WO2009156889A1 - Diaryl compounds and uses thereof - Google Patents

Diaryl compounds and uses thereof Download PDF

Info

Publication number
WO2009156889A1
WO2009156889A1 PCT/IB2009/052495 IB2009052495W WO2009156889A1 WO 2009156889 A1 WO2009156889 A1 WO 2009156889A1 IB 2009052495 W IB2009052495 W IB 2009052495W WO 2009156889 A1 WO2009156889 A1 WO 2009156889A1
Authority
WO
WIPO (PCT)
Prior art keywords
disorder
alkyl
depression
disorders
compound
Prior art date
Application number
PCT/IB2009/052495
Other languages
French (fr)
Inventor
Matthew Merrill Hayward
Stanton Furst Mchardy
Stafford Mclean
Vinod Dipak Parikh
Patrick Robert Verhoest
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to JP2011515678A priority Critical patent/JP2011526881A/en
Priority to EP09769699A priority patent/EP2321011A1/en
Priority to CA2727573A priority patent/CA2727573A1/en
Publication of WO2009156889A1 publication Critical patent/WO2009156889A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/06—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/22—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to diaryl derivatives that are substituted phenyl-phenyl phenyi- heteroaryl, or heteroaryl-heteroary! compounds and the uses thereof for treating diseases, conditions and/or disorders mediated by kappa opioid receptors (KORs) Specifically, the compounds are selective antagonists of KORs and are selective to KORs relative to m ⁇ and delta (u and S) opioid receptors
  • the compounds of the invention can be used for the treatment of CNS diseases, conditions, and/or disorders described herein atone or in combination with any other pharmaceutical agent, where the compound of formula I and/or the agent may be a pharmaceutically acceptable salt thereof
  • the other agent includes an antimanic agent ⁇ mood stabilizers) (including Lithium, Carbamazepine ⁇ 5H-dtbenz$b,fJ azep ⁇ ne-5-ca ⁇ boxarn ⁇ de ⁇ Depakote ⁇ divalproex sodium dissociates to the valproate ion chemically known as sodium hydrogen b ⁇ s(2-propy!pentanoate) ⁇ , and lamot ⁇ gme ⁇ 3,5-d ⁇ ammo-6-(2.3-dichlorophenyl)-as- tnazine ⁇ , and Ability (also known as a ⁇ piprazole that is an atypical antipsychotic), an atypical antipsychotic (including ztpiasidone ⁇ 5
  • US 6 974,824 discusses kappa opioid receptor antagonists that are said to yield significant improvements in functional binding assays to kappa opioid receptors relative to nor-BNi, and the use of these antagonists in treatment of disease states that are ameliorated by binding of the kappa opioid receptor such as heroin or cocaine addictions
  • US 6,559,159 discusses kappa opioid receptor antagonists and the use of these antagonists in treatment of disease states that are said to ameliorated by binding of the kappa opioid receptor such as heroin or cocaine addictions
  • US 6.548,637 discusses compounds, and pharmaceutical preparations thereof, that bind selectively to mammalian opioid receptors where the present set of compounds are said to comprise full agonists, partial agonists, and antagonists of mammalian opioid receptors
  • US 6.528,518 discusses the treatment of depression using kappa opioid receptor antagonists US 5.780.479 discusses a method for treating an individual afflicted with an impulse-control disorder by administering thereto an amount of one or more opioid receptor antagonists US 5,727,570 discusses a method of treatment of humans suffering from hyperlipidemia which comprises administering, by a pharmaceutically effective mode, a drug composition selected from the group consisting of opiate antagonists, and drugs which substantially equally reduce the amounts of catecholamines bound to alt catecholamine binding sites
  • US 5,585,348 discusses a method of preventing hyperalgesia and other undesirable side-effects associated with the administration ot growth factor, including nerve growth factor, utilizing an antagonist capable of inactivating excitatory opioid receptor-mediated functions on neurons in the nociceptive pathway.
  • the invention relates to a composition comprising a growth factor and an antagonist capable of inactivating excitatory opioid receptor-mediated functions on neurons in the nociceptive pathway.
  • US 5,141 962 discusses compounds claimed to have dissociated antagonist affinity for kappa opiate receptor
  • US 5,025.018 discusses methods of inducing optate-receptor antagonistic activity in a patient suffenng from ischemic or traumatic central nervous system injury by administering to said patient an effective amount of an opiate-receptor antagonist having enhanced activity at t ⁇ e kappa-opiate receptor suitable to permit the induction of opiate-receptor antagonistic activity.
  • US 4,906,637 discusses methods of inducing optate-receptor antagonistic activity in a patient suffenng from ischemic or traumatic brain injury by administering to said patient an effective amount of an opiate-receptor antagonist having enhanced activity at the kappa-opiate receptor suitable to permit the induction of opiate-receptor antagonistic activity
  • WO 2007/100335 discusses methods of treating mood disorders, such as manic disorders, and stabilizing moods by administering a kappa agonist or partial agonist to a subject in need thereof.
  • the mesolimbie dopamine system which onginates in the ventral tegmental area and projects to the nucleus accumbe ⁇ s (NAc), is involved in the pleasurable (hedontc) and rewarding effects of a variety of substrates, including drugs of abuse, food, and sexual behavior Drugs of abuse cause complex neuroadaptations in this system, some of which are associated with altered drug sensitivity.
  • One neuroadaptation involves cAMP response element-binding protein (CREB) a transcription factor that is activated in striatal regions by psychostimulants.
  • CREB in the NAc appears to regulate the rewarding and averstve effects of cocaine Stimulation of cAMP-dependenf protein kinase A (PKA), which activates
  • CREB in the NAc decreases cocaine reward.
  • elevation of CREB expression in the NAc decreases cocaine reward and makes low doses of the drug aversive.
  • blockade of PKA activity or overexpression of a dominant-negative CREB, which functions as a CREB antagonist, in the NAc increase cocaine reward
  • Cocaine alters neuronal excitability and neurotransmitter levels in the brain, particularly the mesoitmbfc dopamine system. Cocame withdrawal is accompanied by signs of depression and other mood disorders tn humans.
  • the bioEogical basis of mood disorders like depression is not understood, but may be caused by genetic and environmental factors Physically and emotionally stressful events can aiso influence the etiology of depression, possibly causing subtle brain changes and alterations in gene expression.
  • depression may have an important acquired component, caused by neuroadaptations in response to environment and expe ⁇ eoce The therapeutic actions of antidepressants appear to involve neuroadaptations.
  • antidepressant treatments include tricyclic and atypical antidepressants, selective serotonin reuptake inhibitors, electroconvulsive therapy
  • common actions include activation of PKA and the transcription factor CREB in the hippocampus, a brain region associated with emotion.
  • CREB plays a critical role in the expression of numerous genes Understanding causal relations among CREB function, gene expression, and the therapeutic effects of antidepressants might provide explanations for why antidepressants require sustained treatment for effectiveness Additionally, because some genes regulated by CREB may be therapeutic while others may be pathophysiological, a more genera) understanding of the role CREB in behavior might help to elucidate the biological basis of depressive syndromes Many of the researchers studying depression are focused on the hippocampus. Many antidepressants increase the level of CRE8 in the hippocampus in this region, it is beiseved that increasing CREB activity is beneficial, because CREB controls some growth factors (e.g , BDNF) in the brain. See D 1 Sa C.
  • BDNF growth factors
  • Duman RS Bipolar Disord. 2002: 4: 183-94 providing a discussion between CREB and antidepressant activity
  • Many of the researchers studying depression are focused on the hippocampus.
  • Many antidepressants increase the level of CREB in the hippocampus In this region, it is believed that increasing CREB activity is beneficial, because CREB controls some growth factors (e g., BDNF) in the brain.
  • BDNF growth factors
  • Nomifensine a dopamine reuptake inhibitor
  • Nomifensine was taken off the market because it caused lethal allergic reactions in some people
  • Buprenorphine (8UP) a partial mu agonist/weak parttat kappa agonist
  • BUP Buprenorphine
  • a double blind investigation showed BUP to induce strong antidepressant effects in patients with endogenous depression (Emrich, et ai . Ann NY Acad Set, 1982. v398, p108)
  • depressive symptoms were found to be significantly decreased with BUP treatment in heroin addicted patients who were depressed at intake ⁇ Kosten. J S ⁇ bst Abuse Treat. 1990, v1 , p51)
  • Compounds of Formula (I) have been found to act as selective antagonists at the KOR, and, therefore, may be used In the treatment of diseases, conditions and/or disorders that benefit from such antagonism (e.g., diseases/disorders/conditions related to obesity and obesity-related co-morbidities in addition to those related to the centra! nervous system)
  • the compounds of Formula (I) provide selectivity at the KOR.
  • a method for treating, or preparing a medicament to treat, a disease, condition and/or disorder that is mediated by selectively antagonizing the KOR over the mu and delta opioid receptors in animals that include the step of administering to an animal (preferably, a human) in need of such treatment a therapeutically effective amount of a compound of the present invention (or a pharmaceutical composition thereof) to treat any disease, condition, or disorder mediated by antagonizing the kappa opioid receptor.
  • Diseases, conditions, and/or disorders mediated by selectively antagonizing the kappa opioid receptor include any one individually or combination of any of the following: schizophrenia including negative symptoms; schizophreniform disorder; schizoaffective disorder including of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder; personality disorder of the paranoid type; personality disorder of the schizoid type; panic disorder: phobias; obsessive- compulsive disorder; stress disorders; generalized anxiety disorder: movement disorders involving Huntington's disease; dyskinesia associated with dopamine agonist therapy: Parkinson s disease, restless leg syndrome; disorders comprising as a symptom thereof a deficiency in cognition; dementias; mood disorders and episodes in a mammal; anxiety or psychotic disorders including schizophrenia, of the paranoid, disorganized, catatonic, undifferentiated, or residual type: delusional disorder; personality disorder of the paranoid type, of the schizoid type, or agora
  • phrases "pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically. with the other ingredients comp ⁇ sing a formulation, and/or the mammal being treated therewith
  • the teims 'treating', "treat”, or 'treatment' embrace both pieventative. ⁇ e , piophyiactic. and palliative treatment
  • modulating opioid receptor activity or “optoid-mediated” iefers to the activation or deactivation of the mu, kappa and/or delta opioid receptors
  • compounds of the present invention refer, unless specifically identified otherwise, to compounds of formula (I) and pharmaceutically acceptable salts of the compounds and hydrates of the compounds thereof and salts thereof, as well as, all stereoisomers ⁇ including diastereomers and enantiomers) tautomers and isotopically iabeied compounds.
  • One aspect of the present invention is a compound of formula I,
  • R 1 is Ci ⁇ afkyf C ⁇ alkyl-O-Ci. ⁇ aikyl a ?-, 8-, or 9-membered bridged bicydic carbocyclic ring, a fused bicydic carbocyclic ⁇ ng. (CH ⁇ phenyi, (CH 2 ) a »heteroaryl, or (CH ⁇ beterocycloalkyl. wherein the bridged ong, the fused ⁇ ng, phenyl, heteroaryl, or heterocycloalky! is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, OH. Ci ? alkyt, O-C ⁇ 3 alkyl, NH 2 , NHC ⁇ alkyl. or N(C, ⁇ alkyl),
  • R ? is H or C, ⁇ alkyl, or
  • R' and R 7 are taken together with the nitrogen to which they are attached to form a mono- or bicydic N-nng.
  • said N-nng is a 4- to 7-membered mono-cyclic heterocyctoalkyl ring; a fused bicyclic heterocyclic ⁇ ng. or a 7-. 8-. or 9-membered bridged bicychc heterocyclic ring, wherein said N- ⁇ ng is unsubstituted or substituted with 1 2, or 3 substituents independently selected from halogen.
  • R 3 is H. or Ci salkyl, or when X f or X 3 is > ⁇ C(R 5 ) ⁇ -, R -1 may be taken together with R fl of one of X 1 or X a and the carbon atoms to which they are attached to form a 5- or 6-membered saturated, or partially saturated ⁇ ng, wherein one carbon atom in said 5- or 6-membered ring may be a heteroatom selected from -O-, -N(H)-, •N(C*alkyl ⁇ -, and >N-, and wherein said ring is unsubstituted or substituted where valency permits with 1 substrtuent selected from halogen, -CN. or -Ct ⁇ alkyl,
  • R* is H. halogen. CN, Cj $ alky!, or OC 1 jalkyl.
  • R s is H. halogen. CN. Ci ⁇ alkyi, or OC, 3 alkyl.
  • R 1* is Ci ⁇ alkyl. or C ⁇ alkyl-O-C ⁇ alkyl:
  • R ? is H. or C ⁇ alkyi; or R ⁇ and R 7 are taken together with the nitrogen to which they are attached to form a mono- or bicyclic SN-ring.
  • said SN-ring is a 4- to 7-rnembered mono-cyclic heterocyclic ring containing 0 or 1 additional heteroatom selected from O, NH, or NC « jalkyl, or a 7-, 8-, or 9-membered bridged bicycSic heterocyclic ring, wherein said SN-ring is unsubstituted or substituted wtth 1 or 2 substittients independently selected from halogen, OH, -CN, C, s alkyl. C, .alkyl-OH, 0-C. 3 alkyi, C, % alkyl-O-C,. 5 aikyl. HHz. NHd-salkyi, or NCC ⁇ alky! ⁇
  • X $ , and X ⁇ are independently >(C(R iS ))- or >N-, and each R ? is independently H, halogen, -CN, -C h alky), -0C ⁇ S alkyl. provided that when X 1 or X ? is > ⁇ C(R' i ))- one R s of X 1 or X 3 may be taken together with R s and the carbon atoms to which they are attached to form said 5- or 6-roembered saturated, or partially saturated ring
  • X 1 , X 2 , X J , and X 4 are >(C(R $ ))- wherein R* is selected from any definition discussed herein, and also include wherein each R E is independently H. haiogen, -CN. -C,. • ? a!kyf. Qr -OC 1 . s alkyl
  • R ⁇ and R ? are taken together with the nitrogen to which they are attached to form the monocyclic SN-rtng wherein said SN-nng is uns ⁇ bstituted or substituted with C» ,-,alkyl
  • Preferred monocyclic moieties making this SN-nng include pyrrolidinyl or morpholinyl wherein said SN ring is unsubststuted or substituted with methyl.
  • R 1 is C ⁇ . s a)kyi or the ?-memb ⁇ r «d bridged bicyciic carbocycSic ring, and R " is H
  • R 1 and R° are taken together with the nitrogen to which they are attached to form the 5- to 6-membered mono-heterocycloalkyl ring, or the 8-membered bridged bicyclic heterocyclic ring, wherein said N-ring is unsubstituted or substituted with 1 or 2 substitutents independently selected from OH, methyl, or metboxy
  • X s is ⁇ N- and X ' , X 2 , X*. X 4 , and X $ are >(C(R S )K or. alternatively y? is >N- and X', X ⁇ X 3 . X 4 , and X $ are >(C(R 8 ))-, wherein R* is independently H. halogen, - CN, -C,. 5 alkyi, or -OC ⁇ alky!
  • X ; or X i are both > ⁇ C(R*) ⁇ - and oniy one R* of X 1 and X 3 is H and the other R* is halogen, -CN, -C ⁇ alkyl, or -OC t ⁇ alkyl
  • R* is halogen, -CN, -C ⁇ alkyl, or -OC t ⁇ alkyl
  • at least one of X 1 or X J is >(C(R*))- and R* of formula I forms a ⁇ ng with R 8 of X !
  • X s and the carbon atoms to which they are attached to form a 5- or 6-membered saturated, or partially saturated ring, wherein one carbon atom in said 5- or 6-membered nng may be a heteroatom selected from -O-, -N(H)-, -N(C ⁇ s alkyl)- and >N-, and wherein said ring is unsubstituted or substituted where valency permits with 1 substituent selected from halogen, CN, or -C h alky!.
  • the invention includes the free base or a pharmaceutically acceptable salt of every example of compounds of formula I, by itself or in a group of any combination of the compounds of formula I prepared herein
  • Halogen "1 and 'halo" and the like include fluoro, chloro. bromo and todo.
  • alky! * includes straight or branched alkyl groups of C 8 ⁇ number of carbons where e is the least number of carbon atoms and g is the largest number of carbon atoms possible
  • said alky! includes cycioalkyl moieties
  • Each alkyl moiety may be substituted with up to three substttuents independently selected from halogen. OH, -CN, O-Ci 3 alkyl, NH.>, NHC ⁇ alkyl. or N(C,. s alkyl) 2 , wherein the alky! moieties that are substituents are not further substituted unless otherwise indicated.
  • Ci ⁇ aikyi examples include methyl, trifiuoromethyf. ethyl, n-propyl, i-propyl. cyciopropyl, methyl-cyci ⁇ propyl, t-butyl, and cyclobutyl.
  • heterocycloalkyi as used herein, unless indicated otherwise, includes a 4- to 7- membered saturated cycloaSky! moiety in which up to two carbon atoms are replaced with a nitrogen, O, or S atom or any combination thereof. When nitrogen replaces an atom, to satisfy velancy requirements, the nitrogen is substituted with H or C h alky!
  • heterocycloalkyi is a substituent or is created by two substituents combining to form a heterocycloalkyi moiety, e g , when R 1 and R 2 are taken together with the atom to which they are attached to make pyrrolidinyf.
  • Non-ftmiting examples of heterocycloalkyi include oxetanyl. tetrahydrofuranyl, tetrahydropyran, azetidinyl, pyrrolidinyl, pyrazolidinyf. piperidinyl. dtoxanyi, morpholinyf, thiomorpholinyl, and piperazinyl.
  • aryl refers to carbocyclic aromatic moieties having a single ring (e.g., phenyl).
  • heteroaryl as used herein, unless indicated otherwise, is a 5- to 6-membered ring that is aromatic or partially saturated, where at least one heteroatom is present and no more that three heteroatoms are present, wherein the heteroatom is nitrogen. O, or S or any combination thereof.
  • nitrogen replaces an atom, to satisfy velancy requirements, the nitrogen is substituted with H or C 1 ⁇ alky! or is the point of attachment when heteroaryi is a substituent or is formed by two substituents combining to form a heteroaryi moiety.
  • Non-iimlting examples of heteroaryi include pyridyl, pyrimidyl, pyridazyl pyrazinyl.
  • a fused bicyclic carbocyclic ring as used herein, unless indicated otherwise, has the two rings that share adjacent carbon atoms.
  • the fused rings form a 5-6 or 6-6 fused bicyclic ring.
  • either ring may be aromatic, or partially or fully saturated.
  • a non-limiting example of a fused aromatic ring moiety is naphthyl.
  • a non-limiting example of a saturated or partially saturated fused ring moiety ss decahydronaphthyf and tetrahydronaphthyl, respectively. Other non- limiting examples include indanyt.
  • a fused bicyclic heterocyclic ring as used herein, unless indicated otherwise, is a bicyclic fused ring where up to 3 atoms are independently selected from O, nitrogen, or S or any combination thereof in either ring, including the atom where the rings are fused where valency permits.
  • nitrogen ts the heteroatom to satisfy valency requirements, it is substituted wtth H or Ct ⁇ alkyi. or is a point of attachment when a fused bicyclic heterocyclic ring is a substituent or is the point of attachment when formed by two substituents combining to form a fused bicyclic heterocyclic moiety.
  • a bridged bicyc ⁇ c carbocyctic ring as used herein, unless indicated otherwise, is formed when two rings do not share adjacent carbon atoms to make the bicyclic ring.
  • the bridged nng contains from 7 to 9 carbon atoms.
  • Non-limtting examples include b ⁇ cyclo(2.2.1]heptaoy! and bicyclo ⁇ 3.i.i)heptanyl.
  • a bridged bicyclic heterocyclic ring as used herein, unless indicated otherwise, is a bridged bicyclic carbocyclic ring where 1 to 2 carbon atoms are replaced by a nitrogen atom that is substituted where valency requires by H or C h alky! or provides the point of attachment for the ring when the ring is a substituent or is formed, for example, when R' and R 3 or R ⁇ and R* combine to form a bridged bicyclic heterocyclic ring.
  • Non-limiting examples include quinudidinyl.
  • compositions that comprises (i) a compound of the present invention, and (2) a pharmaceutically acceptable excipient.
  • diluent or earner Preferably the composition comprises a therapeutically effective amount of a compound of the present invention
  • the composition may also contain at least one additional pharmaceutical agent ⁇ described herein) in yet another embodiment of the present invention a method for treating, or preparing a medicament to treat a disease, condition and/or disorder that is mediated by selectively antagonizing the KOR over the mu and delta opioid receptors tn animals that include the step of administering to an anima! (preferably a human) in need of such treatment a therapeutically effective amount of a compound of the present invention (or a pharmaceutical composition thereof) to treat any disease, condition or disorder mediated by antagonizing the kappa opioid receptor
  • Compounds of the present invention may be administered in combination with other pharmaceutical agents
  • the combination therapy may be administered as (a) a single pharmaceutical composition which composes a compound of the present invention, at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable ex ⁇ pient, diluent, or carrier, or (b) two separate pharmaceutical compositions compnsmg ( ⁇ ) a first composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or earner, and (it) a second composition comprising at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient diluent, or earner
  • the pharmaceutical compositions may be administered simultaneously or sequentially and in any order
  • Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts particularly in light of the description contained herein
  • the starting matenais are generally commercially available or are readily prepared using methods well known to those skilled in the art (e g , prepared by methods generally
  • the compounds of this invention can be prepared starting from the aryl sulphonyl chloride with a group ortho that can be utilized to couple in a palladium-catalyzed reaction such as a Suzuki coupling (see for example Miyaura, N ; et a! Chem Rev. 1995, 95, 2457)
  • Standard ortho groups for R 10 are a chloride, bromide, iodide or boronic acid These compounds are commercially available or can be prepared by one who is skilled in the art
  • the sulfonamide can be treated with LDA in tetrahydrofuran or potentially an alternative organic aprotic solvent and the anion quenched with bromine to provide the Suzuki coupling partner 2(ii). If either R ⁇ or R 7 are a proton, an additional equivalent of base (LOA) will be required to carry out this sequence. Suzuki couplings are well precendented in the literature (see for example ivfeyaura, N ; et ai
  • the compounds of the present invention may be isolated and used per $ ⁇ or in the form of any pharmaceutically acceptable salt
  • the term 'salts * refers to inorganic and organic salts of a compound of the present invention. These salts can be prepared in situ dunng the final isolation and purification of a compound, or by separately reacting the compound with a suitable organic or inorganic acid or base and isolating the sait thus formed
  • Representative salts include the hydrobromide, hydrochloride, hydr ⁇ odide, sulfate, bisulfate, nitrate, acetate, tnfluoroacetate.
  • oxalate besylate, palmitate, pamoate, malonate, stearate, laurate, malate, borate, benzoate.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to. ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethyfamtne. t ⁇ methytamine, triethylamine, ethylamine. and the like. See, e.g., Berge, et at, J. Pharm. Set., 66, 1-19 (1977).
  • the compounds of the present invention may contain asymmetric or chiral centers, and.
  • Diastereome ⁇ c mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art. such as by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomenc mixture by reaction with an appropriate optically active compound (e.g.. chirai auxiliary such as a chirai alcohol or Moshers acid chloride), separating the diastereomers and converting (e.g , bydroiyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g. chirai auxiliary such as a chirai alcohol or Moshers acid chloride
  • the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chirat HPLC column. It is also possible that the intennediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.
  • the term ' iautomer” or 'tautomeric form" refers to structural isomers of different energies which are interconvertible v/a a low energy barrier.
  • proton tautomers also known as prototropic tautomers ⁇ include interconversions via migration of a proton, such as keto-enol and imtne-enamme tsomerizattons.
  • a specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlonne. such as 2 H, 5 H. 11 C, "C, W C, 13 N, K ⁇ , " 5 0, 17 O. 1S O, 31 P 1 32 P, «S. ' 8 F. 1 ⁇ 3 l. 125 I and ?6 CI, respectively.
  • Certain isotopieally-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e . a H) and carbon ⁇ i4 (i.e.. 14 C) isotopes ate particularly preferred for their ease of preparation and detectabiiity.
  • substitution with heavier isotopes such as deuterium (i.e., 'H) may afford certain therapeutic advantages resulting from greater metabolic stability (e g , increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Positron emitting isotopes such as ib Q, 13 N, 11 C, and " '*F are useful for positron emission tomography (PET) studies to examine substrate occupancy lsotopicaily labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein belovv, by substituting an isotopicaliy labeled reagent for a non-isotopicaity labeled reagent
  • Another embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable ex ⁇ pient, difuent or earner
  • the compounds of the present invention may also be used m the manufacture of a medicament for the therapeutic applications described herein
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier diluent or exciptent Suitable carriers diluents and exciptents are well known io those skilled in the art and include mate ⁇ als such as carbohydrates waxes water soluble and/or swellabte polymers, hydrophific or hydrophobic materials gelatin, oils solvents, water, and the like
  • the particular carrier, diluent or ex ⁇ plent used wili depend upon the means and purpose fot which the compound of the present invention is being applied
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GKAS) to be administered to a mammal
  • GKAS solvents
  • sate solvents are norvtoxtc aqueous solvents such as water and other non-toxic solvents that are soluble or mis ⁇ ble in water
  • Suitable aqueous solvents include water, ethanol propylene glycol, polyethylene glycols (e g ,
  • the formulations may be prepared using conventional dissolution and mixing procedures
  • the bulk drug substance ⁇ e compound of the present invention or stabilized form of the compound (e g complex with a cyclodextrin derivative or other known complexation agent)
  • a suitable solvent in the presence of one or more of the excipients described above
  • the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropnate form Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package
  • the container has
  • the present invention further provides a method of treating diseases, conditions and'or disorders modulated by the opioid receptor(s) in an animal that includes administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable exc ⁇ tent diluent or earner
  • the method is particularly useful for treating diseases conditions and/or disorders that benefit from antagonizing the mu, kappa and/or delta opioid receptors
  • a dosage m For a normal adult human having a body weight of about 100 kg a dosage m the range of from about 0001 mg to about 10 mg per kilogram body weight is typically sufficient preferably from about 0005 mg/kg to about 50 mg/kg, more preferably from about 0 01 mg/kg to about 3 mg/kg
  • some variability in the general dosage range may be required depending upon the age and weight of the subject being treated, trie intended route of administration trie particular compound being administered and the iike
  • the determination of dosage ranges and optimal dosages for a particular patient is well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure It is a ⁇ so noted that the compounds of the present invention can be used in sustained release, controlled release, and delayed release formulations which forms are also well known to one of ordinary skill in the art
  • the compounds of this invention may also be used in conjunction wfth other pharmaceutical agents for the treatment of lhe diseases, conditions and/or disorders described herein Therefore methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include anti obesity agents
  • Binding assays on membranes from CHO celts expressing either human kappa, mu or delta opioid receptors were performed according to standard procedures Briefly, fro?en cell paste (70-80-mgs per 96 welt plate) is homogenized in 50 mM Tris HCI buffer (pH 74 @ 4 degrees C) containing 2 0 mM

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Virology (AREA)
  • Reproductive Health (AREA)
  • Psychology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Molecular Biology (AREA)
  • Nutrition Science (AREA)
  • Hospice & Palliative Care (AREA)
  • AIDS & HIV (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Anesthesiology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Rheumatology (AREA)

Abstract

The invention relates to derivatives of a compound of formula I: wherein R1 to R7 and X1 to X7 are as defined herein The invention relates to the uses thereof for treating diseases, conditions and/or disorders mediated by kappa opioid receptors (KORs). Specifically, the compounds are selective antagonists of KORs and are highly selective to KORs relative to mu and delta opioid receptors.

Description

DlARYL COMPOUNDS AND USES THEREOF
FELD OF THE INVENTION The present invention relates to diaryl derivatives that are substituted phenyl-phenyl phenyi- heteroaryl, or heteroaryl-heteroary! compounds and the uses thereof for treating diseases, conditions and/or disorders mediated by kappa opioid receptors (KORs) Specifically, the compounds are selective antagonists of KORs and are selective to KORs relative to mυ and delta (u and S) opioid receptors
BACKGROUND The compounds of the invention can be used for the treatment of CNS diseases, conditions, and/or disorders described herein atone or in combination with any other pharmaceutical agent, where the compound of formula I and/or the agent may be a pharmaceutically acceptable salt thereof The other agent includes an antimanic agent {mood stabilizers) (including Lithium, Carbamazepine {5H-dtbenz$b,fJ azepιne-5-caιboxarnιde} Depakote {divalproex sodium dissociates to the valproate ion chemically known as sodium hydrogen bιs(2-propy!pentanoate)}, and lamotπgme { 3,5-dιammo-6-(2.3-dichlorophenyl)-as- tnazine}, and Ability (also known as aπpiprazole that is an atypical antipsychotic), an atypical antipsychotic (including ztpiasidone {5-[2[-4-(1,2-beιv:ιso{hιa/of-3-yl)pipe{azιrι-1- ylJ)ethyl-]-6-chloro-1 3-dιhydro-2H-ιndol-2-one (see e g . U S Pat Nos 4,831 ,031. 6,312 295, 6.38? 904 6245.765. and 6,245.766 and European Patent application EP901781 , published Mar 17, 1999)}, olanzapine {2-methyl-4-(4-methy!-1-pιperazιnyl)-10H-thteno-[2,3-b|[1.5|beπzodιa2epine (see, e g , U S
Pat No 5,229,382)}; clozapine {(8-ch!oro-11-{4-methy!-1-pιpera2tnyl)-5H-dιbenzo[b,el[1,4jdιa2epιne (see, e g , U S Pat No 3,539 573, see also Hanes et al , Psychopharmacol Bull 24. 62 (1998))}, nsperidone
{3-[2-|4-{6-ftuoro-1.2-benzisoxa2Ol-3-y{)piperidtnolethyl]-2-methyl-6.7 8,9-te^ahydro-4H-pyndo-[i.2- a]pyrtmιdιn-4-one (see e g , U S Pat No 4,804,663)}, sertιndole {1-[2-[4-(5-cnloro-1-<4-fluorophenyl)-1H- ιndol-3-yl]-1 pipeπdιnyl}ethyl3lιmιdazoi!dtn-2 one (see, e g U S Pa! Nos 4,710,500, 5,112,838 and
5,238.945)}, quetiapme {(2-|2-(4-dibenzo[b,f|π,43tπiazepιn-11-yl-1-pιperazιny!)ethoxy}ethano!, see e g.,
U S Pat No 4879288}} aπptprazole {{7-{4-(4-(2,3-dtchloropr>enyl}-1-ptpera2inyl-butoxy}-3-4- dihydrocarbostynt or 7-{4-{4-(2,3-dιctilorophenyl)-1pιperazιnylj-butoxy}-34-dιhydro~2(1H)-qu!nolιnone (see e g . U S Pat Nos 4,734,416 and 5,006,528)] amisulpπde {{4-amino-N-(1-ethyi-2- pyrrolιdιnyf)methyt]-5-(ethylsulfony!)-2-methoxyben2amιde (see, e g , U S Pat No 4401,822; see also P
Protais et al Neuropharmacol. 24, 861 (1985))}, mirtazepine (1 2,3,4,10.14b-hexa-hydro-2-methyl pyrazιno[2, 1-a|pyrιdo[23-c}-[2Jbenzazepιne (see, U S Pat No 4,062,848)}. and asenapine {trans-5- chloro-2-methyl-2,3,3a,12b-lelrahydro-1H-dιberiz-[2.36 7]oxepιno[4 5-c}pyrrole (see, e g , U S Pat Nos 4 145434 and 5. /63 4 /6))} or a 5-HT re-uptake inhibitor (including sertraline, paroxetine, fluoxetine, citafopram, and βscitaiopram)
US 6 974,824 discusses kappa opioid receptor antagonists that are said to yield significant improvements in functional binding assays to kappa opioid receptors relative to nor-BNi, and the use of these antagonists in treatment of disease states that are ameliorated by binding of the kappa opioid receptor such as heroin or cocaine addictions US 6,559,159 discusses kappa opioid receptor antagonists and the use of these antagonists in treatment of disease states that are said to ameliorated by binding of the kappa opioid receptor such as heroin or cocaine addictions
US 6.548,637 discusses compounds, and pharmaceutical preparations thereof, that bind selectively to mammalian opioid receptors where the present set of compounds are said to comprise full agonists, partial agonists, and antagonists of mammalian opioid receptors
US 6.528,518 discusses the treatment of depression using kappa opioid receptor antagonists US 5.780.479 discusses a method for treating an individual afflicted with an impulse-control disorder by administering thereto an amount of one or more opioid receptor antagonists US 5,727,570 discusses a method of treatment of humans suffering from hyperlipidemia which comprises administering, by a pharmaceutically effective mode, a drug composition selected from the group consisting of opiate antagonists, and drugs which substantially equally reduce the amounts of catecholamines bound to alt catecholamine binding sites
US 5,585,348 discusses a method of preventing hyperalgesia and other undesirable side-effects associated with the administration ot growth factor, including nerve growth factor, utilizing an antagonist capable of inactivating excitatory opioid receptor-mediated functions on neurons in the nociceptive pathway. In addition, the invention relates to a composition comprising a growth factor and an antagonist capable of inactivating excitatory opioid receptor-mediated functions on neurons in the nociceptive pathway US 5,141 962 discusses compounds claimed to have dissociated antagonist affinity for kappa opiate receptor
US 5,025.018 discusses methods of inducing optate-receptor antagonistic activity in a patient suffenng from ischemic or traumatic central nervous system injury by administering to said patient an effective amount of an opiate-receptor antagonist having enhanced activity at t\\e kappa-opiate receptor suitable to permit the induction of opiate-receptor antagonistic activity.
US 4,906,637 discusses methods of inducing optate-receptor antagonistic activity in a patient suffenng from ischemic or traumatic brain injury by administering to said patient an effective amount of an opiate-receptor antagonist having enhanced activity at the kappa-opiate receptor suitable to permit the induction of opiate-receptor antagonistic activity WO 2007/100335 discusses methods of treating mood disorders, such as manic disorders, and stabilizing moods by administering a kappa agonist or partial agonist to a subject in need thereof.
The mesolimbie dopamine system, which onginates in the ventral tegmental area and projects to the nucleus accumbeπs (NAc), is involved in the pleasurable (hedontc) and rewarding effects of a variety of substrates, including drugs of abuse, food, and sexual behavior Drugs of abuse cause complex neuroadaptations in this system, some of which are associated with altered drug sensitivity. One neuroadaptation involves cAMP response element-binding protein (CREB) a transcription factor that is activated in striatal regions by psychostimulants. CREB in the NAc appears to regulate the rewarding and averstve effects of cocaine Stimulation of cAMP-dependenf protein kinase A (PKA), which activates
CREB, in the NAc decreases cocaine reward. Similarly, elevation of CREB expression in the NAc decreases cocaine reward and makes low doses of the drug aversive. Conversely, blockade of PKA activity or overexpression of a dominant-negative CREB, which functions as a CREB antagonist, in the NAc increase cocaine reward These findings suggest that CREB activation in the NAc counteracts drug reward and increases drug aversion.
Cocaine alters neuronal excitability and neurotransmitter levels in the brain, particularly the mesoitmbfc dopamine system. Cocame withdrawal is accompanied by signs of depression and other mood disorders tn humans. The bioEogical basis of mood disorders like depression is not understood, but may be caused by genetic and environmental factors Physically and emotionally stressful events can aiso influence the etiology of depression, possibly causing subtle brain changes and alterations in gene expression. Thus, depression may have an important acquired component, caused by neuroadaptations in response to environment and expeπeoce The therapeutic actions of antidepressants appear to involve neuroadaptations. Most antidepressant treatments (including tricyclic and atypical antidepressants, selective serotonin reuptake inhibitors, electroconvulsive therapy) have common actions on components of the cAMP pathway Common actions include activation of PKA and the transcription factor CREB in the hippocampus, a brain region associated with emotion. CREB plays a critical role in the expression of numerous genes Understanding causal relations among CREB function, gene expression, and the therapeutic effects of antidepressants might provide explanations for why antidepressants require sustained treatment for effectiveness Additionally, because some genes regulated by CREB may be therapeutic while others may be pathophysiological, a more genera) understanding of the role CREB in behavior might help to elucidate the biological basis of depressive syndromes Many of the researchers studying depression are focused on the hippocampus. Many antidepressants increase the level of CRE8 in the hippocampus in this region, it is beiseved that increasing CREB activity is beneficial, because CREB controls some growth factors (e.g , BDNF) in the brain. See D1Sa C. Duman RS Bipolar Disord. 2002: 4: 183-94, providing a discussion between CREB and antidepressant activity Many of the researchers studying depression are focused on the hippocampus. Many antidepressants increase the level of CREB in the hippocampus In this region, it is believed that increasing CREB activity is beneficial, because CREB controls some growth factors (e g., BDNF) in the brain. However, there is no evidence that increasing CREB in the hippocampus is associated with the therapeutic effects of antidepressants Although much research on the molecular mechanisms of depression and antidepressant actions has focused on the hippocampus, the NAc may also have relevance This basal forebrain region is innervated by dopamine neurons of the ventral tegmental area, as well as by noradrenergic and serotonergic inputs The NAc contributes importantly to the pleasurable effects of food, sexual behavior, novelty, and addictive drugs. Most current antidepressants act primarily on brain levels of noradrenaline or serotonin. There is some evidence that dopamine systems might be involved in depressive syndromes. Blocking dopamine receptors in the brain causes anhedonia (a decreased ability to experience pleasure), a defining feature of depression Nomifensine, a dopamine reuptake inhibitor, was a clinically effective antidepressant further implicating dopaminergic dysfunction in depression. Nomifensine was taken off the market because it caused lethal allergic reactions in some people Buprenorphine (8UP), a partial mu agonist/weak parttat kappa agonist, was reported to be effective in the pharmacoiogicai treatment of affective disorders A double blind investigation showed BUP to induce strong antidepressant effects in patients with endogenous depression (Emrich, et ai . Ann NY Acad Set, 1982. v398, p108) Additionally, depressive symptoms were found to be significantly decreased with BUP treatment in heroin addicted patients who were depressed at intake {Kosten. J Sυbst Abuse Treat. 1990, v1 , p51)
Recently, Gerra et ai. (Gerra et al, Prog. Neuropsychopharmacol Biol. Psychiatry, 2006. v30, p265) reported a better outcome m heroin addicts co-morbid for depression, as a result of the improvement of depressive symptoms that was tentatively attributed to the specific pharmacoiogicai profile of BUP In contrast to antagonists, kappa receptor agonists, such as butorphanoi and enadoiine have been reported to increase dysphoria, confusion, sedation and to produce feelings of depersonalisation in humans (Greenwafd and Stiteer, Drug Alcohol Depend , 1998, v1, p17, and Walsh et al., Psychopharmacology 2001, v157, p151). thus supporting the use of antagonists ot partial agonists in depressed subjects. Preclinical^, immobilization stress, forced swim, or induction ot teamed helplessness (LH) increase dynorphin (endogenous ligand for kappa receptors) immunoreactivity in specific subregions of the hippocampus, as weii as NAc Conversely, KOR antagonists to these regions produces an antidepressant response in the LH model of depression (Shirayama et al., J. Neurochem., 2004, v90. p1258). consistent with antidepressant effects observed after systemic administration of kappa receptor antagonists
Changes in dynorphin ieveis in the NAc in response to stress may also be noteworthy Most depressed patients exhibit a reduced ability to experience pleasure (anhedonia) and loss of motivation Reward is mediated by the dopaminergic neurons located in the ventral tegmenta! area (VTA) that project to the NAc and is modulated (inhibited) by the kappa receptors located directly on dopamine cells. Thus blockade of kappa receptors m the NAc has antidepressant activity in several animal models and likely to blunt the decreased reward associated with excessive stimulation of kappa receptors Dynorphin upregulation in the NAc shell has been shown to be stimulated by stress and various drugs of abuse, and to cause anhedonia-like effects (Newton et at J Neurosci . 2002,v22, p10833)
Depressed patients perform significantly worse than controls in learning and memory tasks (Hasier et al.. Neuropsychopharm.. 2004 v 29 p1765 and Zakzanis, Neuropsychiatry Neυropsychol. Behav Neurol , 1998 V11. p11i) consistent with imaging studies suggesting decreased hippocampai volume Hippocampai changes are also observed in bipolar disorder (Frey. et al Ben Pharmacol VoI 18(5-6), pp 419-430) wiβi some evidence of reduced glutamatergic transmission that may contribute to impairments in learning and memory observed in bipolar patients Interestingly, dynorphin is co-localized with glutamate in granule cells of the hippocampus and exerts a potent inhibitory control over giutamate release in the hippocampus Furthermore, a kappa receptor antagonist can potentiate LTP induced by prolonged stimulation (Terman et al, J Neurosci. 2000. v20, p437θ) suggesting that a kappa antagonist may facilitate learning and memory
Although many opioid receptor antagonists are known, there remains a need to identify compounds having improved selectivity at file KOR over other receptors SUMMARY
Compounds of Formula (I) have been found to act as selective antagonists at the KOR, and, therefore, may be used In the treatment of diseases, conditions and/or disorders that benefit from such antagonism (e.g., diseases/disorders/conditions related to obesity and obesity-related co-morbidities in addition to those related to the centra! nervous system) In particular, the compounds of Formula (I) provide selectivity at the KOR.
Figure imgf000007_0001
formula (I) wherein the variables are described herein.
In an embodiment of the present invention, a method for treating, or preparing a medicament to treat, a disease, condition and/or disorder that is mediated by selectively antagonizing the KOR over the mu and delta opioid receptors in animals that include the step of administering to an animal (preferably, a human) in need of such treatment a therapeutically effective amount of a compound of the present invention (or a pharmaceutical composition thereof) to treat any disease, condition, or disorder mediated by antagonizing the kappa opioid receptor.
Diseases, conditions, and/or disorders mediated by selectively antagonizing the kappa opioid receptor include any one individually or combination of any of the following: schizophrenia including negative symptoms; schizophreniform disorder; schizoaffective disorder including of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder; personality disorder of the paranoid type; personality disorder of the schizoid type; panic disorder: phobias; obsessive- compulsive disorder; stress disorders; generalized anxiety disorder: movement disorders involving Huntington's disease; dyskinesia associated with dopamine agonist therapy: Parkinson s disease, restless leg syndrome; disorders comprising as a symptom thereof a deficiency in cognition; dementias; mood disorders and episodes in a mammal; anxiety or psychotic disorders including schizophrenia, of the paranoid, disorganized, catatonic, undifferentiated, or residual type: delusional disorder; personality disorder of the paranoid type, of the schizoid type, or agoraphobia; post-traumatic stress disorder; acute stress disorder; chemical dependencies including alcohol, amphetamine, cocaine, heroin, phenobarbital, opiate, nicotine and benzodiazepines addiction; deficiency in memory, intellect, or learning and logic ability; reduction in any particular individual's functioning in one or more cognitive aspects; age-related cognitive decline; dementia: Alzheimer's disease; multi-mfarct dementia; alcoholic dementia or other drug-related dementia: dementia associated with intracranial tumors or cerebral trauma; dementia associated with Huntmgtαn's disease or Parkinsons disease, AfDS-related dementia, deiiπum amnestic disorder, mental retardation, a learning disorder including reading disorder, mathematics disorder, or a disorder of written expression attention-deficit/hyperactivity disorder; mood disorders or mood episodes, a manic or mixed mood episode, a hypomawc mood episode, a depressive episode with atypical features, a depressive episode With melancholic features, a depressive episode with catatonic features, a mood episode with postpartum onset, post-stroke depression, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder, delusional disorder or schizophrenia, a bipolar disorder including bipolar I disorder bipolar tl disorder, cyclothymic disorder, hypertension, and depression, depression in cancer patients, Parkinson's patients, infertile women, and pediatrics depression as a single episode depression or recurrent episodes, including depression associated with postmyocardial infarction subsyndromal symptomatic depression, induced by child abuse, post partum depression, and major depression of the miid, moderate or severe type avoidant personality disorder, premature ejaculation, eating disorders including anorexia nervosa and bulimia nervosa, obesity, cluster headache, migraine, pain neuroiepttc-induced parkinsonism and tardive dyskinestas, endocrine disorders, hyperprolaetinaemia, vasospasm, vasospasm in the cerebral vasculature, cerebellar ataxia, gastrointestinal tract disorders involving changes in motility and secretion, mania, premenstrual syndrome, fibromyalgia syndrome, stress incontinence Tourette's syndrome, trichotillomania, kleptomania; male impotence cancer, small cell iung carcinoma, chronic paroxysmal hemicrania, and headache associated with vascular disorders Of most particular interest is schizophrenia, using the compounds of formula in combination with an atypical antipsychotic and also depression and/or bipolar using the compounds of formula I as monotherapy or in combination with an antimanic agent (mood stabilizers, including Lithium, Carbamazepine Valproate, Lamotngine, and Abilify), or with a 5-HT reuptake inhibitor (including sertraline) The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (ι) treats or prevents the particular disease, condition or disorder (iι) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (m) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein The term "animal" refers to humans (male or female), companion animals (e g dogs, cats and horses), food-source animals, 200 animals manne animals, birds and other similar animal species 'Edible animals' refers to food-source animals such as cows, pigs, sheep and poultry
The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically. with the other ingredients compπsing a formulation, and/or the mammal being treated therewith
The teims 'treating', "treat", or 'treatment' embrace both pieventative. ι e , piophyiactic. and palliative treatment
The terms "modulating opioid receptor activity" or "optoid-mediated" iefers to the activation or deactivation of the mu, kappa and/or delta opioid receptors The term "compounds of the present invention" refer, unless specifically identified otherwise, to compounds of formula (I) and pharmaceutically acceptable salts of the compounds and hydrates of the compounds thereof and salts thereof, as well as, all stereoisomers {including diastereomers and enantiomers) tautomers and isotopically iabeied compounds.
DETAILED DESCRIPTION One aspect of the present invention is a compound of formula I,
Figure imgf000009_0001
formula I, or a pharmaceutically acceptable sait thereof, wherein
R1 is Ci^afkyf C^alkyl-O-Ci.^aikyl a ?-, 8-, or 9-membered bridged bicydic carbocyclic ring, a fused bicydic carbocyclic πng. (CH^ phenyi, (CH2)a»heteroaryl, or (CH^beterocycloalkyl. wherein the bridged ong, the fused πng, phenyl, heteroaryl, or heterocycloalky! is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, OH. Ci ?alkyt, O-C< 3alkyl, NH2, NHC^alkyl. or N(C, <alkyl),
R? is H or C, ^alkyl, or
R' and R7 are taken together with the nitrogen to which they are attached to form a mono- or bicydic N-nng. where said N-nng is a 4- to 7-membered mono-cyclic heterocyctoalkyl ring; a fused bicyclic heterocyclic πng. or a 7-. 8-. or 9-membered bridged bicychc heterocyclic ring, wherein said N-πng is unsubstituted or substituted with 1 2, or 3 substituents independently selected from halogen. OH. -CN, Ci.3alKyl, C^alkyl-OH O-C^alkyl, Ct^alkyl-O-d.saikyl, NH^. NHC^alkyl. or N(C1.,alkyl)/. a is O1 1. or 2;
R3 is H. or Ci salkyl, or when Xf or X3 is >{C(R5)}-, R-1 may be taken together with Rfl of one of X1 or Xa and the carbon atoms to which they are attached to form a 5- or 6-membered saturated, or partially saturated πng, wherein one carbon atom in said 5- or 6-membered ring may be a heteroatom selected from -O-, -N(H)-, •N(C*alkyl}-, and >N-, and wherein said ring is unsubstituted or substituted where valency permits with 1 substrtuent selected from halogen, -CN. or -Ct ^alkyl,
R* is H. halogen. CN, Cj $alky!, or OC1 jalkyl.
Rs is H. halogen. CN. Ci ^alkyi, or OC, 3alkyl.
R1* is Ci^alkyl. or C^alkyl-O-C^alkyl:
R? is H. or C^alkyi; or Rδ and R7 are taken together with the nitrogen to which they are attached to form a mono- or bicyclic SN-ring. where said SN-ring is a 4- to 7-rnembered mono-cyclic heterocyclic ring containing 0 or 1 additional heteroatom selected from O, NH, or NC« jalkyl, or a 7-, 8-, or 9-membered bridged bicycSic heterocyclic ring, wherein said SN-ring is unsubstituted or substituted wtth 1 or 2 substittients independently selected from halogen, OH, -CN, C, salkyl. C, .alkyl-OH, 0-C. 3alkyi, C, % alkyl-O-C,.5 aikyl. HHz. NHd-salkyi, or NCC^alky!)^
X!, X?, X*, X*. X$, and Xβ are independently >(C(RiS))- or >N-, and each R? is independently H, halogen, -CN, -Chalky), -0CκSalkyl. provided that when X1 or X? is >{C(R'i))- one Rs of X1 or X3 may be taken together with Rs and the carbon atoms to which they are attached to form said 5- or 6-roembered saturated, or partially saturated ring
In the invention, it ss preferable that X1, X2, XJ, and X4 are >(C(R$))- wherein R* is selected from any definition discussed herein, and also include wherein each RE is independently H. haiogen, -CN. -C,. •?a!kyf. Qr -OC1. salkyl
Another aspect of the invention is where Rδ and R? are taken together with the nitrogen to which they are attached to form the monocyclic SN-rtng wherein said SN-nng is unsυbstituted or substituted with C» ,-,alkyl Preferred monocyclic moieties making this SN-nng include pyrrolidinyl or morpholinyl wherein said SN ring is unsubststuted or substituted with methyl.
Another aspect of the invention is wherein R1 is C<.sa)kyi or the ?-membβr«d bridged bicyciic carbocycSic ring, and R" is H Yet, another aspect of the invention is wherein R1 and R° are taken together with the nitrogen to which they are attached to form the 5- to 6-membered mono-heterocycloalkyl ring, or the 8-membered bridged bicyclic heterocyclic ring, wherein said N-ring is unsubstituted or substituted with 1 or 2 substitutents independently selected from OH, methyl, or metboxy
Another aspect of the invention is wherein Xs is <N- and X', X2, X*. X4, and X$ are >(C(RS)K or. alternatively y? is >N- and X', X\ X3. X4, and X$ are >(C(R8))-, wherein R* is independently H. halogen, - CN, -C,.5alkyi, or -OC^alky!
Another aspect of the invention is wherein X; or Xi are both >{C(R*)}- and oniy one R* of X1 and X3 is H and the other R* is halogen, -CN, -C^alkyl, or -OCt^alkyl Another aspect of the invention is wherein at least one of X1 or XJ is >(C(R*))- and R* of formula I forms a πng with R8 of X! or' Xs and the carbon atoms to which they are attached to form a 5- or 6-membered saturated, or partially saturated ring, wherein one carbon atom in said 5- or 6-membered nng may be a heteroatom selected from -O-, -N(H)-, -N(C^ salkyl)- and >N-, and wherein said ring is unsubstituted or substituted where valency permits with 1 substituent selected from halogen, CN, or -Chalky!.
The invention includes the free base or a pharmaceutically acceptable salt of every example of compounds of formula I, by itself or in a group of any combination of the compounds of formula I prepared herein
"Halogen"1 and 'halo" and the like include fluoro, chloro. bromo and todo.
The term "alky!*, as used herein, unless indicated otherwise, includes straight or branched alkyl groups of C8^ number of carbons where e is the least number of carbon atoms and g is the largest number of carbon atoms possible When an alkyl moiety contains at least 3 carbon atoms, said alky! includes cycioalkyl moieties Each alkyl moiety may be substituted with up to three substttuents independently selected from halogen. OH, -CN, O-Ci 3alkyl, NH.>, NHC^alkyl. or N(C,.salkyl)2, wherein the alky! moieties that are substituents are not further substituted unless otherwise indicated. Therefore, non-limiting examples of Ci^aikyi include methyl, trifiuoromethyf. ethyl, n-propyl, i-propyl. cyciopropyl, methyl-cyciαpropyl, t-butyl, and cyclobutyl. The term "heterocycloalkyi" as used herein, unless indicated otherwise, includes a 4- to 7- membered saturated cycloaSky! moiety in which up to two carbon atoms are replaced with a nitrogen, O, or S atom or any combination thereof. When nitrogen replaces an atom, to satisfy velancy requirements, the nitrogen is substituted with H or Chalky! or is a point of attachment when heterocycloalkyi is a substituent or is created by two substituents combining to form a heterocycloalkyi moiety, e g , when R1 and R2 are taken together with the atom to which they are attached to make pyrrolidinyf. Non-ftmiting examples of heterocycloalkyi include oxetanyl. tetrahydrofuranyl, tetrahydropyran, azetidinyl, pyrrolidinyl, pyrazolidinyf. piperidinyl. dtoxanyi, morpholinyf, thiomorpholinyl, and piperazinyl.
The term "aryl" refers to carbocyclic aromatic moieties having a single ring (e.g., phenyl).
The term "heteroaryl" as used herein, unless indicated otherwise, is a 5- to 6-membered ring that is aromatic or partially saturated, where at least one heteroatom is present and no more that three heteroatoms are present, wherein the heteroatom is nitrogen. O, or S or any combination thereof. When nitrogen replaces an atom, to satisfy velancy requirements, the nitrogen is substituted with H or C1 ^ alky! or is the point of attachment when heteroaryi is a substituent or is formed by two substituents combining to form a heteroaryi moiety. Non-iimlting examples of heteroaryi include pyridyl, pyrimidyl, pyridazyl pyrazinyl. furanyl, thiophenyl, pyrrolyl. pyrrolinyl. oxazolyl. isoxazolyl, thiazolyl, isothiazolyl, imtdazolyl, irmdazolinyl, pyrazolyl, pyrazolsnyt. pyranyl, and azapmyl.
A fused bicyclic carbocyclic ring as used herein, unless indicated otherwise, has the two rings that share adjacent carbon atoms. The fused rings form a 5-6 or 6-6 fused bicyclic ring. In the fused ring, unless otherwise specified, either ring may be aromatic, or partially or fully saturated. A non-limiting example of a fused aromatic ring moiety is naphthyl. A non-limiting example of a saturated or partially saturated fused ring moiety ss decahydronaphthyf and tetrahydronaphthyl, respectively. Other non- limiting examples include indanyt.
A fused bicyclic heterocyclic ring as used herein, unless indicated otherwise, is a bicyclic fused ring where up to 3 atoms are independently selected from O, nitrogen, or S or any combination thereof in either ring, including the atom where the rings are fused where valency permits. When nitrogen ts the heteroatom, to satisfy valency requirements, it is substituted wtth H or Ct^alkyi. or is a point of attachment when a fused bicyclic heterocyclic ring is a substituent or is the point of attachment when formed by two substituents combining to form a fused bicyclic heterocyclic moiety.
A bridged bicycϋc carbocyctic ring as used herein, unless indicated otherwise, is formed when two rings do not share adjacent carbon atoms to make the bicyclic ring. The bridged nng contains from 7 to 9 carbon atoms. Non-limtting examples include bιcyclo(2.2.1]heptaoy! and bicyclo{3.i.i)heptanyl.
A bridged bicyclic heterocyclic ring as used herein, unless indicated otherwise, is a bridged bicyclic carbocyclic ring where 1 to 2 carbon atoms are replaced by a nitrogen atom that is substituted where valency requires by H or Chalky! or provides the point of attachment for the ring when the ring is a substituent or is formed, for example, when R' and R3 or Rβ and R* combine to form a bridged bicyclic heterocyclic ring. Non-limiting examples include quinudidinyl. 6-aza-[3.2.13-octanyl, 2- azabicycioβ 2 1)heptaπyl, 3-azabιcycJo{3 3 2jdecanyl, 2-azabtcyc!o(2 22]octanyi, and 3- azabιcyc!o[3 2 1]octanyf
Another aspect of the present invention is a pharmaceutical composition that comprises (i) a compound of the present invention, and (2) a pharmaceutically acceptable excipient. diluent or earner Preferably the composition comprises a therapeutically effective amount of a compound of the present invention The composition may also contain at least one additional pharmaceutical agent {described herein) in yet another embodiment of the present invention a method for treating, or preparing a medicament to treat a disease, condition and/or disorder that is mediated by selectively antagonizing the KOR over the mu and delta opioid receptors tn animals that include the step of administering to an anima! (preferably a human) in need of such treatment a therapeutically effective amount of a compound of the present invention (or a pharmaceutical composition thereof) to treat any disease, condition or disorder mediated by antagonizing the kappa opioid receptor
Diseases conditions, and/or disorders mediated by selectively antagonizing the kappa opioid receptor incfude any one individually or combination of any of the diseases discussed herein
Compounds of the present invention may be administered in combination with other pharmaceutical agents The combination therapy may be administered as (a) a single pharmaceutical composition which composes a compound of the present invention, at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable exαpient, diluent, or carrier, or (b) two separate pharmaceutical compositions compnsmg (ι) a first composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or earner, and (it) a second composition comprising at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient diluent, or earner The pharmaceutical compositions may be administered simultaneously or sequentially and in any order Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts particularly in light of the description contained herein The starting matenais are generally commercially available or are readily prepared using methods well known to those skilled in the art (e g , prepared by methods generally described in Louis F Fieser and Mary Fieser, Reagents foi Organic Synthesis, v 1-19, Wiley, New York (1967-1999 ed ), or Beilstems Haπdbuch der orqanischen Chemie 4, Aufl ed Spπnger-Verlag Berlin, including supplements (also available via the Beiistem onfine database))
For illustrative purposes the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates For a more detailed description of the individual reaction steps, see the Examples section below Those skilled m the art wiii appreciate that other synthetic routes may be used to synthesize the inventive compounds Although specific starting materials and reagents aie depicted in the schemes and discussed below, other starting matenais and reagents can be easily substituted to provide a variety of denvatrves and/or reaction conditions In addition, many of the compounds prepared by *he methods descπbed below can be further modified in light of this disclosure using conventional chemistry well known to those skied m the art In the preparation of compounds of the present invention, protection of remote functionality (e g , pnmary or secondary amine) of intermediates may be necessary The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods Suitable amino-protecting groups (NH-Pg) include acetyl, trtfJuoroacetyl. f-butoxycarbonyl (BOC), benzyloxycarbonyl (CSz) and 9-fluorenyimethyleneoxycarbonyi (Fmoc) The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene. Protective Groups in Organic Synthesis. John Wiley & Sons. New York, 1991
The following schemes outhne the general procedures one could use to provide compounds of the present invention.
The compounds of this invention can be prepared starting from the aryl sulphonyl chloride with a group ortho that can be utilized to couple in a palladium-catalyzed reaction such as a Suzuki coupling (see for example Miyaura, N ; et a! Chem Rev. 1995, 95, 2457) Standard ortho groups for R10 are a chloride, bromide, iodide or boronic acid These compounds are commercially available or can be prepared by one who is skilled in the art
Scheme 1
Figure imgf000013_0001
Treatment of the sulphonyl chloride with an organic tertiary amine base in organic solvent such as tetrahydrofuran followed by the addition of the secondary or primary amine readily affords the sulfonamide.
When X" ss >N- and R1t is H, the halogenated intermediate 2(8) can be prepared as outlined in Scheme 2: Scheme 2
Figure imgf000013_0002
The sulfonamide can be treated with LDA in tetrahydrofuran or potentially an alternative organic aprotic solvent and the anion quenched with bromine to provide the Suzuki coupling partner 2(ii). If either Rδ or R7 are a proton, an additional equivalent of base (LOA) will be required to carry out this sequence. Suzuki couplings are well precendented in the literature (see for example ivfeyaura, N ; et ai
Chem Rev 1995, 95, 2457) and are very effective in coupling aryl halides with aryi boronic acids This can be accomplished with a variety of palladium catalysts and itgands which can improve the coupling or aryl chlorides (Buchwald et a!.. Angwandte Chemie, International addition. 1999, 38(16) 2413-2416). One of these ligands and palladium catalysts is DPPF (IM'- Bιs(d)phenylphosphιno)ferrocene)dιchtoropalladtum (H). Scheme 3
Figure imgf000014_0001
Compounds like 3(t) (Scheme 3) can be coupled to compounds like 3(«) utilizing DPPF as the catalyst'ϊigand source TNs can be conducted in a variety of organic solvents with one such being dimethyiacetamide or ethylene gioco!. These reactions can be conducted at ambient temperature or may require heating, either condition readily being determined by one of ordinary skill in the art
Compounds like 3(«i) can be converted to compounds of Formula I through a standard reductive amination (Scheme 4). Treatment of aldehyde 3(1») with a secondary or primary amine in an organic solvent such as tetrahyrdofuran in the presence of catalytic aαd (e g , acetic acid) followed by addition of a reducing reagent affords the desired compounds of formula I. The variety of reducing agents can be utilized, one such reagent is sodium tnacetoxy borohydrtde
Scheme 4
Figure imgf000014_0002
When one of X1 -X* is H, the pyndyi borontc acid aidehyde is commercially available and coupled as described in Scheme 4
The compounds of the present invention may be isolated and used per $β or in the form of any pharmaceutically acceptable salt The term 'salts* refers to inorganic and organic salts of a compound of the present invention. These salts can be prepared in situ dunng the final isolation and purification of a compound, or by separately reacting the compound with a suitable organic or inorganic acid or base and isolating the sait thus formed Representative salts include the hydrobromide, hydrochloride, hydrαodide, sulfate, bisulfate, nitrate, acetate, tnfluoroacetate. oxalate, besylate, palmitate, pamoate, malonate, stearate, laurate, malate, borate, benzoate. lactate phosphate, hexafluorophosphate, benzene suifonate, tosylate, fomnate. citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate lactobionate, and iaurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to. ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethyfamtne. tπmethytamine, triethylamine, ethylamine. and the like. See, e.g., Berge, et at, J. Pharm. Set., 66, 1-19 (1977). The compounds of the present invention may contain asymmetric or chiral centers, and. therefore, exist in different stereoisomer^ forms. It is intended that all stereoisomers forms of the compounds of the present invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of the present invention incorporates a double bond or a fused ring, both the OS- and trans- forms, as well as mixtures, are embraced within the scope of the invention.
Diastereomeπc mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art. such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomenc mixture by reaction with an appropriate optically active compound (e.g.. chirai auxiliary such as a chirai alcohol or Moshers acid chloride), separating the diastereomers and converting (e.g , bydroiyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chirat HPLC column. It is also possible that the intennediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term ' iautomer" or 'tautomeric form" refers to structural isomers of different energies which are interconvertible v/a a low energy barrier. For example, proton tautomers (also known as prototropic tautomers} include interconversions via migration of a proton, such as keto-enol and imtne-enamme tsomerizattons. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens Valence tautomers include interconversions by reorganization of some of the bonding electrons.
The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlonne. such as 2H, 5H. 11C, "C, WC, 13N, KΗ, "50, 17O. 1SO, 31P1 32P, «S. '8F. 1ϊ3l.125I and ?6CI, respectively.
Certain isotopieally-labeled compounds of the present invention (e.g.. those labeled with 3H and UC) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e . aH) and carbon~i4 (i.e.. 14C) isotopes ate particularly preferred for their ease of preparation and detectabiiity. Further, substitution with heavier isotopes such as deuterium (i.e., 'H) may afford certain therapeutic advantages resulting from greater metabolic stability (e g , increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as ibQ, 13N, 11C, and "'*F are useful for positron emission tomography (PET) studies to examine substrate occupancy lsotopicaily labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein belovv, by substituting an isotopicaliy labeled reagent for a non-isotopicaity labeled reagent
Compounds of the present Invention are useful for treating diseases conditions and/or disorders modulated by the mu, kappa and/or delta opioid receptors, therefore, another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable exαpient, difuent or earner The compounds of the present invention (including the compositions and processes used therein) may also be used m the manufacture of a medicament for the therapeutic applications described herein
A typical formulation is prepared by mixing a compound of the present invention and a carrier diluent or exciptent Suitable carriers diluents and exciptents are well known io those skilled in the art and include mateπals such as carbohydrates waxes water soluble and/or swellabte polymers, hydrophific or hydrophobic materials gelatin, oils solvents, water, and the like The particular carrier, diluent or exαplent used wili depend upon the means and purpose fot which the compound of the present invention is being applied Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GKAS) to be administered to a mammal In general, sate solvents are norvtoxtc aqueous solvents such as water and other non-toxic solvents that are soluble or misαble in water Suitable aqueous solvents include water, ethanol propylene glycol, polyethylene glycols (e g , PEG400, PEG3Q0), etc and mixtures thereof The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents lubncating agents, emuisifiers, suspending agents, preservatives antioxidants, opaquing agents glidants processing aids, colorants, sweeteners, perfuming agents flavoring agents and other known additives to provide an elegant presentation of the drug (ι e , a compound of the present invention or pharmaceutical composition thereof) or aid in the manufactunng of the pharmaceutical product (ι e medicament)
The formulations may be prepared using conventional dissolution and mixing procedures For example, the bulk drug substance (ι e compound of the present invention or stabilized form of the compound (e g complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropnate form Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package In addition, the container has deposited thereon a label mat describes the contents of the container The label may also include appropriate warnings
The present invention further provides a method of treating diseases, conditions and'or disorders modulated by the opioid receptor(s) in an animal that includes administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable excφtent diluent or earner The method is particularly useful for treating diseases conditions and/or disorders that benefit from antagonizing the mu, kappa and/or delta opioid receptors
For a normal adult human having a body weight of about 100 kg a dosage m the range of from about 0001 mg to about 10 mg per kilogram body weight is typically sufficient preferably from about 0005 mg/kg to about 50 mg/kg, more preferably from about 0 01 mg/kg to about 3 mg/kg However, some variability in the general dosage range may be required depending upon the age and weight of the subject being treated, trie intended route of administration trie particular compound being administered and the iike The determination of dosage ranges and optimal dosages for a particular patient is weil within the ability of one of ordinary skill in the art having the benefit of the instant disclosure It is aϊso noted that the compounds of the present invention can be used in sustained release, controlled release, and delayed release formulations which forms are also well known to one of ordinary skill in the art
The compounds of this invention may also be used in conjunction wfth other pharmaceutical agents for the treatment of lhe diseases, conditions and/or disorders described herein Therefore methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include anti obesity agents
Another aspect of the present invention is the treatment of central nervous system diseases disorders, and/or conditions as discussed herein Embodiments of the present invention are illustrated by the following Examples It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof wilt be known or apparent m light of the instant disclosure, to one of ordinary skill in the art
EXAMPLES Unless specified otherwise, starting materials are generally available from commercial sources such as AJdrich Chemicals Co (Milwaukee, Wl), Lancaster Synthesis, lnc (Windham, NH), Acros Organics (Fairlawn, NJ) Maybndge Chemical Company, Ltd (Cornwall, England), Tyger Scientific (Pnnceton, NJ) and AstraZeneca Pharmaceuticals (London, England)
PHARMACOLOGtCAL TESTING The practice of the instant invention for treating the diseases or conditions discussed herein can be evidenced by activity in at feast one ot the protocols described hereinbelow
In Vitro Biological Assays Binding Assay
Binding assays on membranes from CHO celts expressing either human kappa, mu or delta opioid receptors were performed according to standard procedures Briefly, fro?en cell paste (70-80-mgs per 96 welt plate) is homogenized in 50 mM Tris HCI buffer (pH 74 @ 4 degrees C) containing 2 0 mM
MgCl2 using a Polytron and spun in a centnfuge at 4000Og for ten minutes The final pellet is resuspended in assay buffer (50 mM Tris HCI buffer (pH 74) containing 1 mM EOTA. 5 mM MgCU.)
Incubations were initiated by the addition of tissue to 96-well plates containing test drugs and 04-1 nM (3H]diprenorphιne in a final volume of 250 ul) Non-specific binding was determined by radioligand binding in the presence of a saturating concentration of naltrexone (10 uM) After one hour incubation penod at room temperature, assay sampfes were rapidly filtered through Whatman GF/B filters and nnsed with ice-cold 50 mM Iris buffer (pH 74) Membrane bound [3H]dtprenorphine levels were determined by liquid scintillation counting of the filters in BetaScint The ICw value (concentration at which 50% inhibition of specific binding occurs) was calculated by linear regression of the concentration-response data. Ki values were calculated according to the Cheng Prusoff equation, Ki = !Cac'{1 + (UKa)), where L is the concentration of the radioligand used in the experiment and the Kd value ts the dissociation constant for the radioligand {determined previously by saturation analysis)
Compounds not exemplified but ptepared making non-critical changes to conditions provided herein were tested in the kappa assay discussed above and had a Ki value within the range of 02 nM and 10,00O nM
The compounds of the present invention tested in the kappa assay discussed above had the following specific Ki value(s)/ranges with ranges being provided when there is more than one date point"
Figure imgf000018_0001
General Experimental Procedures
NMR spectra were recorded on a Vartan Unity™ 400 (available from Vanan Inc., Palo Alto, CA) at room temperature at 400 MHz for proton. Chemical shifts are expressed in parts per million (δ) relative to residua! solvent as an internal reference The peak shapes are denoted as follows' s, singlet; d, doublet, t, tnpfet q, quartet; m, multiple!, bs broad singlet, 2s. two singlets Atmosphenc pressure chemical ionization mass spectra (APCI) were obtained on a Fisons™ Platform If Spectrometer (carrier gas acetonitnSe available from Micromass Ltd. Manchester, UK) Chemical ionization mass spectra (Cl) were obtained on a Hewlett-Packard™ 5989 instrument (ammonia ionization. PBMS available from Hewlett-Packard Company Palo Alto, CA). Electrospray ionization mass spectra (ES) were obtained on a Waters™ ZMD instrument (carrier gas acetonitnle: available from Waters Corp., Milford, MA). Where the intensity of chlorine or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3 1 for 3:Cl/17Cl-contaιning ions and 1.1 tor ^Br/^Br-containtng tons) and the intensity of only the lower mass ion is given. In some cases only representative 5H NMR peaks are given. MS peaks are reported for aii examples Optical rotations were determined on a Perkm£lmerrM 241 poianmeter (available from PerkinElmer lnc , Wellesley. MA) using the sodium D tine (λ - 589 nm) at the indicated temperature and are reported as follows (αjo'T concentration (c - g/100 mi), and solvent.
Column chromatography was performed with either Baker™ silica gel (40 urn; J T Baker, Phiflipsbufg, NJ) or Silica Gel 50 (EM Sciences1*1, Gibbstown, NJ) in glass columns or in Flash 40 Biotage™ columns (ISC Inc., Shelton, CT) under low nitrogen pressure. Preparation of intermediates KH):
To a solution of amine of formula HNR1R7 (198 mmol) in anhydrous dichloromethane (CH2CI;) (80 mL) was added triethylamine (2.0 g, 19.8 mmol). This was followed by dropwise addition of bromobenzene sulfonyl chloride (4.21 g. 16 5 romol) and was stirred overnight at room temperature The reaction was washed with IN HCI (2 x 30 mL), the aqueous layer was extracted with CH-Ct and dπed over MgSO^, that was removed by filtration and the filtrate was concentrated and the intermediate was taken on to next step without further purification, intermediates made by this process
Figure imgf000020_0001
(ft)-1-(2-Bromo-benzenesulfonyi}-2Hrriethyl-pyrrofιdιrιe (i(ιι)<a)) 84% yield, MS (APCI) (M+1) m/z
305.
{SH-(2-Broπv3-benzenesυtfonyl)-3-methyf-moφholιne <1(n)(b)) 64% yield . MS (APCI) (M+1) m/z 321
2-(Pyrrolιdιne-1-sulfonyi)-pyridιne (i{ιt)<c»- 36% yield, MS (APCI) (M+1) m/z 213. 2-chloro-3-(pyrrolidine-1yi-sulfony!)pyπdιne (1<H>(d». 96% yield. MS (APCI) (M> 1) m/z 246 Preparation of intermediates 2uή
3-8romo-2-{pyrro8dιne-1-su!fofiyl)-pyridιne (2(«), where -NR6R' is pyrrolidinyl). 21% yield, MS (APCi) (M+1) m/z 292
To a solution of lithium diisopropylamide mono THF in cyclohexane (? 54 mL, 11 3 mmol) in tetrahydfofuran (5mL) at -60C was added a solution of the 1c (12 g, 5.7 mmol) in tetrahydrofuran (10 mL) at -60C and was allowed to stir for 1-1.5 hrs Bromine (1.8 g. 11.3 mmol) was added dropwise and stirred at -60C for 1 hr The reaction was quenched with water at -60C and warmed to room temperature The solution was extracted with ethyl acetate, dneά and concentrated to give crude oil Chromatographed on silica using a 0-50% ethyl acetate/heptane gradient Preparation of intermediates 30») Method III:
To 16.4 ml of a 2M aq sodium carbonate solution was added a solution of 25 mL of dimethyiacetamide/dimethy! ethylene glycol, bromo or chloro sulfonamide (2 g. 6.6mmol) and boronic acid (1 48g. θ ββmmol) FinaHy, (1.1'-Bιs(dιphenylphospNno)ferrocene}dichloropalladιum (II) (537 mg,
00657 mmoi) was added and then heated overnight at 1OO°C. Reaction was filtered through a fritted funnel and «nsed with water and copious amounts of ethyl acetate The filtrate was concentrated to 1/4 the volume and poured into seperarory funnel The aqueous phase was extracted wrth ethyl acetate (3 x 25 mi.) and me organic phase was dried over sodium sulfate filtered and concentrated The crude product was chromatographed on siltca ge! using 10-40% ethyl acetate/heptane gradient
Method )V
To 1 95 ml of a 2M aq sodium carbonate solution was added a solution of 2 ml of dιmethy!acetamιde/d»methyl ethylene glycol, bromo sulfonamide (500 mg, 1 56 mmol) and boronic acid (351 mg. 2 34 mmo!) Finally, [1,i -Bιs{dφhenylphosphino)ferrocene]dιchloropaffadium (If) (12 δ mg, 00156 mmol) was added and then the reaction was microwaved at 100-140C for 20-40 minutes Reaction was filtered through a fritted funnel and rinsed with water and copious amounts of ethyl acetate The filtrate was concentrated to 1/4 the volume and poured into seperarory funnel The aqueous phase was extracted wrth ethyl acetate (3 x 25 mL) and the organic phase was ύned over sodium sulfate, filtered and concentrated The crude pjoduct was chromatographed on stlica gel using 10-40% ethyl acetate/heptane gradient
Figure imgf000021_0001
Figure imgf000022_0001
2M(R)-2-Methylψytτoitdine~1-sulfonyf)-bipr»eny!-4^rbaldehyde (3(HfKa)) <99% yiekl, MS (APCI) (M+1 ) m/z 329
2'-({R)-3-(Vtetriyi-moφrioiιne-4-suffony{)-t)tphenyl-4-carbaωehycie {3<ιιt)(b) ) 92 7% yield, MS (APCi) (M+1) m/z 346
4-[2κPyrroi(dme~1-suifonyl)-pyridin-3-y!]~benzaldehyde (3(Ht)(C)) 854 % yield, MS (APCI) (M+ 1 ) m/z 317
3-Fluoro-2'-((R)-3-methyl-morpholine-4-sulfonyl)-biphenyl-4-carbaldehyde (3(»ι)(d)) <99% yield, MS (APCI) (M+1 ) m/Z 364 3-Metrtoxy-2'-(pyfrolιdιrte-1-suifonyl)-btphenyl-4-carbaldehydβ (3(κι)(e)) 74 0% yield. MS (APCI)
(M+1) m/z 346
2'-(Pytτolιdfne-1-sulfonyl)-bfphenyl-4-carbaidehyde (3(m)(f)> 97 5% yield, MS (APCI) (M+1) m/2
316
4-[3-(pyyrrolιdtn-1-y!su!fonyl)-pyπdin-2-yl3benzaldehyde 3(ifi)(g) 28% yield, MS (APCI) (M+1) m/z 317
Preparation of compounds of formula I. Method V
Aldehyde (3(w)) (50 mg. 0 159 mmol) was dissolved in 2 ml of anhydrous tetrohydrofuran or dichloromethane followed by {he addition of amine (29 5 mg 0 200 mmol) Catalytic acettc acid (5υL) and 4A molecular sieves were added to the solution and allowed to shake for 15-30 minutes After winch time was added MP-tnacetoxyborohydπde (180 mg, 0 396 mmol) The reaction was shaken overnight at room temperature MP-carbonate (300 mg, 0 765 mmol) was added to scavenge excess acefec acid along with 5eq of the respective scavenging agent (PS-tsocyanate resin fot secondary amines ot PS- benzafdehyde for primary amines) and let shake overnight Reaction was loaded onto a pre-equilibrated (with methanol) Waters Oasts 500 mg MCX cartndge and washed with methanol (10 x 2mL) Compounds of formula I were released from the column using IN ammonia in methanol solution (5 x 2mL) Product was isolated and chromatographed on silica gel using 1-10% methanol/dichloromelriane giadient Method Vl
Aldehyde (3{i»» (20 mg. 0.063 mrnol) was dissolved in 2 mL of dichloromethane followed by addition of amine (96 mg, 0 0950mmol). and the reaction was stirred for about 30 minutes, after which time was added sodium tnacetoxyborohydnde (26.7 mg, 0 126 mmol) and stirred overnight at room temperature The reaction was quenched with ethyt acetate (3mL) and water (3mL) and allowed to stir for (en minutes after which time the aqueous layer was made basic by adding 10% ammonium hydroxide solution The solution was extracted with ethyl acetate (3 x 5 mL) The organic layer was dried over sodium sulfate, filtered and concentrated. Compounds of formula I were chromatographed on silica get using 5-20% methanol/dfchioromethane gradtent Examples:
4(a): (IR^Si-Bicyclo^^.ijhept^-yl-P'^pyrroiidtne-i-sulfonyD-bii^enyi-Φ-ylmethylJ-amme
Prepared by Method V starting with 3(niχf) and bicyclo(22 1βiep!an-2-amine, giving 4(a) in 63 4% yield 1H NMR (400 MHz. CHLOROFORM-cQ ppm 1.08 - 1.18 (m. 1 H), 1.22 {br. S . 2 H), 1.25 - 1 32 (m, 1 H),
1 38 • 1 49 (m, 2 H), 1 48 • 1 54 (m, 4 H), 1 59 - 1 70 (m. 1 H). 1 74 - 1 86 (m. 1 H). 202 - 2.09 (m. 1 H) 2.19 - 2.26 <m. 1 H). 2.62 - 2J4 (m. 4 H), 2.91 - 301 (m, 1 H). 363 (t, 2 H), 7.13 - 7.21 (m. 2 H)1 7 32 -
7 39 (m, 2 H) 740 - 749 (m, 2 H). 799 - 806 <m, 2 H) MS (APCI) (M+1) m/2411
4(b): (IS.δRj-€-^' ξPyrroiidine-i sulfonylJ btphenyl ^ ylmethyll-e aza bicyclop 2 1]octane
Prepared by Method Vl starting with 3{iii)(f) and 6-azabicycio{3,2.13octane, giving 4(b) in 37.8% yield. 1H
NMR (400 MHZ, METHANOL-Cf4) ppm 1 13 - 1 22 (m, 1 H). 1 64 - 1 98 (m, 8 H), 227 - 239 (m, 2 H) 263 - 2 77 (m, 2 H), 2.82 - 2 94 (m, 4 H), 3.36 - 3.44 (m. 2 H). 3.45 - 3.54 (m 1 H). 3 56 - 3.64 (m, 2 H),
395 - 4.03 (m 2 H), 442 (s, 2 H) 7.31 - 739 (m. 2 H), 7.52 (d, 2 H)x 7 56 - 7.72 (m. 2 H), 8 02 - 8.10 (m,
2 H) MS (APCI) (M+1 ) m/2 411
4(c): 4-Methyl-1-[2'-(pyrrolfdine-1-sulfonyi)-bιphenyl-4-ylmethylj-pιperidιn-4-o} Prepared by
Method V starting with 3(m)(f) and 4-methylpιpeπdιn-4-ol, giving 4(c) tn 75 3% yield 1H NMR (400 MHz CHLOROFORM-d) ppm 1 15 (s, 3 H), 1 42 - 1.55 (m. 6 H), 1 57 {dd. J=10 17. 3.94 Hz, 2 H), 224 -
2 36 (m, 2 H), 241 - 253 (m. 2 H), 260 - 2 72 (m, 4 H), 347 (s, 2 H), 7 17 - 7.23 (m, 2 H). 7 34 - 740 (m,
2 H). 7.43 - 7 50 (m. 2 H). 8.01 - 8 09 (m. 2 H). MS (APCi) (M+1) m/z 415
4(d): lsobutyl-(2'-(pyrrotιdfne-1-sulfonyl)-fc«phenyl-4-ylmethyf]-amine Prepared by Method Vi starting with 3(ιιι)(f) and 2-methylpropan-i -amine, giving 4(d) in 82.1% yield 1H NMR (400 MHz, CHLOROFORM-d) ppm 1 03 - 1.15 (m. 6 H), 1 59 - 1.76 (m, 4 H) 2.21 - 2.35 (m, 1 H), 2.64 (br. s., 2
H), 279 - 289 <m. 4 H), 424 (br s , 2 H), 7 22 - 7 27 (m 1 H), 7 43 - 760 (m, 4 H), 767 - 7 7? (m. 2 H).
808 - 8 14 (m, 1 H) MS (APCI) (M+1) m'z 373
4(e): 3,3- Dimethyl Λ \Z- (pyrrolidine- 1 sulfonyl) biphenyl-4 ylmethylj piperidine. Prepared by
Method V starting with 3(nt){f) and 3,3-dimethyipιperidine giving 4(e) in 840% yield. 1H NMR (400 MHz, CHLOROFORMS) ppm 084 (s, 6 H), 1.08 - 1 20 (m, 2 H), 1 41 - 1 5S (m. 6 H). 1 93 (br. s . 2 H), 2.25
(br. s.. 2 H). 2.59 - 2.72 <m, 4 H), 3.38 (s. 2 H), 7.21 (d, J=747 Hz 2 H), 7.37 (d, J=1.66 Hz, 2 H), 7 45
(dd. J=747. 1 66 Hz. 2 H), 8.07 (d, J=788 Hz 2 H) MS (APCI) (M+1) m/z 413.
4<f): (3-Mefhyl-oxetan-3-y!methyl)-[2'-(pyriOiidιne-1-suifonyl)-biphenyi-4-ytmethytj-amine
Prepared by Method Vl starting with 3(ιiι)(f) and 1~(3-metbyloxetan-3-yl)methanamme, giving 4(f) in 38 0% yield *H NMR (400 MHz1 CHLOROFORM-d) ppm 1 33 (s. 3 H), 1 59 - 1 68 (m, 4 H), 278 - 286 (m. 4 H)1 3.84 (S, 2 H), 3.89 (S, 2 H), 4.38 (d, 2 H): 4.48 <d, 2 H), 7.28 - 7.43 (m, 4 H), 7.45 - 7.52 (m. 1 H), 7.54 - 7.61 (m, 1 H), 8.11 - 8.17 (m, 1 H). MS (APCf) (M-M) m/2401.
4(9)- ({S)-2-Methoxy-i-methy!-etbyl)-I2<-(ρyrrolictlr>e-1-suffonyi)-biphenyi-4-y}meth^}-amine
Prepared by Method Vl starting with 3(iii){f) and (2S)-1methoxypropan-2-amine. giving 4(g) in 47.0% yield. 1H NMR (400 MHz, CHLOROFORM-cf) ..; ppm 1.46 (s. 3 H), 1.66 (s. 4 H), 2.82 (s, 4 H). 3.27 (br. s ., 1 H). 3.42 (st 3 H), 3.60 (br. s., 1 H), 3.85 {br. s ., 1 H). 4.11 - 4.49 (m: 2 H), 7.15 - 7.24 (m, 1 H), 7.38 -
7.60 (m, 4 H)1 7.75 (br. s., 2 H), 8.10 (d. 1 H). MS (APCI) (M+1) m/z 389.
4(tι): [2'-(Pyrrolκ3fne-i-su!fonyl)-bipher»yl-4-ylmethyl]-(tetrahydro-pyfan-4-yi)-amine. Prepared by
Method Vl starting with 3{iii)(f) and tetrahydro-2H-pyran-4-amine, giving 4(h) in 87 0% yield. 1H NMR (400 MH2, METHANOL-^) : ppm 1.63 - 1.84 (m, 4 H), 2.06 - 2.19 (m, 2 H)1 2.87 - 2.99 (m, 3 H), 3.24 -
3.36 (m, 4 H), 3.39 - 3.54 (m. 2 H), 4.00 - 4 12 (m, 2 H), 4.31 (s, 2 H), 7.30 - 7.36 (m. 1 H). 7.46 - 7.63 (m,
5 H), 7.63 - 7.71 (m, 1 H)1 8.03 (d. 1 H). MS (APCl) (M+1) m/z 400.
4(1): {2-(Pyrrolidirte-1-sulfonyi)-biphenyl-4-ylm6thylJ-(tetrahydro-furatv3-yl)-amirte. Prepared by
Method Vl starting with 3(tii)(f) and tetrahydrofuraπ-3-amine, giving 4(j) in 27.1% yield. 1H NMR (400 MHz, CHLOROFORM-d) : ppm 1.42 - 1.58 (m, 4 H), 1.63 - 1.79 (m. 1 H), 1.94 - 2.09 (m, 1 H). 2.59 -
2.79 (m, 4 H). 3.25 - 3.44 (m, 1 H), 3.50 - 3.62 (m, 1 H), 3.62 - 3.78 (m, 4 H), 3.79 - 3.92 (m, 1 H)1 7.11 -
7.21 (m, 2 H)s 7.32 • 7.39 (m, 2 H), 7.41 • 7.48 (m, 2 H), 7 97 •• 8.04 (m, 2 H). MS (APCI) (M+1) m/2 387.
4{|): lsobυlyl-[2'-((f?)-2-methyi-pyrroiidine-1-sulfor»yl)-biphenyl-4-ylmethyf]-amine. Prepared by
Method Vl starting with 3(itt)(a) and 2-methylρroρan-i-amine, giving 4(j) in 77.9% yield. ''H NMR (400 MHz, METHANOLS) ; Ppm 0.96 (d. 3 H). 1.05 (d, 6 H). 1.40 - 1.52 (m, 2 H), 1.60 - 1.71 (m. 1 H), 1.73 -
1.92 (m, 2 H), 2.00 - 2.12 (m. 1 H), 2.85 - 3.04 (m, 3 H), 3.53 - 3.61 (m, 1 H), 4.28 (br. s... 2 H), 7.33 (dd, 2
H), 7.45 - 7.76 (m: 4 H), 8.05 (d, 2 H). MS (APCI) (M+1) rn/z 387
4(k): (S.S-Dirnethyi-butylvp'^^-S-methyl-morpholine^-suffonyl^biphenyW-ylrnethylJ-arriine. Prepared by Method V starting with 3(»i)(b) and 3,3-dimethylbutan-i-amine, giving 4(k) in 36 1% yield. 1H NMR (400 MHz. CHLOROFORM-d) ;:: ppm 0.82 - 0.96 (m. 9 H), 1.06 - 1.19 (m. 3 H). 1.58 - 1.71 (m. 2 H), 2.67 - 2.79 (m, 1 H), 2.85 - 3.03 (m, 3 H), 3.03 - 3.16 (m. 2 H). 3.30 - 3.40 (mt 2 H), 3.50 - 3.61 (m. 1 H), 4.10 (s: 2 H), 7.19 - 7.26 (m, 1 H), 7.41 - 7.52 (m, 4 H), 7.53 - 7.61 (m, 1 H). 8.10 - 8.15 (m, 1 H), 8.39 (s. 1 H). MS (APCf) (M+1) m/z 431.
4(1): lsobυtyl42'-((S)-3-metriyl-morpholine-4-suffonyi)-biphenyl-4-ylrnethySJ-afriine. Prepared by Method Vi starting with 3(iii)(b) and 2-methylpropan-i-amine, giving 4(1) in 42.2% yield. 1H NMR (400
MHZ. METHANOL-**,) : ppm 1.03 (d. 6 H), 1.16 (d, 3 H), 1.97 - 2.15 (m. 1 H), 2.72 - 2.83 (m, 1 H), 2.87 -
2.97 (m, 2 H). 2.98 - 3.10 (m, 1 H), 3 10 - 3.23 (m, 2 H), 3 23 - 3.45 (m, 2 H).. 3.53 - 3.65 (m, 1 H). 4.29 (s,
2 H). 7.36 (d, 1 H). 7.51 • 7.64 (m, 5 H), 7.66 •• 7.76 (m. 1 H), 8.14 (d, 1 H). MS (APCI) (M+1) m/2403.
4(m): (1 S,5/?)-6-(3-Fluoro-2'-(pyrroltdine-1-sυlfonyl)-biphenyM-ylmethyl]-6-aza- bicyclo[3.2.1 Joctane. Prepared by Method Vl starting with 3(iii)(f) and 6-azabicyclo(3.2.1]octane, in 58.1 % yield. 1H NMR (400 MHz, METHANOL-^) ; ppm 1.10 - 1.25 (m, 1 H), 1.60 - 2.01 (m, 8 H). 2.06 - 2.40 (tn, 1 H): 2.62 - 2.84 (m, 2 H), 2.87 - 3.05 (m. 4 H). 3.38 - 3.62 (m, 1 H), 3.63 - 3.76 (m, 1 H). 3.97 (br. s.. 1 H), 4.43 - 4.68 (m. 3 H), 7.30 - 7.42 <m; 3 H), 7.58 - 7.82 (m, 3 H), 8.00 - 8.08 (m, 1 H). MS (APCi) (M+1 ) m/z 429. 4(n): 2-{1-[2'-(2-Hydroxymethyf-piperidine-1 -sulfonyf)-biphenyl-4-ylmethyS}-pipertdin-4-yl}-ethanol.
Prepared by Method Vi, starting with 2'-{[2-(hydroxymethyl)piperidtn-1-yij$utfonyf}-biphenyi-4~ carbaldehyde and 2-piperidin-4~yiethanoi, giving 4(n) in 67.0% yield 1H NMR (400 MHz, METHANOL d,) ppm 1.09 - 1.27 (m. 2 H), 1.35 - 1.58 (m. 6 H), 1.64 - 1.88 (m. 2 H), 1.94 - 2.08 (m, 2 H), 2.64 - 2.79 (m,
1 H), 2.97 - 3.12 (m, 3 H); 3.38 - 3.58 (m, 5 H), 3.56 - 3.69 (m. 3 H), 4.37 (br S., 2 H), 7.34 (d. 1 H), 7.54 - 7.63 (m. 5 H). 7.64 - 7.71 (m, 1 H). 8.14 (d. 1 H). MS (APCI) (M+1) m/z 473. 4(o}: BicydolS.S.Ilhept^-yi-lS^uoro-SM^ffJ-a-methyl-moφholtne^-sulfonyO-biphenyM- ylmethyl}-amine. Prepared by Method V starting with 3{iii}(d) and 3,3-dimetnyibutan-i -amine, giving 4{o) in 26.0% yield. 1H NMR (400 MHz. CHLOROFORM-^ ppm 0.91 (s, 9 H), 1.17 (d. 3 H)1 1.60 - 1.71 (m,
2 H). 2.77 - 2.87 <m. 1 H), 2.89 - 2.99 (m, 1 H), 3.01 - 3.11 <m, 1 H), 3.13 - 3.26 (m, 2 H)1 3.38 - 3.49 (m, 2 H). 3.59 - 3.69 (m. 1 H). 4 19 (s, 2 H), 7 21 - 7 33 (rα 2 H)1 7.52 (dd. 1 H), 7.60 (dd: 2 H), 8.12 <dd, 1 H), 8.39 (S, 2 H). MS (APCl) (M+1) m/z 449.
4(p): B(cydo(2.2.1]hept-2-yK3-ftuotO-2*-({f?)-3-niethy{-morpholfne-4-sulfbnyl)-biphenyl-4- ylmethylj-amine. Prepared by Method V starting with 3(iii)(d) and bicyclo[2.2.1]heptan-2-amine. giving 4(p) in 35.1% yield. 5H NMR (400 MHz, CHLOROFORM-tf) ppm 0.66 - 0.80 <m: 1 H). 1.16 (d, 3 H), 1.19 • 1 28 (m, 1 H), 1.28 - 1 51 (m, 2 H), 1.52 - 1 66 (m. 1 H). 1 72 - 1.83 (m. 1 H). 1.88 - 2.01 (m, 2 H), 2.00 - 2.14 (m, 1 H), 2.17 - 2.31 (m, 2 H), 2.40 - 2.48 (m, 1 H), 2.57 (br. s., 1 H), 2.63 (S, 1 H). 2.81 «3. 1 H), 2.99 - 3.11 (m. 1 H), 3.15 - 3.26 (m, 2 H), 3.33 • 3.49 (m, 3 H), 3.60 - 3 69 (m, 1 H), 4.06 - 4 22 <rn. 3 H), 7.19 • 7.32 (m, 1 H). 7.48 •• 7.55 (m, 1 H), 7.56 • 7.65 (m. 2 H), 8.08 • 8.15 (m, 1 H). 8.34 (s, 2 H). MS (APCi) (M+ 1) m/z 459.
4(q): [3-FJuoro-2'-((S)-3-metnyl-moφho!ine-4-su(fonyf)-btphenyt-4-yimethyfHsobutyi-amJne Prepared by Method Vl starting with 3(«iχd) and 2-methylpropan-1 -amine., starting with 3(ιii)(d) giving 4(q) in 45.6% yield. 1H NMR (400 MHz, METHANOL-d.) ppm 1.06 (d, 6 H), 1.18 (d, 3 H), 2.02 - 2.17 (m. 1 H), 2.81 - 2.90 (rn. 1 H), 2.93 - 3.01 (m. 2 H). 3.05 - 3.16 (m. 1 H), 3.17 - 3.28 (m, 2 H), 3.39 - 3.50 (m, 2 H), 3.60 - 3.70 (m, 1 H), 4.37 (s, 2 H), 7.35 - 743 (m. 3 H), 7.59 - 7.67 <m, 2 H). 7.69 - 7.76 (m, 1 H). 8.11 - 8.16 (m, 1 H). MS (APCi) (M+1) m/z 421. 4(r): [3-Fiuoro-2'-<(R)-2-rnethyl-pyrroiidme- 1 -sulfonyl)-biphenyl-4-yimethyl)-isobutyl-amine.
Prepared by Method Vl starting with 3(HtKa) and 2-methyfpropan-1 -amine, giving 4(r) in 95.0% yield. 1H NMR (400 MHz, METHANOL-*) ppm 1.01 (d, 4 H), 1.08 ((J. 7 H), 1.46 - 1.58 (m, 1 H), 1.64 - 1.77 (m, 1 H), 1.78 - 2.00 (m, 3 H), 2.00 - 2.15 (m, 1 H), 2.87 - 3.14 (m. 5 H), 3.57 - 3.77 (m, 1 H), 4.35 (S, 2 H). 7.30 - 7.39 (m, 3 H), 7.57 - 7.66 (m, 2 H). 7.66 - 7.74 (m, 1 H). 8.02 - 8.07 (m, 1 H). MS (APCI) (M+1) m/z 405.
4(s): (3,3-Oimethy!-butyf)-{4-l2-(pyrrolidine-i-suffonyl)-ρyπdιn-3-yll-benzyl>-amine. Prepared by Method V starting with 3(iii)(c) and 3,3-dimethylbutan-1-amtne, giving 4(s) in 64.0% yield 1H NMR (400 MHz. CHLOROFORM (S) ppm 0.89 (S, 9 H), 1.45 • 1.56 (m. 2 H), 1.95 • 2.04 (m, 4 H), 2.67 • 2.78 (m, 2 H), 3.45 - 3.56 (m, 4 H), 3.89 (s, 2 H). 7.40 - 7.53 (m, 5 H), 7.70 - 7.77 (m, 1 H), 8.49 - 8.57 (m, 1 H). MS (APCi) (M+1) mlz 402.
4(t): (5S,6R)-Bιcycio{2.2.i}tøpt-2-yl-{4-}2-(pyffθiιd(ne-i-sulfonyi)-pyrκ}ιn-3-yl3-benzyf}-amine. Prepared by Method V starting with 3(iii)(c) and bicycio[2.2.1]heptan-2~amine. giving 4(t) in 17 0% yield. 1H NMR (400 MHz, CHLOROFORM S) ppm 0.67 - 0.77 (m, 1 H), 1.18 - 1.29 (m, 1 H), 129 - 1.44 (m, 1 H), 1.48 - 1.61 (m; 1 H), 1.66 - 1.81 (m, 3 H), 1.88 - 1.98 (m, 1 H). 1.98 - 2.04 (m, 4 H), 2.13 - 2,21 (m. 1 H), 2.30 - 2.40 (m, 1 H), 3.07 - 3.17 (m. 1 H), 3.45 - 3.56 (m, 4 H), 3.76 (dd. 2 H), 7.40 - 7.51 (m. 5 H). 7.72 - 7.79 (m, 1 H), 8.49 - 8.57 (m, 1 H) MS (APCi) (M+1) m/z 412. 4<u): 4^Cyclopentylaminomethyl biphenyl-2 su}fonic acid isopropyl methy) amide. Prepared by Method Vi starting with 4>-fcrTOyt-N-isopropyM\l-methytbiphenyl-2-sulfonamide and cydopentanamine. giving 4(u) In 40.0% yield. 1H NMR (400 MHz.. CHLOROFORM-d) ; .: ppm 0.88 <d, 6 H), 1.32 - 1.63 (m, 4 H). 1.66 - 1.78 (m, 2 H), 1.81 - 1.94 (m, 2 H), 2.20 (s. 3 H), 3.09 - 3.20 (m. 1 H). 3.64 - 3.76 <m, 1 H). 3.82 {s. 2 H). 7.25 - 7.32 (ro. 1 H). 7.32 - 7.43 (m, 4 H), 7.42 - 7.50 (m, 1 H)1 7.51 - 7.59 <m. 1 H), 8.10 - 8.18 (ro. 1 H). MS (APCl) (M+1) m/z 387.
4(v): 4'-0sobutylamino-methyl)-btphenyt-2~sutfonic acid isopropyf-methyl-amide. Prepared by
Method Vl starting with starting with 3(iiiKg) and 2-methyipropan-i -amine, giving 4<v) in 24.3% yield. 1H
NMR (400 MHz. METHANOL-(Z4) ppm 0.90 - 0.98 (m, 6 H), 0.98 - 1.11 (m. 6 H). 1.93 - 2.15 (m, 1 H), 2.26 - 2.41 (m, 3 H), 2.82 - 2.98 (m. 2 H), 3.62 - 3.83 (m, 1 H), 4.27 {br. s., 2 H). 7.27 - 7.36 (m, 1 H), 7.45
- 7.63 {m, 5 H), 7.63 - 7.73 (m, 1 H), 8.02 - 8.11 (m, 1 H). MS (APCI) (M+1 ) m/z 375.
4(w): (3,3-Dimethy)-butyl)-{4-{3-(pyrro!idtne-1-sulfonyl)-pyridiπ-2-yf]-benzyl}-amtne. Prepared by
Method V stalling with 3(iii)(g) and 3.3-dlmethyibutan-1-amine, giving 4(w) in 52.0% yield. 1H NMR (400
MHz. CHLOROFORM-d) J ppm 0.91 (s, 9 H), 1.52 - 1.59 (m, 2 H), 1.60 - 1.65 (m, 4 H), 2.67 - 2.74 (m, 2 H), 2.78 - 2.86 (m, 4 H), 3.96 (S, 2 H). 7.42 - 7.47 (nr 1 H). 7.49 - 7.54 (m, 2 H), 7.58 - 7.63 (m. 2 H), 8.46
(dd, 1 H), 8.80 (dd, 1 H). MS (APCI) (M+1) m/z 402.
4(x): (1S.4R)-8icycio{2.2.13hept-2-yl {4 J3 (pyιτofidine-1 suifonyi>pyridin-2 yl3 benzy^ amine. Prepared by Method V starting Yi'ith4-(3-(pyyrrotidin-1-y|$ulfonyl)-pyridin-2-yi]benzaldehyde and bicycio^.iJheptan-Σ-amine, giving 4<x) in 67 0% yield. 1H NMR (400 MHz, CHLOROFORM-cf) : ppm 0.63 - 0.74 (ro, 1 H), 1.16 - 1.26 (m, 1 H), 1.27 - 1.42 (m, 3 H), 1.46 - 1.65 (m. 5 H), 1.67 - 1.78 (m, 1 H), 1.81 - 1.93 (m, 1 H), 2.10 - 2.18 (m, 1 H), 2.24 - 2.33 (m, 1 H), 2.73 - 2.85 (m: 4 H), 2.98 - 3.07 (m, 1 H), 3.75 (dd, 2 H), 7.37 - 7.45 (rn. 3 H), 7.55 (d. 2 H), 8.40 - 8.48 (m: 1 H), 8 74 - 8.82 (m, 1 H). MS (APC!) (M+1) m/z 412.
4(y): lsobutyi-{3-methoxy-2>-(pyrroSdine-1-sυ!fonyl)-bipheπyl-4-ylmethyl]-amine. Prepared by Method Vi starting with 3(iti)(f) and 2-methylpfopan-1-amine, giving 4(y) in 72.0% yield. 1H NMR (400
MHz, METHANOL-Cf4) : ppm 0.96 - 1.14 (m. 4 H), 1.15 - 1.47 (m. 3 H), 1.60 - 1.90 (m, 4 H), 1.97 - 2.19
(m, 1 H), 2.76 - 3.05 (m, 5 H), 3.94 (s, 3 H), 4.28 (s, 2 H). 7.04 (d, 1 H), 7.20 (br. s., 1 H), 7.32 - 7 50 (m, 2
H), 7.54 - 7.74 (m, 2 H). 8.05 (d, 1 H). MS (APCI) (M+1) m/z 403.
Ail of the above recited U.S. patents and publications are incorporated herein by reference.

Claims

1 A compound of formula I
R3 R6
N
Figure imgf000027_0001
^X2 O2S^ ^R7
R2 Xl I
R5
Figure imgf000027_0002
R4 formula I, or a pharmaceutically acceptable salt thereof, wherein
R1 is Chalky!. C^alkyl-O-d ?a!kyl. a 7-, 8-. or 9-membered bridged bicyclic carbocyclic ππg, a fused bicyclic carbocyclic ring, -(CH;),,-prtenyi -{CHa^-heteroaryl, or -(CH^JieterocycloaJkyl, wherein the bridged ring, the fused nng, phenyl heteroaryl or heterocycioalkyl is unsubstituled or substituted with 1 2, or 3 substituertts independently selected from halogen, OH, Chalky! O C, 3aikyl. NH2, NHC1 ^aikyl, or N(C, ialkyl)*,
R? is H or C1 4alkyl, or
R1 and R^ are taken together with the nitrogen to which they are attached to form a mono- or bicyclic N-πng, where said N-ring is a 4- to 7-membered mono-cyclic hetetocycloalkyl nng. a fused bicyclic heterocyclic ring, or a 7- 8-, or 9-membered bridged bicyclic heterocyclic nng, wherein said N-πng is unsubstituted or substituted with 1. 2 or 3 substituents independently selected from halogen, OH, -CN, C1 .salkyl. C, 4alkyl-OH. O-C, ^alkyl, Ci 3aikyl-O-C^a!kyl, NH;. NHCMalkyl, or N(C, saikyt)?. a is 0, 1, or 2, R3 is H, or C, jalkyS, or when X1 or X' is >(C<R*)K R3 may be taken together with R8 of on© of X' or Xi and the carbon atoms to which they are attached to form a 5- or 6-membered saturated, or partially saturated ring, wherein one carbon atom in said 5- or 6-membered ring may be a heteroatom selected from -O-. -N(H)-, -N{C< *alkyi)-, and >N-, and wherein said nng is unsubstituted or substituted where valency permits with 1 substituent selected from halogen, -CN or -C^alkyl, R* is H, halogen, CN, Chalky!, or OC1 ?alkyl,
R5 is H1 halogen. CN1 Chalky!, or OCκ<alkyl. Rβ is C1 4alkyl, or Ca^alkyl-O-d jalkyl R? ιs H, or Cl <alkyS1 or R" and R7 are taken together with the nitrogen to which they are attached to form a mono- or bicyclic SN-nng, where said SN-nng is a 4- to 7-membered mono-cyclic heterocyclic ring containing 0 or 1 additional heferαatom selected from O NH, or NC-. salkyl, or a 7-, 8«. or 9-membered bridged bicycitc heterocyclic ring, wherein said SN-rcng is urtsubstftuted or substituted with 1 or 2 substituertts independently selected from hatogen. OH. -CN, Chalky!, C1 *aikyl-OH, O-C^alkyi, d j aikyl-O-Ct$ alkyl, NH,, NHC,.3alkyl, or NfCwaikylb, X\ X2, Xa, X*. X3, and X8 are independently >{C(Re))- or >N-; and each Rs is independently H. halogen. -CN, -Ct^aikyi, -OCt.^alkyl, provided that when X1 or Xs is >{C(R8))-. one Ra of Xf or X5 may be taken together with Rs and the carbon atoms to which they are attached to form said 5- or 6-rrsembered saturated, or partially saturated πng
2 The compound of claim 1. or pharmaceutically acceptable salt thereof wherein R8 and R? are taken together with the nitrogen to which they are attached to form the monocyclic SN-ring wherein said SN-ring is unsubstituted or substituted with d^alkyt.
3 The compound of any of claims 1 to 2, or pharmaceutically acceptable salt thereof, wherein the monocyclic SN-ring is pyrroiidinyi or mofpholinyi, and wherein said SN-πng is unsubstituted or substituted with methyl. 4. The compound of any ot claims 1 to 3, or pharmaceutically acceptable sait thereof, wherein R1 is Ci βalkyl or the 7-membered bridged btcyclic carbocyclic ring, and R7 is H
5 The compound of any of claims 1 to 3, or pharmaceutically acceptable salt thereof, wherein R1 and R^ are taken together with the nitrogen to which they are attached to form the 5- to 6- membered mono-heterocycloatkyi ring, or the 8-membered bridged bicyclic heterocyclic ring, wherein said N-nng ts unsubstituted or substituted with 1 or 2 substitutents independently selected from OH, methyl, or methoxy
6 The compound of any of claims 1 to 5, or pharmaceutically acceptable salt thereof, wherein X8 is N and X1, X?, X*, X4, and X$ are >{C(R<<))-, wherein each R*1 is independently H1 halogen. - CN. -C^alkyl. or -OC^aikyS 7 The compound of any of claims 1 to 5, or pharmaceutically acceptable sait thereof, wherein X5 is N and X1. X*, x\ X4, and Xs are >(C(Ra))-, wherein R8 is independently H. halogen, -CN. - Ct.3alkyl, or -OC^alkyl.
8 The compound of any of claims 1 to 5, or pharmaceutically acceptable salt thereof wherein X1, X2, Xs, X4, Xs. and X* are KC(R8))-, where R* is independently H, halogen. -CN, -C,.3alkyl, or -OCtalkyl.
9 The compound of any of claims 1 to 8, or pharmaceutically acceptable salt thereof, wherein X1 or Y? are both ><C(R*))- and only one R8 of X' and XJ is H and the other R* is halogen -CN, - Chalky!, or OC1 ^alkyl
10 The compound of claim 1. wherein the compound is selected from the group consisting of (IΛ^S^N-CPHpyrrolidin-i-yisulfonyObiphenyl^-ylJmethyl^icyclop^.iJheptan^-amine:
{IR.SSJ-θ-ilZ-tpyriOUdin-i-ylsulfonyDbiphenyM-ylJmethylJ-e-azabicyclolS.a.iJoctane. 4-methyl-1-g2'-(pyrrolidin-1-ylsulfonyl)bipheny!-4-yl}me*yl}pipendin-4-ol; 2 methyl-N-{{2"-(pyrrol!dιn-1 -ylsulfonyl)bιpheny(-4-yl)methyl}propan- 1 -amine; 3.3-dimethyl-1-{(2'-<pyrroiidιn-1-ylsulfony!)bιphenyl-4-yl]methyl}piperidιne, 1-(3-methyloxetan-3-yl)-N-{[2'-<pyrral!din-1-ylsulfonyl)biphenyl-4-yl]methyl}methanamine;
(2S)-1-methoxy-N-{(2'-(pyfτolidtn-1-ylsulfonyl)bιphenyl-4-ylJmethyl}propan-2-amine; N-{[2'-(pyiTθlidιn-1-y!su!fonyt)biphenyl-4-y!]methyl}tetrahy<lro-2H-pyran-4-amine; N-C^-Cpyrroiidiπ-i-ylsυlfonytJbiphenyM-yiJfnethyl^etrahydrcrfυraft-S-arTune; 2-methyi-N-((2'-{l{2S)-2-methy}ρyrro!lcftn-i-yfIsu!fonyt}blphenyi-4-yl}(τiethyS]propan-i-amlne; 3.3^imethyl-N-[{2-{[(3R)-3-methy{morpholtri-4-yl]suffonyf}biphenyl-4-yl)rnethyij3utan-1-amfrte; 2-methyl-N-[{2'-{[{3R)^-methy!morphoiιn-4-yl]sutfonyl}btphenyl-4-yl)methyljpropan-1-amtne:
(1S,5R)-6-{[3-fluorø-2'-{pyn*o!<d>π-1-ylsulfonyi)biphenyl-4-ytJme{byl}-6-azabicyclo[3.2.1]octarιe; 2-{1-|{2'-{{2-(hydfoxymethyt)piperidin-1-ytJsuifonyi}bipheny!-4-yf)methyl|piperidin-4-y)}elhanoi; N-lCS-fluoro-Z^KSR^S-me^ylmorpholfn^yllsulfonyfJtophenyi^-yOmeJhytl-S.S-dimethyibutan-i- amine: N-[p4iuoiO-2'-{((3R)-3-methylmoφholtn-4-yl]solfonyi}bfphenyl-4-yt)rnethyf]bicyclof2.2.1Jheptan-2- amine;
N-[(3-fiuoro-2'^[(3R)-3-me^ylmorphoitn-4-yl3sulfonyf}btphenyi-4-yf)rnethyt]-2-iτiethytpropan-1- amine,
N-[(3'fiuoro-2'-{f(2S)'2-m8tbylpyrrotidin-1-yllsu(fonyi}btpheπyl-4-yt)methy{|-2-methy}propan-1- amine;
3I3-dimethyUN-{4-[2-(pyfro!fdin~1-ylsulfonyl)pyridtn-3-y!lbenzyl}butan-1-amine; <1R4S) N- {4 |2 (pyrroitdtn- 1 ylsulfony!)pyridin-3 yljbenzyl}bicyclo(22.1]beptan~2 amine; 4'-[(cycloρentyiannιno)methyl}-N-isopropyl-N-rne(hylbiph«nyl-2-$ulfonamicie; 4'-[(»sobutylamino)methyf{-N-isopropyl-N-methyibiρheny!-2-su!fonamιde: 3.3-dimethyl-N-(4-[3-{pyrroiidm-1-ylsu}fonyl)pyndtn-2-yl]benzyl}butan-1-am)ne;
( 1 S,4R)-N-{4-|3-(pyrroiιdin-1 -yJsulfonyl )pyridin-2-ytJbenzyi}bicyclo(2.2.1 Jheptan-2-amine; and N-{[3-methoxy-Z-(pyrrotidin-1-y!suifonyt)biph€nyl-4-yi|rriethyl}-2-methylpropan-1-amine; or a pharmaceutically acceptable salt thereof.
11 A pharmaceutical composition comprising a compound of any of claims 1 to 10. or pharmaceutically acceptable salt thereof, for treating or preventing a disease or disorder selected from the group consisting of schizophrenia including negative symptoms; schizophreniform disorder; schizoaffective disorder including of the delusional type or the depressive type; delusional disorder, substance-induced psychotic disorder, personality disorder of the paranoid type; personality disorder of the schizoid type, panic disorder: phobias; obsessive-compulsive disorder; stress disorders; generalized anxiety disorder, movement disorders involving Huntingtons disease, dyskinesia associated with dopamine agonist therapy; Parkinson's disease; restless ieg syndrome; disorders comprising as a symptom thereof a deficiency in cognition; dementias; mood disorders and episodes in a mammal; anxiety or psychotic disorders including schizophrenia, of the paranoid, disorganized, catatonic, undifferentiated, or residua! type, delusional disorder, personality disorder of the paranoid type, of the schizoid type., or agoraphobia, post-traumatic stress disorder, acute stress disorder, chemical dependencies including alcohol, amphetamine, cocaine., heroin, phenobarbrtai. opiate, nicotine and benzodiazepines addiction; deficiency in memory, intellect, or learning and logic ability; reduction in any particular individual's functioning in one or more cognitive aspects; age-related cognitive decline; dementia; Alzheimer's disease; multi-infarct dementia; alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma: dementia associated with Huntingtons disease or Parkinson s disease. AIDS-related dementia; delirium; amnestic disorder; mental retardation; a learning disorder including reading disorder, mathematics disorder, or a disoider of written expression, attention-deficit/hyperactivity disorder, mood disorders or mood episodes a manic or mixed mood episode; a hypomanic mood episode, a depressive episode with atypical features; a depressive episode with melancholic features, a depressive episode with catatonic features, a mood episode with postpartum onset, post-stroke depression; dysthymic disorder; minor depressive disorder, premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia a major depressive disorder superimposed on a psychotic disorder; delusional disorder or schizophrenia, a bipolar disorder including bipolar I disorder, bipolar Il disorder, cyclothymic disorder, hypertension, and depression, depression in cancer patients, Parkinson's patients, infertile women, and pediatrics, depression as a single episode depression or recurrent episodes; including depression associated with postmyocardial infarction, subsyndromal symptomatic depression, induced by child abuse, post partum depression, and major depression of the mild, moderate or severe type, avoidant personality disorder, premature ejaculation, eating disorders including anorexia nervosa and bulimia nervosa, obesity: cluster headache: migraine, pain, neurolepβo induced parkinsonism and tardive dyskinesias, endocrine disorders, hyperprolactiπaemia. vasospasm vasospasm in the cerebrai vasculature; cerebellar ataxia, gastrointestinal tract disorders involving changes in motility and secretion mania, premenstrual syndrome; fibromyalgia syndrome; stress incontinence; Tourette's syndrome, tnchotillomania, kleptomania; male impotence, cancer; small cell lung carcinoma, chronic paroxysmal bermcrania. and headache associated with vascular disorders and a pharmaceutical carrier 12. A method of treating or preventing a disease or disorder selected from the group consisting of schizophrenia including negative symptoms, schizophreniform disorder; schizoaffective disorder including of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, personality disorder of the paranoid type, personality disorder of the schizoid type, panic disorder, phobias, obsessive-compulsive disorder' stress disorders; generalized anxiety disorder movement disorders involving Huntingtons disease; dyskinesia associated with dopamine agonist therapy, Parkinson's disease; restless leg syndrome: disorders comprising as a symptom thereof a deficiency in cognition, dementias, mood disorders and episodes in a mammal, anxiety or psychotic disorders including schizophrenia, of the paranoid, disorganized, catatonic, undifferentiated, or residual type; delusional disorder, personality disorder of the paranoid type, of the schizoid type, or agoraphobia, post-traumatic stress disorder, acute stress disorder, chemical dependencies including alcohol, amphetamine, cocaine, heroin phenobarbital, opiate, nicotine and benzodiazepines addiction; deficiency in memory intellect or learning and logic ability; reduction m any particular individual's functioning in one or more cognitive aspects; age- related cognitive decline; dementia. Alzheimer's disease; rnultt infarct dementia, alcoholic dementia or other drug-related dementia; dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntingtons disease or Parkinson's disease, AIDS- related dementia, delirium, amnestic disorder, mental retardation, a learning disorder including reading disorder, mathematics disorder, or a disorder of wntten expression; attention-deftαt/hyperactivity disorder, mood disorders or mood episodes, a manic or mixed mood episode a hypomanic mood episode a depressive episode with atypical features, a depressive episode with melancholic features; a depressive episode with catatonic features: a mood episode with postpartum onset, post-stroke depression, dysthymic disorder; minor depressive disorder, premenstrual dysphoric disorder post-psychotic depressive disorder of schizophrenia a major depressive disorder superimposed on a psychotic disorder, delusional disorder or schizophrenia: a bipolar disorder including bipolar J disorder, bipolar It disorder, cyclothymic disorder, hypertension, and depression; depression in cancer patients, Parkinson's patients, infertile women, and pediatrics, depression as a smgle episode depression or recurrent episodes, including depression associated with postmyocardial infarction, subsyndromal symptomatic depression induced by child abuse, post partum depression, and major depression of the mild moderate or severe type; avoidant personality disorder, premature ejaculation, eating disorders including anorexia nervosa and bulimia nervosa, obesity, cluster headache, migraine; pain; neuroJeptic-tnduced parkinsonism and tardive dyskinesias, endocrine disorders' hyperprolactinaemia; vasospasm; vasospasm sn the cerebral vasculature; cerebellar ataxia; gastrointestinal tract disorders involving changes in motility and secretion' mama, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourettes syndrome, tπchotillomania, kleptomania, male impotence, cancer, small ceil lung carcinoma, chronic paroxysmal hemicrania: and headache associated with vascular disorders by administering to a mammal in need thereof an effective amount of a compound of any of claims 1 to 10, or pharmaceutically acceptable salt thereof.
13 The method of claim 12 wherein the compound of any of claims 1 to 10 is administered with at least one additional pharmaceutical agent.
14 A pharmaceutical composition comprising (i) a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of Claims 1 to 10; and (ιi) at least one a pharmaceutically acceptable excipient, diluent, or earner.
15. The composition of Claim 14 further compnsing at least one additional pharmaceutical agent 16 A method for treating a disease, condition or disorder that is mediated by antagonizing the kappa opioid receptor in animals comprising the step of administering to an animal in need of such treatment a therapeutically effective amount of a compound of any one of Claims 1 to 10. 17 The method of Claim 16 wherein said disease, condition and/or disorder is schizophrenia, depression, or bipolar
18. The method of claim 16 or 17, wherein the compound of any of claims 1 to 10 is administered with at least one additional pharmaceutical agent
PCT/IB2009/052495 2008-06-25 2009-06-11 Diaryl compounds and uses thereof WO2009156889A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2011515678A JP2011526881A (en) 2008-06-25 2009-06-11 Diaryl compounds and their use
EP09769699A EP2321011A1 (en) 2008-06-25 2009-06-11 Diaryl compounds and uses thereof
CA2727573A CA2727573A1 (en) 2008-06-25 2009-06-11 Diaryl compounds and uses thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7542008P 2008-06-25 2008-06-25
US61/075,420 2008-06-25

Publications (1)

Publication Number Publication Date
WO2009156889A1 true WO2009156889A1 (en) 2009-12-30

Family

ID=41100490

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/052495 WO2009156889A1 (en) 2008-06-25 2009-06-11 Diaryl compounds and uses thereof

Country Status (8)

Country Link
US (1) US20100035873A1 (en)
EP (1) EP2321011A1 (en)
JP (1) JP2011526881A (en)
AR (1) AR072318A1 (en)
CA (1) CA2727573A1 (en)
TW (1) TW201000470A (en)
UY (1) UY31931A (en)
WO (1) WO2009156889A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017211272A1 (en) * 2016-06-07 2017-12-14 江苏恒瑞医药股份有限公司 Phenyl propanamide derivative, and manufacturing method and pharmaceutical application thereof
WO2018170492A1 (en) 2017-03-17 2018-09-20 The Scripps Research Institute Kappa opioid receptor antagonists and products and methods related thereto

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017184765A1 (en) * 2016-04-21 2017-10-26 MediSynergics, LLC Kappa opioid receptor compounds and methods of using same

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0400974A2 (en) * 1989-05-30 1990-12-05 Merck & Co. Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
US5223499A (en) * 1989-05-30 1993-06-29 Merck & Co., Inc. 6-amino substituted imidazo[4,5-bipyridines as angiotensin II antagonists
GB2268743A (en) * 1992-07-17 1994-01-19 Merck & Co Inc Substituted carbamoyl and oxycarbonyl derivatives of biphenylmethylamines
DE4318813A1 (en) * 1993-06-07 1994-12-08 Merck Patent Gmbh imidazopyridines
US5412097A (en) * 1991-03-08 1995-05-02 Merck & Co., Inc. Heterocyclic compounds bearing acidic functional groups as angiotensin II antagonists
EP0702013A2 (en) * 1994-09-15 1996-03-20 MERCK PATENT GmbH Imidazopyridines
JPH08143552A (en) * 1994-11-21 1996-06-04 Kotobuki Seiyaku Kk Cycloheptimidazole derivative, its production and medicine containing the same
EP1354871A1 (en) * 2000-12-26 2003-10-22 Pola Chemical Industries, Inc. Biphenyl derivatives
WO2003101381A2 (en) * 2002-05-29 2003-12-11 Merck & Co., Inc. 1,2 diamido cycloalkyl sodium channel blockers
WO2008021849A2 (en) * 2006-08-09 2008-02-21 Smithkline Beecham Corporation Novel compounds as antagonists or inverse agonists at opioid receptors

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3539573A (en) * 1967-03-22 1970-11-10 Jean Schmutz 11-basic substituted dibenzodiazepines and dibenzothiazepines
NL189199C (en) * 1975-04-05 1993-02-01 Akzo Nv PROCESS FOR THE PREPARATION OF PHARMACEUTICAL PREPARATIONS WITH ACTION ON THE CENTRAL NERVOUS SYSTEM BASED ON BENZ (ARYL) AZEPINE DERIVATIVES, THE PHARMACEUTICAL PREPARATIONS OBTAINED, AND METHOD FOR PREPARING THE PRODUCT TO BE USED.
NL7605526A (en) * 1976-05-24 1977-11-28 Akzo Nv NEW TETRACYCLICAL DERIVATIVES.
FR2415099A1 (en) * 1978-01-20 1979-08-17 Ile De France NEW DERIVATIVES OF 4-AMINO-5-ALKYLSULFONYL ORTHO-ANISAMIDES, THEIR METHODS OF PREPARATION AND THEIR APPLICATION AS PSYCHOTROPES
JPS54130587A (en) * 1978-03-30 1979-10-09 Otsuka Pharmaceut Co Ltd Carbostyryl derivative
US4401622A (en) * 1981-04-20 1983-08-30 The International Nickel Co., Inc. Nickel-chromium-iron alloy
US4804663A (en) * 1985-03-27 1989-02-14 Janssen Pharmaceutica N.V. 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
IE58370B1 (en) * 1985-04-10 1993-09-08 Lundbeck & Co As H Indole derivatives
GB8607684D0 (en) * 1986-03-27 1986-04-30 Ici America Inc Thiazepine compounds
US4906637A (en) * 1987-06-05 1990-03-06 Faden Alan I Traumatic and ischemic brain injury treatment with opiate-receptor antagonists
US5025018A (en) * 1987-06-05 1991-06-18 Medicis Corporation Central nervous system injury treatment with opiate-receptor antagonist
US4831031A (en) * 1988-01-22 1989-05-16 Pfizer Inc. Aryl piperazinyl-(C2 or C4) alkylene heterocyclic compounds having neuroleptic activity
US5006528A (en) * 1988-10-31 1991-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives
US5238945A (en) * 1989-04-11 1993-08-24 H. Lundbeck A/S Method of treating psychoses
GB8908085D0 (en) * 1989-04-11 1989-05-24 Lundbeck & Co As H New therapeutic use
FR2646347B1 (en) * 1989-04-28 1991-08-23 Roussel Uclaf NOVEL HYDROXYPHENETHYLAMINE DERIVATIVE AND ITS SALTS, METHOD OF PREPARATION, APPLICATION AS MEDICAMENTS AND USE AS A SPECIFIC PHARMACOLOGICAL TOOL
US5229382A (en) * 1990-04-25 1993-07-20 Lilly Industries Limited 2-methyl-thieno-benzodiazepine
US5585348A (en) * 1993-02-10 1996-12-17 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Use of excitatory opioid receptor antagonists to prevent growth factor-induced hyperalgesia
US5312295A (en) * 1993-08-23 1994-05-17 Young James E Subterranean transformer enclosure vent
KR100330942B1 (en) * 1994-03-02 2002-11-16 악조 노벨 엔.브이. Sublingual or buccal pharmaceutical composition
US7078075B1 (en) * 1995-02-23 2006-07-18 H.B. Fuller Licensing & Financing Inc. Method for producing a continuous thermoplastic coating and articles constructed therefrom
US6245768B1 (en) * 1995-06-05 2001-06-12 Neurogen Corporation 1-(N′-(arylalkylaminoalkyl)) aminoisoindoles; a new class of dopamine receptor subtype specific ligands
TW491847B (en) * 1996-05-07 2002-06-21 Pfizer Mesylate dihydrate salts of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2h-indol-2-one
US5727570A (en) * 1996-11-14 1998-03-17 Clemens; Anton H. Method of treating hyperlipidemia in humans
US5780479A (en) * 1997-04-04 1998-07-14 Regents Of The University Of Minnesota Use of opioid antagonists to treat impulse-control disorders
US6387904B2 (en) * 1998-05-18 2002-05-14 Pfizer Inc Method of treating glaucoma and ischemic retinopathy
AU4572999A (en) * 1998-06-18 2000-01-05 Sepracor, Inc. Tetrapeptides, analogs and peptidomimetics which bind selectively mammalian opioid receptors
EP1353665A4 (en) * 2000-12-21 2004-05-06 Mclean Hospital Corp Treatment of depression
US6974824B2 (en) * 2001-01-08 2005-12-13 Research Triangle Institute Kappa opioid receptor ligands
US6559159B2 (en) * 2001-02-01 2003-05-06 Research Triangle Institute Kappa opioid receptor ligands
WO2008066916A1 (en) * 2006-11-30 2008-06-05 The Mclean Hospital Corporation Methods for the treatment of mood disorders

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0400974A2 (en) * 1989-05-30 1990-12-05 Merck & Co. Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
US5223499A (en) * 1989-05-30 1993-06-29 Merck & Co., Inc. 6-amino substituted imidazo[4,5-bipyridines as angiotensin II antagonists
US5412097A (en) * 1991-03-08 1995-05-02 Merck & Co., Inc. Heterocyclic compounds bearing acidic functional groups as angiotensin II antagonists
GB2268743A (en) * 1992-07-17 1994-01-19 Merck & Co Inc Substituted carbamoyl and oxycarbonyl derivatives of biphenylmethylamines
DE4318813A1 (en) * 1993-06-07 1994-12-08 Merck Patent Gmbh imidazopyridines
EP0702013A2 (en) * 1994-09-15 1996-03-20 MERCK PATENT GmbH Imidazopyridines
JPH08143552A (en) * 1994-11-21 1996-06-04 Kotobuki Seiyaku Kk Cycloheptimidazole derivative, its production and medicine containing the same
EP1354871A1 (en) * 2000-12-26 2003-10-22 Pola Chemical Industries, Inc. Biphenyl derivatives
WO2003101381A2 (en) * 2002-05-29 2003-12-11 Merck & Co., Inc. 1,2 diamido cycloalkyl sodium channel blockers
WO2008021849A2 (en) * 2006-08-09 2008-02-21 Smithkline Beecham Corporation Novel compounds as antagonists or inverse agonists at opioid receptors

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002548358, retrieved from STN Database accession no. 125:167991 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002548359, retrieved from STN Database accession no. 1026631-70-8 (RN) *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002548360, retrieved from STN Database accession no. 10-27033-67-5 (RN) *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002548361, retrieved from STN Database accession no. 10-25819-15-1 (RN) *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002548362, retrieved from STN Database accession no. 1026595-94-7 (RN) *
WERMUTH C G: "MOLECULAR VARIATIONS BASED ON ISOSTERIC REPLACEMENTS", PRACTICE OF MEDICINAL CHEMISTRY, XX, XX, 1 January 1996 (1996-01-01), pages 203 - 237, XP002190259 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017211272A1 (en) * 2016-06-07 2017-12-14 江苏恒瑞医药股份有限公司 Phenyl propanamide derivative, and manufacturing method and pharmaceutical application thereof
WO2018170492A1 (en) 2017-03-17 2018-09-20 The Scripps Research Institute Kappa opioid receptor antagonists and products and methods related thereto
EP4141001A1 (en) 2017-03-17 2023-03-01 The Scripps Research Institute Kappa opioid receptor antagonists and products and methods related thereto

Also Published As

Publication number Publication date
TW201000470A (en) 2010-01-01
CA2727573A1 (en) 2009-12-30
UY31931A (en) 2010-01-29
EP2321011A1 (en) 2011-05-18
US20100035873A1 (en) 2010-02-11
JP2011526881A (en) 2011-10-20
AR072318A1 (en) 2010-08-18

Similar Documents

Publication Publication Date Title
EP1893566B1 (en) Cyclohexanesulfonyl derivatives as glyt1 inhibitors to treat schizophrenia
WO2019158019A1 (en) Pyrimidine-fused cyclic compound, preparation method therefor and application thereof
EP3580220B1 (en) Aminotriazolopyridines as kinase inhibitors
JP5619773B2 (en) Novel benzenesulfonamides as calcium channel blockers
WO2021087093A1 (en) Small molecule degraders of helios and methods of use
JP4756031B2 (en) Heteroaryl piperidine glycine transporter inhibitors
TW200815412A (en) A pharmaceutical combination comprising 3-or 4-monosubstituted phenol and thiophenol derivatives
JP5175736B2 (en) Piperidine glycine transporter inhibitor
NZ749202A (en) Modulators of the beta-3 adrenergic receptor useful for the treatment or prevention of disorders related thereto
JP6186440B2 (en) Dihydropyrrolidinopyrimidines as kinase inhibitors
BRPI0911990A2 (en) prolinamide pyridine compounds and their use in therapy
EP2321011A1 (en) Diaryl compounds and uses thereof
CN115066423B (en) PD-L1 antagonist compounds
JP2023535932A (en) tricyclic heterocycle
JP2024513227A (en) NEK7 inhibitor
JP2023524863A (en) tricyclic heterocycle
WO2024077057A1 (en) Phenyl oxy amide kinase inhibitors
WO2024044570A1 (en) Compounds and methods for modulating her2

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09769699

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2727573

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2011515678

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2009769699

Country of ref document: EP