give tert-butyl 9-ethyl-2-hydroxy-5,6,8,9-tetrahydro-7H- pyrido[2,3-d]azepine-7-carboxylate. This intermediate was mixed with diisopropylethyaimine (1 mL) and triflic anhydride (420μL, 2.5 mmol)) in dichloromethane at -50 0C and stirred overnight. After work-up, purified by column chromatography with 20 % ethyl acetate in hexanes to give the title compound 284 mg (37 % in total). 1H NMR (300 MHz1 CDCI3): δ(ppm) 7.58 (d, 1H), S.93 (d, 1H), 2.6-39 (m, 7H), 1.95 (m, 2H)1 1.49 (S, 9H), 1.37 (m. 3H).
Using the above general procedure, the following compounds were synthesized-
Figure imgf000075_0002
Example 21.1; tert-Butyl ester 2-cyaπo-5,6,8,9-tetrahydro-pyrido[2,3- d]azepine-7-carboxylatβ
Figure imgf000075_0001
A mixture of tert-Butyl 2-{[(trifluoromethyl)sulfonyl]oxy}-5I618,9-tetrahydro-7H- pyrido[2,3-d]azepine-7-carboxylate (50 mg, 0.13 mmol). zinc cyanide (50 mg, 0.4 rnmol), tetrakis(triphenylphosphine)palladium (25 mg) and N1N- dimethylformamide (0.6 mL) was stirred at 100° C for 30 minutes. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated, washed with water (3x1 mL), dried over sodium sulfate and concentrated. The residue was purified on silica gel using hexanes:ethyl acetate (10:0 to 7:3) to give the product (12 mg, 33.6 %). 1H NMR (300 MHz, CDCI3): δ(ppm) 7.55 (d, 1H)1 7.49 (d, 1H), 3.62 (m, 4H)1 3.21 (m. 2H), 2.96 (m, 2H)1 1.50 (s, 9H). Example 21.2: tθrt-Butyl 2-isopropβnyl-5,6,8,9-tetrahydro-pyrldo[2,3- d]azepine-7'Carboxylate
Figure imgf000076_0001
To a solution of 2-bromopropene (266 mL, 3.0 mmol) in diethyl ether (3 mL) at -78° C, was added tert-butyllithium (1.7M in pentane, 3.5 mL, 6.0 mmol). The reaction mixture was stirred at -78° C for 1 hour and then a solution of zinc bromide (810 mg, 3.6 mmol) in tetrahydrofuran (3.6 mL) was added. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. A separate mixture of tert-butyl 2- trifluoromethanesulfonyloxy-516,8ιg-tetrahydro-pyridol2,3-d]azepiπe-7- carboxylate (100 mg, 0.26 mmol), bis(dibenzytideneacetone)palladium (5 mg, 0 01 mmol), tri-2-furylphosphine (4.5 mg, 0.02 mmol) and tetrahydrofuran (0.6 mL) was stirred at room temperature for 15 minutes. To this reaction mixture was added the zinc reagent described above (2 equivalents taken from the above reaction mixture) at room temperature. The reaction mixture was heated at 50° C for 45 minutes. After work-up, the residue was purified on silica gel using hexanes:ethyl acetate (10:0 to 8.5:1.5) to give the product (45 mg, 64 "Jt)-1H NMR (300 MHz, CDCl3): δ(ppm) 7.37(d, 1H), 7.21 (d. 1H), 5.89 (s, 1H). 5.25 (S, 1H), 3.60 (m, 4H), 3.17 (m, 2H), 2.87 (rn, 2H), 2.19 (s, 3H), 1.50 (S, 9H).
Using the above general procedure, the following compounds were synthesized:
Example
Structure Name Yield tert-butyl 2- 63 mg, 51 %
Example isopropenyl-9- 213
Figure imgf000076_0002
methyl-5,6,8,9- tetrahydro-7H- pyrido[2,3-
Figure imgf000077_0002
Example 21.4: tert-Butyl 2-phenyl-5,6,B,9-tetrahydro-pyrido[2,3- d]azβpl ne-7-carboxylate
Figure imgf000077_0001
A mixture of 2-trifluoromethanesulfonyloxy-5,6,819-tetrahydro-pyrido[2,3- d]azepiπe-7-carboχylic acid tert-butyl ester (100 mg, 0.26 mmol}, aqueous sodium carbonate (2M, 0.5 mL), tetrakis(tripheny]phosphine)palladium (15 mg), pheπylboroπic acid (80 mg, 0.5 mmol) and N,N-dimethylformamide (1.5 mL) was heated at 88 ° C under nitrogen for 2 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was concentrated. The residue was purified on silica get using hexanes: ethyl acetate (10:0 to 7:3) to give the product. 1H NMR (300 MHz, CDCI3): δ(ppm) 7.98 (d, 2H)1 7.40 (m, 5H), 3.64 (m, 4H)1 3.26 (m, 2H), 2.92 (m, 2H), 1.52(s, 9H). Using the above general procedure, the following compounds were synthesized:
Figure imgf000077_0003
Figure imgf000078_0001
Example 21.9: tart-Butyl 2-vinyl-5,6,8,9-tetrahydro-7H-pyrido[2,3- d]azepine-7-carboxylate
Figure imgf000079_0001
The title compound from Example 17.1 (0.454 g, 1.15 rnmol), lithium chloride (0.146, 3.44 mmol) and tetrakis(tripheny!phosphine)palladium (0 132 g, 0 115 mmol) were suspended in toluene (10 ml.) under a nitrogen atmosphere Tributyl vinyl tin (0 40 g, 1.26 mmol) was added to this suspension and the reaction was refluxed for 2 hours. The reaction mixture was concentrated onto silica gel and purified by column chromatography (20% EtOAc/Hexanes) to give the title compound (0.175 g, 56%) 1H NMR (300 MHz, CDCI3)- δ(ppm) 7.29 (d, 1 H), 7.05 (d, 1H)1 6.71 (q, 1H)1 6.08 (d, 1H), 5.35 (d, 1H), 3.52
(br t, 4H), 3.10 (br, 2H), 2.80 (br, 2H), 1.44 (s, 9H).
Example 21.10: tert-butyl 2-methyl-5,618,9-tetrahydro-7H-pyrido[2,3- d]azepine-7-carboxylatβ
Figure imgf000079_0002
The title compound from Example 17.1 (100 mg, 0.26 mmol), Pd(dba)2 (10 mg, 0 017 mmol) and PPh3 (8 mg, 0 034 mmol) were mixed in tetrahydrofuran (2ml_) at room temperature under N2 and stirred for 20 min. MβzZn (2M in THF, 0 3 mL, 0.6 mmol)) was added The reaction mixture was heated to 50 0C for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate and purified by column chromatography (EtOAc/Hexanes=1/2) to give the title compound (55 mg, 76%) 1H NMR (300 MHz, CDCI3). δ(ppm) 7 30 (d, 1 H), 6.93 (d, 1 H)1 3 57 (m, 4H)1 3.12 (m. 2H1 2.84 (m, 2H), 1 50 (S, 9H)
Example 21.11 : 2-(Mβthvl-phenγl-amiπo)-5,6,8,9-tetrahydro-pyridor2,3- d]azepiπe-7-carboxy1ic acid tert-butyl ester
Figure imgf000080_0001
The title compound from Example 10.2 (0.200 g, 0.526 mmol), Pd2(dba>3 (0.01 O g, 0.0105 mmol), BiNAP (0.0131 g, 0.0210 mmol), sodium tert- butoxide (0.071 g, 0.736 mmol) and methyl-phenyl -amine (0.068 g, 0.631 mmol) were stirred in toluene (5.0 mL) under a nitrogen atmosphere at 100 UC overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic extracts were dried over magnesium sulfate, filtered, concentrated and purified by column chromatography to give the title compound (0. 020 g, 11%). 1H NMR (300 MHz, CDCI3): δ(ppm) 7.37 (t, 2H)1 7.26 (m, 2H), 7.16 (t. H), 7.06 (d, 1 H), $.37 (d, 1H), 3.59 (m, 4H), 3.49 (s, 3H)1 3.06 (m, 2H). 2.75 (m, 2H), 1.50 (s, 9H).
Using the above general procedure, the following compounds were synthesized:
Figure imgf000080_0002
Examola 21.13: tert-Butyl 2-formyl-5,6,8,9-tetrahydro-7H-pyrido[2,3- d]azeplne-7-carboxylate
Figure imgf000081_0001
The title compound from Example 18.4 (0.175 g, 0.639 mmol) was dissolved in dichloromethaπe (20 mL) and cooled to -78 0C. Ozone was piped into the solution until it turned blue. The reaction was stirred for a further 15 minutes at -78 0C after which oxygen was piped into the reaction for 5 minutes. The reaction mixture was removed from the ice bath and methylsulfonyfmethane (0.169 g. 2.72 mmol) was added with stirring. After 15 minutes, the reaction was concentrated to give the title product with no further purification. 1H NMR (300 MHz, CDCI3): δ(ppm) 9.98 (s. 1H), 7.98 (d, 1H), 7.72 (d, 1H), 3.61 (t, 4H)1 3.24 (m. 2H)1 2.96 (m, 2H), 1.46 (s, 9H).
Example 21.14: tert-Butyl 2-[(dimethylamino}carbonyl]-5,6,8,9- tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate
Figure imgf000081_0002
To a tetrahydrofuran (6.0 mL) solution of the title compound from Example 17.1 (0.120 g, 0.303 mmol) degassed with carbon monoxide, lithium bromide (0.0026 g, 0.030 mmol) and dimethyl amine (0.413 mL, 0.91 mmol) and Tetrakis palladium triphosphine (0.034 g, 0.030 mmol) in tetrahydrofuran (1 mL) were added. The reaction mixture was heated to 60 0C under a carbon monoxide atmosphere for 4 hours. The reaction was quenched and the product was purified by automated column chromatography to yield the title compound (0.040 g, 41%). 1H NMR (300 MHz, CDCI3): δ (ppm) 7.49 (d, 1 H), 7.39 (d, 1H), 3.57 (br, 4H), 3.16 (br, 2H), 3.10 (d, 6H), 2.88 (br, 2H), 1.47 (s, 9H).
Using the above general procedure, the following compounds were synthesized:
Figure imgf000082_0001
Example 21.17: tert-Butyl 2-tert-bυtyl-5,6,8,9-tθtrahydro-7H-pyrido[2,3- d]azepine-7-carboxyfatβ
Figure imgf000083_0001
Ted-butyl lithium (1 93 mL, 3.28 mmol) was added to a suspension of copper cyanide (0 158 g, 1.77 mmol) in tetrahydrofuran (4.0 mL) under nitrogen at - 40 0C. A solution of the title compound from Example 17.1 (0 200 g, 0.505 mmol) in tetrahydrofuran (2.0 mL) was added slowly to the reaction mixture The reaction was stirred at -40 0C for 24 hours and then warmed to r t over 6 hours The reaction mixture was quenched with saturated ammonium chloride (20 mL) and diluted with ethyl acetate. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried with magnesium sulfate, filtered and concentrated. The product was purified by column chromatograph to give the title compound (101 mg, 66%) 1H NMR (300 MHz, CDCI3) δ(ppm) 7 29 (d, 1H), 7.07 (d. 1H), 3 57 (br t, 4H), 3.13 (m. 2H), 2.82 (br, 2H), 1.49 (s, 9H), 1.33 (s, 9H),
Example 21.18: tert-Butyl e 2-DIbuty1amino-5F6,8,9-tetrahydro- pyrldo[2,3-d]azepine-7-carboxylate ZH396Θ 062.1
Figure imgf000083_0002
The title compound from Example 17.1 (0 10 g, 0 25 mmol) and dibutyl amine (0 5 mL) dissolved in dimethyl sulfoxide (2 mL) were heated to 120-150 0C in a microwave for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate, dried and concentrated. The product was purified by column chromatography to give the title compound (34 mg, 36%). 1H NMR (300 MHz, CDCI3): δ(ppm) 7.12 {d. 1 H)1 6.18 (d, 1H), 3.56 {br m, 4H), 3.44 (t, 4H), 2.97 (m, 2H), 2.71 (br, 2H), 1.55 (m, 6H). 1.50 (s, 9H), 1.36 (m, 5H), 0.94 (t, 7H).
Using the above general procedure, the following compounds were synthesized:
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
2H), 2.00 (m, 2H), 2.55 (t, 2H), 2.36 (s, 6H), 1.49 (s, 9H)
Tert-butyl 2- 35.5 mg, 84
{methyl[2-
(methylamino)ethyl]
Figure imgf000093_0001
Example amino}-5, 6,8,9- 21.48 tetrahydro-7H- pyrido[2,3- dJazepine-7- carboxylate
NMR 1H NMR (300 MHz, CDCI3): δ(ppm) 7.i9(d, 1 H), 6.29 (d, 1 H), 3.68 (t, 2H)1 3.52 (m, 4H), 3.13 <br, 1H), 3.02 (s, 3H)1 2.95 (m, 2H), 2.86 (t, 2H), 2.71 (m, 2H), 2.51 (s, 3H), 1.48 (S, 9H).
Tert-butyl 2-(8- 9 mg, 20 %
XCH azabicyclo[3.2.1]oct
-8-yl)-5,6,8,9-
Example tetrahydro-7H- 21.49 pyrido[2,3- d]azepine-7- carboxylate
NMR 1H NMR (300 MHz, CDCI3): δ(ppm) 7.17(d, 1H)1 6.31 (d, 1H), 4.45 (m, 2H), 3.55 (m, 4H), 2.99 (m, 2H)1 2.75 (m, 2H), 2.08 (m, 2H), 1.83 (m, 5H), 1.50 (s & m. 10H)1 1.36 (m, 2H). ryCCK Tert-butyl 2-(1 ,1- 10 mg, 21 % dioxidothiomorpholi n-4-yl)-S,6,8,9-
Example tetrahydro-7H- 21.50 pyrido[2,3- d]azepine-7- carboxylate
NMR H NMR {300 MHz, CDCI3): δ(ppm) 7.29(d, 1H)1 6.62 (d, 1 H), 4.14 (m, 4H), 3.57 (m, 4H), 3.03 (m, 6H), 2.78 (m, 2H), 1.50 (S1 9H).
Figure imgf000094_0001
(mτ 4H), (s.
(m, 4H), (s,
(d, 1H), 1.32
Figure imgf000095_0001
Figure imgf000096_0001
Tert-butyl 2-(1.4- 22 mg, 51%
[„! oxazepan-4-yl)-9- 6,8,9-
Example r --f methyl-5, tetrahydro-7H-
21.65 pyrido[2,3- d]azepine-7- carboxylate
NMR 1H NMR (300 MHz, CDCI3) : δ(ppm) 7.16 (d, 1 H), 6.26 (d, 1 H),
2.60-3.95 (m, 15H), 2.03 (m, 2H)1 1.48 (s, 9H), 1 30 (m, 3H)
Tert-butyl 2-(4- 21.7 mg, 50
-V fIouropiperidin-1- % yl)-9-me(hyl-
Example XT
5,6,8,9-tetrahydro-
21.66
7H-pyrido[2,3- d]azepine-7- carboxylate
NMR 1H NMR (300 MHz1 CDCI3) : δ(ppm) 7.20 (d, 1 H), 6.43 (d, 1 H),
4.84 (drr , 1H) , 3.56 (m, 8H), 3.13 (m, 1H)1 2.80 (m, 2H), 1.95
(m, 4H), 1.49 (s, 9H), 1.31 (m, 3H)
Tert-butyl 2-(4,4- 23.1 mg, 50 diflouropiperidin-1- %
* -^ yl)-9-methyl-
Example
5,6,8,9-tetrahydro-
21.67 7H-pyrido[2,3- dJazepiπe-7- carboxylate
NMR 1H NMR (300 MHz1 CDCI3) δ(ppm) 7.22 (d, 1H), 6.46 (d, 1H),
3.71 (m, 4H), 3.38 (m, 4H), 3.14 (m, 1 H), 2.75 (rr i, 2H), 2.01
(m, 4H), 1.48 (S, 9H), 1.31 (m, 3H)
Tert-butyl 2-(4,4- 39 mg, 41.3
Example difluoroazepan-1- %
21.68 yl)-9-methyl-
5,6,8,9-tetrahydro-
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
tert-butyl 2-(benzyl-methyl-amino)-5,6,8,9-tetrahydro-pyrido[2,3-d]azepine-7- carboxylate (98.5 mg, 0.27 mmol) was mixed with 20 % Pd(OH)2 (20mg)in methanol (2m L) and stirred under H2 overnight. The reaction mixture was filtered and purified by column chromatography to give the title compound 35.4 mg (47 %)
Example 21.76: tert-ButvJ 2-[acβtyl(methyl)amiπo]-5,6,8,9-tetrahydro-7H- pyrido[2,3-d]azepiπe-7-carboxylate
Figure imgf000100_0002
The title compound (68 mg, 53 3 %) was prepared from tert-butyl 2-
(methylamiπo)-5τ6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (110.6 mg, 0.4 mmol) reacted with acetyl chloride (37.3 μL, 0 53 mmol) and triethylamiπe (54 mg, 0.53 mmol) in dichloromethane (2 mL) at 0 0C. 1H NMR (300 MHz, CDCI3): δ(ppm) 7 45 (d, 1H), 6.97 (br, 1H), 3.57 (m, 4H), 3 30 (S1 3H), 3.08 (m, 2H), 2 86 (m, 2H), 2.02 (s, 3H), 1.46 (S, 9H).
Example 21.77: tert-Butvl 2-(1 -oxidothiomorpholin-4-yl)-5,6,8,9-tetrahydro- 7H-pyrido[2,3-d]azepine-7-carboxylate
Figure imgf000100_0003
To a solution of NaIO4 (132.6 mg, 0.62 mmol) in water (2mL) at 0 0C1 tert-butyl a-Chiomorpholin^-yO-S.e.S.Θ-tetrahydro^H-pyrido^.S-dlazepine^- carboxylate (143.3 mg, 0-41 mmol) in methanol (4mL) and DMF (4mL) was added the reaction mixture was stirred at 00C for 24 hours and then filtered. The filtrate was extracted with dichloromethane and concentrated. The residue was purified by column chromatography to give the title compound 116.9 mg (78 %). 1H NMR (300 MHz1 CDCI3): δ(ppm) 7.23 (d, 1H)1 6.46 (d, 1H), 4.10 (m, 4H), 3.52 (m, 4H), 2.96 (m, 2H), 2.75 (m, 6H)1 1.45 (s, 9H).
Example 21.78: Tert-butvl 3-chloro-2-piperidin-1-yl 5,6,8,9-tetrahydro-7H- pyrido[2, 3-d]azepiπe-7~carboxylate
Figure imgf000101_0001
tert-Butyl 2-piperidin-1-yl 5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7- carboxylate (50 mg, 0.153 mmol) was mixed with N-chlrorosuccinimide (24 mg, 0.18 mmol) in acetonitπϊe (1.5 mL) and heated at 68 0C overnight. The reaction mixture was concentrated with silical gel and purified by column chromatography with 15 % ethyl acetate in hexanes to give the title compound 50 mg (91 %). 1H NMR (300 MHz, CDCI3): δ(ppm) 7.30 (s, 1 H), 3.56 (m, 4H)f 3.28 (m, 4H), 3.03 (m, 2H), 2.75 (m, 2H), 1.68 (m, 6H), 1.49 (s, 9H). In a similar manner the following compounds were synthesized:
Example Structure Name Yield
Tert-Butyl 3-chloro- 43 mg,
2-morpholiπ-4-yl- 77 %
5,6,8,9-tetrahydro-
Example
7H-pyridθ[2,3-
21.79
Figure imgf000101_0002
d]azepiπe-7- carboxylate
1H NMR (300 MHz, CDCI3): δ(ppm) 7.34 (s, 1 H), 3.86 (m, 4H)1 3.85
NMR (m, 4H), 3.57 (m, 4H), 3.32 (m, 4H), 3.02 (m, 2H), 2.77 (m, 2H)1 1.49 (s, 9H).
Tert-Butyl 3-chloro- 15.3
Example 2 (4,4- mg, 56 21.80 difluoropiperidin-1- yO-5,6,8,9-
Figure imgf000102_0001
Example 21.83: (9R)- and (9S)-tert-butyl 2-[ethyl(methyl)ammo]-9-methyl- 5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepiπe-7-carboxylate
Figure imgf000103_0001
The (9R)-tert-butyl 2-[ethyl{methyl)amino]-9-methyl-5,6,8,9-tetrahydro-7H- pyrido[2,3-d]azepine-7-carboxylate and the (9S)-tert-butyl 2- [ethy\{π\eihy\)am\no]-9-m&by\-5fiβ,§Aeftahyόro-7H-pyr\do[2,Z-d}azepme-7- carboxylate (Rt= 6.6 miπ, 36 mg ; Rt= 7.8min, 35.1 mg) were separated from racemic tert-butyl 2-[ethyl(methyl)aminoJ-9-methyl-516,8f9-tetrahydra-7H- pyrido[2,3-d]azepine-7-carboxylate by Chiralcel OJ with 1 % ethanol in hexanes.
Example 21.84: OR)- and (9S)-tert-butyl 9-methyl-2-pipendin-1-yl-5,6,8,9- tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxy)ate
Figure imgf000103_0002
The (9R)-tert-butyl 9-methyl-2-piperιdin-1-y[-5,6,8,9-tetrahydro-7H-pyrido[2,3- d]azepine-7-carboxylate and the {9S)-tert-butyl 9-methyl-2-piperidin-1-yl- 6,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxyiate.
(Rt= 6.95 min, 42.5 mg,; Rt= 8.56min, 42 mg,) were separated from racemic tert-butyl 9-metnyl-2-piperidin-1-yl-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine- 7-carboxylate by Chiralcel OJ with 1% ethanol in hexanes
Example 21.85: (9RV and (9S)~tert-butyl 9-methyl-2-morpholin-4-yl-5,6%8,9- tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate
Figure imgf000103_0003
The (9R)-tert-butyl 9-methyl-2-morpholiπ-4-yl-5,6,8,9-tetrahydro-7H- pyrido[2,3-d]azepine-7-carboxylate and the (9S)-tert-butyl 9-methyl-2- morpholin-4-yl-5,6.8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (Rt= 21.26mιn, 48.2 mg,; Rt= 17 4 min, 47.5 mg,) were separated from racemic tert-butyt 9-methyl-2-piperidin-1-y|-5,6,8,9-tetrahydro-7H-pyrido[2,3- d]azepine-7-carboxylate by Chiralcel OJ with 1 % ethanαJ in hexaπes
Example 21.86: OR)- and (9S)-2-(4-fluoropipeπdιn-1-yl)-9-methy|-5,6,8,9- tetrahydro-7H-pyπdo[2,3-d]azepine-7-carboxylate
Figure imgf000104_0001
The {9R)-2-(4-fluoropιperidin-1-y|)-9-methyl-5,6,8,9-tetrahydro-7H-pyrιdo[2,3- dJazepine-7-carboxylatβ and the (S)-2-(4-fluoropipeπdin-1-yl)-9-methyl- 5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (Rt= 7.51 mm, 11 mg; Rt=9.68 mm, 8 7mg) were separated from racemic 2-(4-fluoropιpeπdin-1 - yl)-9-methyl-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]aiepιne-7-carboxylate by CHIRALPACK AD-H with 2.5% EtOH in Hexanes.
Example 21.87: (9R)- and (9S)-2-(4-fluoropiperidin-1-yl)-9-methyl-5,6,8,9- tetrahydro-7H-pyrido[2,3-d]azepine-7-carboχylate
Figure imgf000104_0002
The (9R)'2-(4-fluoropiperidin-1-yl)-9-methyl-5,6,8,9-tetrahydro-7H-pyrido[2,3- d]a2epιne-7-carboxylate and the (S)-2-{4-fluoropiperidin-1-yl)-9-methyl'
S.β.β.θ-tetrahydro^H-pyπdo^^-dlazepine^-carboxyJate (Rt= 5.12 min, 12.8 mg; Rt=6.62 mm, 13 mg) were separated from 2-(4-fluoropιperidin-1-yt)-9- methyl-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate by CHIRALPACK AD-H with EtOH in Hexanes.
Example 21.88: (9R)- and (9S)-tert-butyl 9-methyl-2-(1,4-oxazepan-4-yl)- 5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate
Figure imgf000105_0001
(9R)-tert-butyl 9-methyl-2-(1 ,4-oxazepan-4-yl)-5,6,8,9-tetrahydro-7H- pyrido[2,3-d]azepiπe-7-carboxylate and (9S)-tert-butyl 9-methyl-2-(1,4- oxazepan^ylJ-δpepβ.θ-tetrahydro^H-pyrido^.S-dJazepine^-carboxylate (Rt=10.2 min, 10 mg; Rt= 14.4 min, 10 mg) were separated from racemic tert- butyl 9-methyl-2-(1,4-oxazepan-4-yl)-5,6,8,9-tetrahydro-7H-pyrido[2T3- d]azepine-7-carboxylate by CHIRALPACK AD-H with 2.5% EtOH in Hexaπes.
Method A: (TFA-DCM)
Example 22.1: 6,7,8,9-Tetrahydro-5H-pyridoP,3-d]azepine-2-carbonitrile
Figure imgf000105_0002
To a soiution of tert-butyl 2-cyano-5,6,8,9-tetrahydro-pyrido[2,3-d]azepine-7- carboxylate (12 mg) in dichloromethane (1 mL) at 0° C, was added trϊfluoroacetic acid (0.5 mL). The reaction mixture was stirred at 0° C for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous sodium carbonate. The organic layer was dried over sodium sulfate and concentrated to give the product. The product was treated with hydrochloric acid in diethyl ether to give the hydrochloric acid salt (2 salt equivalents, 5 mg).
Method B: (HCI in Et2O) Example 22.2: azapine-2-carboxvlic acid dimethylamide; dihydrochloride
Figure imgf000106_0001
The title compound from Example 15 (0.04Og, 0.126 mrnol) was dissolved m dichloromethane (2 mL) and 2M hydrochloric acid in diethyl ether (3 mL) for 6 hours. The reaction was concentrated to give the title compound as a hygroscopic brown solid (0.038 g, 100%). 1H NMR {300 MHz, CDCI3 +MeOD): δ{ppm) 8.48 {d, 1H), 8.01 (d, 1 H), 3.74 (br, 2H)1 3.59 <br, 2H), 3.52 (br. 4H), 3.14 (d, 6H).
In a similar manner the following compounds were synthesized:
1H)1
1H), (d, 3H).
(m, 2H),
Figure imgf000106_0002
H), 7.40
8.46 (d,
(m,
1H),
(m, 2H),
Figure imgf000107_0001
3.36 (m,
(m, 1H)T
3.02 (m,
(d, 1H)1 (m,
2H),
Figure imgf000108_0001
Figure imgf000109_0001
(t, 2H),
(brs, 095
(d,
2H),
(d,
Figure imgf000110_0001
(d, 1H), (m, 6H), (m, 4H),
(m, 5H),
Figure imgf000111_0001
Figure imgf000112_0001
(m, 5H)1 (d, 3H),
(m, 4H).
<m, 4H),
(m,
Figure imgf000113_0001
Figure imgf000114_0001
(m, 4H),
(m, 4H), <t, 2H),
(m, 2H),
Figure imgf000115_0001
Figure imgf000116_0001
(m, 1H),
2H).
2H),
{m, 8H),
Figure imgf000117_0001
Figure imgf000118_0001
Example (9S)-2-(4,4- B 7.5 mg
J2.62 difluoropiperidin-1- yl)-9-mβthyl-6,7,8,9-
M-Cl H-Cl tetrahydro-5H- pyrido[2,3-d]a2epine dihydrochloride
Example 2-(4-fluoropiperidin- B 22.6mg,
22.63 1-yl)-6,7,8,9- 100 % tetrahydro-5H-
Figure imgf000119_0001
H-Cl py rido[2 , 3-d]azepine dihydrochloride
NMR 1H NMR {300 MHz1 MeOD): δ(ppm) 7.92 (d, 1 H)1 7.29 (d, 1 H), 5.06, 4.91 (d m, 1 H), 3.83 (m, 4H), 3.52 (m, 4H), 3.37 (m, 2H)1 3.18 (m 2H) , 2.08 (m, 4H),
Example 2-(4-fluoropiperidin- B 20.2mg,
22.64 1-yl)-9-methyl- 100 %
6,7,8, 9-tetrahydro-
Figure imgf000119_0002
5H-pyrido[2,3- d]azepine dihydrochloride
NMR 1H NMR (300 MHz, MeOD): δ(ppm) 7.89 (d, 1 H), 7.30 {d, 1H), 5.06, 4.92 (d m, 1H), 3.86 (m, 5H), 3.58 (m, 3H), 3.25 (m, 3H), 2.08 (m. 4H) 1.56 (d, 3H).
Example (9R)-2-(4- B 11.1 mg
22.65 fluoropiperidin-1-yl)-
T 9-methyl-6,7,8,9-
H-Cl H-Cl tetrahydro-5H- pyrido[2 , 3-d]azepi ne dihydrochloride
Example (9S)-2-(4- B 8.7 mg
22.66 JL r fluoropiperidin-1-yl)-
9-methyl-6,7,8,9-
H-Ol H-Cl tetrahydro-5H- pyrido[2,3-d]azepiπe dihydrochloride
Figure imgf000120_0001
(m, 6H). 2 05 (m, 7H),
Figure imgf000121_0001
Figure imgf000122_0001
(m, 2H)1 4H), 1.53
1H), 3.40-
(br, 1H),
3.22 (m,
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0003
Figure imgf000125_0001
Example 22.90: 2-lsopropyt-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepinβ
Figure imgf000125_0002
2-lsopropenyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepiπe (8.5 mg) was treated with palladium hydroxide and methanol under hydrogen (1 atm) for 3 hours. The reaction mixture was concentrated, diluted with dichloromethane, filtered and concentrated again to give the product. The product was treated with hydrochloric acid in diethyl ether to give the hydrochloric acid salt (2 salt equivalents, 9.2 mg). 1H NMR (300 MHz, CDCI3): δ (ppm): free base 7.33(d, 1 H), 6.93 (d, 1H), 3.18 (m, 2H), 3.02 (m, 4H), 2.90 (m, 2H), 1.67 (br, 1 H), 1.29 (S, 3H).
In a similar manner the following compound was synthesized:
3.26
Figure imgf000127_0001
Evaluation of Biological activity
Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo and in vivo assays that are well known in the art, including the assays described in the fo/lowing examples.
MATERIALS AND METHODS
Activation of the Gq coupled 5-HT2 receptors stimulates phospholipase C activity and leads to formation of inositol trisphosphate (IP3) and the subsequent release of calcium from intracellular stores. Functional activity of Gq coupled receptors can be quantified in a FLIPR assay by measuring intracellular calcium levels with calcium sensitive dyes (using a fluorescence imaging plate reader, FLIPR) and in a Phosphatidyl Inositol Hydrolysis Assay (IP accumulation assay) which measures IPs derived from IP3. Both assays provide robust functional readouts of receptor activation.
Cell Culture: Stable cell lines expressing human 5-HT2A, 5-HT2B and 5HT- 2C (both INI and VSV isoforms) receptors were created in an MHEK cell background (an HEK293-based cell background which also expresses the Macrophage Scavenger Receptor 1, to increase the adherence of cells to tissue culture plates). Recombinant cell lines were cultured in Growth Medium (High glucose DMEM (Hyclone) with 10% dialyzed fetal bovine serum (Hyclone), and L-glutamme (Gibco; 0.8mM for 5HT2A and 2C, 2.0 mM for 5HT2B), and grown under selection with 200μg/ml Zeocin (Iπvitrogen), and either 200μg/ml Hygromyciπ B (Invitrogen for 5HT2A and 5HT2C) or 500 ug/ml Geneticin (Invitrogen for 5HT2B)
FLIPR assay methodology: Cells that recombinant^ expressed the 5HT2 receptors were enzymatically dissociated with Trypsin/EDTA 0 25 % (Hyclone) 24 hours pπor to testing, and seeded at 60,000 cells per well in 100 μl Growth Medium in black sided, clear bottom 96 well plates (Greiner, BioExpress) at 37QC and 5% CO2. On the day of the assay, Growth Medium was removed by aspiration, and 80μl of Assay Buffer (2OmM HEPES, 146 mM Sodium Chloride, 5 mM Potassium Chloride, 1 mM Magnesium Chloride, 1mg/mL BSA, 1mg/mL Glucose, 1mM CaCk, pH 7.4, supplied by Amresco), containing 6μM Fluo-3 AM and 0.01% pluronic acid (Biotiurn Inc., Hawyard, CA) was added. Cells were rncubated in the Fluo-3 solution for 60 minutes in the dark at room temperature. The Fluo-3 solution was then removed by aspiration and cells were washed twice with assay buffer leaving 160μl in each well.
All compounds were prepared at 5 times their final concentration prior to the online addition (40μl) in the FLlPR (MDS lnc , Sunnyvale, CA) The fluorescent intensity was measured at 1 second intervals for 10 seconds prior to the compound addition and 65 seconds after the compound addition. All responses were measured as the peak height of the fluorescent response over baseline, within the sample period. Non-linear regression of the relative fluorescence unit (RFU) change was used to determine agonist potency.
Antagonist activity was measured after pre-incubatioπ of cells with compound for 30 minutes at room temperature, followed by the online addition of agonrst (5-HT, EC80) in the FLFPR. Antagonist activity was determined by normalizing the response to the maximal 5-HT response in the absence of test compound.
Phosphatidyl Inositol Hydrolysis Assay: 24 hours prior to testing, cells were plated in poly-D-Lysine-coated 96 well plates (VWR) at 100,000 cells/ well in 200μl culture medium containing 10μCi/ml of [3HJ-myo-lnositol (Perkiπ Elmer} CeIi monolayers were washed twice with HBSS (HEPES Buffered Saline solution: 20 mM HEPES, 146mM NaCl, 4 2mM KCl, 0.5mM MgCI2, 0.1% Glucose, pH 7.4) The cell monolayers were pre-incubated for 5 minutes at 37°C in 100μl/well HBSS containing 1OmM LiCI Compounds were tested for agonist activity in duplicate at concentrations ranging from 3nM to 30μM. Compounds were added (100 μl) at 2 times the required final concentration and incubated for 30 minutes at 370C Medium was aspirated and the soluble 3H-iπositol phosphates were extracted from the cells by adding 100 μl/well of ice-cold 5% perchloroacetic acid solution Plates were placed on ice for 1 hour, and extracts collected in a 2ml, 96 well, polypropylene, round bottom Uniplate (VWR). Cell extracts were neutralized with 150-170μl HEPES / KOH (0 375 / 0.75 M) containing a pH indicator until all solutions turned pale green. 600μl HEPES / EDTA (2 5/0.5mM, pH 7 4) was then added to all tubes, and contents were transferred to a 96 well PALL Filter Plate (VWR) loaded with 600 μl/well of Dowex resin (Dowex AG-1X8 formate form, 200-400 mesh, Bio- Rad, equilibrated in HEPES / EDTA (2.5/0.5mM, pH 7 4). The Filter Plate was then placed in a vacuum manifold and a gentle vacuum was applied Total phosphatidyl inositols were eluted with 800μl 3OmM ammonium formate, and the eluate was discarded Total inositol phosphates were eluted with 600μl (2X 300μl) 70OmM ammonium formate / 10OmM formic acid and collected in a clean 2ml, 96 well, polypropylene, round bottom Uniplate. 75μl eluate was transferred to a Hewlett Packard Optiplate and 150μJ Scint 40 was added to each well The plate was sealed with a Topseal (Packard) and shaken for 1 minute on a platform plate shaker Plates were counted in the Hewlett Packard Topcount to quantify the amount of radioactivity in each well
Animals and housing: Male, Sprague-Dawley rats or CD-1 mice were used for all studies. All animals were allowed ad-lib access to food and water except during experiment. Animals were housed within an animal vivarium maintained under a 12h light:dark cycle (lights on: 07.0Oh), and all experiments were conducted in the animals' light phase. For all experiments, animals were habituated to the vivarium for a minimum of 72h before experimentation The experimental procedures used in the present investigation were conducted under the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) and the Canadian Council on Animal Care (CCAC) guidelines.
Teat Compounds: All compounds were dissolved in 5% Tween 80 in saline and injected in a dose volume of 5ml/kg or 10ml/kg (rat), and 10m!/kg (mouse). Compounds were administered by either the oral or intraperitoneal route.
Mouse hypolocomotioπ assay: Selective 5-HT2C receptor agonists have been reported to produce hypolocomotion in rodent species by a relatively well defined CNS mechanism. A mouse locomotor assay was therefore used to screen compounds. Mafe, CD-1 mice were administered test compound 15min before placement in a chamber where locomotor activity was measured through photocell beam breaks. Test compounds were administered either by the oral or intraperitoneal route.
Deprivation-induced feeding in the rat: Male Sprague-Dawley rats (Charles River, St. Constant, Quebec, Canada) of approximate weight 180-20Og were pair housed on arrival in the animaf facility (lights on 7:00-19:00h) After a 7 day acclimitisatϊon period where the animals received ad-libitum access to standard rodent lab chow (Harlaπ Teklad rodent maintenance diet, 2014; Harlan Teklad, Madison, Wl)1 the animals were trained to receive a daily ration of lab chow in distinct chambers over a 2h period. Animals were singly housed for the duration of this period and food intakes over the 2h access period were measured by weighing food containers before and after feeding periods, with correction for spillage. After the daily 2h food access period, the animals were returned to their holding cage with no further daily food allowance Water was available ad-libitum. Body weights were recorded daily.
Once the daily food intake had stabilized (after one to two weeks training), a dose of a test compound (or vehicle as control) was administered 10 to 1 S minutes before the beginning of the 2 hr. food access period, and food intake over that period was measured as during the training period. Test compound or vehicle was administered on Tuesdays and Fridays, with drug free (washout) days in between Typically the animals received 3 doses of test compound and vehicle in a counterbalanced sequence
Schedule-induced polydipsia
Food deprived rats exposed to intermittent, uncontrollable presentations of food will drink quantities of water that are far in excess of their normal daily intake and in excess of their intake when given food at one time (FaIk JL (1961) Production of polydipsia in normal rats by an intermittent food schedule. Science 133. 195-196). This excessive behaviour is persistent and has been proposed as a model of obsessive-compufsive disorder based on pharmacological validation and symptomatic similarities (Woods, A βt al (1993) Selective serotonin re-uptake inhibitors decrease schedule-induced polydipsia in rats a potential model for obsessive compulsive disorder Psyohopharmacology 1121 195-198)
Male Sprague-Dawley rats (Charles River, St Constant, Quebec. Canada) of approximate weight 180-20Og are pair housed on arrival in the animal facility (lights on 7 00-19 0Oh). After a 7 day acclimitisation period where the animals receive ad-hbitum access to standard rodent lab chow (HarJan Teklad rodent maintenance diet, 2014; Harlan Teklad, Madison, Wl)1 the animals are trained to receive single 45mg food pellets under a fixed time interval of 60s over a 2h peπod within an operant chamber equipped with a water bottle Thus during the 2h session, the rats can earn a maximum of 120 pellets The total volume of water consumed by rats dunng this 2h penod is recorded Daily food allowance is supplemented by a 45mιn access period sometime between 15' 00-18 OOh
Once daily fluid intakes within the 2h test session become stable over days (approximately +15%), the rats may be dosed orally or parentally with vehicle or test compound. Test compound or vehicfe is administered on Tuesdays and Fridays with drug free (washout) days in between Typically the animals will receive 3 closes of test compound and vehicle in a counterbalanced sequence.
A modification to the above procedure <s to pre-treat rats with either vehicle or a selective 5-HT2c receptor antagonist, 6-chloro-5-methyl-N-(2-(2- methylpyndιn-3-yl-oxy)pyrιdine-5-yl)amιnocarbonyl)-2,3-dihydroindoie (1 mg/kg in 8% HPCD, 25mM citric acid in saline) prior to the oral or parental dose of test compound.
s.c Pentylenetetrazol assay
Antagonism of clomc-toπic seizures produced by chemical convulsants such as pentylenetetrazol have been widely utilized to identify novel anttconvulsants
Male, CD-1 mice (Charles River, St. Constant, Quebec, Canada) of approximate body weight 20-3Og are housed in groups of four on arrival at the facility. Food (Harlan Teklad rodent maintenance diet, 2014; Harlan Teklad, Madison, Wl) and water are available ad-libitum After a minimum 3 day acclimatization period the animals would be tested in a s c pentylenetetrazol assay - which is considered both a model of primary generalized convulsive seizures and non-convulsive absence (petit rnal) seizures (Upton, N (1994) Mechanisms of action of new antiepileptic drugs, rational design and serendipitous findings Trends Pharmacol. Sci 15: 456-463)
The experiment is conducted within a single day with animals receiving a single pretreatment, Le independent groups design. Following drug or vehicle control treatment by either oral, or parenteral route, the animals would receive pentylenetetrazol (85mg/kg mice) administered by the subcutaneous route The dose of pentylenetetrazol is selected as it is of sufficient intensity to induce a clonic seizure in the majority of animals, i e a CD97 dose. The animals are restrained by hand to deliver the chemical convulsaπt, following which the animals are released and transferred to a test cage to permit observation of the subsequent seizure throughout its course The animal would receive a single pentylenetetrazol injection and would be terminated on reaching endpoint, i.e clonic seizure If an animal displays no seizure activity after 60min it is considered protected and the experiment completed as endpoint reached
Approximately 10-20min prior to the PTZ test, a parallel tests of motor function using the rotorod would be undertaken to establish a therapeutic index (Tl), e g ratio between the ED50 dose required to block seizures, compared to ED50 dose required to disrupt motor function in same species The rotorod test consists of placing the animal on a rotating treadmill (a rod) traveling at a constant speed of 16r p.m. The dependant measure is the time that the animal remains on the rod before falling. Up to three separate measures may be taken to get a meaningful measure αf performance.
A modification to the above procedure is to pretreat mice with either vehicle or a selective 5-HT2c receptor antagonist, 6-chloro-5-methyl-N-(2-(2- methylpyridin-3-yl-oxy)pyridine-5-yl)amιnocarbonyl)-2,3-dihydroιndole (1 mg/kg in 8% HPCD, 25mM citric acid in saline) pπor to the oral or parental dose of test compound,
Amphetamine-induced hyperlocomotion
Antagonism of increased locomotion produced by the psychostimulant amphetamine in rodents is a feature of many drugs with antipsychotic property in man As such reversal of amphetamine hyperlocomotion is a widely used preclinical test to detect novel drugs for the treatment of schizophrenia
Male Sprague-Dawley rats (Charles River, St. Constant, Quebec, Canada) of approximate weight 20Og are pair housed on arrival in the animal facility
(lights on 7 00-19:00h) After a 7 day acclimitisation period where the animals receive ad-libitum access to standard rodent lab chow (Harlan Teklad rodent maintenance diet, 2014; Harlan Teklad, Madison, Wl) the animals may undergo behavioural testing. Animals would be singly placed within the test apparatus (Perspex chamber of dimensions: rat 42cm x 42cm x 30cm (L x W x H)) for a limited time period {approximately 30min) to habituate to the novel environment. After such habituation period has passed, animals will be treated with test article or vehicle control via the oral, or parental route, and then returned to the observation test chambers. After a predetermined peπod, the animals would be dosed with either saline vehicle or d-amphetamine (0.5mg/kg) by the intraperitoneal route and returned to the test chamber for 2h. While in the test chamber, the animal's activity will be monitored automatically by infrared sensors and/or manually by an experimenter for expression of 'normal' behaviors such as sniffing, grooming, rearing, and 'abnormal' behaviors such as 'circling' At the completion of such test, the animals will be returned to their holding cages.
A modification to the above procedure is to pretreat rats with either vehicle or a selective 5-HT2C receptor antagonist, 6-chloro-5-methyl-N-(2-(2- methylpyndιn-3-yl-oxy)pyridine-&-yl)amιnocarbonyl)-2,3-dihydroindole (1 mg/kg in 8% HPCD, 25mM citric acid in saline) prior to the oral or parental dose of test compound.
5-HT?c Agonist Activity
Table 1 shows the 6-HT2C agonist potency of compounds in accordance with the invention, determined by FLIPR assay described above.
Mouse Hypolocomotion
Figure 1 shows the effect of two exemplary compounds of the invention on mouse locomotion after either oral or intraperitoneal injection.
Pre-treatment with the 5-HT2C antagonist SB242084 blocked the effect of the test compounds (data not shown).
Rat Deprivation induced Feeding Assay
Figure 2 shows the dose-related reduction in food intake in rats treated intraperitoneal^ with two exemplary compounds of the invention.
Pre-treatmeπt of rats with the selective S-HT∑c antagonist SB 242084 blocked the effect of the agonist compounds, as shown by the hatched bars.
The description as set forth is not intended to be exhaustive or to limit the scope of the invention. Many modifications and variations are possible in light of the above teaching without departing from the spirit and scope of the following claims. It is intended that the scope of the present invention be defined by the claims appended hereto, giving full cognizance to equivalents in all respects.
Table 1
Figure imgf000136_0001
Table 1 conf d
Figure imgf000137_0001
Table 1 cont'd
Figure imgf000138_0001
Table 1 cont'd
Figure imgf000139_0001
Table 1 cont'd
Figure imgf000140_0001

Claims

WE CLAIM:
1. A compound of Formula I:
Figure imgf000141_0001
wherein:
R1 to R3 and R5 to R12 are independently selected from H, halo, hydroxy, cyano, nitro, alkyJ, alkoxy, CH2OH, haloalkyi, O-ha!oalkyl, hydroxyalkyl, cyanoalkyl, alkeπyl, alkynyl, cycloalkyl, cycloalkeπyl, heterocycloalkyl, heterocycloalkenyl. aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O- heterocycloalkyl, alkylene-O-alkyl, alkyleπe-O-cycloalkyl, alkyleπe-O- heterocydoalkyl, alkylene-O-alkylene-cycloalkyl, alkylene-O-alkylene- heterocycloalkyl, S-alkyl, S(O)-alkyl, S(O)2*alkyl, S-cycloalkyl, S(O)-cydoalky|1 S(O)2-cycloalkyl, S-heterocycloalkyl, S(O)-heterocycloalkyl, S(O)2- heterocycloalkyl, O-aryl, O-heteroaryl, N(H)alkyl, N(alkyl)alkyl, N(H)-aryl,
N(aJkyl)-ary], N(H)-heteroaryl, N(alkyl)-heteroaryl, alkylene-O-aryl, alkylene-O- heteroaryl, alkylene-O-alkyfene-aryl, aJkyfene-O-alkyleπe-heteroaryl, S-aryl, S- heteroaryl, S(O)-aryl, S(0)-heteroaryl, S(O)2-aryf, S(O)2-rieteroaryl, C(O)alkyl, OC(O)alkyl, C(O)Oalkyl, C(O)N(H)alkyl, C(O)N(alkyl)atkyl, S(O)2N(H)alkyl or S(O)2N(alkyl)alkyl; R2 and R3, R5 and R8, R9 and R10, and/or R11 and R12, together with the carbon atom to which they are attached, form a cycloalkyl group; and
R* is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylene- O-alkyl, alkylene-O-cycloalkyl, alkylene-O-alkylene-cycloalkyl; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
2. A compound according to Claim 1, wherein any cyclic group is
5 substituted with one or more R13, R13 being selected from F, Cl1 Br, I, CN, nitro, hydroxy, oxo, C1-8-atkyl, OC^-alky!, C1-6-alkylhalo or OCi-β-alkyihalo.
3. A compound according to Claim 1 or Claim 2, wherein R4 is selected from H, alkyl, cycloalkyl, or cycloalkenyl, 0
4. A compound according to Claim 3, wherein R4 is selected from H or alkyl.
5. A compound according to any one of Claims 1 to 4, wherein R9 to R1ZS are independently selected from H, alkyl, alkenyf, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.
6. A compound according to Claim 5, wherein R9 to R12 are independently selected from H, alkyl or cycloalkyl. 0
7. A compound according to any one of Claims 1 to 6, wherein the compound is a pharmaceutically-acceptable salt, optical isomer, or combination thereof. 5
8. A compound according to any one of Claims 1 to 7, wherein the pharmaceutically-acceptable salt comprises an acid addition salt or a basic addition salt.
9. A compound according to Claim 8, wherein the acid addition salt is formed from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acid metal salt, monocarboxylic acids, dicarboxylic acids, or tricarboxylic acids.
10. A compound according to any one of Claims 1 to 9, wherein the compound of Formula I comprises a compound of Formula IA:
Figure imgf000143_0001
IA wherein:
R2 and R5 are independently selected from H, alkyl, afkyleπe-O-alkyl, C(O}Oalkyl, C(O)N(H)alkyl, haloalkyl, halogen or CH2OH; and
R3 and R6 are each H; or R2 and R3 and/or Rδ and R6, together with the carbon atom to which they are attached form a cycloalkyl group;
and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
11. A compound according to any one of Claims 1 to 10, wherein the compound of Formula I comprises a compound of Formula IB:
Figure imgf000143_0002
IB wherein : Z is selected from CR14R15, O, NR16, C=O1 S=O1 SO2 or S, and
R14 to R16 are independently selected from from H, halo, hydroxy, cyano, πitro, alkyl, alkoxy, CH2OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cyaπoalkyl, alkenyl, alkyπyl, cycloalkyl, cydoalkenyi, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyf, O-hθterocycloalkyl, alkylene-O-alkyl, alkyleπe-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene- O-alkylene-cydoalkyl, alkylene-O-alkyJene-heterocycloalkyl, S-alkyl, S(O)- a/kyl, S(O)2-alkyl, S-cycloalkyl, S(O)-cyc!oalkyl, S(O)2-CyClOaIkVl1 S- heteracydoalky!, S(O)-heterocycloalkyl, S(O).-heterocycloalkyl, O-aryl, O- heteroaryl, N(H)alkyl, N(alkyl)alkyl, N(H)-aryl, N(alkyl)-aryl, N(H)-heteroaryl, N(alkyl)-heteroaryl, alkylene-O-aryl, alkyJene-O-heteroaryl, alkylene-O- alkyleπe-aryl, alkylene-O-aikyleπe-heteroaryl, S-aryl, S-heteroaryl, S(O)-aryl, S(O)-heteroaryl, S(O)2-ary[, S(O)2-heteroaryl, C(O)alkyl, OC(O)alkyl, C(O)Oalkyl. C{O)N(H)alkyl, C(O)N(alkyl)alkyl, S(O)2N(H)alkyl or S(O)2N(alkyl)alkyl;
and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
12. A compound according to Claim 11 , wherein R1 is selected from H or halo; Rz and R3 are independently selected from H or alkyl; R14 and R15 are independently selected from H, haio, or alkyl; and R16 is selected from H or alkyl.
13. A compound according to Claim 12, wherein the halo is bromo, chloro, or fluoro.
14. A compound according to Claim 13, wherein Z is CR14R15, wherein R14 is H or fluoro and R15 is fluoro.
15. A compound according to Claim 14, wherein R1 is H and Z is CR14R15, wherein R14 is H and R15 is fluoro.
16. A compound according to any one of Claims 1 to 10, wherein the compound of Formula I comprises a compound of Formula IC:
Figure imgf000145_0001
IC wherein :
Z is selected from CR14R15, O, NR16, C=O1 S=O, SO2 or S; and
RH to R16 are independently selected from from H1 halo, hydroxy, cyano, nitro, alkyl, alkoxy. CH2OH1 haloalkyl, O-haloalkyl, hydroxyalkyl, cyaπoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cydoalkyl, O-heterocycloalkyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene- O-alkyleπe-cydoalkyl, alkylene-O-alkylene-heterocydoalkyl, S-alkyl, S(O)- alkyl, S(O)2-alkyl, S-cycloalkyl, S(O)-cycloalkyl, S(O)2-cycloalkyl, S- heterocycloalkyl, S(O)-heterocycloalkyl, S(0)2-heterocycloalkyl, O-aryl, O- heteroaryl, N(H)alkyl. N(alkyl)alkyl, N(H)-aryl, N(atky!)-aryl, N(H)-heteroaryl. N(alkyl)-heteroaryl, alkylene-O-aryl, alkylene-O-heteroaryl, alkylene-O- alkylene-aryl, alkylene-O-alkylenβ-hβtβroaryl, S-aryl, S-heteroaryl, S(O)-aryl, S{O)-heteroaryl, S(O)2-aryl, S(O)2-heteroaryl, C(O)aIkyt, OC(O)alkyl, C(O)Oalkyl, C(O)N(H)alkyl, C(O)N(alkyl)alkyl, S(O)2N (H)alkyl or S(O)2N(alkyl)alkyl;
and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
17. A compound according to Claim 16, wherein R1 is selected from H or halo; R2 and R3 are independently selected from H or alkyl; R14 and R15 are independently selected from H, halo, or alkyl; and R15 is selected from H or alkyl.
18. A compound according to Claim 17, wherein the halo is bromo, chloro, or fluoro.
19. A compound according to Claim 18, wherein Z is O.
20. A compound according to any one of Claims 1 to 10, wherein the compound of Formula I comprises a compound of Formula II:
Figure imgf000146_0001
21. A compound according to to any one of Claims 1 to 10, wherein the compound of Formula I comprises a compound of Formula III:
Figure imgf000146_0002
22. A compound according to to any one of Claims 1 to 10, wherein the compound of Formula I comprises a compound of Formula IV:
Figure imgf000147_0001
IV
23. A compound according to Claim 22, wherein R1 is selected from H1 alkyl or halo; R2, R3 and R8 are independently selected from H or alkyl; R4 is selected from H or alkyl; and R7 is selected from H1 alkyf, alkoxy. CH2OH, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
24. A compound selected from: (9R)-2-(4,4-difluoropiperidin-1-yl)-9-methyl-6,7,8,9-tetrahydro-5H- pyrido[2,3d]azepine;
(9R)-2-(4-fluoropiperidin-1-yl)-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3- d]azepine;
(9R)~9-methyl-2-(1,4-oxa..epan-4-yl)-6J,8>tetrahydro-5H-pyrido[2,3- djazepine;
(9R)-9-methy]-2-moφholin-4-yl-6,7,8τ9-tetrahydro-5H-pyrido[2,3-d]azepine;
(gRJ-θ-methyl^-piperidin-i-yl-ej.β.θ-tetrahydro-SH-pyrido^.S-dlazepine;
(9R)-N-ethyl-N,9-dfmethyl-6,7,819-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
(9S)-2-(4,4-difluoropiperidin-1-yl)-9-methyl-6,7,8l9-tetrahydro-5H-pyrido[2,3- d]azepine;
(9S)-2-(4-fluoropiperidin-1-yl)-9'methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3- djazepine;
(9S)-9-methyl-2-(1 ,4-oxazepan-4-yl)-6,7,819-tetrahydro-5H-pyrido[2,3- d]azepine (9S)-9-methyl-2-morpholin-4-yl-6,7,8,9-tetrahydro-5H"pyrido[2,3-d]azepine;
(9S)-9-methyl-2-piperidin-i-yl-6,7,8,9-tetrahydro-5H-pyrido[2(3-d]azepine;
(9S)-N-ethyl-N,9-dimethyl-6,7,8.9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine; 2-(1 ,4-dιazepan-1'yl)-6,7,8,9-tetrahydro-5H-pyπdo[2,3'd]azepιne,
2-(1 ,4-oxazepan-4-yl)-6,7,8,9-tetrahydro-5H-pyndo[2,3-d]azepine,
2-(1-oxιdothιomorpholιπ-4-yl)-6,7,a,9-tetrahydrα-5H-pyrido[2,3-d]a2:epine,
2-(3-thienyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-djazepine, 2-(4,4-difluoroazepaπ-1-yl)-617,8,9-tetrahydro-5H-pyπdo[2,3-d]azepιnel
2-(4,4-difluoroazepan-1-yl)-9-methyl-6>7l8,9-tetrahydro-5H-pyndo[2)3- djazepiπe;
2-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-(4,4-difluoropιperidιn-1-yl)-9-methyl-6,7,8l9-tetrahydro-SH-pyrido[2,3- d]azepine;
2-(4-fluoropιperιdιπ-1-yl)-6,7,8,9-tetrahydrθ'5H-pyrido[2,3-d]azepine;
2-(4-fluDropiperidin-1-yl)-9-metiiyl-6,7,8,9-tetrahydro-5H-pyndot2,3-d]azepine,
2-(4-methyipiperazin-1-yl)-6,7-8,9-tetrahydro-5H-pyndo[2,3-d]azepine;
2-(8-azabicyclo[3.2 1]oct-8-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepιπe, 2-(trifluoromethyl)-6,7,819-tetrahydro-5H-pyrido[2,3-d]azepιne,
2,9-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-dIazepiπe,
2-[methyl(6,7,8,9-tetrahydro-5H-pyrιdo[2,3-d]azepin-2-yl)amιπo]ethaπol,
2-azepan-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepιnet
2-azepan-1-yl-9-isopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; 2-azepaπ-1-yl-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepιnel
2-cyclopropyl-6,7,8,9-tetrahydro-5H-pyndo[2,3-d]azepine;
2-cyclopropyl-9-methyl-6,7I8I9-tetrahydro-5H-pyπdo[213-d]azepine;
Σ-isopropeπyl-ej.δ^-tetrahydro-SH-pyπdop.S-dlazepine;
2-ιsopropenyl-9-methyl-6,7,8.9-tetrahydro-5H-pyrido[2,3-d]azepιne, 2-isopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepιπe,
2-isopropyl-9-methyl-6,7,8,9-tetrahydro-5H'pyπdo[2,3-d]azepine;
2-methoxy-6,7,8,9-tetrahydro-5H-py(1do[2,3-d]azepine,
2'methoxy-9-methyl-6,7,8,9-tetrahydro-5H-pyπdo[2,3'd]azepine;
2-methyl-617,8,9-tetrahydro-5H-pyπdo[2,3-d]azepiπe, 2-morpho!iπ-4-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine,
2-piperazin-1-yl-6,7,8,9-tetrahydro-5H-pyπdo[2,3-d]azepine;
2-pιpeπd ιn-1 -yl-6, 7, 8,9-tetra hydro-5H-pyrido[2, 3-d]azepιne,
2-pyrrolidιn-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine,
2-tert-butyl-6,7,8,9-tetrahydro-5H-pyndo[2l3-d]azepine, 2-thiomorphoHn-4-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-vinyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepiπe;
3-brσmo-2-methoxy-6, 7, 8, 9-tetrahydro-5H-pyrido[2, 3-d]azepi πe;
3-bromo-2-morpholin-4-yl-6I718,9-tetrahydro-5H-pyrido[2,3-d]azepine; 3-bromo-2-piperidin-1-yl-6,7I8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
3-bromo-N-ethyl-N-methyl-6τ7,8,9-tetrahydro-5H-pyrιdo[2,3-d]azepin-2-aminβ;
3-chloro-2-(1 ,4-oxazepan-4-yl)'6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
3-chioro-2-(4>4-difluoropiperidiπ-1-yl)-6,7l8,9-tetrahydro-5H-pyrido[2,3- d]azeptne; 3-chloro-2-(4-fluoropιpeπdin-1-yl)-6,7,8,9-tetrahydro-5H-pyrιdo[2,3-d]azepιne;
3-chloro-2-morpholin-4-yl-6l7,8,9-tetrahydro-5H-pyrιdo[2,3-d]azepine;
3-chloro-2-piperidin-1-yl-6,7,8,9-tetrahydro-5H-pyrιdo[2,3-d]azepine;
6,7,8,9-tetrahydro-5H-pyrido[2.3-d]azepine-2-carbaldehyde,
6,7,8,9-tetrahydro-5H-pyrido[2,3-d]a2epine-2-carbonitrile; 9-ethyl-2-morpholin-4-yl-6,7,8,9-tetrahydro-5H-pyπdo[2,3-d]azepine;
9-ethyl-2-piperidin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepinβ;
9-i5θpropyl-2-moφholin-4-yl-6,718,9-tetrahydro-5H-pyrido[2,3-d]azepiπe; θ-isopropyl^-pipendin-i-yl-βJ.S.Θ-tetrahydrα-SH-pyrido^^-dJazepine;
9-methyl-2-(1 ,4-oxazepan-4-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepme; 9-methyl-2-morpholιn-4-yl-6,7,8,9-tetrahydro-5H-pyrido[2.3-d]azepine;
9-methyi-2-piperidin-1-yl-6,7,8,9-tβtrahydro-5H-pyrido[2,3-d]azepine; ethyl 4-(6,7τ8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)piperazιne-1- carboxylate,
N,9-diethyl-N-methyl-6.7.8,9-tetrahydro-5H-pyrido[2,3-d]azepiπ-2-amiπe; N,N,9-trimethyl-6,7,8,9-tetrahydro-5l-l-pyrido[2,3-d]azepin-2-annine;
N, N-dialiyl-6, 7, 8, 9-tetrahydro-5H-pyrido[2, 3-d]azepiπ-2-amine ;
N,N-diethyl-6T7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
N,N-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
N , N-dimethyl-6, 7, 8, 9-tetrahydro-5H-pyrido[2, 3-d]azepιne-2-carboxamide; N-benzyl-N-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3'd]azepin-2-amine;
N-ethyl-N , 9-d i methy I-6 , 7 , 8,9-tetrahydro-5H -pyrido[2 , 3-d]azepi π-2-a m iπe;
N-ethy!-N-methyi-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amiπe;
N-isopropyl-N-methyl-6,7,8,9-tetrahydiO-5H-pyrido[2,3-d]azepin-2-amine;
N-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine; N-methyl-N-(6,718,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)acetamιde; 2-Phenyl-6,7,8,9-tetrahydro-5H-pyιidθ[2,3-d]azepiπe; 6,7,8,9-Tetrahydro-5H-pyπdo[2,3-d]azepine-2-carbonitrile; 2-Chloro-6,7,8,9'tetrahydro-5H-pyπdo[2,3-d]3zepine; [2-(6-Methoxy-3-methyl-pyrιdιπ-2-yl)-ethyl]-methyl-amine; and/or 7,8,9-Tetrahydro-5H-pyrido[2,3-d]azepin-2-o!,
and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
25. A compound selected from:
(9R)-2-(4,4-difluoropiperιdιn-1-yl)-9-methyl-6,7,8,9-tetrahydro-5H- pyrido[2,3d]azepine;
(9R)-2-(4-fluoropiperidin-1-yl)-9-methyl-6,7l8,9-tetrahydro-5H-pyrido[2,3- djazepine;
(9R)-9-methyl-2-(1 ,4-oxazepan-4-yl)-6,7,8,9-tetrahydro-5H-pyrιdo[2,3- d]azepine;
(9R)-9-methyl-2-moφholin-4-yl-617,8r9-tetrahydro-5H-pyrido[2,3-d3azepine;
(9R)-9-methyl-2-piperidin-1-yl-6,7.8,9'tetrahydro-5H-pyrido[2l3-d]azepine; (9R)-N-ethyl-N,9-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
(9S}-2-(4,4-dιfluorDpιperιdin-1-yl)-9-methyi-8,7,8,9-tetrahydro-5H-pyπdo[2,3- d]azepine;
(9S)-2-(4-fluoropιperιdιn-1-yl)-9-methyl-6l7,8,9-tetrahydro-5H-pyrido[213- djazepine; (9S)-9-methyl-2-(1 ,4-oxazepan-4-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3- d]azepine
(9S)-9-methyl-2-morpholin-4-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
(ΘSJ-θ-methyl^-piperidin-i-yl-e/.β.θ-tetrahydro-SH-pyridop.S-dJazepine;
{9S)-N-ethyl-N,9-dιmethyl-6,7,8,9-tetrahydrα-5H-pyndo[2,3-d]azepιπ-2-amine; 2-(1 ,4-diazepari'1 -yl)"6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-(1,4-oxazepaπ-4-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepiπe;
2-(4,4-difluoroazeρan-i-yl)-617,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-{4,4-dif(uoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2l3-d]azepine;
2-(4-fluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; 2-azepan-1-yl-6l7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-azepaπ-1-yl-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-cyclopropyl-9-methyl-6,7,8,9-tetrahydro~5H-pyrido[2,3-d]azepine;
2-isopropenyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; 2-isopropenyl-9-methyl-6(7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-isopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-isopropyl-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-morpholin-4-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
2-piperidin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; 2-tert-butyl-6,7,8,9-tetrahydro-5H-pyridoj:2,3-d]azepine;
2-thiomorpholin-4-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-ρyrido[2,3-d]azepine;
3-chloro-2-(1,4-oxazepaπ-4-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
3-chloro-2-(4,4-difluoroptperidin-1-yl)-6,7,8i9-tetrahydro-5H-pyrido[2,3- djazepine;
3-chloro-2-(4-fluoropipβridiπ-1-yl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepiπe;
3-chloro-2-morpholirv4-yU6,7,8l9-tetrahydro-5H-pyrido[2,3-d]azepine;
3'Chloro-2-piperidin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
9-isopropyt-2-piperidin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine; g-methyl^-morpholiπ^-yl-ej.δ.θ-tetrahydro-δH-pyrido^.S-dlazepiπe;
9-methyl-2-piperidin-1-yl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine;
N , N-diethyl-6, 7, 8, 9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
N , N-d imethyl-6, 7, 8,9-tetrahyd ro-5H-pyrido[2, 3-d]azepin-2-amine;
N-ethyl-N.Θ-dimetbyl-βJ.β.g-tetrahydro-SH-pyridop.S-dJazepin^-amine; and/or
N-ethyl-N-metnyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-amine;
and/or a pharmaceutical ly-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
26. A compound according to any one of claims 1 to 25, wherein the compound has an EC50 for a human 5-HT2C receptor selected from less than 1000 πM, less than 500 πM, less than 300 nM, or less than 100 nM.
27. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 26 and at least one pharmaceutically acceptable carrier and/or excipient.
28. A Boc-protected precusor of the compound according to any one of Claims 1 to 27 or mixtures thereof.
29. A method for making a compound of Claim 1, wherein R11 and R12 are H, the method comprising:
Figure imgf000152_0001
reacting a compound of Formula A under conditions (a), wherein said (a) comprises heat and base assisted cydization of the compound of Formula A to provide an amide of Formula B; and reducing the carbonyl of the amide of Formula B, whereby R' is alkyl or cycloalkyl.
30. A method for making a compound of Claim 1 , wherein R9 and R10 are H1 the method comprising:
Figure imgf000153_0001
BB reacting a compound of Formula AA under conditions (a), wherein said (a) comprises heat and base assisted cydization of the compound of Formula AA to provide an amide of Formula BB; and reducing the carboπyl of the amide of Formula BB, whereby R' is alkyl or cycloalkyl.
31. A method for making a compound of Claim 1, wherein R11 and R12 are H, the method comprising: reducing a carbony! of an amide:
Figure imgf000153_0002
32. A method for making a compound of Claim 1 , wherein R9 and R10 are H, the method comprising: reducing a carbonyl of an amide:
Figure imgf000154_0001
33. A method for making a compound of Claim 1 , wherein R9, R10, R11 and R12 are H1 the method comprising: reducing carbonyl groups of an amide:
Figure imgf000154_0002
34. A method for making a compound of Claim 1, wherein R11 and R12 are H, the method comprising:
Figure imgf000154_0003
reacting a compound of Formula C under conditions (a), wherein said (a) comprises selective cyano reduction followed by cyclization of the compound of Formula C to provide Formula I1 whereby R' is alkyl or cydoalkyl.
35. A method for making a compound of Claim 1, wherein R0 and R10 are H, the method comprising:
Figure imgf000155_0001
CC
reacting a compound of Formula CC under conditions (a), wherein safd (a) comprises selective cyano reduction followed by cyclizatioπ of the compound of Formula CC to provide Formula I1 whereby R' is alkyl or cydoalkyl.
36. A method for making a compound of Claim 1 , wherein the method comprises:
Figure imgf000155_0002
I
reacting a compound of Formula D under conditions (a), wherein said (a) comprises cyclization of the compound of Formula D to provide Formula I, whereby R' is alkyl or cycloalkyl.
37. A method for making a compound of Claim 1, wherein the method comprises:
Figure imgf000156_0001
DD
reacting a compound of Formula DD under conditions (a), wherein said (a) comprises cyclization of the compound of Formula DD to provide Formula I, whereby R1 is alkyl or cycloalkyl.
38. A method for treating a 5-HTzc receptor-mediated disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound according to any one of Claims 1 to 26 or a therapeutically effective amount of a composition according to Claim 27.
39. The method according to Claim 38, wherein the mammal is a human.
40. The method according to Claim 38 or 39, wherein the disorder is selected from the group consisting of a depressive disorder, an anxiety disorder, including panic attack, agoraphobia, and specific or social phobia, bipolar disorder, post-traumatic stress, an eating disorder, obesity, a gastrointestinal disorder, alcoholism, drug addiction, schizophrenia, a psychotic disorder, a sleep disorder, including sleep apnea, migraine, sexual dysfunction, a central nervous system disorder, including trauma, stroke and spinal cord injury, a cardio-vascular disorder, diabetes insipidus, obsessive compulsive disorder, premenstrual tension, chronic fatigue syndrome, age- related memory disorder, personality disorder and raised intracranial pressure.
41. The method according to Claim 40, wherein the disorder is selected from the group consisting of obesity, schizophrenia, epilepsy, a depressive disorder, panic attack, alcoholism, drug addiction or obsessive compulsive disorder.
42. The method according to any one of Claims 38 to 41 , wherein the compound is administered orally and/or pareπterally.
43. The method according to Claim 42, wherein the compound is administered intravenously and/or
Figure imgf000157_0001
44. Use of a compound according to any one of Claims 1 to 26 or a composition according to Claim 27 for the manufacture of a medicament for treatment of a 5-HT2c receptor-mediated disorder m a mammal
45 Use of a compound according to any one of Claims 1 to 26 or a composition according to Claim 27 to treat a 5-HT2C receptor-mediated disorder in a mammal
46. The use according to Claim 44 or 45, wherein the mammal is a human
47. The use according to any one of Claims 44 to 46, wherein the disorder is selected from the group consisting of a depressive disorder, an anxiety disorder, including panic attack, agoraphobia, and specific or social phobia, bipolar disorder, post-traumatic stress, an eating disorder, obesity, a gastrointestinal disorder, alcoholism, drug addiction, schizophrenia, a psychotic disorder, a sleep disorder, including sleep apnea, migraine, sexual dysfunction, a centra! nervous system disorder, including trauma, stroke and spinal cord injury, a cardio-vascular disorder, diabetes insipidus, obsessive compulsive disorder, premenstrual tension, chronic fatigue syndrome, age- related memory disorder, personality disorder and raised intracranial pressure.
48. The use according to claim 47, wherein the disorder is selected from the group consi$ting of obesity, schizophrenia, epilepsy, a depressive disorder, panic attack, alcoholism, drug addiction or obsessive compulsive disorder,
49. The use according to any one of claims 44 to 48, wherein the compound is administrate orally and/or parenterally.
50. The use according to Claim 49, wherein the compound is administrable intravenously and/or intraperitoneal^
51. A method for decreasing food intake in a mammal comprising administering to the mammal a therapeutically effective amount of a compound according to any one of Claims 1 to 26 or a therapeutically effective amount of a composition according to Claim 27
52. A method of controlling weight gain in a mammal compπsing administering to the mammal a therapeutically effective amount of a compound according to any one of Claims 1 to 26 or a therapeutically effective amount of a composition according to Claim 27
53. Use of a compound according to any one of Claims 1 to 26 or a composition according to Claim 27 for the manufacture of a medicament for decreasing food intake or controlling weight gain in a mammal.
54 Use of a compound according to any one of Claims 1 to 26 or a composition according to Claim 27 for decreasing food intake or controlling weight gain in a mammal
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