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WO2009079765A1 - Composés dont l'activité est dirigée contre le récepteur 5-ht2c - Google Patents

Composés dont l'activité est dirigée contre le récepteur 5-ht2c Download PDF

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Publication number
WO2009079765A1
WO2009079765A1 PCT/CA2008/002223 CA2008002223W WO2009079765A1 WO 2009079765 A1 WO2009079765 A1 WO 2009079765A1 CA 2008002223 W CA2008002223 W CA 2008002223W WO 2009079765 A1 WO2009079765 A1 WO 2009079765A1
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Prior art keywords
tetrahydro
pyrido
alkyl
azepine
compound
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Inventor
Abdelmalik Slassi
Methvin Isaac
Tao Xin
Guy Higgins
Zhi He
Guangri Sun
Tan Quach
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CASCADE THERAPEUTICS Inc
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CASCADE THERAPEUTICS Inc
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This invention relates to compounds which act at the 5-HT 2 c receptor and to the use of such compounds in the treatment of diseases.
  • 5-Hydroxytryptamine 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-HT 2 A, 5-HT 2B and 5-HT 2 c receptors. All the members of this subfamily couple to the activation of the inositol phosphate and diacyl glycerol pathway via the G-protein,G q/ n.
  • Other second messenger systems have been shown to be regulated by 5-HT 2 stimulation including mitogen activated protein kinase (MAP-kinase).
  • 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 2C receptor function.
  • the 5-HT 2C receptor is expressed in many brain regions including the limbic system, extrapyramidal motor pathways, hypothalamus, thalamus and monoaminergic cell groups.
  • 5-HT 2 c receptors have been implicated in the regulation of food intake and anxiety.
  • the non-selective 5-HT 2 c receptor agonist, m- chlorophenylpiperazine 1 (mCPP) produces hypophagic and anxiogenic effects that were attenuated by 5-HT 2 c receptor antagonists.
  • mCPP m- chlorophenylpiperazine 1
  • the propensity of a 5-HT 2C receptor agonist to regulate food intake suggests a critical role for this receptor subtype in controlling obesity (Vickers, S.; Clifton, P.; Dourish, C; Tecott, L. Psychopharmacology (Berlin) 1999, 143:309; Nilsson, B. J. Med. Chem. 2006, 49:4023 ).
  • the 5-HT 2 c receptor is the only seven-transmembrane spanning receptor whose messenger RNA (mRNA) undergoes RNA editing (i.e. adenosine to inosine editing) which change the coding for amino acids within the putative second intracellular domain (i2) of the receptor.
  • mRNA messenger RNA
  • RNA editing i.e. adenosine to inosine editing
  • the non-edited receptor contains the amino acids isoleucine, asparagines, and isoleucine (INI) at positions 156, 158 and 160, respectively while the principle fully edited isoforms express valine, serine and valine (VSV) or valine, glycine and valine (VGV).
  • Partially edited isoforms also exist where alteration of one or two amino acids within i2 occur giving isoforms such as the VNI isoforms.
  • the 5-HT 2 c receptor produces profound changes in receptor function that differ depending upon whether the receptor is unoccupied or occupied by agonist.
  • Many studies have shown that in addition to selectivity for receptor subtypes, agonists have selectivity for different signaling pathways coupled to a single receptor subtype; a process known as 'functional selectivity' (Berg KA et al. Drug Discov Today: Therap Strat. 2006, 4:421 ; Urban et al. J Pharmacol Exp Ther. 2007, 320:1 ).
  • BMI body mass index
  • m 2 body weight index
  • 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 (D 2 ) and serotonin (5-HT2A) receptor antagonism.
  • D 2 dopamine
  • 5-HT2A serotonin
  • these compounds do not appear to adequately treat all the symptoms of schizophrenia and are accompanied by problematic side effects, such as weight gain (Allison, D. B., et. al., Am. J. Psychiatry 1999, 156:1686-1696; Masand, P. S., Exp. Opin. Pharmacother. 2000, 1:377-389; Whitaker, R., Spectrum Life Sciences. Decision Resources. 2000 2:1-9).
  • Atypical antipsychotics also bind with high affinity to 5-HT 2 c receptors and function as 5-HT 2 c receptor antagonists or inverse agonists. Weight gain is a problematic side effect associated with atypical antipsychotics such as clozapine and olanzapine, and it has been suggested that 5-HT 2 c antagonism -A-
  • 5-HT 2 c receptor agonism or partial agonism as a treatment for schizophrenia.
  • 5-HT 2 c antagonist increase synaptic levels of dopamine and may be effective in animal models of Parkinson's disease (Di Matteo, V., et. al., Neuropharmacology 1998, 37:265-272; Fox, S. H., et. al., Experimental Neurology 1998, 151 :35-49).
  • compounds with actions opposite to those of 5-HT 2C antagonists such as 5-HT 2C agonists and partial agonists, should reduce levels of synaptic dopamine.
  • 5-HT 2C agonists decrease levels of dopamine in the prefrontal cortex and nucleus accumbens (Millan, M. J., et. al., Neuropharmacology 1998, 37:953-955; Di Matteo, V., et. al., Neuropharmacology 1999, 38:1195-1205; Di Giovanni, G., et. al., Synapse 2000, 35:53-61 ), brain regions that are thought to mediate critical antipsychotic effects of drugs like clozapine.
  • 5-HT 2 c agonists do not decrease dopamine levels in the striatum, the brain region most closely associated with extrapyramidal side effects.
  • 5-HT 2 c agonists decrease firing in the ventral tegmental area (VTA), but not in the substantia nigra.
  • VTA ventral tegmental area
  • 5-HT 2C agonists have limbic selectivity, and will be less likely to produce extrapyramidal side effects associated with typical antipsychotics.
  • 5-HT 2 c 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; Elmquist, J. K. Neuron 2002, 36:199- 211 ).
  • 5-HT 2 c receptor agonists may decrease dopamine levels in the nucleus accumbens and that reward-related behaviors (e.g., cocaine or nicotine self-administration in rats) may be reduced by 5-HT 2 C receptor activation
  • reward-related behaviors e.g., cocaine or nicotine self-administration in rats
  • 5-HT 2C receptor agonists may reduce the rewarding properties of food should also be considered (Higgins, G. A.; Fletcher, P. J. 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. Neurobiology of Diseases 2000, 7: 549-551 ).
  • 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).
  • mice lacking the 5-HT 2 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.
  • the selective 5- HT 2C receptor antagonist, SB 242084 do not induce pro-convulsant effects in rats, which are characteristic of mutant mice lacking the 5-HT 2 c receptor. This failure to exhibit pro-convulsant properties in rats in contrast to the reported characteristics of mutant mice lacking 5-HT 2 c receptors might be accounted for by species differences (Di Matteo, V.; Di Giovanni, G.; Esposito, E. CNS Drug Rev. 2000, 6:195-205).
  • SSRIs Selective serotonin reuptake inhibitors
  • 5-HT serotonin
  • OCD obsessive compulsive disorder
  • SSRIs have become standard therapy for neuropsychiatric disorders such as obsessive compulsive disorder (OCD), depression, and panic anxiety.
  • OCD obsessive compulsive disorder
  • 5-HT 2 c receptor-mediated functions There is accumulating evidence for the involvement of 5-HT 2 c receptor-mediated functions in the therapeutic efficacy of SSRIs (Palvimaki, E. -P.; Roth, B. L.; Majasuo, H.; Laakso, A.; Kuoppamaki, M.; Syvalahti, E.; Hietala, J.
  • Urinary incontinence (Ul), the involuntary release of urine, may be caused by physiologic, pharmacologic, pathologic, or psychological factors. It is a common condition and often constitutes an embarrassment which can lead to social isolation, depression, loss of quality of life and is a major cause of institutionalization in the elderly population
  • Continence and micturition involve a balance between urethral closure and detrusor muscle activity.
  • Urethral pressure normally exceeds bladder pressure, resulting in urine remaining in the bladder.
  • the proximal urethra and bladder are both within the pelvis.
  • Intraabdominal pressure increases (from coughing and sneezing) are transmitted to both urethra and bladder equally, leaving the pressure differential unchanged, resulting in continence.
  • Urinary incontinence affects more than 10 million Americans according to the the American foundation of Urologic Diseases. Both men and woman suffer from urinary incontinence although women are disproportionately affected.
  • SAI stress urinary incontinenence
  • Ul urge incontinence
  • mixed incontinence stress urinary incontinence
  • SI urinary leakage (loss of small amounts of urine) that occurs during physical activity such as coughing, laughing, sneezing, exercising or other movements that increase intraabdominal pressure and thus increase pressure on the bladder.
  • Physical changes resulting from pregnancy, childbirth, and menopause often cause stress incontinence, and in men it is a common problem following a prostatectomy. It is the most common form of incontinence in men.
  • Urge incontinence (also known as bladder instability, neurogenic bladder, voiding dysfunction, hyperactive bladder, or detrusor overactivity) refers to the involuntary loss of urine occurring for no apparent reason while suddenly feeling the need or urge to urinate. The most common cause of urge incontinence is involuntary and inappropriate detrusor muscle contractions. Urge incontinence may also be called “reflex incontinence” if it results from overactive nerves controlling the bladder.
  • Pain is both a sensory and emotional experience, and is generally associated with tissue damage or inflammation.
  • pain is divided into two general categories - acute pain and chronic pain. Both differ in their etiology, pathophysiology, diagnosis, and most importantly treatment.
  • Acute pain is short term, and is typically of readily identifiable cause. Patients suffering from acute pain typically respond well to medications. In contrast, chronic pain - medically defined as pain that lasts for 3-6 months or longer, is often not associated with an obvious injury; indeed, patients can suffer from protracted pain that persists for months or years after the initial insult. Whilst acute pain is generally favorably treated with medications, chronic pain is often much more difficult to treat, generally requiring expert care.
  • neuropathic pain can, for instance, manifest itself as burning, stabbing, and shock-like sensations.
  • neuropathic pain management is at best inconsistent, and often ineffective. This is in part due to the subjective nature of the pain, but also due to poor diagnosis, especially when the chronic pain is not clearly associated with a nerve injury or other insult.
  • many, if any, ethical drugs have been prospectively developed for the treatment of chronic pain. Instead, the current medications used to treat chronic pain are "borrowed” from other diseases, most commonly antiepileptic drugs and antidepressants.
  • Current first-line treatments for chronic pain include opioids, analgesics such as gabapentin, and tricyclic antidepressants. When opioids are administered over prolonged periods, undesirable side effects such as drug tolerance, chemical dependency and even physiological addiction can occur.
  • opioids are administered over prolonged periods, undesirable side effects such as drug tolerance, chemical dependency and even physiological addiction can occur.
  • Treatment remedies currently available for chronic pain at best approximately
  • serotonin plays a major role in the inhibition of nociceptive transmission. Furthermore, it appears that the 5HT 2 c receptor have an inhibitory role in pain (Eur. J. Pharmacol. 2007, 567(1 -2):89-94; Eur. J. Pharmacol. 2004, 502(3):205-11 ; Pain. 2004108(1 -2): 163-9; Pol. J. Pharmacol. 1994, 46(5):423-8 and U.S. Patent Application Publication 2007/0225277).
  • 5-HT 2 c receptors share substantial sequence homology with the 5-HT 2A and 5-HT 2 B receptor.
  • the interaction of the compound with the target protein which in this case is the 5- HT 2 C receptor (particularly the more prevalent human edited isoforms VSV, VGV and VNI) and its pharmacokinetic profile, that is its ability to access the target protein in sufficient quantity for a sufficient duration of time to have the desired therapeutic effect.
  • the target protein which in this case is the 5- HT 2 C receptor (particularly the more prevalent human edited isoforms VSV, VGV and VNI)
  • the pharmacokinetic profile that is its ability to access the target protein in sufficient quantity for a sufficient duration of time to have the desired therapeutic effect.
  • the present invention relates to 5-HT 2 c receptor agonists with improved drug- like characteristics such as reduced cytochrome P450 inhibition.
  • R 1 is a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heterocycloalkyl containing at least two rings, wherein said rings are fused rings, bridged fused rings and/or spiro rings;
  • R 2 , R 3 and R 5 to R 12 are each independently selected from H, halo, hydroxy, cyano, nitro, alkyl, alkoxy, CH 2 OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O-heterocycloalkyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-
  • R 4 is selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylene- O-alkyl, alkylene-O-cycloalkyl, alkylene-O-alkylene-cycloalkyl;
  • the compound of Formula I comprises a compound of Formula IA:
  • R 1 is a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heterocycloalkyl containing two bridged fused rings;
  • R 3 and R 7 are as outlined above; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • R 1 is a substituted or unsubstituted N-heterocycloalkyl or a substituted or unsubstituted N-heterocycloalkyl containing two bridged fused rings; and R 3 and R 7 are as outlined above; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • R 1 is a substituted N-heterocycloalkyl containing two bridged fused rings substituted with alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and/or haloalkyloxy
  • R 7 is selected from H, halo, alkyl, haloalkyl, haloalkyloxy, cyano, alkoxy
  • R 3 is selected from H, or lower alkyl, and/or a pharmaceutically- acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • the compound of Formula I comprises a compound of Formula IB, IC and/or ID:
  • R 3 and R 7 are each independently selected from H, halo, hydroxy, cyano, nitro, alkyl, alkoxy, CH 2 OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O-heterocycloalkyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene- O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloalkyl, alkylene- O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloalky
  • R 13 and R 14 are each independently selected from the group consisting of H, alkyl, halo and haloalkyl;
  • R 15 is selected from the group consisting of H and alkyl; n is an integer; and m is an integer; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • R 3 is selected from H, or lower alkyl
  • R 7 is selected from H, halo
  • X is O, S, SO, SO 2 , CR 13 R 14 ; NR 15 ; R 13 and R 14 are each independently selected from the group consisting of H, alkyl, halo and haloalkyl; R 15 is selected from the group consisting of H and alkyl of C1 to C6; n is either 0, 1 or 2; and m is 0, 1 or 2; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • R 3 and R 7 are each independently selected from H, halo, hydroxy, cyano, nitro, alkyl, alkoxy, CH 2 OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O-heterocycloalkyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-heterocycloalkyl, alkylene- O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloalkyl, alkylene- O-alkylene-cycloalkyl, alkylene-O-alkylene-heterocycloalky
  • R 15 is selected from the group consisting of H and alkyl; and n is an integer; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • R 3 is selected from H, or lower alkyl;
  • R 7 is selected from H, halo;
  • X is O, S, SO, SO 2 , CR 13 R 14 ;
  • R 13 and R 14 are each independently selected from the group consisting of H, alkyl, halo and haloalkyl;
  • R 15 is selected from the group consisting of H and alkyl of C1 to C6; and n is either O, 1 or 2; and/or a pharmaceutically- acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • the compound of Formula Il comprises a compound of Formula HA and/or MB :
  • R 3 is selected from H, or lower alkyl
  • R 7 is selected from H, halo
  • X is O, S, SO, SO 2 , CR 13 R 14 ; NR 15 ;
  • R 13 and R 14 are each independently selected from the group consisting of H, alkyl, halo and haloalkyl;
  • R 15 is selected from the group consisting of H and alkyl of C1 to C6; and n is either O, 1 or 2; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • composition comprising at least one of the compounds noted above and at least one pharmaceutically acceptable carrier and/or excipient.
  • a method for making the compound of Formula IA to ID and Il comprising: reducing carbonyl groups of a cyclic imide:
  • IA-ID, HA-IIB 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 IA to ID and Il (including MA to MB), whereby R' is alkyl or cycloalkyl.
  • IA-ID, MA-IIB reacting a compound of Formula D under conditions (a), wherein said (a) comprises cyclization of the compound of Formula D to provide Formula IA to ID and Il (including HA to HB), whereby R 1 is alkyl or cycloalkyl.
  • a method for treating a 5-HT 2 c receptor- mediated disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound or composition noted above; the compound or composition exhibiting reduced inhibition of a cytochrome
  • the mammal is a human.
  • the disorder is selected from urinary incontinence, 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 or composition is administered orally and/or parenterally. In yet another aspect, the compound or composition is administered intravenously and/or intraperitoneally.
  • the mammal is a human.
  • the disorder is selected from urinary incontinence 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 or composition is administrable orally and/or parenterally. In yet another aspect, the compound or composition 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; the compound or composition exhibiting reduced inhibition of a cytochrome P450.
  • 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 compound or composition exhibiting reduced inhibition of a cytochrome P450.
  • Figure 1 shows graphically the effect on feeding in adult male Sprague- Dawley rats of one exemplary compound (22.34) of the invention at various doses (mg/ml) or vehicle administered intraperitoneally (X-axis) on rat food consumption (Y-axis).
  • * p ⁇ 0.05 vs. vehicle pretreatment # p ⁇ 0.05 vs. 204 0.6 mg/kg.
  • the compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry 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 branched-chain 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", "alkynyl", “aryl”, 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 encompass radicals having "cis” and “trans” orientations, or alternatively, 11 E” and "Z” orientations.
  • alkynyl 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-propynyl (propargyl), 1- butynyl 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, cyclohexenyl and the like.
  • heterocycloalkyl as used herein means a heterocyclic system (which may be unsaturated) having at least one heteroatom selected from N, 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, piperazinyl, pyrrolidinyl, tetrahydrofuranyl and the like.
  • alkoxy as used herein means a straight- or branched-chain 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, f-butoxy and the like.
  • halo 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.
  • 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.
  • alkenylene 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-propenylene, n-butenylene 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, n-propynylene, n-butynylene 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. In particular embodiments, aryl is one, two or three rings. In one aspect, the aryl has five to twelve ring atoms.
  • aryl encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • the "aryl” group may have 1 to 4 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino 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 rings 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 radicals such as pyridyl, indolyl, furyl, benzofuryl, 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 acids which form suitable salts include the mono-, di- and tricarboxylic acids.
  • lllustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic 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 isolation of compounds of Formula I 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 picoline 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 I 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.
  • 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. It includes mirror image isomers (enantiomers), 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 is 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 2 C receptor-mediated disorder”, as used herein, is a disorder in which there is believed to be involvement of the pathway controlled by the 5-HT 2 c receptor and which is ameliorated by treatment with an agonist of the 5-HT 2C receptor.
  • 5-HT 2C 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 is a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heterocycloalkyl containing at least two rings, wherein said rings are fused rings, bridged fused rings and/or spiro rings;
  • R 2 , R 3 and R 5 to R 12 are each independently selected from H, halo, hydroxy, cyano, nitro, alkyl, alkoxy, CH 2 OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O-heterocycloalkyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O-
  • R 1 is a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heterocycloalkyl containing two bridged fused rings; and R 3 and R 7 are as outlined above; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • R 1 is a substituted or unsubstituted N-heterocycloalkyl containing two bridged fused rings; and R 3 and R 7 are as outlined above; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • R 1 is a substituted N-heterocycloalkyl containing two bridged fused rings substituted with alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and/or haloalkyloxy;
  • R 7 is selected from H, halo, alkyl, haloalkyl, haloalkyloxy, cyano, alkoxy;
  • R 3 is selected from H, or lower alkyl, and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • the compound of Formula I can comprise a compound of Formula IB, IC and/or ID:
  • R 3 and R 7 are each independently selected from H, halo, hydroxy, cyano, nitro, alkyl, alkoxy, CH 2 OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O- heterocycloalkyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O- heterocycloalkyl, alkylene-O-alkylene-cycloalkyl, alkylene-O-alkylene- heterocycloalkyl, S-alkyl, S(O)-alkyl, S(O) 2 -alkyl, S-cycloalkyl, S(O)-
  • R 3 is selected from H, or lower alkyl;
  • R 7 is selected from H, halo;
  • X is O, S, SO, SO 2 , CR 13 R 14 ;
  • R 13 and R 14 are each independently selected from the group consisting of H, alkyl, halo and haloalkyl;
  • R 15 is selected from the group consisting of H and alkyl of C1 to C6; n is either O, 1 or 2; and m is 0, 1 or 2; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • the compound of Formula I comprises a compound of Formula II:
  • R 3 and R 7 are each independently selected from H, halo, hydroxy, cyano, nitro, alkyl, alkoxy, CH 2 OH, haloalkyl, O-haloalkyl, hydroxyalkyl, cyanoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, O-cycloalkyl, O- heterocycloalkyl, alkylene-O-alkyl, alkylene-O-cycloalkyl, alkylene-O- heterocycloalkyl, alkylene-O-alkylene-cycloalkyl, alkylene-O-alkylene- heterocycloalkyl, S-alkyl, S(O)-alkyl, S(O) 2 -alkyl, S-cycloalkyl, S(O)-
  • R 3 is selected from H, or lower alkyl;
  • R 7 is selected from H, halo;
  • X is O 1 S, SO, SO 2 , CR 13 R 14 ;
  • R 13 and R 14 are each independently selected from the group consisting of H, alkyl, halo and haloalkyl;
  • R 15 is selected from the group consisting of H and alkyl of C1 to C6; and n is either O, 1 or 2; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • R 3 and R 7 are as outlined above.
  • R 3 is selected from H, or lower alkyl
  • R 7 is selected from H, halo
  • X is O, S, SO, SO 2 , CR 13 R 14 ;
  • NR 15 is each independently selected from the group consisting of H, alkyl, halo and haloalkyl
  • R 15 is selected from the group consisting of H and alkyl of C1 to C6
  • n is either O, 1 or 2; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.
  • 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 and II are also salts of the compounds of Formula I and II.
  • 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 and Il 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 carbonyl of the amide of the compound of Formula B.
  • (a) comprises heating in DMF and (b) comprises reduction with LiAIH 4 ZAICb.
  • Compounds of Formula I and IA to ID and Il may also be prepared as follows: or, more specific to Formula IA to ID and Il (including MA to HB),
  • R' can be alkyl or cycloalkyl and (a) comprises heat and base assisted cyclization 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 ZAICI 3 .
  • R 11 and R 12 are H or, more specific to Formula IA to ID and Il (including HA to MB),
  • R' can be alkyl or cycloalkyl.
  • cyano reduction using LiAIH 4 ZAICI 3 and DIPEA in acetonitrile for cyclization.
  • the resultant Formula I and IA to ID and Il can be converted to a salt addition of an acid, for example.
  • R' can be alkyl or cycloalkyl.
  • cyano reduction using LiAIH 4 ZAICI 3 and DIPEA in acetonitrile for cyclization.
  • the resultant Formula I and IA to ID and Il can be converted to a salt addition of an acid, for example.
  • (a) comprises cyclization of the compound of Formula D, whereby R' can be alkyl or cycloalkyl.
  • R' can be alkyl 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 intermediate V was prepared from 2-(2- chloroethyl)-3-(chloromethyl)-6-methoxypyridine [Feng, S.; He, X.; Yu, G.; Yu, X.; Bai, D. Org. Prep. Proced. Int. 2004, 36 (2); 129-134] via mono-cyanation and the Finkelstien chloro-iodo exchange.
  • Acid addition salts of the compounds of Formula I and Il 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 acid.
  • Other non- pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I and Il 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 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.
  • the compounds of the invention have an EC 50 value for the human 5-HT 2 c receptor less than 1000 nM, or less than 500 nM, or less than 300 nM, or less than 10O 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, urinary incontinence (such as stress urinary incontinenence (SUI), urge incontinence (Ul) and mixed incontinence), pain, 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.
  • a depressive disorder an anxiety disorder, including panic attack, agoraphobia, and specific or social phobia
  • bipolar disorder post-traumatic stress
  • an eating disorder 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. Compounds of the invention have also been shown to exhibit reduced cytochrome P450 inhibition thus minimizing potential drug-drug interactions.
  • 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, intraperitoneally, 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.
  • 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.
  • useful diluents are lactose and high molecular weight polyethylene glycols. If desired, certain sweetening and/or flavoring agents are added.
  • sterile solutions of the compounds of the invention are usually prepared, and the pHs 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.
  • Such compositions can include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzylchromium chloride, and the usual quantities of diluents and/or carriers.
  • 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.
  • Analogous gels or creams can be used for vaginal, urethral and rectal 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.
  • a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation.
  • Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order will be readily understood to the one skilled in the art of organic synthesis. Examples of transformations are given below, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified.
  • Example 17.1 The title compound from Example 17.1 (5.72 g, 17. 54 mmol) was suspended in dichloromethane (90 ml_) under a nitrogen atmosphere and cooled to 0 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 RT for 2 h.
  • the salt was mixed with diisopropylethyamine (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 h.
  • 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 diisopropylethyalmine (1 mL) and triflic anhydride (420 ⁇ L, 2.5 mmol) in dichloromethane at -50 0 C and stirred overnight.
  • Example 21.45 Oxidation of Example 21.45 to its sulfoxide and sulfones derivatives:
  • Example 21.50 tert-butvl 2-(1.i-dioxidothiomorpholin ⁇ -yO- ⁇ . ⁇ . ⁇ . ⁇ - tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate
  • Example 21.78 Tert-butvl 3-chloro-2-piperidin-1-yl 5,6,8,9-tetrahydro-7H- pyrido[2,3-d]azepine-7-carboxylate
  • Example 21.84 (9R)- and (9S)-tert-butyl 9-methyl-2-piperidin-1-yl-5,6,8,9- tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate were separated from racemic were separated from racemic tert-butyl 2-[ethyl(methyl)amino]-9- methyl-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate by Chiralcel OJ with 1 % ethanol in hexanes by Chiralcel OJ with 1% ethanol in hexanes.
  • 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 following 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-HT 2A , 5-HT 2B and 5-HT 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-glutamine (Gibco; 0.8mM for 5-HT 2 A and 5-HT 2 c. 2.0 mM for 5-HT 2 B), and grown under selection with 200 ⁇ g/ml Zeocin (Invitrogen), and either 200 ⁇ g/ml Hygromycin B (Invitrogen for 5-HT 2A and 5-HT 2 c) or 500 ug/ml Geneticin (Invitrogen) for 5-HT 2B .
  • Growth Medium High glucose DMEM (Hyclone) with 10% dialyzed fetal bovine serum (Hyclone), and L-glutamine (Gibco; 0.8mM for 5-HT 2 A and 5-HT 2 c. 2.0 mM for 5-
  • FLIPR assay methodology Cells that recombinantly expressed the 5-HT 2 receptors were enzymatically dissociated with Trypsin/EDTA 0.25% (Hyclone) 24 h prior 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 0 C and 5% CO 2 .
  • Phosphatidyl Inositol Hydrolysis Assay 24 h 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 H]-myo-lnositol (Perkin Elmer). Cell monolayers were washed twice with HBSS (HEPES Buffered Saline solution: 20 mM HEPES 1 146 mM NaCI, 4.2 mM KCI, 0.5 mM MgCI 2 , 0.1 % Glucose, pH 7.4).
  • HBSS HEPES Buffered Saline solution: 20 mM HEPES 1 146 mM NaCI, 4.2 mM KCI, 0.5 mM MgCI 2 , 0.1 % Glucose, pH 7.4
  • the cell monolayers were pre-incubated for 5 min at 37°C in 100 ⁇ l/well HBSS containing 10 mM LiCI. Compounds were tested for agonist activity in duplicate at concentrations ranging from 3nM to 30 ⁇ M. Compounds were added (100 ⁇ l) at 2 times the required final concentration and incubated for 30 min at 37°C. Medium was aspirated and the soluble 3H- inositol phosphates were extracted from the cells by adding 100 ⁇ l/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).
  • VWR Uniplate
  • Total phosphatidyl inositols were eluted with 800 ⁇ l 30 mM ammonium formate, and the eluate was discarded.
  • Total inositol phosphates were eluted with 600 ⁇ l (2X 300 ⁇ l) 700 mM ammonium formate / 100 mM formic acid and collected in a clean 2ml, 96 well, polypropylene, round bottom Uniplate.
  • 75 ⁇ l eluate was transferred to a Hewlett Packard Optiplate and 150 ⁇ l 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.
  • Topseal Packard
  • Cytochrome P450 Assay In-vitro screening for drugs that inhibit cytochrome P450 enzymes is well established as a means for predicting potential metabolism related drug interactions in-vivo. Pooled human liver microsomes were acquired from a commercial supplier (Human Biologies International, Scottsdale, AZ, USA) and stored at -70 0 C until use. Exact assay conditions (e.g. substrate for the given CYP isoenzyme and positive control inhibitor) varied according to CYP isoenzyme under study (see summary table below). The metabolism reaction is started by the addition of substrate. Final concentration of substrate was measured by HPLC.
  • the extent of metabolism in percentage of a given substrate for the given CYP assay is calculated from the extent of metabolism of the given substrate in the presence test compound compared to incubation of the substrate without test compound.
  • Each assay uses as a positive control an inhibitor with known inhibitory activity for the metabolism of the given substrate in the particular CYP assay, which is used to determine the validity of the given assay.
  • the data shown for the compounds of the present invention in Table 2 are results from assays in which the positive control gave appropriate results for the given CYP assay.
  • Substrate S-Mephenytoin Inhibitor: Omeprazole
  • Inhibitor Concentration 10 ⁇ M (omeprazole) or Buffer 890 the indicated for test compound (1 or 10 ⁇ M) ⁇ l
  • 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 12 h light:dark cycle (lights on: 07:00 h), and all experiments were conducted in the animals' light phase. For all experiments, animals were habituated to the vivarium for a minimum of 72 h 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
  • Test Compounds All compounds were dissolved in 5% Tween 80® in saline and injected in a dose volume of 5 ml/kg or 10 ml/kg (rat), and 10 ml/kg (mouse). Compounds were administered by either the oral or intraperitoneal route.
  • Mouse hypolocomotion assay Selective 5-HT 2 c 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. Male, CD-1 mice were administered test compound 15 min 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.
  • test compound or vehicle as control
  • Test compound or vehicle was administered 10 to 15 min before the beginning of the 2 h 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.
  • 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 7:00-19:00h). 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 are trained to receive single 45mg food pellets under a fixed time interval of 60s over a 2h period 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 during this 2h period is recorded. Daily food allowance is supplemented by a 45min access period sometime between 15:00-18:00h.
  • the rats may be dosed orally or parentally with vehicle or test compound.
  • Test compound or vehicle is administered on Tuesdays and Fridays with drug free (washout) days in between.
  • the animals will receive 3 doses of test compound .and vehicle in a counterbalanced sequence.
  • a modification to the above procedure is to pre-treat rats 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)aminocarbonyl)-2,3-dihydroindole (1 mg/kg in 8% HPCD, 25mM citric acid in saline) prior to the oral or parental dose of test compound.
  • Antagonism of clonic-tonic seizures produced by chemical convulsants such as pentylenetetrazol have been widely utilized to identify novel anticonvulsants.
  • 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 mal) seizures (Upton, N. (1994) Trends Pharmacol. Sci. 15: 456-463).
  • the experiment is conducted within a single day with animals receiving a single pretreatment, i.e 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 convulsant, 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 60 min it is considered protected and the experiment completed as endpoint reached.
  • pentylenetetrazol 85mg/kg mice
  • the dose of pentylenetetrazol is selected as it is of sufficient
  • a parallel tests of motor function using the rotorod would be undertaken to establish a therapeutic index (Tl), e.g ratio between the ED 50 dose required to block seizures, compared to ED 50 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 16 r.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 of 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)aminocarbonyl)-2,3-dihydroindole (1 mg/kg in 8% HPCD, 25mM citric acid in saline) prior 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.
  • mice Male Sprague-Dawley rats (Charles River, St. Constant, Quebec, Canada) of approximate weight 200 g are pair housed on arrival in the animal facility (lights on 7:00-19:00 h). 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.
  • standard rodent lab chow Harlan Teklad rodent maintenance diet, 2014; Harlan Teklad, Madison, Wl
  • Animals would be singly placed within the test apparatus (Perspex chamber of dimensions: rat 42 cm x 42 cm x 30 cm (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 period, 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.
  • 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'.
  • 'normal' behaviors such as sniffing, grooming, rearing, and 'abnormal' behaviors such as 'circling'.
  • 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-HT 2 c receptor antagonist, 6-chloro-5-methyl-N-(2-(2- methylpyridin-3-yl-oxy)pyridine-5-yl)aminocarbonyl)-2,3-dihydroindole (1 mg/kg in 8% HPCD, 25mM citric acid in saline) prior to the oral or parental dose of test compound.
  • a cystometry tube is implanted into the bladder of adult guinea-pigs (600-80Og).
  • the cystometry tube is connected to an infusion pump and pressure transducer to enable fluid perfusion and the recording of intravesicular bladder pressure.
  • Electromyographic (EMG) leads are inserted into the external urethral sphincter (EUS) to allow the measurement of sphincter tone.
  • the bladder was filled at a rate of 150 ⁇ l/min with physiological saline (room temperature) until initiation of a micturition reflex. Following this reflex, the bladder was drained and the filling procedure repeated to establish a mean bladder threshold capacity for initiation of micturition reflex. Further, EUS EMG activity and intravesicular pressure was recorded throughout bladder filling.
  • test drug or vehicle is administered i.v and bladder filling (150 ⁇ l/min) reinitiated until induction of micturition reflex. Bladder pressure and maximum EUS EMG activity is recorded.
  • the formalin test is a chemically-induced tonic pain model in which injection of formalin into a hind paw elicits a biphasic nociceptive behavior.
  • the second phase of formalin response is predominantly due to a central sensitization phenomenon.
  • Most clinically used drugs against neuropathic pain are active on this second phase of formalin response.
  • Formalin test is accepted as a valid model of persistent clinical pain.
  • the test was done by pretreating the rats with the test compound and 30 min later (pretreatment time), 50 ⁇ l of 2.5% formalin was injected into the right hind paw of the animal. The number of paw licking and flinching episodes were scored for 60 min post-formalin injection.
  • the compounds were administered either intraperitoneal ⁇ or orally. The compounds significantly inhibited the second phase of the formalin response.
  • the compounds were tested for their efficacy in reducing mechanical allodynia and cold allodynia in the spared nerve injury (SNI) model of chronic neuropathic pain.
  • SNI spared nerve injury
  • the left sciatic nerve of the rat is exposed under anesthesia.
  • Two of the branches of the sciatic nerve viz. the common peroneal and tibial nerve are ligated and sectioned.
  • the third branch (sural nerve) is left intact.
  • the animals were allowed a post-operative recovery period of 7 days before they were subjected to any test.
  • the presence of mechanical allodynia was assessed using the Dynamic Plantar Aesthesiometer (Ugo Basile, Italy) which is a modified version of the Von Frey Hair test.
  • a test filament is positioned below the animal's hind paw and the unit is activated which causes the filament to move up and touch the plantar surface of the hind paw. Increasing force is applied to the paw via the filament.
  • the unit is inactivated automatically and the threshold force required to elicit the paw withdrawal is displayed.
  • the cut-off force is set at 50 g.
  • the tests were done on both the non-injured (control) and the injured (SNI) paw. Pilot studies showed the presence of mechanical allodynia 7 days after the surgery and lasted up to 4 weeks (end of the test period).
  • Cold allodynia was assessed by using the acetone test. In this model, 25 ⁇ l of acetone is sprayed on to the plantar surface of the hind paw. Evaporation of acetone causes cooling of the skin. The cold stimulus sets up nociceptive responses from the injured paw as evidenced by paw lifting, paw licking and grooming. The duration of the nociceptive responses is noted. Similar stimulus to the uninjured (control) paw usually does not elicit nociceptive responses.
  • test compound or the vehicle was administered (10 ml/kg) either intraperitoneally or orally. The readings were taken 30 min after the administration. Cold allodynia in neuropathic rats was measured as evidenced by the reduced nociceptive duration in these animals.
  • FCA FCA-induced edema
  • 100 ⁇ l of FCA is injected subcutaneously into the dorsal aspect of the left hind paw of the rats.
  • the edema appears within 2 h reaches a peak by 6 h and lasts for about 7 days.
  • the effects of compounds on mechanical allodynia and paw volume were studied 2 days after FCA administration.
  • the effect of the compounds in alleviating mechanical allodynia was assessed in the FCA-treated rats using the modified Randall-Selitto method (Analgesy- Meter, Ugo Basile, Italy).
  • the animal's paw is placed on a small plinth under a cone-shaped pusher. Increasing force is applied to the paw by depressing a pedal until vocalization or withdrawal of the paw occurs. The minimum force required to elicit this vocalization/withdrawal is the paw pressure threshold.
  • the cut-off was set at 150 g.
  • test compound/vehicle was administered orally in a volume of 10 ml/kg.
  • the paw pressure thresholds were measured 30, 60 and 180 min post administration.
  • the inhibition of mechanical allodynia was measured at 30 min by all compounds tested.
  • Table 1 shows examples of selective 5-HT 2C receptor agonists in accordance with the invention, determined by the IP3 assay described above.
  • Table 2 shows examples of compounds with reduced cytochrome P450 inhibition in accordance with the invention, determined by the cytochrome P450 assay described above. The data show the percent inhibition of the metabolism of the substrate in the assay resulting from incubation in the presence of the indicated compound. Compounds having less than 50% inhibition at 1 uM are considered to be a compound with reduced inhibition of cytochrome P450 for the present invention.
  • Figure 1 shows the dose-related reduction in food intake in rats treated intraperitoneally with Example 22.34 of the invention.

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Abstract

La présente invention concerne un compose représenté par la formule (I). Dans cette formule, R1 est un hétérocycloalkyle éventuellement substitué contenant au moins deux cycles, lesdits cycles étant des cycles fusionnés, des cycles fusionnés pontés et/ou des cycles spiro. L'invention concerne également un procédé permettant, d'utiliser ces composés pour traiter chez un mammifère un trouble résultant d'une médiation du récepteur 5-HT2C.
PCT/CA2008/002223 2007-12-21 2008-12-18 Composés dont l'activité est dirigée contre le récepteur 5-ht2c Ceased WO2009079765A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
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WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
WO2012030953A1 (fr) 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Agonistes du récepteur 5-ht2c dans traitement de troubles améliorés par réduction du taux de noradrénaline
CN102887856A (zh) * 2012-10-17 2013-01-23 河北师范大学 一种合成布南色林的方法
CN103130799A (zh) * 2011-12-01 2013-06-05 上海药明康德新药开发有限公司 一种2-羟基吡啶并6,7,8,9-四氢-5H-吡啶并[2,3-d]氮杂卓衍生物的制备方法
WO2015066344A1 (fr) 2013-11-01 2015-05-07 Arena Pharmaceuticals, Inc. Agonistes du récepteur 5-ht2c et compositions et procédés d'utilisation
JP2019501930A (ja) * 2016-01-15 2019-01-24 ファイザー・インク ６，７，８，９−テトラヒドロ−５Ｈ−ピリド［２，３−ｄ］アゼピンドーパミンＤ３リガンド
CN109608451A (zh) * 2018-12-17 2019-04-12 上海药明康德新药开发有限公司 一种2-氧亚基-吡啶并[2,3-d]氮杂卓-7(2H)-甲酸叔丁酯合成方法
US10947257B2 (en) 2017-10-09 2021-03-16 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
EP3733204A4 (fr) * 2017-12-27 2021-09-15 Takeda Pharmaceutical Company Limited Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale
US11564935B2 (en) 2019-04-17 2023-01-31 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin
US12459965B2 (en) 2017-10-09 2025-11-04 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use

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CA2294530A1 (fr) * 1997-07-02 1999-01-14 Soong-Hoon Kim Inhibiteurs de farnesyl proteine transferase
CA2412632A1 (fr) * 2000-06-15 2001-12-20 Bang-Chi Chen Inhibiteurs de la hmg-coa reductase et procede associe
WO2008009125A1 (fr) * 2006-07-20 2008-01-24 Cascade Therapeutics Inc. Tétrahydro-5-pyrido[2,3-d]azépines comme ligands de 5-ht2c

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US5827849A (en) * 1993-02-22 1998-10-27 Karl Thomae Gmbh Cyclic dericatives, pharmaceutical compositions containing these compounds and processes for preparing them
CA2294530A1 (fr) * 1997-07-02 1999-01-14 Soong-Hoon Kim Inhibiteurs de farnesyl proteine transferase
CA2412632A1 (fr) * 2000-06-15 2001-12-20 Bang-Chi Chen Inhibiteurs de la hmg-coa reductase et procede associe
WO2008009125A1 (fr) * 2006-07-20 2008-01-24 Cascade Therapeutics Inc. Tétrahydro-5-pyrido[2,3-d]azépines comme ligands de 5-ht2c

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WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
WO2012030953A1 (fr) 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Agonistes du récepteur 5-ht2c dans traitement de troubles améliorés par réduction du taux de noradrénaline
CN103130799A (zh) * 2011-12-01 2013-06-05 上海药明康德新药开发有限公司 一种2-羟基吡啶并6,7,8,9-四氢-5H-吡啶并[2,3-d]氮杂卓衍生物的制备方法
CN102887856A (zh) * 2012-10-17 2013-01-23 河北师范大学 一种合成布南色林的方法
CN102887856B (zh) * 2012-10-17 2014-05-28 河北师范大学 一种合成布南色林的方法
WO2015066344A1 (fr) 2013-11-01 2015-05-07 Arena Pharmaceuticals, Inc. Agonistes du récepteur 5-ht2c et compositions et procédés d'utilisation
JP2019501930A (ja) * 2016-01-15 2019-01-24 ファイザー・インク ６，７，８，９−テトラヒドロ−５Ｈ−ピリド［２，３−ｄ］アゼピンドーパミンＤ３リガンド
US11180517B2 (en) 2017-10-09 2021-11-23 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US12312375B2 (en) 2017-10-09 2025-05-27 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
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US11149044B2 (en) 2017-10-09 2021-10-19 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US10947257B2 (en) 2017-10-09 2021-03-16 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11447510B2 (en) 2017-10-09 2022-09-20 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11505564B2 (en) 2017-10-09 2022-11-22 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11939346B2 (en) 2017-10-09 2024-03-26 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11629159B2 (en) 2017-10-09 2023-04-18 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11851451B2 (en) 2017-10-09 2023-12-26 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
EP3733204A4 (fr) * 2017-12-27 2021-09-15 Takeda Pharmaceutical Company Limited Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale
CN109608451A (zh) * 2018-12-17 2019-04-12 上海药明康德新药开发有限公司 一种2-氧亚基-吡啶并[2,3-d]氮杂卓-7(2H)-甲酸叔丁酯合成方法
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US11564935B2 (en) 2019-04-17 2023-01-31 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin
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US12447164B2 (en) 2019-04-17 2025-10-21 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin

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