EP1284976A2 - Diazabicyclic central nervous system active agents - Google Patents

Diazabicyclic central nervous system active agents

Info

Publication number
EP1284976A2
EP1284976A2 EP01944118A EP01944118A EP1284976A2 EP 1284976 A2 EP1284976 A2 EP 1284976A2 EP 01944118 A EP01944118 A EP 01944118A EP 01944118 A EP01944118 A EP 01944118A EP 1284976 A2 EP1284976 A2 EP 1284976A2
Authority
EP
European Patent Office
Prior art keywords
pyridinyl
diazabicyclo
compound according
cis
covalent bond
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP01944118A
Other languages
German (de)
English (en)
French (fr)
Inventor
Michael R. Schrimpf
Karin R. Tietje
Richard B. Toupence
Jianguo Ji
Anwer Basha
William H. Bunnelle
Jerome F. Daanen
Jennifer M. Pace
Kevin B. Sippy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Inc
Original Assignee
Abbott Laboratories
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
Priority claimed from US09/833,914 external-priority patent/US6809105B2/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to EP10177450A priority Critical patent/EP2298775A1/en
Priority to EP10177411A priority patent/EP2295437A1/en
Publication of EP1284976A2 publication Critical patent/EP1284976A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • 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
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—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
    • A61P25/34—Tobacco-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention is directed to a series of N-substituted diazabicyclic compounds, a method for selectively controlling neurotransmitter release in mammals using these compounds, and pharmaceutical compositions including those compounds.
  • This utility may arise from controlling either pre-synaptic or post-synaptic chemical transmission.
  • the control of synaptic chemical transmission is, in turn, a direct result of a modulation of the excitability of the synaptic membrane.
  • Presynaptic control of membrane excitability results from the direct effect an active compound has upon the organelles and enzymes present in the nerve terminal for synthesizing, storing, and releasing the neurotransmitter, as well as the process for active re-uptake.
  • Postsynaptic control of membrane excitability results from the influence an active compound has upon the cytoplasmic organelles that respond to neurotransmitter action.
  • excitable cells are cells such as nerves, smooth muscle cells, cardiac cells and glands.
  • the effect of a neurotransmitter upon an excitable cell may be to cause either an excitatory or an inhibitory postsynaptic potential (EPSP or IPSP, respectively) depending upon the nature of the postsynaptic receptor for the particular neurotransmitter and the extent to which other neurotransmitters are present. Whether a particular neurotransmitter causes excitation or inhibition depends principally on the ionic channels that are opened in the postsynaptic membrane (i.e., in the excitable cell).
  • ESP inhibitory postsynaptic potential
  • EPSPs typically result from a local depolarization of the membrane due to a generalized increased permeability to cations (notably Na + and K ), whereas IPSPs are the result of stabilization or hyperpolarization of the membrane excitability due to a increase in permeability to primarily smaller ions (including K and Cl " ).
  • the neurotransmitter acetylcholine excites at skeletal muscle junctions by opening permeability channels for Na and K .
  • acetylcholine can be inhibitory , primarily resulting from an increase in K conductance.
  • the biological effects of the compounds of the present invention result from modulation of a particular subtype of acetylcholine receptor. It is, therefore, important to understand the differences between two receptor subtypes.
  • the two distinct subfamilies of acetylcholine receptors are defined as nicotinic acetylcholine receptors and muscarinic acetylcholine receptors. (See Goodman and Gilman's, The Pharmacological Basis of Therapeutics, op. cit).
  • the responses of these receptor subtypes are mediated by two entirely different classes of second messenger systems. When the nicotinic acetylcholine receptor is activated, the response is an increased flux of specific extracellular ions (e.g.
  • muscarinic acetylcholine receptor activation leads to changes in intracellular systems that contain complex molecules such as G-proteins and inositol phosphates.
  • nicotinic acetylcholine receptor activation are distinct from those of muscarinic receptor activation.
  • inhibition of nicotinic acetylcholine receptors results in still other biological effects, which are distinct and different from those arising from muscarinic receptor inhibition
  • the two principal sites to which drug compounds that affect chemical synaptic transmission may be directed are the presynaptic membrane and the postsynaptic membrane.
  • Actions of drugs directed to the presynaptic site may be mediated through presynaptic receptors that respond to the neurotransmitter which the same secreting structure has released (i.e., through an autoreceptor), or through a presynaptic receptor that responds to another neurotransmitter (i.e., through a heteroreceptor).
  • Actions of drugs directed to the postsynaptic membrane mimic the action of the endogenous neurotransmitter or inhibit the interaction of the endogenous neurotransmitter with a postsynaptic receptor.
  • drugs that modulate postsynaptic membrane excitability are the neuromuscular blocking agents which interact with nicotinic acetylcholine-gated channel receptors on skeletal muscle, for example, competitive (stabilizing) agents, such as curare, or depolarizing agents, such as succinylcholine.
  • competitive (stabilizing) agents such as curare
  • depolarizing agents such as succinylcholine.
  • CNS central nervous system
  • postsynaptic cells can have many neurotransmitters impinging upon them. This makes it difficult to know the precise net balance of chemical synaptic transmission required to control a given cell. Nonetheless, by designing compounds that selectively affect only one pre- or postsynaptic receptor, it is possible to modulate the net balance of all the other inputs. The more that is understood about chemical synaptic transmission in CNS disorders, the easier it would be to design drugs to treat such disorders.
  • dopamine is widely recognized as an important neurotransmitter in the central nervous systems in humans and animals. Many aspects of the pharmacology of dopamine have been reviewed by Roth and Elsworth, "Biochemical Pharmacology of Midbrain Dopamine Neurons"
  • New and selective neurotransmitter controlling agents are still being sought, in the hope that one or more will be useful in important, but as yet poorly controlled, disease states or behavior models.
  • dementia such as is seen with Alzheimer's disease or Parkinsonism, remained largely untreatable.
  • Symptoms of chronic alcoholism and nicotine withdrawal involve aspects of the central nervous system, as does the behavioral disorder Attention Deficit Disorder (ADD).
  • ADD Attention Deficit Disorder
  • acetylcholine agonists are therapeutically suboptimal in treating the conditions discussed above.
  • such compounds have unfavorable pharmacokinetics (e.g., arecoline and nicotine), poor potency and lack of selectivity (e.g., nicotine), poor CNS penetration (e.g., carbachol) or poor oral bioavailability (e.g., nicotine).
  • agents have many unwanted central agonist actions, including hypothermia, hypolocomotion and tremor and peripheral side effects, including miosis, lachrymation, defecation and tachycardia (Benowitz et al., in Nicotine Psychopharmacology, S. Wonnacott, MA.H. Russell, & I.P. Stolerman, eds., Oxford University Press, Oxford, 1990, pp. 112-157; and M. Davidson, et al., in Current Research in Alzheimer Therapy, E. Giacobini and R.
  • WO 94/08922 describes pyridyl ether compounds which enhance cognitive function.
  • U.S. patent applications 08/474,873 and 08/485,537 describe certain substituted pyridyl ether compounds as well as other compounds which also act at the nicotinic acetylcholine receptor to stimulate or inhibit neurotransmitter release.
  • WO 96/31475 describes certain 3-substituted pyridine derivatives which are described as being useful for a variety of disorders as modulators of acetylcholine receptors. While some of these references have alluded to pain control as a potential use of the compounds or analogs recited therein, the Applicants have discovered that compounds of formula I shown below have a surprising and unexpected analgesic effect.
  • cholinergic channel modulators may be useful in treating pain.
  • the search for more potent and more effective pain controllers or analgesics continues to be a significant research goal in the medical community.
  • a substantial number of medical disorders and conditions produce pain as part of the disorder or condition. Relief of this pain is a major aspect of ameliorating or treating the overall disease or condition. Pain and the possible allievation thereof is also attributable to the individual patient's mental condition and physical condition.
  • One pain reliever, or a class may not be effective for a particular patient, or group of patients, which leads to a need for finding additional compounds or pharmaceuticals which are effective analgesics.
  • Opioid and non-opioid drugs are the two major classes of analgesics (Dray, A. and Urban, L., Ann. Rev. Pharmacol. Toxicol., 36: 253-
  • Opioids such as morphine
  • Opioids act at opioid receptors in the brain to block transmission of the pain signals in the brain and spinal cord (Cherney, N.I., Drug, 51:713- 737, 1996).
  • Opioids such as morphine have abuse and addiction liability.
  • Non-opioids such as non-steroid anti-inflammatory agents (NSAIDs) typically, but not exclusively, block the production of prostaglandins to prevent sensitization of nerve endings that facilitate the pain signal to the brain (Dray, et al, Trends in Pharmacol. Sci., 15: 190-197, 1994.; Carty, T.J. and Marfat, A., "COX-2 Inhibitors.
  • OTC over-the-counter
  • TCAs tricyclic antidepressants
  • gabapentin gabapentin
  • the compounds of the present invention may also have utility when administered in combination with an opioid such as morphine, a non-steroid anti-inflammatory agent such as aspirin, a tricyclic antidepressant, or an anticonvulsant such as gabapentin or pregabalin for treating disorders and medical conditions listed herein.
  • an opioid such as morphine
  • a non-steroid anti-inflammatory agent such as aspirin
  • a tricyclic antidepressant such as aspirin
  • an anticonvulsant such as gabapentin or pregabalin for treating disorders and medical conditions listed herein.
  • the present invention discloses N-substituted diazabicyclic compounds, a method for selectively controlling neurotransmitter release in mammals using these compounds, a method for controlling pain in mammals, and pharmaceutical compositions including those compounds. More particularly, the present invention is directed to compounds of formula I
  • A is selected from the group consisting of a covalent bond, CH , CH 2 CH , and CH 2 CH 2 CH 2 ;
  • B is selected from the group consisting of CH and CH 2 CH 2 , provided that when A is
  • Y is selected from the group consisting of a covalent bond, CH 2 , and CH 2 CH ;
  • Z is selected from the group consisting of a covalent bond, CH 2 , and CH 2 CH 2 , provided that when Y is CH 2 CH 2 , then Z is a covalent bond and further provided that when Z is CH CH 2 , then Y is a covalent bond;
  • R ! is selected from the group consisting of
  • R 3 is selected from the group consisting of hydrogen, alkyl, and halogen
  • R_ 4 is selected from the group consisting of hydrogen, alkoxy, alkyl, amino, halogen, and nitro
  • R 5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, amino, aminoalkyl, aminocarbonyl, ammocarbonylalkyl, aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, 5-tetrazolyl, -NR 6 S(O) 2 R 7 , -C(NR 6 )NR 7 R 8 , -CH 2 C(NR 6 )NR 7 R 8 , -C(NOR 6 )R 7 , -C(
  • R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen and alkyl
  • R is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, amino, aminoalkyl, ammocarbonylalkyl, benzyloxycarbonyl, cyanoalkyl, dihydro-3- pyridinylcarbonyl, hydroxy, hydroxyalkyl, and phenoxycarbonyl.
  • R 9 are as defined in formula I.
  • Ri is R 3 N R ; and R 3 , R ⁇ , R 5 and R are as defined in formula I.
  • R 3 , R , R 5 and R are as defined in formula I.
  • compounds of formula II are disclosed wherein Y is a covalent bond; Z is CH 2 CH 2 ; and R] and R 9 are as defined in formula I.
  • compounds of formula II are disclosed wherein Y is a covalent bond; Z is CH 2 CH 2 ; Ri is and R , R 4 , R 5 and R are as defined in formula I.
  • compounds of formula II wherein Y and Z are as defined in formula I; R is selected from hydrogen and lower alkyl wherein hydrogen and methyl are preferred;
  • R ⁇ is 3 4 ;
  • R 3 is selected from hydrogen or halogen;
  • R 4 is selected from hydrogen, halogen, and lower alkyl;
  • R 5 is selected from hydrogen, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, .lower alkenyl, lower alkoxyalkyl, lower alkoxy, lower alkyl, lower alkynyl, and nitro.
  • Representative compounds of formula II include, but are not limited to: (lR,5R)-6-(6-chloro-3-pyridinyl)-2,6-diazabicyclo[3.2.0]heptane;
  • compounds of formula III wherein Y is a covalent bond; Z is a covalent bond; and R 3 , R- t , R 5 and R are as defined in formula I.
  • R ⁇ is are as defined in formula I.
  • compounds of formula III wherein Y and Z are as defined in formula I; R 9 is selected from hydrogen and lower alkyl wherein hydrogen and methyl are preferred; R ⁇ is
  • R 3 is selected from hydrogen or halogen
  • R 4 is selected from hydrogen, halogen, and lower alkyl
  • R 5 is selected from hydrogen, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, lower alkenyl, lower alkoxyalkyl, lower alkoxy, lower alkyl, lower alkynyl, and nitro.
  • Representative compounds of formula III include, but are not limited to: (lR,5R)-2-(3-pyridinyl)-2,6-diazabicyclo[3.2.0]heptane;
  • compounds of formula TV are disclosed wherein Y is a covalent bond; Z is a covalent bond;
  • R x is and R 3 , Rj, R 5 and R 9 are as defined in formula I.
  • compounds of formula TV wherein Y is a covalent bond; Z is CH ; and R and R are as defined in formula I.
  • compounds of formula TV are disclosed wherein Y is CH 2 CH 2 ; Z is a covalent bond; and and R are as defined in formula I.
  • compounds of formula IV are disclosed wherein Y is CH 2 CH 2 ; Z is a covalent bond;
  • Ri is R 3 N R 4 ; and R 3 , R , R 5 and R are as defined in formula I.
  • compounds of formula IV are disclosed wherein Y is CH 2 ; Z is CH 2 ; and Ri and R are as defined in formula I.
  • compounds of formula IV are disclosed wherein Y and Z are as defined in formula I; R 9 is selected from hydrogen and lower alkyl wherein hydrogen and methyl are preferred; R ⁇ is
  • R 5 is selected from hydrogen, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, lower alkenyl, lower alkoxyalkyl, lower alkoxy, lower alkyl, lower alkynyl, and nitro.
  • Representative compounds of formula IV include, but are not limited to: (cis)-5-(6-chloro-3-pyridinyl)octahydrpyrrolo[3,4-b]pyrrole; 3aR,6aR)-5-(6-chloro-3-pyridinyl)octahydropyrrolo[3,4-b]pyrrole; 3aS,6aS)-5-(6-chloro-3-pyridinyl)octahydropyrrolo[3,4-b]pyrrole; 3aR,6aR)-5-(5,6-dichloro-3-pyridinyl)octahydropyrrolo[3,4-b]pyrrole; 3aS,6aS)-5-(5,6-dichloro-3-pyridinyl)octahydropyrrolo[3,4-b]pyrrole; 3aS,6aS)-5-(5,6-dichloro-3-pyridinyl)o
  • compounds of formula V are disclosed wherein Y is CH 2 ; Z is a covalent bond; and R 1 and R are as defined in formula I. In another embodiment of the present invention, compounds of formula V are disclosed wherein Y is a covalent bond; Z is CH ; and R ⁇ and R are as defined in formula I. In another embodiment of the present invention, compounds of formula V are disclosed wherein Y is CH CH 2 ; Z is a covalent bond; and Rj and R are as defined in formula I. In another embodiment of the present invention, compounds of formula V are disclosed wherein Y is CH ; Z is CH ; and R ⁇ and R 9 are as defined in formula I.
  • compounds of formula V are disclosed wherein Y is a covalent bond; Z is CH 2 CH 2 ; and R t and R 9 are as defined in formula I.
  • compounds of formula V are disclosed wherein Y and Z are as defined in formula I; R is selected from hydrogen and lower alkyl wherein hydrogen and methyl are preferred; Ri is
  • Rj j s s lected from hydrogen or halogen;
  • R is selected from hydrogen, halogen, and lower alkyl;
  • R 5 is selected from hydrogen, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, lower alkenyl, lower alkoxyalkyl, lower alkoxy, lower alkyl, lower alkynyl, and nitro.
  • compounds of formula VI are disclosed wherein Y is a covalent bond; Z is a covalent bond; and R ⁇ and R 9 are as defined in formula I.
  • compounds of formula VI are disclosed wherein Y is CH ; Z is a covalent bond; and R and R 9 are as defined in formula I.
  • compounds of formula VI are disclosed wherein Y is a covalent bond; Z is CH ; and R] and R 9 are as defined in formula I.
  • compounds of formula VI are disclosed wherein Y is CH 2 CH 2 ; Z is a covalent bond; and Ri and R are as defined in formula I.
  • compounds of formula VI are disclosed wherein Y is CH 2 ; Z is CH 2 ; and R ⁇ and R are as defined in formula I.
  • compounds of formula VI are disclosed wherein Y is a covalent bond; Z is CH 2 CH 2 ; and Ri and R are as defined in formula I.
  • compounds of formula VI wherein Y and Z are as defined in formula I; R 9 is selected from hydrogen and lower alkyl wherein hydrogen and methyl are preferred; Ri is
  • . 3 j s selected from hydrogen or halogen; is selected from hydrogen, halogen, and lower alkyl;
  • R 5 is selected from hydrogen, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, lower alkenyl, lower alkoxyalkyl, lower alkoxy, lower alkyl, lower alkynyl, and nitro.
  • the following compounds, representative of formula VI may be prepared by one skilled in the art using known synthetic chemistry methodology or by using synthetic chemistry methodology described in the Schemes and Examples contained herein.
  • compounds of formula VII are disclosed wherein Y is a covalent bond; Z is a covalent bond; and R 1 and R 9 are as defined in formula I.
  • Rt is and R 3 , R 4 , R 5 and R are as defined in formula I.
  • compounds of formula VII are disclosed wherein Y is CH 2 ; Z is a covalent bond; and Ri and R 9 are as defined in formula I.
  • Ri is R 3 N R 4 ; and R 3 , R 4 , R 5 and R 9 are as defined in formula I.
  • compounds of formula VII are disclosed wherein Y and Z are as defined in formula I; R is selected from hydrogen and lower alkyl wherein hydrogen and methyl are preferred; Ri is
  • R 5 is selected from hydrogen, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, lower alkenyl, lower alkoxyalkyl, lower alkoxy, lower alkyl, lower alkynyl, and nitro.
  • Representative compounds of formula VII include, but are not limited to:
  • compounds of formula VIII are disclosed wherein Y is CH ; Z is a covalent bond; and Rj and R are as defined in formula I.
  • compounds of formula VIII are disclosed wherein Y is a covalent bond; Z is CH 2 ; and Ri and R 9 are as defined in formula I.
  • R3 j s se ⁇ ec te from hydrogen or halogen;
  • R 4 is selected from hydrogen, halogen, and lower alkyl;
  • R 5 is selected from hydrogen, cyano, cyanoalkyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, lower alkenyl, lower alkoxyalkyl, lower alkoxy, lower alkyl, lower alkynyl, and nitro.
  • the following compounds, representative of formula VIII may be prepared by one skilled in the art using known chemistry methodology or by using chemistry methodology described in the Schemes and Examples contained herein.
  • compounds of formula IX are disclosed wherein Y is a covalent bond; Z is a covalent bond; and Ri and R 9 are as defined in formula I.
  • compounds of formula IX are disclosed wherein Y is CH 2 ; Z is a covalent bond; and Ri and R 9 are as defined in formula I.
  • compounds of formula IX are disclosed wherein Y is a covalent bond; Z is CH ; and Ri and R 9 are as defined in formula I.
  • compounds of formula IX are disclosed wherein Y and Z are as defined in formula I; R is selected from hydrogen and lower alkyl wherein hydrogen and methyl are preferred; Ri is
  • R is selected from hydrogen, halogen, and lower alkyl
  • R 5 is selected from hydrogen, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, lower alkoxy, lower alkyl, lower alkynyl, and nitro.
  • the compounds of formula I-IX may be in either the cis or trans configuration.
  • Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention relates to a method for selectively controlling neurotransmitter release in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I.
  • Another embodiment of the present invention relates to a method of treating a disorder, such as Alzheimer's disease, Parkinson's disease, memory dysfunction, Tourette's syndrome, sleep disorders, attention deficit hyperactivity disorder, neurodegeneration, inflammation, neuroprotection, amyotrophic atral sclerosis, anxiety, depression, mania, schizophrenia, anorexia and other eating disorders, AIDS-induced dementia, epilepsy, urinary incontinence, Crohn's disease, migraines, premenstraul syndrome, erectile dysfunction, substance abuse, smoking cessation and inflammatory bowel syndrome, in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I.
  • Another embodiment of the present invention relates to a method for controlling pain in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention relates to a method for controlling pain in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I in combination with an opioid and a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention relates to a method for controlling pain in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I in combination with a non-steroid anti-inflammatory agent and a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention relates to a method for controlling pain in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I in combination with a tricyclic antidepressant and a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention relates to a method for controlling pain in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I in combination with an anticonvulsant such as gabapentin or pregabalin and a pharmaceutically acceptable carrier.
  • an anticonvulsant such as gabapentin or pregabalin and a pharmaceutically acceptable carrier.
  • alkenyl refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons, preferably 2 to 6 carbon atoms, preferably in a straight chain, and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • alkenyl include, but are not limited to, ethenyl, 2- propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l- heptenyl, and 3-decenyl.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy,
  • alkoxyalkoxy refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein.
  • Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
  • alkoxycarbonyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
  • alkoxycarbonylalkyl refers to an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3- methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-tert-butoxycarbonylethyl.
  • alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and preferably in a straight chain.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylcarbonyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl- 1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
  • alkylcarbonyloxy refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
  • alkylthio refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein.
  • Representative examples of alkylthio include, but are not limited, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, and hexylsulfanyl.
  • alkynyl refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, preferably in a straight chain, and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3- butynyl, 2-pentynyl, and 1-butynyl.
  • amino refers to a -NR 20 R 2 ⁇ group wherein R 20 and R 21 are independently selected from hydrogen, alkyl, and alkylcarbonyl as defined herein.
  • amino include, but are not limited, acetylamino, amino, methylamino, dimethylamino, ethylamino, and methylcarbonylamino.
  • aminoalkyl refers to an amino group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of aminoalkyl include, but are not limited, aminomethyl,
  • aminocarbonyl refers to an amino group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of aminocarbonyl include, but are not limited, aminocarbonyl, dimethylaminocarbonyl, methylaminocarbonyl, and ethylaminocarbonyl.
  • aminocarbonylalkyl refers to an aminocarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • ammocarbonylalkyl include, but are not limited to, 2- amino-2-oxoethyl, 2-(methylamino)-2-oxoethyl, 4-amino-4-oxobutyl, and 4- (dimethylamino)-4-oxobutyl.
  • aminosulfonyl refers to an amino group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of aminosulfonyl include, but are not limited, aminosulfonyl, dimethylaminosulfonyl, methylaminosulfonyl, and ethylaminosulfonyl.
  • aryl refers to a monocyclic-ring system, or a fused bicyclic-ring system wherein one or more of the fused rings are aromatic.
  • Representative examples of aryl include, but are not limited to, azulenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • the aryl groups of the present invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, amino, aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, mercapto, and nitro.
  • substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, amino, aminosulfonyl,
  • carbonyl refers to a -C(O)- group.
  • carboxy refers to a -CO 2 H group.
  • carboxyalkyl refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2- carboxyethyl, and 3-carboxypropyl.
  • cyano refers to a -CN group.
  • cyanoalkyl refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl, and 3-cyanopropyl.
  • formyl refers to a -C(O)H group.
  • formylalkyl refers to a formyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • formylalkyl include, but are not limited to, formylmethyl and 2- formylethyl.
  • halo or halogen
  • halogen refers to -Cl, -Br, -I or -F.
  • haloalkoxy refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • haloalkoxy include, but are not limited to, chloromethoxy, 2- fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • haloalkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • heterocycle refers to a monocyclic, bicyclic, or tricyclic ring system.
  • Monocyclic ring systems are exemplified by any 3- or 4- membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur.
  • the 5-membered ring has from 0-2 double bonds and the 6- and 7-membered ring have from 0-3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidinyl, azepinyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl,
  • Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system.
  • Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofliranyl, benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, indazolyl, indolyl, indolinyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, isoquinolinyl, phthalazinyl, pyranopyridyl,
  • Tricyclic rings systems are exemplified by any of the above bicyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or a monocyclic ring system.
  • Representative examples of tricyclic ring systems include, but are not limited to, acridinyl, carbazolyl, carbolinyl, dibenzofuranyl, dibenzothiophenyl, naphthofuranyl, naphthothiophenyl, oxanthrenyl, phenazinyl, phenoxathiinyl, phenoxazinyl, phenothiazinyl, thianthrenyl, thioxanthenyl, and xanthenyl.
  • heterocycles of the present invention can be substituted with 1, 2,or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, amino, aminosulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, mercapto, and nitro.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl 1 as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety tlirough an alkyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl, and 2-ethyl-4-hydroxyheptyl.
  • lower alkenyl is a subset of alkenyl as defined herein and refers to a straight or branched chain hydrocarbon group containing from 2 to 4 carbon atoms and containing at least one carbon-carbon double bond.
  • Representative examples of lower alkenyl include, but are not limited, to ethenyl, vinyl, allyl, 1-propenyl and 3-butenyl.
  • lower alkoxy is a subset of alkoxy as defined herein and refers to a lower alkyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein.
  • Representative examples of lower alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.
  • lower alkoxyalkyl is a subset of alkoxyalkyl as defined herein and refers to a lower alkoxy group, as defined herein, appended to the parent molecular moiety through a lower alkyl group, as defined herein.
  • Representative examples of lower alkoxyalkyl include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, 2-propoxyethyl, butoxymethyl, and tert-butoxymethyl.
  • lower alkyl is a subset of alkyl as defined herein and refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms. Examples of lower alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.
  • lower alkynyl is a subset of alkynyl as defined herein and refers to a straight or branched chain hydrocarbon group containing from 2 to 4 carbon atoms and containing at least one carbon-carbon triple bond.
  • lower alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, and 3-butynyl.
  • mercapto refers to a -SH group.
  • mercaptoalkyl refers to a mercapto group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of mercaptoalkyl include, but are not limited to, sulfanylmethyl, 2- sulfanylethyl and 3-sulfanylpropyl.
  • nitrogen protecting group refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Nitrogen protecting groups comprise carbamates, amides, N-benzyl derivatives, and imine derivatives. Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc), trifluoroacetyl, and triphenylmethyl (trityl). Commonly used N-protecting groups are disclosed in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • nitro refers to a -NO group.
  • oxy refers to a -O- moiety.
  • sulfonyl refers to a -SO - group.
  • thio refers to a -S- moiety.
  • Compounds of the present invention can exist as stereoisomers, wherein asymmetric or chiral centers are present. Stereoisomers are designated “R” or “S,” depending on the configuration of substituents around the chiral carbon atom.
  • R and S used herein are configurations as defined in (IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45: 13-30).
  • the stereochemistry at the two bridgehead carbon atoms, shown in formula I may independently be either (R) or (S), resulting in a cis or trans configuration, unless specifically noted otherwise.
  • Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers.
  • individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
  • the compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of the present invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • Nicotinic Acetylcholine Receptor Binding Potencies Compounds of the invention were subjected to in vitro assays against the nicotinic acetylcholine receptor as described below and were found to be effective binders to the receptor.
  • the In Vitro protocols for determination of nicotinic acetylcholine channel receptor binding potencies of ligands were determined as follows.
  • Binding of [ H]-cytisine ([ HJ-CYT) to neuronal nicotinic acetylcholine receptors was accomplished using crude synaptic membrane preparations from whole rat brain (Pabreza et al., Molecular Pharmacol., 1990, 39:9). Washed membranes were stored at -80 °C prior to use. Frozen aliquots were slowly thawed and resuspended in 20 volumes of buffer (containing: 120 mM NaCI, 5 mM KC1, 2 mM MgCl 2 , 2 mM CaCl 2 and 50 mM Tris-Cl, pH 7.4 @4 °C). After centrifuging at 20,000x g for 15 minutes, the pellets were resuspended in
  • test compounds were dissolved in water to make 10 mM stock solutions. Each solution was then diluted (1:100) with buffer (as above) and further taken through seven serial log dilutions to produce test solutions from 10 "5 to 10 " ⁇ M. Homogenate (containing 125-150 ⁇ g protein) was added to triplicate tubes containing the range of concentrations of test compound described above and [ 3 H]-CYT (1.25 nM) in a final volume of 500 ⁇ L. Samples were incubated for 60 minutes at 4 °C, then rapidly filtered through Whatman GF/B filters presoaked in 0.5% polyethyleneimine using 3 x 4 mL of ice- cold buffer. The filters are counted in 4 mL of Ecolume® (ICN).
  • ICN Ecolume®
  • Nonspecific binding was determined in the presence of 10 ⁇ M (-)-nicotine and values were expressed as a percentage of total binding.
  • IC 50 values were determined with the RS-1 (BBN) nonlinear least squares curve-fitting program and IC 50 values were converted to Ki values using the Cheng and Prasoff correction of ligand). The results are detailed in Table 1.
  • Table 1 Table 1
  • the hot-plate utilized was an automated analgesia monitor (Model #AHP16AN, Omnitech Electronics, Inc. of Columbus, Ohio). The temperature of the hot plate was maintained at 55 °C and a cut-off time of 180 seconds was utilized. Latency until the tenth jump was recorded as the dependent measure. An increase in the tenth jump latency relative to the control was considered an effect.
  • Table 2 shows the minimally effective dose (MED), among the doses tested, at which a significant effect, as defined above, was observed for compounds of the present invention.
  • the data shows that selected compounds of the invention show a significant antinociceptive effect at doses ranging from 1.9 to 62 ⁇ mol/kg.
  • Phase 1 of the formalin test was defined as the period of time immediately after injection of formalin until 10 minutes after the formalin injection (i.e., 0-10 minutes after formalin).
  • Phase 2 was defined as the 20 minute period from 30 to 50 minutes after formalin injection.
  • the test compound or saline
  • Table 3 shows the minimally effective dose (MED) at which a statistically significant effect was observed for compounds of the present invention.
  • the data shows that selected compounds of the present invention show antinociceptive effect at doses ranging from 0.19 to >19 ⁇ mol/kg.
  • the data in Tables 1, 2 and 3 demonstrates that compounds of the present invention bind to the nicotinic acetylcholine receptor and are useful for treating pain.
  • Compounds of the present invention may also be useful for ameliorating or preventing additional disorders affected by nicotinic acetylcholine receptors such as Alzheimer's disease, Parkinson's disease, memory dysfunction, Tourette's syndrome, sleep disorders, attention deficit hyperactivity disorder, neurodegeneration, inflammation, neuroprotection, amyotrophic atral sclerosis, anxiety, depression, mania, schizophrenia, anorexia and other eating disorders, AIDS-induced dementia, epilepsy, urinary incontinence, Crohn's disease, migraines, PMS, erectile disfunction, substance abuse, smoking cessation and inflammatory bowel syndrome.
  • additional disorders affected by nicotinic acetylcholine receptors such as Alzheimer's disease, Parkinson's disease, memory dysfunction, Tourette's syndrome, sleep disorders, attention deficit hyperactivity disorder, neurodegeneration
  • Dosage forms for topical administration of a compound of the present invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.
  • the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients.
  • therapeutically effective amount means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drags used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the total daily dose of the compounds of the present invention administered to a human or lower animal may range from about 0.001 to about 1000 mg/kg/day.
  • more preferable doses can be in the range of from about 0.001 to about 5 mg/kg/day.
  • the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • the present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. hi some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drag to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h)
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystallme cellulose, aluminum metahydroxide, bentonite, agar-agar, fragacanth and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystallme cellulose, aluminum metahydroxide, bentonite, agar-agar, fragacanth and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Compounds of the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium.
  • any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like.
  • the preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
  • prodrug or "prodrag,”as used herein, represents those prodrags of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Prodrugs of the present invention may be rapidly transformed in vivo to compounds of formula I, for example, by hydrolysis in blood. A thorough discussion is provided in T.
  • esters of compounds of the present invention refers to esters of compounds of the present invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • examples of pharmaceutically acceptable, non-toxic esters of the present invention include C ⁇ -to-C 6 alkyl esters and C 5 -to-C 7 cycloalkyl esters, although C ⁇ -to-C 4 alkyl esters are preferred.
  • Esters of the compounds of formula I may be prepared according to conventional methods.
  • the compounds of the present invention may have activity against disorders which are mediated through the central nervous system.
  • the following references describe various disorders affected by nicotinic acetylcholine receptors: 1) Williams, M.; Arneric, S. P.: Beyond the Tobacco Debate: dissecting out the therapeutic potential of nicotine. Exp. Opin. Invest. Drugs (1996)5(8): 1035-1045; 2) Arneric, S. P.; Sullivan, J. P.; Williams, W.: Neuronal nicotinic acetylcholine receptors. Novel targets for central nervous system theraputics.
  • Psychopharmacology The Fourth Generation of Progress. Bloom FE,
  • Parkinson's disease (references 1, 4 and 5), memory dysfunction, Tourette's syndrome (references 1, 2 and 4), sleep disorders (reference 1), attention deficit hyperactivity disorder (references 1 and 3), neurodegeneration, inflammation, neuroprotection (references 2 and 3), amyotrophic atral sclerosis, anxiety (references 1, 2 and 3), depression (reference 2), mania, schizophrenia (references 1, 2 and 4), anorexia and other eating disorders, AIDS-induced dementia, epilepsy (references 1,2 and 4), urinary incontinence (reference 1), Crohn's disease, migraines, PMS, erectile disfunction, substance abuse, smoking cessation (references 1 and 2) and inflammatory bowel syndrome (references 1 and 4) among others.
  • EtOH for ethanol; eq for equivalents; formalin for a solution of formaldehyde (37% by weight) in water; HPLC for high pressure liquid chromatography; LAH for lithium aluminum hydride; MeOH for methanol; Ms for mesylate (SO 2 CH 3 ); Tf for triflate (SO 2 CF 3 ); TFA for trifluoroacetic acid; THF for tetrahydrofuran; TMS for trimethylsilyl; Ts for tosylate; and
  • Bicyclic diamines of general formula (5) wherein Y and Z are as defined in formula I and P is a nitrogen protecting group such as tert-butoxycarbonyl (Boc), can be prepared as described in Scheme 1.
  • ⁇ -Keto esters of general formula (1), wherein R is lower alkyl such as methyl or ethyl, can be purchased commercially or prepared as described in (J. Chem. Soc.
  • ⁇ -Keto esters of general formula (1) can be treated with benzylamine and then sodium borohydride in the presence of acetic acid to provide ammoalcohols of general formula (2).
  • Ammoalcohols of general formula (2) can be treated with a palladium catalyst such as palladium on carbon under a hydrogen atmosphere to provide ammoalcohols of general formula (3).
  • Ammoalcohols of general formula (3) can be treated with 2.0 equivalents of 2-nitrobenzenesulfonyl chloride in the presence of a base such as triethylamine to provide sulfonamides of general formula (4).
  • Sulfonamides of general formula (4) can be treated with alkyl or aryl mercaptans such as thiophenol to provide monoprotected bicyclic diamines of general formula (5).
  • Bis sulfonates of general formula (7) can be treated with sodium azide and then hydrogenated in the presence of a platinum catalyst such as platinum( ⁇ V) oxide to provide amines of general formula (8).
  • Amines of general formula (8) can be treated with a nitrogen protecting group such as trifluoro acetic anhydride and then treated with sodium hydride to effect ring closure to provide bicyclic diamines of general formula (5).
  • bis sulfonates of general formula (7) can be treated with amines such as benzyl amine to provide bicyclic amines of general formula (5).
  • Octahydropy ⁇ Olo[3,4-c]pyrroles of general formula (10), wherein Pi and P are independently selected from hydrogen or a nitrogen protecting group can be prepared as described in Scheme 3.
  • lH-Pyrrole-2,5-dione can be treated with N-benzyl-N- (methoxymethyl)-N-[(trimethylsilyl)methyl]amine in the presence of a catalytic amoimt of acid such as trifluoroacetic acid to provide 5-benzyltetrahydropyrrolo[3,4-c]pyrrole- l,3(2H,3aH)-dione.
  • the tetrahydropyrrolo[3,4-c]pyrrole can be treated with lithium aluminum hydride to provide octahydropyrrolo[3,4-c]pyrroles of general formula (10).
  • Octahydropyrrolo[3,2-b]pyrroles of general formula (11), wherein Pi and P are independently selected from hydrogen or a nitrogen protecting group, can be prepared as described in (US 5,071,999).
  • Octahydropyrrolo[3,4-b]pyrroles of general formula (12), wherein Pi and P 2 are independently selected from hydrogen or a nitrogen protecting group, can be prepared as described in (Cope and Shen, JACS (1956) 78, 5916-5920).
  • Octahydro-1 H-pyrrolo [3, 4-c]pyridines of general formula (14), wherein Pi and P 2 are independently selected from hydrogen or a nitrogen protecting group can be prepared as described in Scheme 4.
  • lH-Pyrrolo[3,4-c]pyridine-l,3(2H)-dione commercially available, can be treated with a base and a nitrogen protecting group such as benzyl bromide and then treated with a transition metal catalyst such as a platinum catalyst, platinum on carbon for example, under a hydrogen atmosphere to provide 2-benzylhexahydro-lH-pyrrolo[3,4- c]pyridine-l,3(2H)-dione.
  • the dione can then be treated with a reducing agent such as lithium aluminum hydride to provide octahydro-lH-pyrrolo[3,4-c]pyridines of general formula (14).
  • Octahydro-1 H-pyrrolo [3 ,4-b]pyridines of general formula (15), wherein Pi and P 2 are independently selected from hydrogen or a nitrogen protecting group, can be prepared as described in (EP 0603887 A2).
  • Octahydro-lH-pyrrolo[3,2-b]pyridines of general formula (16), wherein Pi and P are independently selected from hydrogen or a nitrogen protecting group can be prepared as described in Scheme 5.
  • lH-Pyrrolo[3,2-b]pyridine prepared as described in (J.Chem.Soc. (1948) 198), can be treated with a nitrogen protecting reagent such as benzyl bromide or di- tert-butyl dicarbonate to provide N-protected pyrrolopyridines which can then be treated with a platinum catalyst such as platinum on carbon under a hydrogen atmosphere to provide octahydro-lH-pyrrolo[3,2-b]pyridines of general formula (16).
  • a nitrogen protecting reagent such as benzyl bromide or di- tert-butyl dicarbonate
  • platinum catalyst such as platinum on carbon under a hydrogen atmosphere
  • lH-Pyrrolo[3,2-c]pyridine prepared as described in (Tetrahedron (1993) 49(4), 2885- 2914) can be processed as described above to provide octahydro-1 H-pyrrolo [3 ,2-c]pyridines of general formula (17).
  • lH-Pyrrolo[2,3-c]pyridine prepared as described in (Synthesis (1996) 877-882) can be processed as described above to provide octahydro-lH-pyrrolo[2,3-c]pyridines of general formula (18).
  • Pi Bn Decahydropyrrolo[2,3-c]azepines of general formula (20), wherein Pi and P 2 are independently selected from hydrogen or a nitrogen protecting group, can be prepared as described in Scheme 6. Benzyl 2,3,3a,4,5,7a-hexahydro-lH-indole-l-carboxylate, prepared as described in (Ronn and Andersson, Tetrahedron Lett., (1995) 36(42) 7749-7752), can be treated with ozone and methyl sulfide to provide the dialdehyde.
  • the dialdehyde can be treated with amines such as benzyl amine in the presence of acetic acid and sodium cyanoborohydride to provide decahydropyrrolo[2,3-c]azepines of general formula (20).
  • Decal ⁇ ydropyrrolo[3,4-c]azepines of general formula (22), wherein Pi and P 2 are independently selected from hydrogen or a nitrogen protecting group, can be prepared as described in Scheme 6.
  • l,5,6,7-Tetrahydro-2H-azepin-2-one prepared as described in (Reimschuessel and Pascale, JOC (1969) 34(4) 959-963), can be treated with a nitrogen protecting reagent and then treated with N-benzyl-N-(methoxymethyl)-N- [(trimethylsilyl)methyl] amine in the presence of a catalytic amount of acid such as trifluoroacetic acid to provide octahydropyrrolo[3,4-c]azepinones of general formula (21).
  • a catalytic amount of acid such as trifluoroacetic acid
  • Octahydropyrrolo[3,4-c]azepinones of general formula (21) can be treated with a reducing agent such as lithium aluminum hydride to provide decahydropyrrolo[3,4-c]azepines of general formula (22).
  • a reducing agent such as lithium aluminum hydride
  • Bicyclic diamines of general formula (26), (28), and (30), wherein Pi and P 2 are independently selected from hydrogen or a nitrogen protecting group can be prepared as described in Scheme 7.
  • [2,7]Naphthyridine prepared as described in (Numata, et. al., Synthesis (1999) 2, 306-311) can be treated with palladium such as palladium on calcium carbonate under a hydrogen atmosphere as described in (Chem.Pharm.BulL, (1958) 6, 408) and then treated with a nitrogen protecting reagent to provide tetrahydro[2,7]naphthyridines of general formula (25).
  • Tetrahydro[2,7]naphthyridines of general formula (25) can be further reduced with platinum on carbon under a hydrogen atmosphere to provide bicyclic diamines of general formula (26).
  • Bicyclic diamines of general formula (32), wherein P 2 is a nitrogen protecting group can be prepared as described in (Org. Mass Spectrum. (1984) 19(9), 459-460).
  • Amino(4- hydroxyphenyl)acetic acid purchased commercially, can be treated with Raney nickel and heat to provide amino(4-hydroxycyclohexyl)acetic acid.
  • Amino(4-hydroxycyclohexyl)acetic acid can be treated with benzoyl chloride and then oxidized with Jones' reagent to provide
  • (benzoylamino)(4-oxocyclohexyl)acetic acid (Benzoylamino)(4-oxocyclohexyl)acetic acid can be subjected to a Beckmann rearrangement using hydroxyl amine and a sulfonyl chloride such as phenyl sulfonyl chloride to provide (benzoylamino)(7-oxo-4-azepanyl)acetic acid.
  • (Benzoylamino)(7-oxo-4-azepanyl)acetic acid can be treated with concentrated HCI and heat to provide 2-amino-3-(2-aminoethyl)hexanedioic acid.
  • 2-Amino-3-(2- aminoethyl)hexanedioic acid can be distilled at 180-200 °C/0.1 torr to provide octahydro[l,7]naphthyridine-2,8-dione.
  • Octahydro[l,7]naphthyridine-2,8-dione can be treated with lithium aluminum hydride and monoprotected with a nitrogen protecting reagent such as acetyl chloride/acetic anhydride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, or benzyl bromide to provide bicyclic diamines of general formula (32).
  • Bicyclic amines of general formula (33), wherein Pi and P 2 are independently selected from hydrogen or a nitrogen protecting group can be prepared as described in (Frydman, et. al, JOC (1971) 36(3), 450-454.
  • Bicyclic diamines of general formula (38), wherein A, B, Y, Z, Ri, and R 9 are as defined in formula I, can be prepared as described in Scheme 9.
  • Bicyclic diamines of general formula (35) from Schemes 1-8, wherein P 2 is a nitrogen protecting group, can be treated with a heterocyclic halide of general formula (36) and a base such as triethyl amine to provide compounds of general formula (37).
  • bicyclic diamines of general formula (35) can be treated with heterocyclic halides of general formula (36), a palladium catalyst, BINAP, and a base such as sodium tert-butoxide as described in (Wagaw and Buchwald, JOC (1996) 61, 7240-7241) to provide compounds of general formula (37).
  • Compounds of general formula (37) can be deprotected and then optionally treated with alkylating or acylating agents to provide bicyclic diamines of general formula (38).
  • R alkyl
  • Bromides of general formula (40) can be treated with an organohthium reagent and trialkyltin chloride to provide starmanes of general formula (41).
  • Stannaries of general formula (41) can be treated with a palladium catalyst and an aryl or heterocyclic halide (or triflate) to provide compounds of general formula (42).
  • Bromides of general formula (40) can also be treated with an organohthium reagent, trialkoxy boranes, and water to provide boronic acids of general formula (43).
  • Boronic acids of general formula (43) can be treated with a palladium catalyst and an aryl or heterocyclic halide (or triflate) to provide compounds of general formula (42).
  • Bromides of general formula (40) can also be treated with a palladium catalyst and aryl or heterocyclic boronic acids (or aryl or heterocyclic starmanes) to provide compounds of general formula (42).
  • Bromides of general formula (40) can also be treated with a palladium catalyst and alkenes or alkynes to provide compounds of general formula (46).
  • Bromides of general formula (40) from Scheme 10, can be further elaborated to nitrides of general formula (48).
  • Nitriles of general formula (48) can be subjected to conditions well known to those skilled in the art of organic chemistry to provide carboxylic acids, esters, amides, and aminomethyl compounds of general formula (49).
  • Aminomethyl compounds of general formula (49) can be treated with trimethylsilyl azide as described in (Wittenberger and Donner, JOC (1993) 58, 4139) to provide tetrazoles of general formula
  • Bromides of general formula (40) from Scheme 10, can also be further elaborated to aldehydes of general formula (50).
  • Aldehydes of general formula (50) can be treated with carbon tetrabromide, triphenylphosphine, and butyllithium as described in (Tetrahedron Lett. (1972) 3769-3772) to provide terminal alkynes of general formula (51).
  • Aldehydes of general formula (50) can also be elaborated in ways well known to those skilled in the art of organic chemistry such as formation of oximes, hydrazones, olefins, and mono and disubstituted amino compounds.
  • Grignard reagents can also be added to aldehydes of general formula (50) to provide secondary alcohols which can be oxidized to ketones.
  • Bromides of general formula (40) from Scheme (10), can be treated with diphenylmethanimine and then treated with acid or treated with a palladium catalyst under a hydrogen atmosphere to provide amines of general formula (54).
  • Amines of general formula (40) from Scheme (10) can be treated with diphenylmethanimine and then treated with acid or treated with a palladium catalyst under a hydrogen atmosphere to provide amines of general formula (54).
  • (54) can be engaged in acylation, sulfonylation, and/or alkylation processes well known to those skilled in the art of organic chemistry. Combinations of alkylations, sufonylations, and acylations maybe employed to prepare other compounds of the present invention.
  • Example 1A cis-5-benzyltetrahydrop yrrolo r3 ,4-clpyrrole- 1 ,3 (2H,3 aHVdione lH-Pyrrole-2,5-dione (8.0 g, 82 mmol) in dichloromethane (220 mL) at 0 °C was treated with trifluoroacetic acid (0.93 g, 8.2 mmol) and then treated with N-benzyl-N- (methoxymethyl)-N-[(trimethylsilyl)methyl]amine (26 g, 110 mmol) prepared according to
  • Example IB cis-2-benzyloctahydrop yrrolo r3 ,4-clpyrrole
  • a suspension of lithium aluminum hydride (2.87 g, 76 mmol) in dry tetrahydrofuran (250 mL) was treated with the product from Example 1A (5.80 g, 25 mmol) portionwise.
  • Example IC tert-butyl cis-5-benzylhexahydropyrrolor3,4-clpyrrole-2(lH)-carboxylate
  • dichloromethane 80 mL
  • di-tert-butyl dicarbonate 5.2 g, 24 mmol
  • the mixture was stirred at ambient temperature for 1.5 hours and then concentrated under reduced pressure.
  • the residue was purified by chromatography (SiO 2 , hexane:ethyl acetate (7:3)) to provide the title compound as a colorless oil (4.89 g, 71% yield).
  • Example ID tert-butyl cis-hexahydropyrrolo [3 ,4-c
  • the product from Example IC (4.89 g, 16.2 mmol) in ethanol (150 mL) was treated with 10% Pd/C (0.45 g) at ambient temperature under a hydrogen (1 arm) overnight.
  • the catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was passed through a small plug of silica gel with ether to provide the title compound as a white solid (3.01 g, 88% yield). !
  • Example IE tert-butyl cis-5-(3-pyridinyl)hexahvdropyrrolo[3,4-c1pyrrole-2(lH)-carboxylate
  • the product from Example ID (0.52 g, 2.45 mmol) in toluene (30 mL) was concentrated by distillation under N (1 atm) to a volume of ⁇ 20 mL.
  • Example IE The product from Example IE (310 mg, 1.07 mmol) in ethanol (5 mL) was treated with a solution of HCI in 1,4-dioxane (4M, 2 mL, 8 mmol) at ambient temperature for 4 hours. The solution was concentrated under reduced pressure, and the residual solid was crystallized from ethanohethyl acetate (1 :5) to provide the title compound as a white solid (203 mg, 72% yield), mp 250-252 °C (dec); 1H NMR (CD 3 OD, 300 MHz) ⁇ 3.32 (m, 4H),
  • Example 2 cis-2-methyl-5-(3-pyridinyl octahv ⁇ ropyrrolo[3,4-c]pyrrole hvdrochloride
  • the product from Example IE (200 mg, 0.69 mmol) was treated with 88% formic acid (1.8 mL) and 37% formalin (3.5 mL) and then warmed to 95 °C for 3 hours.
  • the solution was concentrated under reduced pressure and the resulting pale yellow solid was taken up in 20% aqueous KOH (5 mL) and extracted into ethyl acetate (2 x 20 mL). The organic phases were combined, dried (MgSO 4 ), and concentrated under reduced pressure.
  • Example 3A tert-butyl cis-5-(6-chloro-3-pyridinyl)hexahydropyrrolo[3,4-clpyrrole-2(lH)-carboxylate
  • the product from Example ID (1.70 g, 8 mmol) and 2-choro-5-iodopyridine (2.11 g, 8.8 mmol) prepared as described in (Tetrahedron Lett. (1993), 34, 7493-7496) were processed as described in Example IE to provide the title compound as a yellow solid (1.18 g, 46% yield).
  • MS (DCI/NH 3 ) m/z 324, 326 (M+H) + .
  • Example 3 A The product from Example 3 A (360 mg, 1.11 mmol) in dichloromethane (20 mL) was treated with a solution of HCI in 1,4-dioxane (4M, 2 mL, 8 mmol). After stirring at ambient temperature for 2 hours, the mixture was concentrated under reduced pressure. The yellow solid was crystallized from ethanol: ethyl acetate (2:1) after carbon treatment to provide the title compound as a white solid (198 mg, 69% yield), mp 230-236 °C (dec); 1H NMR
  • Example 4 cis-2-(6-chloro-3-pyridinyl -5-methyloctahv ⁇ o ⁇ yrrolor3,4-clpyrrole dihvdrochloride
  • Example 4A cis-2-(6-chloro-3-pyridinyl)-5-methyloctahydropyrrolo[3,4-c]pyrrole
  • the product from Example 3A (207 mg, 0.64 mmol) was treated with 88% formic acid (1.8 mL) and formalin (3.5 mL) and then heated at 95 °C for 2 hours.
  • Example 5A tert-butyl cis-5-(3-quinolinyl)hexahydropyrrolo[3,4-clpyrrole-2(lH)-carboxylate The product from Example ID (250 mg, 1.18 mmol) and 3-bromoquinoline (270 mg,
  • Example 5B cis-2-(3-quinolinyl)octahvdropyrrolor3,4-clpyrrole dihydrochloride
  • the product from Example 5A (360 mg, 1.06 mmol) in ethyl acetate: ethanol (1:1, 20 mL) was treated with HCl/l,4-dioxane (4M, 3 mL, 12 mmol). After stirring at ambient temperature for 2 hours, the mixture was concentrated under reduced pressure.
  • Example ID 1.0 g, 4.7 mmol
  • 3-(benzyloxy)-5-bromopyridine (1.37 g, 5.2 mmol)
  • Example IE 3-(benzyloxy)-5-bromopyridine
  • Example 6B tert-butyl cis-5-(5-hvdroxy-3-pyridinyl)hexahvdropyrrolo[3,4-c1pyrrole-2(lH)-carboxylate
  • the product from Example 6A (1.3 g, 3.8 mmol) in 2-propanol (100 mL) was treated with 10%) Pd/C (0.65 g) and then shaken under a hydrogen (4 atm) at ambient temperature for 18 hours.
  • the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the residue was triturated with a minimum amount of ethyl acetate and filtered to provide the title compound as a solid (0.76 g, 66% yield).
  • Example 6C cis-2-(5-hvdroxy-3-pyridinyl)octahydropyrrolor3,4-clpyrrole dihydrochloride
  • the product from Example 6B (150 mg, 0.49 mmol) in ethyl acetate:methanol (1:2, 15 mL) was treated with HCl/l,4-dioxane (4M, 1 mL, 4 mmol). The mixture was stirred at ambient temperature overnight and then cooled in ice to complete precipitation. The mixture was filtered to provide the title compound as a white solid (136 mg, 99% yield).
  • Example 7A 3 -bromo-5 -methoxyp yridine A solution of methanol (180 mL) was treated with sodium spheres (4.7 g, 0.20 mol) portionwise, evaporated to dryness, azeotroped with toluene (100 mL), and then concentrated under reduced pressure. The sodium methoxide in dry DMF (130 mL) was treated with 3,5- dibromopyridine (32 g, 135 mmol), from Avocado Chemicals. After heating at 70 °C for 4 hours, the mixture was poured onto ice/water (300 g) and filtered. The filter cake was dried under reduced pressure to provide the title compound (15.6 g, 62% yield). MS (DCI/NH 3 ) m/z 188/190 (M+H) + .
  • Example 7B tert-butyl cis-5-(5-methoxy-3-pyridinyl)hexahvdropyrrolo[3,4-clpyrrole-2(lH)-carboxylate The product from Example ID (300 mg, 1.4 mmol) and the product from Example 7A
  • Example 7B The product from Example 7B (310 mg, 0.97 mmol) was processed as described in Example 5B to provide the title compound as a white crystalline solid (150 mg, 53% yield).
  • Example ID 600 mg, 2.8 mmol
  • product from Example 8A 625 mg, 3.1 mmol
  • Example 8C cis-2-(5-ethoxy-3-pyridinyl octahvdropyrrolo[3,4-clpyrrole dihydrochloride
  • the product from Example 8B (600 mg, 1.8 mmol) in ethyl acetate: ethanol (3:1, 20 mL) was treated with HCl/l,4-dioxane (4M, 3 mL, 12 mmol). After heating to reflux for 1.5 hours, the mixture was cooled in ice and filtered to provide the title compound as a white crystalline solid (435 mg, 79% yield), mp 226-227 °C; 1H NMR (CD 3 OD, 300 MHz) ⁇ 1.57
  • Example 9 cis-2-(5-propoxy-3-pyridinyl)octahydropyr ⁇ olo[3,4-c]pyrrole semi(fumarate)
  • Example 9A 3-bromo-5-propoxypyridine n-Propanol and 3,5-dibromopyridine were processed as described in Example 7 A except that the heating time was extended to 4 hours. The reaction mixture was quenched onto ice/water, extracted with ethyl ether, and concentrated under reduced pressure. The residue was purified on silica gel (hexanes: ethyl acetate, 8:2) to provide the title compound as a colorless oil (25 % yield). MS (DCJ NH 3 ) m/z 216/218 (M+H) + .
  • Example 9B tert-butyl cis-5-(5-propoxy-3-pyridiriyl)hexahvdropyrrolor3,4-c]pyrrole-2(lH)-carboxylate
  • the product from Example ID 300 mg, 1.4 mmol
  • the product from Example 9A 333 mg, 1.5 mmol
  • Example 9C cis-3-(5-propyloxy-3-pyridinyl)-3,7-diazabicyclor3.3.0]octane semi(fumarate)
  • the product from Example 9B (130 mg, 0.38 mmol) in ethyl acetate (8 mL) and ethanol (2 mL) was treated with HCl/l,4-dioxane (4M, 1 mL, 1 mmol). After heating at reflux for 3 hours, the mixture was concentrated under reduced pressure to provide a hygroscopic oil.
  • the oil was coated onto silica gel and eluted with CH 2 Cl 2 :EtOH:NH 4 OH (96:3:0.5) to provide the free base (70 mg).
  • Example 10A The product from Example 10A (9.8g, 56.3 mmol) was treated with aqueous NaOCl (35 mL of 10% solution), water (100 mL), and NaOH (2.40 g, 100 mmol). The reaction mixture was stirred at ambient temperature for 16 hours, quenched with acetic acid (5 ml), and then extracted with ethyl acetate (500 mL). The organic phase was dried (MgSO ) and concentrated under reduced pressure. The residue was purified on SiO 2 (3% MeOH/CH 2 Cl 2 ) to provide the title compound as a yellow solid (11.20 g, 96%). MS (DCI/NH 3 ) m/e 208, 210 (M+H) + .
  • a suspension of sodium hydride (181 mg, 7.5 mmol) in dry DMF (30 mL) and diethyl ether (6 mL) was treated with the product from Example 10B (1.2 g, 5.8 mmol) in diethyl ether (5 mL). After stirring at ambient temperature for 30 minutes, the reaction mixture was treated with a solution of iodomethane (1.06 g, 7.5 mmol) in diethyl ether (3 mL) and stirring was continued for 30 minutes longer. The mixture was quenched with water (20 mL), extracted with diethyl ether (100 mL), dried (MgSO ), and concentrated under reduced pressure.
  • Example 10D tert-butyl cis-5-(6-chloro-5-methoxy-3-pyridinyl)hexahy(hopyrrolo[3,4-clpyrrole-2(lH - carboxylate
  • the product from Example ID (864 mg, 4.1 mmol) and the product from Example IOC (1.0 g, 4.5 mmol) were processed as described in Example IE to provide the title compound (480 mg, 34% yield).
  • Example 10E cis-2-(6-chloro-5-methoxy-3-pyridinyl octahvdropyrrolo[3,4-clpyrrole dihydrochloride
  • the product from Example 10D (480 mg, 1.36 mmol) was processed as described in Example 5B to provide the title compound as a white solid (325 mg, 73%).
  • Example 11A 5 -bromo-2-hvdroxy-3 -methylp yridine 2-Amino-5-bromo-3-methylpyridine (5.0 g, 26.7 mmol) in 2.6M H 2 SO 4 (70 mL) was treated with sodium nitrite (5.0 g, 72.5 mmol) in water (10 mL) dropwise at 0 °C. The mixture was allowed to warm to ambient temperature and stir for 1.5 hours. The mixture was filtered and the filtercake washed with cold water. The filtercake was dissolved in dichloromethane (100 mL), dried (MgSO 4 ), and concentrated to provide the title compound (4.2 g, 84% yield). MS (DCI/NH 3 ) m/z 188/190 (M+H) + .
  • Example 1 IB 5 -bromo-2-chloro-3 -methylp yridine The product from Example 11A (4.1 g, 221.8 mmol) in DMF (40 mL) was treated with phosphorus oxychloride (10 g, 65.4 mmol) dropwise at 0 °C. After heating at 120 °C for 2 hours, the mixture was cooled and poured onto ice/water. The mixture was made basic with NH 4 OH, filtered, and the filtercake washed with ice water. The obtained solid was dissolved in dichloromethane (100 mL), washed with brine, and dried (MgSO ).
  • Example 11C tert-butyl cis-5-(6-chloro-5-methyl-3-pyridinyl)hexahvdropyrrolo[3.4-clpyrrole-2(lH)- carboxylate
  • the product from Example ID (320 mg, 1.5 mmol) and the product from Example 1 IB (340 mg, 1.7 mmol) were processed as described in Example IE to provide the title compound (190 mg, 37% yield).
  • Example 1 ID cis-2-(6-chloro-5-methyl-3-pyridinyl)octahvdropyrrolor3,4-c1pyrrole dihydrochloride
  • the product from Example 1 IC (190 mg, 0.56 mmol) was processed as described in Example 8C to provide, after crystallization from ethyl acetate/methanol, the title compound
  • Example 12B tert-butyl cis-5-r5-(2.2,2-trifluoroethoxy)-3-pyridinyl1hexahvdropyrrolo[3,4-c1pyrrole-2(lH)- carboxylate
  • the product from Example ID 300 mg, 1.4 mmol
  • the product from Example 12A 397 mg, 1.5 mmol
  • Example IE Example IE
  • Example 12C cis-2-[5-(2,2,2-trifluoroethoxy)-3-pyridinylloctahydropyrrolor3,4-clpyrrole dihydrochloride
  • the product from Example 12B (480 mg, 1.24 mmol) was processed as described in Example 8C to provide, after crystallization from ethyl acetate/methanol, the title compound
  • Example 13 A cis-l-benzyl-5-(6-chloro-3-pyridinyl)octahvdropyrrolo[3,4-b]pyrrole cis-l-Benzyloctahydropyrrolo[3,4-b]pyrrole (500 mg, 2.48 mmol), prepared as described in (US 5071999), and 2-chloro-5-iodopyridine (643 mg, 2.69 mmol), prepared as described in (Tetrahedron Lett. (1993), 34, 7493-7496), were processed as described in Example IE to provide the title compound as a tan solid (508 mg, 65%> yield). MS (DCI NH3) m z 314, 316 (M+H) + .
  • Example 13B cis-7-(6-chloro-3-pyridinyl)-2,7-diazabicyclo[3.3.0]octane
  • the product from Example 13A (506 mg, 1.62 mmol) in chloroform (10 mL) was treated with 1-chloroethyl chloroformate (Aldrich; 1.35 mL, 12.5 mmol) at ambient temperature for 15 minutes and then warmed to reflux for 1 hour. The mixture was concentrated under reduced pressure, and the residue was stirred with methanol (10 mL) for 60 hours.
  • Example 13C cis-5-(6-chloro-3-p idinyl)octahvdropyrrolo[3,4-blpyrrole hvdrochloride
  • the product from Example 13B (202 mg, 0.906 mmol) was treated with a solution of HCI in 1,4-dioxane (Aldrich; 4 M, 240 ⁇ L, 0.96 mmol) as described in Example IF to provide the title compound as a white solid (151 mg, 64% yield).
  • Example 14B [( 1 R)- 1 -phenylethyll amino I acetic acid
  • the product from Example 14A (4.5 g; 15.6 mmol) in water (100 mL) was heated to reflux for 18 hours. The mixture was cooled to 30 °C and concentrated under reduced pressure to provide the title compounds as a white solid (2.7 g; 80%> yield).
  • Example 14C ethyl cis-l-r(lR)-l-phenylethyl1hexahydropyrrolo[3,4-blpyrrole-5(lH)-carboxylate
  • the product from Example 14B (27.5 g, 154 mmol) and ethyl allyl(2- oxoethyl)carbamate (26.3 g, 154 mmol), prepared as described in (US 5071999), in toluene
  • Example 14D (3 aR,6aR)- l-fOlRV 1 -phenylethyll octahydrop yrrolo [3 ,4-blpyrrole
  • hydrochloric acid (12N, 200 mL)
  • the more mobile diastereomer from Example 14C (17 g, 59.0 mmol) in hydrochloric acid (12N, 200 mL) was heated in an oil bath at 120 °C for 20 hours. The mixture was cooled to 20 °C and concentrated under reduced pressure to remove excess HCI. The residue was taken in 10% Na 2 CO 3 (100 mL) and extracted with CH 2 C1 (3 x 200 mL). The organic layers were combined, washed with brine, dried (Na CO 3 ), and concentrated.
  • Example 14E (3aR,6aR)-5-r(4-nitrophenyl)sulfonyn-l-[(lR)-l-phenylethylloctahydropyrrolo[3,4- blpyrrole
  • the product from Example 14D was processed as described in Example 15B to provide the title compound.
  • the stereocenters were determined to be (R,R) using X-ray diffraction as described in Example 15B.
  • Example 14F (3aR,6aR -l-r(lR)-l-phenylethyll-5-(trifluoroacetyl)octahvdropyrrolo 3,4-b1pyrrole
  • the product from Example 14D (11.3 g, 52 mmol) and triethylamine (6.8 g, 68 mmol) in anhydrous THF (200 mL) at 0-5 °C was treated with trifluoroacetic anhydride (25.2 g, 63 mmol) dropwise.
  • the reaction mixture was allowed to warm to room temperature overnight.
  • the THF was removed under reduced pressure and replaced with CH C1 2 (200 mL).
  • Example 14G tert-butyl (3 aR,6aR)-5-(trifluoroacetyl)hexahydropyrrolo ⁇ 3 ,4-blpyrrole- 1 (2H)-carboxylate
  • the product from Example 14F (11.2 g; 35.8 mmol) and di-tert-butyl dicarbonate
  • Example 14H tert-butyl (3 aR.6aR -hexahvdropyrrolo [3 ,4-blpyrrole- 1 (2H)-carboxylate
  • the product from Example 14G (9.88 g, 32 mmol) in methanol (200 mL) and water (40 mL) was treated with solid potassium carbonate (4.86 g; 35 mmol). After stirring at 20
  • Example 141 tert-butyl (3 aR,6aR)-5 -(6-chloro-3-p yridinvDhexahydropyrrolo [3 ,4-blpyrrole- 1 (2H)- carboxylate
  • the product from example 14H (2 g, 4.9 mmol) and 2-chloro-5-iodopyridine (1.55 g, 6.5 mmol) were processed as described in Example IE except that a larger amount of sodium tert-butoxide (1.24 g, 12.9 mmol) was used.
  • the crude product was purified by chromatography (SiO 2 , 20% ethyl acetate in pentane) to provide the title compound (600 mg, 38% yield). MS (DCI/NH 3 ) m/z 324/326 (M+H) + .
  • Example 141 The product from Example 141 (211 mg, 0.65 mmol) in ethanol (5 mL) was treated with HCI in 1,4-dioxane (4M, 2 mL, 8 mmol). After stirring at ambient temperature for 4 hours, the solution was concentrated under reduced pressure and the residue crystallized from ethanol :ethyl acetate (1:5) to provide the title compound as a white solid (165 mg, 85% yield).
  • Example 15A (3aS,6aS)-l-r(lR)-l-phenylethylloctahydropyrrolor3,4-blpyrrole
  • the less mobile diastereomer from Example 14C was processed as described in
  • Example 14D to provide the title compound as a brownish oil (11.3 g,76% yield). MS (DCI/NH 3 ) m/z 217 (M+H) + .
  • Example 15B (3aS,6aS)-5-r(4-nitrophenyl)sulfonyll-l-[(lR)-l-phenylethylloctahydropyrrolor3,4-blpyrrole
  • the product from Example 15A 148 mg, 0.68 mmol
  • triethyl amine (0.15 mL, 1.08 mmol
  • dichloromethane 5 mL
  • 4-nitrobenzenesulfonyl chloride 166 mg, 0.75 mmol
  • Example 15C (3aS.6aS)-l-r(lR)-l-phenylethyll-5-(trifluoroacetyl)octahvdropyr ⁇ olor3,4-blpyrrole
  • the product from Example 15 A (11.3 g, 52 mmol) was processed as described in
  • Example 15D was processed as described in the Example 14H to provide the title compound.
  • Example 15F tert-butyl (3aS,6aS)-5-(6-chloro-3-pyridinyl)hexahvdropyrrolo
  • Example 15E was processed as described in the Example 141 to provide the title compound (49% yield).
  • Example 15G (3aS.6aS -5-(6-chloro-3-pyridinyl)octahvdropyrrolo[3,4-blpyrrole dihydrochloride
  • the product from example 15F was processed as described in the example 14J to provide the title compound (45% yield).
  • Example IE (1993), 34, 7493-7496), were processed as described in Example IE to provide the title compound as a tan foam (750 mg, 89% yield). MS (DCI/NH 3 ) m/z 324, 326 (M+H) + .
  • Example 16B cis- 1 -(6-chloro-3-pyridinyl)octahydropyrrolo r3 ,4-blpyrrole
  • dichloromethane 10 mL
  • trifluoroacetic acid 10 mL
  • Example 16B The product from Example 16B (368 mg, 1.65 mmol) was treated with a solution of HCI in 1,4-dioxane (Aldrich; 4 M, 0.43 mL, 1.72 mmol) as described in Example IF to provide the title compound as a white solid (300 mg, 70% yield).
  • Example 18 A (2S,3S)-l-(tert-butoxycarbonyl -3-hvdroxy-2-pyrrolidinecarboxylic acid trans-3 -Hydroxy (L)-proline (10.0 g, 76.3 mmol) in THF (50 mL) was treated with sodium hydroxide (3.36 g, 84 mmol) in water (34 mL) at ambient temperature. After 10 minutes of stirring, the mixture was treated with di-tert-butyl dicarbonate (16.63 g, 76.3 mmol) portionwise. After stirring at ambient temperature for 10 hours, the mixture was concentrated under reduced pressure, acidified to pH 2-3 with saturated KHSO 4 (aq), and extracted with ethyl acetate (2x200 mL). The organic extracts were combined, washed with brine (2x30 mL), and concentrated to provide the title compound as a white solid (12.3 g, 70%, yield), mp 156-157 °C.
  • Example 18B tert-butyl (2R,3 S)-3 -hvdroxy-2-(hvdroxymethvD- 1 -p yrrolidinecarboxylate
  • the product from Example 18A (7.73 g, 33.5 mmol) in dry THF (100 mL) was treated with borane-methyl sulfide complex (10M in THF, 7.4 mL, 74 mmol) dropwise over 10 minutes.
  • the solution was warmed to reflux for 1 hour, then cooled to 10-20 °C.
  • Example 18C tert-butyl (2R,3S)-3-[(methylsulfonvnoxyl-2- ⁇ r(methylsulfonyl oxylmethyl>-l- pyrrolidinecarboxylate
  • the product from Example 18B (4.6 g, 21.2 mmol) and triethylamine (9.0g, 89.0 mmol) in dichloromethane (100 mL) 0 °C was treated with methansulfonyl chloride (4.9 mL, 63.5 mmol) over 20 minutes. After stirring at ambient temperature overnight, the mixture was quenched with saturated sodium bicarbonate (50 mL) and extracted with dichloromethane (2x100 mL).
  • Example 18D tert-butyl (lR,5R)-6-benzyl-2,6-diazabicyclor3.2.01heptane-2-carboxylate
  • the product from Example 18C (4.5g, 12 mmol) in anhydrous toluene (100 mL) was treated with benzylamine (7.7g, 36 mmol) and heated at reflux for 20 hours. After cooling to ambient temperature, the mixture was filtered off and the filtrate was concentrated. The residue was purified by chromatography (SiO 2 , hexanes:ethyl acetate 40:60) to provide the title compound as a white solid (2.4 g, 70% yield).
  • Example 18E (lR,5R)-6-benzyl-2,6-diazabicyclor3.2.01heptane
  • the product from Example 18D (1.00 g, 3.4 mmol) in ethanol (10 mL) was treated with 12M HCI (1 mL) and heated at 50 °C for 1 hour. After cooling to ambient temperature, the mixture was concentrated under reduced pressure and then azeotroped from isopropyl acetate. The residue was purified by recrystallization from isopropyl acetate:heptane (1:1) to provide a white solid (0.74g, 84% yield).
  • Example 18F (lR,5R -6-benzyl-2-(3-pyridinyl)-2,6-diazabicyclo[3.2.01heptane
  • the product from Example 18E (260 mg, 1.0 mmol) and 3-bromopyridine were processed as described in Example IE, except that a larger amount of sodium tert-butoxide (384 mg, 4.0 mmol) was used to neutralize the salt.
  • the crude product was purified by chromatography (SiO 2 , CH 2 Cl :MeOH, 95:5, R 0.3) to provide the title compound (0.26 g, 98% yield).
  • Example 18F The product from Example 18F (0.26g, 0.98 mmol) in ethanol (10 mL) was treated with 10%) Pd/C (0.13g) under a hydrogen atmosphere at 50 °C for 16 hours. After cooling to ambient temperature, the mixture was filtered through diatomaceous earth with an ethanol (2x10 mL) rinse. The filtrate was concentrated under reduced pressure and the brown residue in isopropyl alcohol (10 mL) was treated with 4-methylbenzenesulfonic acid monohydrate
  • Example 18D The product from Example 18D (1.25 g, 4.3 mmol) in ethanol (25 mL) was treated with 10%) Pd/C (0.25 g) under a hydrogen atmosphere at 60 °C for 16 hours. The mixture was filtered through diatomaceous earth with an ethanol rinse (2x10 mL). The filtrate was concentrated under reduced pressure to provide the title compound as a yellow oil (0.85 g, 99% yield).
  • Example 19B tert-butyl (lR,5R)-6-(6-chloro-3-pyridinyl)-2,6-diazabicvclor3.2.01heptane-2-carboxylate
  • the product from Example 19A 200 mg, 1.0 mmol) and 2-chloro-5-iodopyridine (288 mg, 1.2 mmol), prepared as described in (Tetrahedron Lett.
  • Example 19C (lR,5R)-6-(6-chloro-3-pyridinyl)-2,6-diazabicyclo[3.2.01heptane bis(4-methylbenzenesulfonate
  • the product from Example 19B (250 mg, 0.83 mmol) in ethanol (10 mL) was treated with 4-methylbenzenesulfonic acid monohydrate (480 mg, 2.49 mmol). The mixture was heated to reflux for 2 hours, cooled to 25 °C, and concentrated under reduced pressure.
  • Example 20A tert-butyl (lR,5R)-6-(3-pyridinyl)-2,6-diazabicyclo[3.2.01heptane-2-carboxylate
  • the product from Example 19A 200 mg, 1.0 mmol
  • 3-bromopyridine 190 mg, 1.2 mmol
  • Example IE 99% yield
  • Example 20A The product from Example 20A was processed as described in Example 19C to provide the title compound (0.32 g, 62% yield).
  • Example 22A tert-butyl cis-6-(6-chloro-3-pyridinyl)octahvdro-lH-pyrrolo[3,4-blpyridine-l-carboxylate
  • tert-Butyl cis-octahydro-lH-pyrrolo[3,4-b]pyridine-l-carboxylate (374 mg, 1.65 mmol), prepared as described in (EP0603887A2) and 5-bromo-2-chloropyridine (314 mg, 1.65 mmol), prepared as described in (Tetrahedron Lett. (1998), 39, 2059-2062) were processed as described in Example IE to provide the title compound (273 mg, 49% yield).
  • MS (DCI/NH3) m/z 338/340 (M+H) + .
  • Example 22A The product from Example 22A in methanol (1 mL) was treated with a solution of HCI in ether (IN, 4 mL, 4 mmol). The mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. The resulting solid was crystallized from ethanol/diethyl ether to provide the title compound (191 mg, 76%> yield).
  • Example 23A tert-butyl cis-6-(3 -pyridinvDoctahydro- 1 H-pyrrolo[3 ,4-blpyridine- 1 -carboxylate
  • the product from Example 22A 232 mg, 1.03 mmol
  • 3-bromopyridine 162 mg, 1.03 mmol
  • Example 23B cis-6-(3-pyridinyl)octahvdro-lH-pyrrolor3,4-blpyridine dihydrochloride
  • the product from Example 23A in methanol (1 mL) was treated with a solution of HCI in ether (IN, 4 mL, 4 mmol). The mixture was stirred at ambient temperature for 3 hours and then concentrated under reduced pressure. The resulting solid was crystallized from ethanol/diethyl ether to provide the title compound (169 mg, 83% yield).
  • Example 24A tert-butyl (3 aR,6aR)-5-(5 ,6-dichloro-3 -pyridinvDhexahydrop yrrolo ⁇ 3 ,4-blpyrrole- 1 (2H)- carboxylate
  • Example 24B (3aR,6aR)-5-(5,6-dichloro-3-pyridinyl)octahydropyrrolo[3,4-blpyrrole hvdrochloride
  • the product from Example 24A was processed as described in Example 14J to provide the title compound (65% yield).
  • Example 15E The product from Example 15E and 2,3-dichloro-5-iodopyridine, prepared as described in (US 5,773,912), were processed as described in Example IE (41% yield) to provide the title compound.
  • Example 26B (3aS,6aS)-5-(6-chloro-5-methyl-3-pyridinyl)octahvdropyrrolo[3,4-blpyrrole hydrochloride
  • the product from Example 26 A was processed as described in Example 14J to provide the title compound (42% yield).
  • Example 27A The product from Example 27A was processed as described in Example 14J to provide the title compound. (40% yield).
  • Example 14H 800 mg, 1.96 mmol
  • 3-bromopyridine 400 mg, 2.5 mmol
  • the crude product was purified by chromatography (SiO , 4% MeOH in CH 2 C1 2 ) to provide the title compound as a pale yellow solid (400 mg, 70%).
  • Example 28B (3aR,6aR)-5-(3-pyridinyl)octahvdropyrrolo[3,4-blpyrrole dihydrochloride
  • the product from Example 28 A 400 mg, 1.38 mmol) in ethanol (3 mL) was treated with HCl/l,4-dioxane (4 M, 4 mL). After stirring at 20 °C for 2 hours, the mixture was concentrated under reduced pressure. The yellow oily residue was purified by chromatography (SiO 2 , 90:10:1 CH 2 Cl 2 :MeOH:NH 4 OH) to provide the free base as a pale oil (208 mg).
  • Example 29A tert-butyl (3 aR,6aR)-5-(5-methoxy-3-pyridinyl)hexahydropyrrolo[3 ,4-blpyrrole- 1 (2H)- carboxylate
  • the product from Example 14H (0.80 g, 1.96 mmol) and 3-bromo-5-methoxypyridine (478 mg, 2.54 mmol) from Example 7A were processed as described in Example IE (with the modification that 2.1 eq. of sodium t-butoxide (400 mg, 4.2 mmol) was used) to provide the title compound as a pale yellow oil (0.62 g, 100% yield).
  • Example 29B (3aR,6aR)-5-r5-methoxy-3-pyridinyl)octahydropyrrolo[3,4-blpyrrole dihydrochloride
  • the product from Example 29A (620 mg, 1.96 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid(lO-mL). After stirring at ambient temperature for 2 hours, the mixture was concentrated under reduced pressure. The resulting yellow oil was purified by flash chromatography (89:10:1 CH 2 Cl 2 :MeOH:NH 4 OH) to provide the free base as a pale oil (210 mg).
  • Example 30A tert-butyl (3aS,6aS)-5-(3-pyridinyl)hexahvdropyrrolor3,4-blpyrrole-l(2H)-carboxylate
  • the product from Example 15E (0.71g, 3.30 mmol) in toluene (33 mL) was treated with tris(dibenzylideneacetone)dipalladium(0) (Pd (dba) 3 , available from Alfa Aesar) (61 mg, 0.10 mmol), 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (BINAP, available from Strem Chemicals) (83 mg, 0.10 mmol), 3-bromopyridine (available from Aldrich Chemical Co.,) (0.58 g, 3.70 mmol), and sodium tert-butoxide (available from Aldrich Chemical Co.,) (0.54 g, 5.60 mmol).
  • Example 30 B (3aS,6aS)-5-(3-pyridinyl)octahydropy ⁇ olor3,4-blpyrrole 4-methylbenzenesulfonate
  • the product from Example 30A (0.87 g, 3.0 mmol) in CH 2 C1 2 (10 mL) was treated with trifluoroacetic acid (10 mL). After stirring at ambient temperature for one hour, the mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , 10%MeOH/CH 2 Cl 2 /l%NH 4 OH) to provide the free base of the title compound as a colorless oil (0.45g, 79% yield).
  • Example 31 A tert-butyl (3aS,6aS)-5-(5-bromo-3-pyridinyl)hexahvdropyrrolo 3,4-blpyrrole-l(2H)- carboxylate
  • Example 15E The product from Example 15E (0.56g, 2.70 mmol) in toluene (27 mL) was treated with tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 , available from Alfa Aesar) (50 mg, 0.10 mmol), 2,2'-bis(diphenylphospl ⁇ ino)-l,l '-binaphthyl (BINAP, available from Strem Chemicals) (68 mg, 0.10 mmol), 3,5-dibromopyridine (available from Aldrich Chemical Co.,) (0.69 g, 2.90 mmol) and sodium tert-butoxide (available from Aldrich Chemical Co.,) (0.44 g, 4.60 mmol).
  • Pd 2 (dba) 3 available from Alfa Aesar
  • BINAP 2,2'-bis(diphenylphospl ⁇ ino)-l,l '-binaph
  • Example 31A The product from Example 31A (0.47 g, 1.30 mmol) in CH 2 C1 2 (10 mL) was treated with trifluoroacetic acid (10 mL). After stirring at ambient temperature for one hour, the mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , 10%MeOH/CH 2 Cl 2 /l %NH 4 OH) to provide the free base of the title compound as a colorless oil (0.32 g, 91% yield). The salt was formed by combination with 4- metnhybenzenesulfonic acid and crystallized from ethanohethyl acetate (1:10) to provide the title compound as a light brown solid.
  • Example 15E The product from Example 15E (0.549 g, 2.30 mmol) in toluene (23 mL) was treated with tris(dibenzylideneacetone)dipalladium(0) (Pd (dba) 3 , available from Alfa Aesar) (43 mg, 0.10 mmol), 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (BINAP, available from Strem Chemicals) (58 mg, 0.10 mmol), 3-bromo-5-methoxypyridine from Example 7A (0.43 g, 2.30 mmol) and sodium tert-butoxide (available from Aldrich Chemical Co.,) (0.38 g, 3.90 mmol). After heating at 80 °C for 16 hours, the mixture was poured into diethyl ether (100 mL), washed with brine (100 mL), dried (MgSO 4 ) and concentrated under reduced pressure.
  • Example 32B (3aS,6aS -5-(5-methoxy-3-pyridinyl)octahydropyrrolo[3,4-blpyrrole 4- methylbenzenesulfonate
  • the product from Example 32A (0.47 g, 1.50 mmol) in CH 2 C1 2 (10 mL) was treated with trifluoroacetic acid (10 mL). After stirring at ambient temperature for one hour, the mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , 10%MeOH/CH 2 Cl 2 /l %NH 4 OH) to provide the free base of the title compound as a colorless oil (0.22g, 63%> yield).
  • Example 33A 1 -tert-butyl 4-ethyl 3-oxo-l,4-piperidinedicarboxylate Ethyl l-benzyl-3-oxopiperidine-4-carboxylate hydrochloride (24.16 g, 81.1 mmol ) in ethanol (250 mL) was treated with triethyl amine (11.3 mL, 81.1mmol), di-tert-butyl dicarbonate (18.6g, 85.3 mmol) and 10% Pd/C (0.13g). After stirring under H 2 (1 atm) at 50 °C for 1 hour, the mixture was allowed to cool to ambient temperature and filtered through diatomaceous earth with an ethanol (2x20 mL) rinse.
  • Example 33B tert-butyl 3-hydroxy-4-(hvdroxymethyl)-l-piperidinecarboxylate
  • the product from Example 33A (10.84 g, 40 mmol) in methanol (200 mL) was treated with sodium borohydride (9.12 g, 240 mmol) slowly over 20 minutes at 0-10 °C.
  • the mixture was allowed to warm to ambient temperature and stirred for 20 hours.
  • the mixture was concentrated under reduced pressure, treated with water (50 mL), and extracted with chloroform (2x100 mL).
  • the organic phase was concentrated under reduced pressure to provide the title compound (8.0 g, 86% yield).
  • Example 33D tert-butyl (cis)-8-benzyl-3,8-diazabicvclo[4.2.01octane-3-carboxylate
  • the product from Example 33C (5.8 g, 15 mmol) in anhydrous toluene (100 mL) was treated with benzylamine (4.8 g, 45 mmol). After heating at reflux for 20 hours, the mixture was allowed to cool to 25 °C and then filtered. The filtrate was concentrated and the residue purified by chromatography (SiO 2 , hexanes:ethyl acetate, 40:60) to provide the title compound as a brown oil (0.73 g, 15% yield). MS (DCI NH 3 ) m/z 303 (M+H) + .
  • Example 33E (cis)- 8 -benzyl-3 , 8 -diazabicyclo f4.2.01 octane 4-methylbenzenesulfonate
  • the product from Example 33D (0.30 g, 1.0 mmol) in ethanol (10 mL) was treated with 4-methylbenzenesulfonic acid monohydrate (0.57g, 3 mmol). After heating at 80 °C for
  • Example 33E and 3-bromopyridine were processed according to the procedure of Example IE, except that a larger amount of sodium tert-butoxide (384 mg, 4.0 mmol) was used.
  • the residue was purified by chromatography (SiO 2 , hexanes: ethyl acetate, 20:80, R f 0.2) to provide the title compound (0.16g, 57% yield).
  • Example 36A The product of Example 36A (980 mg, 2.66 mmol) was treated with ethynyltrimethylsilane (0.73 mL, 5.2 mmol) in dry DMF (15 mL) in the presence of PdCl 2 (Ph 3 P) 2 (93.4 mg, 0.133mmol), cuprous iodide (25.3 mg, 0.133 mmol) and triethylamine (1.0 g, 9.9 mmol) at 56-60 °C for lhr. The mixture was diluted with water and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried (MgSO 4 ), filtered and the filtrate evaporated under reduced pressure.
  • PdCl 2 (Ph 3 P) 2 93.4 mg, 0.133mmol
  • cuprous iodide 25.3 mg, 0.133 mmol
  • triethylamine 1.0 g, 9.9 mmol
  • Example 35B tert-butyl (3 aR,6aR)-5-(5 -ethynyl-3-p yridinvDhexahydropyrrolo ⁇ ,4-blpyrrole- 1 (2H)- carboxylate
  • the product of Example 35A (550 mg, 1.42 mmol) in dry tetrahydrofuran (10 mL) was treated with tetrabutyl ammonium fluoride (4 mL, 4mmol, 1M solution in tetrahydrofuran) at room temp for 1 hour.
  • Example 35C (3aR,6aR)-5-(5-ethvnyl-3-pyridinyl)octahvdropyrrolo[3,4-blpyrrole hydrochloride dihydrochloride
  • the product of Example 35B (280 mg, 0.89 mmol) was processed according to the procedure of the example 14J to provide the title compound (180 mg, 94% yield).
  • Example 36A tert-butyl r3aR,6aR -5-(5-bromo-3-pyridinyl)hexahvdropyrrolo[3,4-blpyrrole-l(2H)- carboxylate
  • the product of Example 14H 910 mg, 4.3mmol
  • 3,5-dibromopyridine 1.0 g, 4.3 mmol
  • Example 36B (3aR,6-u )-5-(5-bromo-3-pyridinyl)octahydropyrrolor3,4-blpyrrole dihydrochloride
  • the product of Example 36A (210 mg, 0.57 mmol) was processed according to the procedure of Example 14J to provide the title compound (169 mg, (87% yield).
  • Example 37 5-((3aR,6aR)-hexahvdropyrrolor3,4-blpyrrol-5(lH)-yl)nicotinonitrile
  • Example 37A 3 -bromo-5 -c yanopyridine
  • Phosphorus oxychloride 5 ml was added to 5-bromonicotinamide (2 g, 10 mmol, Avocado Research Chemicals, Ltd.) and the mixture was heated to gentle reflux for 3 hours.
  • Example 14H The product of Example 14H (1.7 g, 8 mmol) and 3-bromo-5-cyanopyridine (1.46 g, 8 mmol, from Example 37A) were processed according to the procedure described for Example IE, to provide the title compound (600 mg, 24% yield). MS (DCI/NH 3 ) m/z 315 (M+H) + .
  • Example 38A benzyl 2,2-dimethoxyethylcarbamate Benzyl chloroformate (231.3 g, 1.3 mol) was added gradually to a mixture of aminoacetaldehyde dimethyl acetal (152.0 g, 1.3 mol) in toluene (750 mL) and aqueous
  • Example 38B benzyl allyl(2,2-dimethoxyethyl)carbamate
  • the product of Example 38 A (281.0 g, 1.18 mol) in dry toluene (1.0 L) was treated with powdered KOH (291.2 g, 5.20 mol) and triethylbenzylammonium chloride (4.4 g, 0.02 mol).
  • a solution of allyl bromide (188.7 g, 1.56 mol) in toluene (300 mL) was then added dropwise over 1 hour at 20-30 °C. The mixture was stirred overnight at room temperature and then water (300 mL) was added over 20 minutes at 20-30 °C .
  • Example 38C benzyl allyl(2-oxoethyl)carbamate
  • Example 38D benzyl allyl[2-(hvdroxyimino)ethyllcarbamate
  • the product of Example 38C (260 g, 1.115 mol) in acetonitrile (1.5 L) was treated with sodium acetate trihydrate (170.6 g, 4.41 mol, in 0.75L distilled water) and NH 2 OH hydrochloride (98.0 g, 4.41 mol) under N 2 .
  • the mixture was stirred at room temperature over 20 hours.
  • the volatiles were removed under reduced pressure and the residue was extracted with ethyl acetate (2 x 750 mL).
  • the organic phase was concentrated to provide the title compound as an oil (271 g, 98% yield).
  • Example 38E benzyl (cis)-3-amino-4-(hvdroxymethyl)-l-pyrrolidinecarboxylate
  • xylene 1.0 L
  • Example 38F benzyl (cis -3-r(tert-butoxycarbonyl)aminol-4-(hvdroxymethyl)-l-pyrrolidinecarboxylate
  • the product of Example 38E (7.0 g, 28 mmol) in ethanol (50 mL) was treated with
  • Example 38G benzyl (cis)-3 -r(tert-butoxycarbonyl)aminol -4- ⁇ r(methylsulfonyl oxylmethyl ⁇ - 1 - pyrrolidinecarboxylate
  • the product of Example 38F (4.80 g, 13.7 mmol) in CH C1 2 (60 mL) was treated with triethylamine (2.77 g, 27.4 mmol). The mixture was stirred at room temperature over 5 minutes, cooled down to -10 °C and then treated with methanesulfonyl chloride (1.73 g, 15.1 mmol) in CH 2 C1 2 (10 mL) dropwise over 10 minutes.
  • Example 381 3 -benzyl (cis)- 6-tert-butyl 3 ,6-diazabicyclo [3.2.01heptane-3 ,6-dicarboxylate
  • the product of Example 38H in ethanol (25 mL) was treated with 5% aqueous NaOH
  • Example 38J tert-butyl (cis)-3,6-diazabicyclor3.2.01heptane-6-carboxylate
  • methanol 30 mL
  • 10%) palladium on carbon 0.23 g
  • the catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated to provide the title compound as a yellow oil. (1.27 g, 92% yield).
  • Example 38J 150 mg, 0.75 mmol
  • 3-bromopyridine were processed according to the procedure described in Example IE.
  • the crude product was purified by chromatography (SiO 2 , CH 2 C1 2 : MeOH, 95:5, R f . 0.3) to provide the title compound (110 mg, 53% yield), which was used directly in the next step without further purification.
  • Example 39A The product of Example 39A (300 mg, 2.8 mmol) in tetrahydrofuran (10 mL) was treated with sodium bis(trimethylsilyl)amide (5.5 mL, 1M solution in tetrahydrofuran) at room temperature followed by addition of di-tert-butyl dicarbonate (605 mg, 2.8 mmol). The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water (20 mL). The organic layer was separated, dried (MgSO 4 ) and concentrated under reduced pressure.
  • Example 39C tert-butyl 2-hydroxy-2,3-dihydro- lH-pyrrolor2,3-clpyridine- 1 -carboxylate
  • the product of Example 39B (900 mg, 4.32 mmol) in tetrahydrofuran (20 mL) was cooled to -40 °C and treated with n-butyllithium (5.4 mL, 1.6M solution in hexane, 8.6 mmol) at -40 °C.
  • the mixture was allowed to warm to room temperature over 2 hours and then N,N-dimethylformamide (0.2 mL) was added.
  • the reaction mixture was stirred for 0.5 hours, poured into water (20 mL) and extracted with ethyl acetate (100 mL).
  • Example 39D tert-butyl lH-pyrrolo[2,3-clpyridine-l-carboxylate
  • the product of Example 39C (1.5 g, 6.4 mmol) and triethylamine (1.6 g, 15.8 mmol) in methylene chloride (50 mL) were treated with methanesulfonyl chloride (0.54 ml, 7 mmol). After stirring at room temperature for 18 hours, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x lOOmL). The organic layer was dried (MgSO 4 ) and concentrated under reduced pressure.
  • Example 39D The product of Example 39D (360 mg, 1.65 mmol) in methanol (10 mL) was treated with 10%) palladium on carbon (750 mg) and agitated under H 2 (4 atm) for 3 days. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide the title compound (240 mg, 64% yield). MS (DCI/NH 3 ) m/z 227 (M+H) + .
  • Example 39F tert-butyl 6-(3-pyridinyl)octahydro-lH-pyrrolo 2,3-clpyridine-l-carboxylate
  • the product of Example 39E (226 mg, 1.0 mmol) and 3-bromopyridine (158 mg, 1.0 mmol) were processed according to the procedure described in Example IE to provide the title compound (60 mg, 20% yield).
  • Example 39G (cis)-6-(3-pyridinyl)octahydro-lH-pyrrolor2,3-clpyridine dihydrochloride
  • the product of Example 39F (60 mg, 0.19 mmol) was processed according to the procedure of Example 14J to provide the title compound (37 mg, 71% yield).
  • Example 40 (cis)-6-(3-pyridinyl)-3,6-diazabicvclor3.2.01heptane fumarate
  • Example 40A benzyl (cis -3,6-diazabicyclo[3.2.01heptane-3-carboxylate
  • CH 2 C1 2 5 mL
  • trifluoroacetic acid 5 mL
  • the mixture was concentrated and the residue was diluted with CHCI 3 (50 mL).
  • Example 40B benzyl (cis)-6-(3-pyridinyl -3,6-diazabicvclor3.2.01heptane-3-carboxylate
  • the product of Example 40A 230 mg, 1.0 mmol
  • the crude product was purified by chromatography (SiO 2 , CH 2 C1 2 : MeOH, 95:5, R f .
  • Example 40C 6-(3-pyridinyl)-3,6-diazabicvclo[3,2,01heptane
  • MeOH MeOH
  • 10% palladium on carbon 120 mg
  • the mixture was filtered and the filtrate was concentrated to provide the title compound as a brown oil (65 mg, 94% yield).
  • Example 40D (cis)-6-(3-pyridinyl)-3,6-diazabicyclo 3.2.01heptane fumarate
  • the product of Example 40C (65 mg, 0.37 mmol) was treated with fiimaric acid (46.4 mg, 0.4 mmol) in methanol/isopropylacetate (1:10 v/v, 20 mL). The mixture was stirred at room temperature overnight.
  • Example 41 A tert-butyl (cis)-3-(6-chloro-3-pyridinyl)-3,6-diazabicvclor3.2.01heptane-6-carboxylate
  • the product of Example 38J 150 mg, 0.75 mmol
  • 5-bromo-2-chloropyridine were processed according to the procedure described in Example IE.
  • Example 4 IB (cis)-3-(6-chloro-3-pyridinyl)-3,6-diazabicyclor3.2.01heptane
  • Example 41 C (cis)-3-(6-chloro-3-pyridinyl)-3,6-diazabicvclor3.2.01heptane fumarate
  • the product of Example 41B (90 mg, 0.43 mmol) was treated with fumaric acid (53.0 mg, 0.47 mmol) according to the procedure described in Example 40D to privde the title compound (100.2 mg, 73% yield).
  • Example 42A tert-butyl (cis)-3-(benzylamino)-4-(hydroxymethyl)- 1 -piperidinecarboxylate Benzylamine (17.8 g, 0.166 mol) and the product of Example 33A (41.0 g, 0.151 mol) in a mixture of acetic acid (27.3 g, 0.454 mol) and CH 2 C1 2 (600 mL) were treated with solid
  • Example 42B tert-butyl (cis)-3-amino-4-(hvdroxymethyl)- 1 -piperidinecarboxylate
  • the product of Example 42A 28.2 g, 0.088 mol) in ethanol (400 mL) was treated with 10% palladium on carbon (2 g) and the mixture was stirred under H 2 at 50 °C for 4 hours.
  • the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to provide the title compound (18.0 g, 89%).
  • Example 42C tert-butyl (cis)-8-r(2-nitrophenyl)sulfonyll-3,8-diazabicvclo[4.2.01octane-3-carboxylate
  • a solution of the product of Example 42B (11.2 g, 48.7 mmol) in triethylamine (14.8 g, 146 mmol) and CH 2 C1 2 (500 mL) was treated with 2-nitrobenzenesulfonyl chloride (23.6 g, 107 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was taken up in ethanol (150 mL) and treated with potassium carbonate (7.4 g, 53.6 mmol). After stirring at room temperature for 40 hours, the solids were removed by filtration and the filtrate was concentrated to provide the title compound (6.1 g, 30% yield). MS (DCI/NH 3 ) m/z 415 (M+NH 4 ) + .
  • Example 42D benzvKcis)-8-r(2-nitrophenyl)sulfonvn-3,8-diazabicvclor4.2.01octane-3-carboxylate
  • the product of Example 42C (1.25 g, 3.2 mmol) in CH 2 C1 2 (20 mL) was treated with trifluoroacetic acid (20 mL) and the solution was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was taken up in 5%> NaOH
  • Example 42E benzyl (cis)-8-(te_rt-butoxycarbonyl)-3,8-diazabicyclo 4.2.01octane-3-carboxylate
  • the product of Example 42D (3.1 g, 7.2 mmol) in DMF (25 mL) was treated with K CO 3 (2.98 g, 21.6 mmol) and thiophenol (0.95 g, 8.6 mmol) and allowed to stir at room temperature for 16 hours.
  • the mixture was further treated with di-tert-butyl dicarbonate (3.14 g, 14.4 mmol) and allowed to stir for an additional 4 hours at room temperature.
  • Example 42F tert-butyl (cis)-3,8-diazabicyclo[4.2.01octane-8-carboxylate
  • methanol 10 mL
  • Example 42G tert-butyl (cis)-3-(6-chloro-3-pyridinyl)-3,8-diazabicvclor4.2.01octane-8-carboxylate
  • 2-chloro-5-bromopyridine 0.319 g, 1.70 mmol
  • Pd (dba) 3 0.22 g, 0.03 mmol
  • BINAP 0.038 g, 0.010 mmol
  • sodium tert-butoxide (0.29 g, 3.0 mmol
  • Example 43A tert-butyl (3aR,6aR -5-(6-bromo-5-methoxy-3-pyridinyl hexahvdropyrrolo[3,4-blpyrrole- l(2H)-carboxylate hydrochloride
  • the product of Example 29A (260 mg, 0.81 mmol) at 0-5 °C in acetonitrile (8 mL) was treated with N-bromosuccinimide (215 mg , 1.2 mmol) precooled to 0-5 °C in acetonitrile (4 mL). The mixture was allowed to warm to room temperature over 1 hour and then concentrated under reduced pressure. The residue was purified by chromatography
  • Example 43B tert-butyl (3 aR, 6aR)-5 -(6-bromo-5 -methoxy-3 -pyridinyDhexahydropyrrolo ⁇ ,4-blp yrrole- l(2H)-carboxylate hydrochloride
  • the product of Example 43 A (200 mg, 0.5 mmol) was processed according to the procedure described in Example 14J to provide the title compound (142.5 mg, 78%> yield).
  • Example 44A tert-butyl (cis)-3,8-diazabicyclo[4.2.01octane-3-carboxylate
  • DMF dimethyl methyl
  • K CO 3 2.62 g, 18.9 mmol
  • thiophenol 0.84 g, 7.6 mmol
  • the mixture was allowed to stir at room temperature for 12 hours.
  • the mixture was poured into diethyl ether (100 mL) and washed with brine (4 x 50 mL).
  • the organic phase was dried (MgSO 4 ), filtered and the filtrate concentrated under reduced pressure.
  • Example 44B tert-butyl (cis)-8-(3-pyridinyl)-3,8-diazabicyclof4.2.01octane-3-carboxylate
  • the product of Example 44A (0.090 g, 0.40 mmol) in toluene (14 mL) was treated with 3-bromopyridine (0.074 g, 0.50 mmol), Pd 2 (dba) 3 (8.0 mg, 0.008 mmol), BINAP (11 mg, 0.010 mmol) and sodium tert-butoxide (0.70 g, 0.7 mmol) and heated at 80 °C for 12 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure.
  • Example 44B The product of Example 44B (0.15 g , 0.5 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (10 mL), stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , 10% methanol/CH 2 Cl 2 /l%NH 4 OH) to provide a yellow oil (0.09 g) in 99% yield. The bis(4- methylbenzenesulfonate) salt was formed to afford a white solid. 1H NMR (MeOH, 300
  • Example 45A tert-butyl (cis)-8-(6-chloro-3-pyridinyl)-3,8-diazabicvclo[4.2.01octane-3-carboxyate
  • the product of Example 44A (0.391 g, 1.8 mmol) in toluene..(50 mL) was (0.391 g,
  • Example 45B (cis)-8-(6-chloro-3-pyridinyl)-3,8-diazabicvclor4.2.01octane bis(4-methylbenzenesulfonate
  • the product of Example 45A (0.215 g , 0.7 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (20 mL), stirred at room temperature for 1 hour and > concentrated under reduced pressure. The residue was purified by chromatography (SiO , 10% methanol/CH 2 Cl 2 /l%NH 4 OH) to provide a yellow oil (0.1 OOg) in 67% yield.
  • the bis(4- methylbenzenesulfonate) salt was formed to afford a yellow foam.
  • Example 46 (cis -6-(6-chloro-3-pyridinyl)-3,6-diazabicyclo[3.2.01heptane fumarate
  • Example 46A benzyl (cis -6-(6-chloro-3-pyridinyl)-3,6-diazabicyclo[3.2.01heptane-3-carboxylate
  • the product of Example 40A (0.8 g, 3.4 mmol) and 2-chloro-5-bromopyridine (0.98 g, 5.1 mmol) was processed according to the procedure described in Example IE.
  • Example 46B 6-(6-chloro-3-pyridinyl)-3,6-diazabicyclor3,2,01heptane
  • the product of Example 46A 250 mg, 0.73 mmol was treated with trifluroacetic acid (10 mL) at ambient temperature and allowed to stir for 50 hours. The mixture was concentrated and the residue was purified by chromatography (SiO 2 , CH 2 Cl 2 :methanol:_NH 3 -H 2 O, 90:10:1, R f 0.4) to provide the title compound(140 mg, 86% yield).
  • Example 46B (cis)-6-(6-chloro-3-pyridinyl)-3,6-diazabicyclor3.2.01heptane fi ⁇ marate
  • fumaric acid (78.4 mg, 0.70 mmol) according to the procedure described in Example 40D to provide the title compound (195 mg, 99% yield).
  • Example 47A tert-butyl (lS,6R)-8-(6-chloro-3-pyridinyl)-3,8-diazabicvclo[4.2.01octane-3-carboxylate
  • the product of Example 61F (212 mg, 1.0 mmol) and 5-bromo-2-chloropyridine were processed according to the procedure described in Example IE.
  • the crude product was purified by chromatography (SiO 2 , hexane:ethyl acetate, 60:40, R f 0.45) to provide the title compound (220 mg, 68% yield).
  • Example 47B (lS,6R -8-(6-chloro-3-pyridinyl)-3,8-diazabicyclo[4.2.01octane difumarate
  • Example 48 (lR,6S)-8-(6-chloro-3-pyridinyl -3,8-diazabicvclor4.2.01octane fumarate
  • Example 48A tert-butyl (lR,6S -8-(6-chloro-3-pyridinyl)-3,8-diazabicvclo[4.2.01octane-3-carboxylate
  • 2-chloro-5-brornopyridine 0.08 g, 1.60 mmol
  • Pd 2 (dba) 3 (0.28 g, 0.03 mmol)
  • BINAP 0.038 g, 0.010 mmol
  • sodium tert-butoxide 0.246 g, 2.60 mmol
  • Example 48B (lR,6S)-8-(6-chloro-3-pyridinyl -3,8-diazabicyclo[4.2.01octane fumarate
  • dichloromethane 10 mL
  • trifluoroacetic acid 10 mL
  • the residue was purified by chromatography (SiO 2 , methanol:CH 2 Cl 2 :NH 4 OH, 10:89:1) to provide a colorless oil (0.119g) in 53% yield.
  • the fumarate salt was formed to afford a white foam.
  • Example 49A tert-butyl (lR,6S -3,8-diazabicvclor4.2.01octane-8-carboxylate
  • the product of Example 90B was processed according to the procedures of Examples 42D, 42E, and 42F to provide the title compound.
  • Example 49B tert-butyl (lR,6S)-3-(6-chloro-3-pyridinyl)-3,8-diazabicyclo[4.2.01octane-8-carboxylate
  • the product of Example 49A (0.265 g, 1.30 mmol) in toluene (13 mL) was treated with 2-chloro-5-bromopyridine (0.263 g, 1.40 mmol), Pd 2 (dba) 3 (0.0.24 g, 0.03 mmol), BINAP (0.032 g, 0.010 mmol) and sodium tert-butoxide (0.204 g, 2.10 mmol) and heated at 80 °C for 16 hours.
  • Example 50A tert-butyl (lR,6S)-8-(5-cvano-3-pyridinyl)-3,8-diazabicvclo[4.2.01octane-3-carboxylate
  • the product from Example 90C (0.726 g, 3.40 mmol) in toluene (34 mL) was treated with 3-cyano-5-bromo ⁇ yridine (0.748 g, 4.10 mmol), Pd 2 (dba) 3 (0.0.63 g, 0.10 mmol),
  • Example 50A 5-r(lR,6S)-3,8-diazabicvclo[4.2.01oct-8-yllnicotinonitrile fumarate
  • dichloromethane 10 mL
  • trifluoroacetic acid 10 mL
  • the reaction mixture was purified by chromatography (SiO 2 , methanol:CH 2 Cl 2 :NH 4 OH, 10:89: 1) to provide a colorless oil (0.062 g) in 41% yield.
  • the fumarate salt was formed to afford a white foam.
  • Example 51 A tert-butyl (3aR,6aR)-5-(6-bromo-5-cyano-3-pyridinyl)hexahvdropyrrolo[3,4-blpyrrole-
  • Example 5 5-((3 aR,6aR)-hexahydropyrrolo [3 ,4-blpyrrol-5 ( lH)-yl)-2-bromonicotinonitrile fumarate
  • the product of Example 51A 250 mg, 0.63 mmol) in methylene chloride (4 mL) was treated with trifluoroacetic acid (2 mL) at room temperature for 2 hours.
  • the solution was concentrated under reduced pressure and the residue was purified by chromatography (SiO , CH 2 C1 2 .methanol :NH 4 OH (a q ) , 94:5:1) to provide the free base of the title compound
  • Example 52B benzyl (3S,4S “ )-3-[(tert-butoxycarbonyl)aminol-4-(hvdroxymethyl)-l-pyrrolidinecarboxylate
  • the product of Example 52A (56 g, 127 mmol) in ethanol (50 mL) was treated with 5% aqueous H SO (100 mL) at room temperature and allowed to stir for 16 hours.
  • the mixture was basified to pH ⁇ 10 with 20% aqueous NaOH (50 mL) and then the mixture was treated with di-t-butyl dicarbonate (41.5 g, 190 mmol) in ethanol (50 mL) 10-20 °C.
  • Example 52C benzyl (3 S ,4S)-3 -[(tert-butoxycarbonyl aminol -4- ⁇ [(methylsulfonvDoxylmethyll - 1 - pyrrolidinecarboxylate
  • the product of Example 52B (43.7 g, 125 mmol) and triethylamine (25.2 g, 250 mmol) in CH 2 C1 2 (600 mL) was treated with methanesulfonyl chloride (12.6 L, 163 mmol) over 30 minutes at -10 °C.
  • the solution was allowed to warm to room temperature over 1 hour and then quenched with water (100 mL).
  • the layers were separated and the aqueous phase was extracted with CH 2 C1 2 (2 x 400 mL).
  • Example 52D benzyl (lS,5S)-3,6-diazabicvclor3.2.01heptane-3-carboxylate
  • CH 2 C1 2 150 mL
  • trifluoroacetic acid 50 mL
  • the mixture was concentrated under reduced pressure and the residue was dissolved in ethanol (250 mL) and basified to pH -10 with 10% aqueous NaOH.
  • the mixture was warmed to 60 °C at 10 hours.
  • the reaction was allowed to cool to room temperature and was concentrated under reduced pressure to remove most of the ethanol.
  • the residue was extracted with CHC1 3 (2 x 500 mL).
  • Example 52D The product of Example 52D (230 mg, 1.0 mmol) and 3-bromopyridine were processed according to the procedure described in Example IE.
  • the crude product was purified by chromatography (SiO 2 , CH 2 Cl 2 :methanol, 95:5, R f . 0.3) to provide the title compound (190 mg, 61% yield).
  • Example 52E The product of Example 52E (190 mg, 0.61mmol) in methanol (10 mL) was treated with 10%) palladium on carbon (100 mg) under H 2 according to the procedure described in Example 40C.
  • the title compound was obtained as a yellow oil (100 mg, yield, 94%>).
  • Example 52G (lR,5S)-6-(3-pyridinyl)-3,6-diazabicyclo[3.2.01heptane fumarate
  • the product (100 mg, 0.57 mmol) of Example 52F was treated with fumaric acid according to the procedure of Example 40D. The title compound was obtained as white solid
  • Example 53 A benzyl (IS, 5S)-6-(5-bromo-3-pyridinyl)-3,6-diazabicyclor3.2.01heptane-3-carboxylate
  • the product of Example 52D (230 mg, 1.0 mmol) and 3,5-dibromopyridine were processed as described in Example IE.
  • the crude product was purified by chromatography (SiO 2 , ethyl acetate, R f 0.2) to provide the title compound (180 mg, 47% yield).
  • Example 53C ( 1 R, 5 S)-6-(5-bromo-3-p yridin yl)-3 , ⁇ -diazabicycloP .2. Olheptane fumarate
  • Example 53B The product of Example 53B (100 mg, 0.57 mmol) was treated with fumaric acid according to the procedure described in Example 40D. The title compound was obtained as a white solid (100 mg, 48% yield).
  • Example 54A The product of Example 54A (6.2 g, 14 mmol) was treated with 5% aqueous H 2 SO 4 for 2 hours, then neutralized with 20% aqueous NaOH, and treated with di-tert-butyl dicarbonate according to the procedure described in Example 52B. The title compound was obtained as a slightly yellow oil (4.4 g, yield, 90%).
  • Example 54C benzyl (3R,4R)-3-[(tert-butoxycarbonyl)aminol-4- ⁇ [(methylsulfonyl)oxylmethyl)-l- pyrrolidinecarboxylate
  • the product of Example 54B (4.2 g, 12 mmol) was treated with methanesulfonyl chloride according to the procedure described in Example 38G.
  • the title compound was obtained as a brown oil (5.10, 99% yield).
  • Example 54C The product of Example 54C (5.10 g, 11.9 mmol) was processed according to the procedure of Example 52D.
  • the crade product was purified by chromatography (SiO 2 , CH 2 Cl 2 :MeOH:NH 4 OH, 90:10:1, R f 0.1) to provide the title compound (1.91g, 69% yield).
  • Example 54E benzyl (lR,5R)-6-(6-chloro-3-pyridinyl)-3,6-diazabicvclor3.2.01heptane-3-carboxylate
  • the product of Example 54D (230 mg, 1.0 mmol) and 2-chloro-5-bromopyridine were processed according to the procedure described in Example IE.
  • the crade product was purified by chromatography (SiO 2 , ethyl acetate:hexane, 50:50, R f 0.4) to provide the title compound (120 mg, 35% yield).
  • Example 54F (lS,5R -6-(6-chloro-3-pyridinyl -3,6-diazabicyclo[3.2.01heptane
  • the product of Example 54E 120 mg, 0.35 mmol
  • the crude product was purified by chromatography (SiO 2 , CH 2 Cl 2 :MeOH:NH 4 OH, 90:10:1, R f 0.2) to provide the title compound(70 mg, yield, 94%).
  • Example 54G (IS, 5R -6-(6-chloro-3-pyridinyl)-3,6-diazabicyclo[3.2.01heptane fumarate
  • the product of Example 54F (70 mg, 0.33 mmol) was treated with fumaric acid according to the procedure of Example 46C.
  • Example 55 A benzyl (lR,5R -6-(3-pyridinyl)-3,6-diazabicyclo[3.2.01heptane-3-carboxylate
  • the product of Example 54D (230 mg, 1.0 mmol) and 3-bromopyridine were processed according to the procedure described in Example IE.
  • the crade product was purified by chromatography (SiO 2 , CH 2 Cl 2 :MeOH, 95:5, R f 0.2) to provide the title compound (210 mg, 68% yield).
  • Example 55A The product of Example 55A (210 mg, 0.68mmol) in methanol (10 mL) was treated with palladium on carbon under H 2 according to the procedure described in Example 40C. The title compound was obtained as oil (1 lOmg, 92% yield).
  • Example 55B The product of Example 55B (105 mg, 0.60 mmol) was treated with fumaric acid according to the procedure described in Example 40D. The title compound was obtained as a white solid (155 mg, 90% yield).
  • Example 56A tert-butyl (3aR,6aR)-5-(5-bromo-3-pyridinyl)hexahydropyrrolo[3,4-blpyrrole-l(2H)- carboxylate
  • the product of Example 14H (4.50 g, 21.2 mmol) in toluene (200 mL) was refluxed with a Dean-Stark trap to remove any water.
  • Example 56B tert-butyl (3aR,6aR)-5-(5-vinyl-3-pyridinyl)hexahvdropyrrolo[3,4-blpyrrole-l(2H)- carboxylate
  • the product of Example 56A (2.40 g, 6.52 mmol) and Pd(PPh 3 ) 4 (0.301 g, 0.261 mmol) in toluene (50 mL) were treated with tributylvinyltin (2.87 mL, 9.78 mmol).
  • the solution was warmed to 100 °C and allowed to stir for 36 hours.
  • the reaction mixture was allowed to cool to ambient temperature, filtered through Celite and concentrated under reduced pressure.
  • Example 56C (3 aR,6aRV 5-(5-vinyl-3 -pyridinvDoctahydropyrrolo [3 ,4-blpyrrole
  • the product of Example 56B (0.500 g, 1.59 mmol) in CH 2 C1 2 (5 mL) at 0 °C was treated with trifluoroacetic acid (1 mL) dropwise via syringe. The mixture stirred at 0 °C for 2 hours and then concentrated under reduced pressure. The residue was purified via chromatography (SiO 2 , 9:1:0.1 CH 2 Cl 2 :CH 3 OH:NH 4 OH) to provide the title compound (0.180 g, 0.836 mmol, 52% yield).
  • Example 56D (3aR,6aR)-5-(5-vinyl-3-pyridinyl)octahvdropyrrolo[3,4-blpyrrole dihydrochloride
  • the product of Example 56C (0.170 g, 0.790 mmol) in ethyl acetate (5 mL) was treated with 4N HCI in 1 ,4-dioxane (2 mL).
  • the precipitate which formed immediately upon addition of the acid, was isolated via filtration and was recrystallized from methanol and ethyl acetate to provide the title compound (0.190 g, 0.620 mmol, 79% yield).
  • Example 57A benzyl (IS, 5S)-6-(6-chloro-3-pyridinyl)-3,6-diazabicvclo[3.2.01heptane-3-carboxylate
  • the product of Example 52D (0.23 g, 1.0 mmol) and 2-chloro-5-bromopyridine (0.29 g, 1.5 mmol) were processed according to the procedure described in Example IE.
  • the crade product was purified by chromatography (SiO 2 , hexane:ethyl acetate, 60:40, R f 0.3) to provide the title compound (0.13 g, 38%> yield).
  • Example 57B (lR,5S)-6-(6-chloro-3-pyridinyl -3,6-diazabicyclor3.2.01heptane
  • the product of Example 57A (130 mg, 0.38 mmol) was treated with trifluoroacetic acid according to the procedure of Example 46B.
  • the product was purified by chromatography (SiO 2 , CH 2 Cl 2 :MeOH:NH 4 OH, 90:10:1, R f 0.4) to provide the title compound (70 mg, 88% yield).
  • Example 57C (lR,5S -6-(6-chloro-3-pyridinyl)-3,6-diazabicyclo 3.2.01heptane fumarate
  • the product of Example 57B (70 mg, 0.33 mmol) was treated with fumaric acid according to the procedure described in Example 46C to provide the title compound (195 mg,
  • Example 58B tert-butyl (3 aR, 6aR)-5 -(5 -methyl-3 -pyridi vDhexahydro yrrolo[3 ,4-blpyrrole- 1 (2H)- carboxylate
  • the product of Example 58A (0.880 g, 2.61 mmol) in ethanol (200 proof, 15 mL) was treated with 30 mg of Pd/C (10 wt%) and triethylamine (1.00 mL, 7.17 mmol) under 1 atmosphere of H 2 . After stirring for 36 hours, the mixture was filtered tlirough Celite and the filtrate was concentrated under reduced pressure.
  • Example 58C (3aR,6aR -5-(5-methyl-3-pyridinyl)octahydropyrrolo[3,4-blpyrrole
  • the product of Example 58B (0.500 g, 1.65 mmol) in CH 2 C1 2 (7 mL) at 0 °C was treated with trifluoroacetic acid (1.50 mL) dropwise. The mixture was stirred at 0 °C for 3 hours and then was concentrated under reduced pressure. The residue was purified via chromatography (SiO 2 , 9:1:0.1 CH 2 Cl 2 :CH 3 OH:NH 4 OH) to provide the title compound (0.300 g, 1.48 mmol, 89% yield). MS (DCI NH 3 ) m/z 204 (M+H) + .
  • Example 58D (3aR,6aR)-5-(5-methyl-3-pyridinyl)octahvdropyrrolo[3,4-blpyrrole trihydrochloride
  • the product of Example 58C (0.300 g, 1.48 mmol) in ethyl acetate (5 mL) was treated with 4N HCI in 1,4-dioxane (1 mL).
  • a precipitate formed immediately upon addition of the acid and was isolated via filtration to provide the title compound (0.385 g, 1.10 mmol, 75%> yield). !
  • Example 59 (3aR,6aR -5-(6-bromo-5-chloro-3-pyridinyl)octahvdropyrrolo[3,4-blpyrrole fumarate
  • the product of Example 24A (330 mg, 0.92 mmol) in HBr (30% in AcOH, 5 mL) was heated at 110 °C for 3 hours. The mixture was allowed to cool to room temperature and concentrated to dryness under reduced pressure. The residue was purified by chromatography (SiO 2 , CH 2 C1 2 methanol :NH 4 OH (aq) , 94:5:1) to provide the free base of the title compound (119 mg, 43% yield).
  • Example 58A (3aR,6aR -5-(6-bromo-5-methyl-3-pyridinyl)octahvdropyrrolor3,4-blpyrrole
  • the product of Example 58A (0.250 g, 0.740 mmol) in 30% HBr/acetic acid (20 mL) was warmed to 100 °C in a sealed tube for 4 hours. The mixture was cooled to 0 °C, the contents were transferred to a separatory funnel and the layers were separated.
  • Example 61 A l-tert-butyl 4-ethyl 5- ⁇ r(lS -l-phenylethyllaminoi-3,6-dihydro-l,4(2H)- pyridinedicarboxylate
  • the product of Example 33A (90.4 g, 0.333 mol) in toluene (250 mL) was treated with (S)- -methylbenzylamine (42.4 g, 0.350 mol).
  • the mixture was warmed to reflux with a Dean-Stark trap until the distillate was clear (7 hours) and -7 mL of H 2 O had been collected.
  • the mixture was concentrated under reduced pressure to provide the title compound which was carried on directly to the next step without further purification.
  • Example 61A The product of Example 61A (62.3 g, 0.167 mol), NaBH(OAc) 3 (150.0 g, 0.708 mol), and powdered 4A molecular sieves (133.0 g) in toluene (730 mL) in a 3-neck round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel at 0 °C was treated with acetic acid (191 mL, 3.30 mol) dropwise. After the addition was complete, the ice-bath was removed and the mixture was stirred for 20 hours, filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1000 mL) and quenched by slow addition of saturated aqueous NaHCO 3 .
  • Example 6 ID tert-butyl (3S,4S)-3-amino-4-(hydroxymethyl)-l-piperidinecarboxylate
  • the more mobile diastereomer of Example 61C (13.3 g, 39.8 mmol) in ethanol (200 mL) was treated with 10% Pd/C (1.95 g) under 1 atmosphere of H 2 at 50 °C. After stirring for 20 hours, the mixture was allowed to cool to ambient temperature, filtered through Celite, and the filtrate concentrated under reduced pressure to provide the title compound which was carried on directly to the next step without further purification.
  • Example 61D The product of Example 61D (39.8 mmol) in CH 2 C1 2 (200 mL) at 0 °C was treated with triethylamine (16.7 mL, 0.120 mol) followed by 2-nitrobenzenesulfonyl chloride (19.5 g, 88.0 mmol). The ice-bath was removed and the solution stirred at ambient temperature for 20 hours. The mixture was concentrated under reduced pressure and the residue dissolved in a mixture of ethanol and 5% aqueous NaOH (2:1, 200 mL). The mixture was stirred for 30 minutes, concentrated under reduced pressure, diluted with ethyl acetate (200 mL) and the layers were separated.
  • Example 6 IF tert-butyl (lS,6R -3,8-diazabicvclo[4.2.01octane-3-carboxylate The product of Example 61E (11.0 g, 27.7 mmol) in N,N-dimethylformamide (110 mL) was treated with K 2 CO 3 (11.8 g, 85.8 mmol) followed by thiophenol (3.70 mL, 36.0 mmol) at ambient temperature. The mixture stirred for 20 hours, filtered and the filtrate concentrated under reduced pressure. The residue was -purified via chromatography (SiO 2 ,
  • Example 61F The product of Example 61F (0.780 g, 3.68 mmol) was treated with Pd 2 (dba) 3 (34 mg, 0.0368 mmol), BINAP (69 mg, 0.110 mmol), 3-bromo-5-cyanopyridine (0.810 g, 4.41 mmol), Cs 2 CO 3 (2.60 g, 8.09 mmol) and processed according to the procedure described in Example 56A to provide the title compound (0.630 g, 2.01 mmol, 55% yield). MS (DCI/NH3) m/z 315 (M+H) + .
  • Example 61H 5-[(lS,6R)-3,8-diazabicvclor4.2.01oct-8-yllnicotmonitrile
  • the product of Example 61G (0.630 g, 2.01 mmol) in CH 2 CI 2 (10 mL) was treated with trifluoroacetic acid (7 mL) according to the procedure described in Example 64C to provide tht title compound (0.500 g,>100% yield).
  • Example 611 5-[(lS,6R)-3,8-diazabicvclo[4.2.01oct-8-yllnicotinonitrile fumarate The title compound was prepared according to the procedure described in Example
  • Example 62A tert butyl (cis)-3-(5-cyano-3-pyridinyl)-3,8-diazabicvclo[4.2.01octane-8-carboxylate
  • the product of Example 42F (0.220 g, 1.0 mmol) in (0.220 g, 1.0 mmol) in toluene (10 mL) was treated with 3-cyano-5-bromopyridine (0.206 g, 1.10 mmol), Pd 2 (dba) 3 (0.0.19 g, 0.02 mmol), BINAP (0.026 g, 0.040 mmol) and sodium tert-butoxide (0.170 g, 1.80 mmol) and heated at 80 °C for 4 hours.
  • Example 62B (cis)-5-r3,8-diazabicvclor4.2.01oct-3-yllnicotinonitrile fumarate
  • the product of Example 62A (0.212 g , 0.70 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (10 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO 2 , methanol: CH 2 Cl 2 :NH 4 OH, 10:89:1) to provide a yellow oil (0.059 g) in 39%o yield. The fumarate salt was formed to afford an off-white foam.
  • Example 63A tert-butyl (3aR,6aR)-5-(5-ethyl-3-pyridinyl)hexahydropyrrolor3,4-blpyrrole-l(2H)- carboxylate
  • the product of Example 56B (1.00 g, 3.17 mmol) and Pd/C (0.100 g, 10 wt%) in ethanol (20 mL) were placed under 1 atmosphere of hydrogen. After stirring at ambient temperature for 5 hours, the mixture was filtered through Celite and the filtrate concentrated under reduced pressure to provide the title compound (0.900 g, 2.84 mmol, 89%> yield).
  • Example 63B (3aR,6aR -5-(5-ethyl-3-pyridinyl)octahvdropyrrolo[3,4-blpyrrole
  • the product of Example 63A (0.360 g, 1.13 mmol) in CH 2 CI 2 (10 mL) was treated with trifluoroacetic acid (3 mL) dropwise at 0 °C.
  • the mixture was stirred at 0 °C for 1 hour, allowed to warm to ambient temperature and stirred an additional 3 hours.
  • Example 64B tert-butyl (3aR,6aR)-5-[6-bromo-5-(hvdroxymethyl)-3-pyridinyllhexahvdropyrrolor3,4- blpyrrole-l (2H)-carboxylate
  • the product of Example 64A (1.11 g, 3.48 mmol) in CH 3 CN (30 mL) was treated with N-bromosuccinimide (0.606 g, 3.41 mmol) in CH 3 CN (10 mL) dropwise -10 °C. The mixture was stirred for 1 hour at -10 °C and then was quenched with H 2 O (10 mL).
  • Example 64C [5-((3aR,6aR -hexahydropy ⁇ olo[3,4-blpyrrol-5(lH)-yl)-2-bromo-3-pyridinyllmethanol
  • the product of Example 64B (0.143 g, 0.359 mmol) in CH 2 CI 2 (5 mL) was treated with trifluoroacetic acid (5 mL) dropwise at 0 °C. After the addition, the mixture was allowed to warm to ambient temperature and stirred for 2 hours.
  • Example 65A tert-butyl (3aR,6aR)-5-(6-bromo-5-vinyl-3-pyridinyl)hexahydropyrrolo[3,4-blpyrrole-l(2H)- carboxylate
  • the product of Example 56B (0.550 g, 1.74 mmol) in CH 3 CN (10 mL) was treated with solid N-bromosuccinimide (0.330 g, 1.83 mmol). The mixture was stirred at ambient temperature for 1 hour, quenched with water and extracted with CH 2 CI 2 . The organic phase was dried over Na 2 SO 4 , filtered and the filtrate concentrated under reduced pressure. The residue was purified via chromatography to provide the title compound (0.210 g, 0.533 mmol, 31% yield). MS (DCI/NH 3 ) m/z 394 (M+H) + .
  • Example 65B (3aR,6aR -5-(6-bromo-5-vinyl-3-pyridinyl)octahydropyrrolo 3,4-blpyrrole
  • the product of Example 65A (0.200 g, 0.507 mmol) in CH 2 C1 2 (5 mL) was treated with trifluoroacetic acid (2 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 3 hours and then was concentrated under reduced pressure. The residue was purified via chromatography (SiO 2 , 9:1:0.1 CH 2 Cl 2 :CH 3 OH:NH 4 OH) to provide the title compound (0.140 g, 0.476 mmol, 94% yield). MS (DCI/NH 3 ) m/z 295 (M+H) + .
  • Example 65C (3aR,6aR)-5-(6-bromo-5-vinyl-3-pyridinyl)octahydropyr ⁇ olo[3 ,4-blpyrrole dihydrochloride
  • the product of Example 65B (0.140 g, 0.476 mmol) in ethyl acetate (10 mL) was treated with 4N HCI in 1,4-dioxane (1 mL). The mixture was stirred at ambient temperature for 15 minutes and then concentrated under reduced pressure. The crade material was crystallized from CH 3 OH and ethyl acetate to provide the title compound (50.0 mg, 0.130 mmol, 27% yield).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Addiction (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Gynecology & Obstetrics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP01944118A 2000-04-27 2001-04-27 Diazabicyclic central nervous system active agents Withdrawn EP1284976A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP10177450A EP2298775A1 (en) 2000-04-27 2001-04-27 Diazabicyclic central nervous system active agents
EP10177411A EP2295437A1 (en) 2000-04-27 2001-04-27 Diazabicyclic central nervous system active agents

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US55994300A 2000-04-27 2000-04-27
US559943 2000-04-27
US833914 2001-04-12
US09/833,914 US6809105B2 (en) 2000-04-27 2001-04-12 Diazabicyclic central nervous system active agents
PCT/US2001/013798 WO2001081347A2 (en) 2000-04-27 2001-04-27 Diazabicyclic central nervous system active agents

Publications (1)

Publication Number Publication Date
EP1284976A2 true EP1284976A2 (en) 2003-02-26

Family

ID=27072208

Family Applications (3)

Application Number Title Priority Date Filing Date
EP01944118A Withdrawn EP1284976A2 (en) 2000-04-27 2001-04-27 Diazabicyclic central nervous system active agents
EP10177411A Withdrawn EP2295437A1 (en) 2000-04-27 2001-04-27 Diazabicyclic central nervous system active agents
EP10177450A Withdrawn EP2298775A1 (en) 2000-04-27 2001-04-27 Diazabicyclic central nervous system active agents

Family Applications After (2)

Application Number Title Priority Date Filing Date
EP10177411A Withdrawn EP2295437A1 (en) 2000-04-27 2001-04-27 Diazabicyclic central nervous system active agents
EP10177450A Withdrawn EP2298775A1 (en) 2000-04-27 2001-04-27 Diazabicyclic central nervous system active agents

Country Status (22)

Country Link
EP (3) EP1284976A2 (cs)
JP (2) JP4981232B2 (cs)
KR (4) KR100947187B1 (cs)
CN (3) CN102863441A (cs)
AR (1) AR030421A1 (cs)
AU (2) AU2001266559C1 (cs)
BG (2) BG66151B1 (cs)
BR (1) BR0107246A (cs)
CA (2) CA2683045A1 (cs)
CZ (4) CZ301324B6 (cs)
HK (1) HK1054375A1 (cs)
HU (1) HUP0300602A3 (cs)
IL (3) IL152231A0 (cs)
MX (1) MXPA02010594A (cs)
MY (3) MY145722A (cs)
NO (1) NO324250B1 (cs)
NZ (1) NZ521734A (cs)
PE (1) PE20011305A1 (cs)
PL (2) PL398491A1 (cs)
SK (2) SK287273B6 (cs)
TW (4) TWI311137B (cs)
WO (1) WO2001081347A2 (cs)

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EE05351B1 (et) 1999-12-10 2010-10-15 Pfizer Products Inc. Prrolo[2,3-d]primidiinhendid
SE0100326D0 (sv) * 2001-02-02 2001-02-02 Astrazeneca Ab New compounds
CA2506016C (en) 2002-11-21 2009-03-17 Pfizer Products Inc. 3-amino-piperidine derivatives and processes for their preparation
US7354937B2 (en) 2004-05-21 2008-04-08 Abbott Laboratories (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane
US20040242641A1 (en) * 2003-05-27 2004-12-02 Buckley Michael J. (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane is an effective analgesic agent
US20050261348A1 (en) * 2004-05-21 2005-11-24 Buckley Michael J (1S,5S)-3-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane is an effective analgesic agent
US20050043407A1 (en) * 2003-08-22 2005-02-24 Pfizer Inc Pharmaceutical composition for the prevention and treatment of addiction in a mammal
US20050065178A1 (en) * 2003-09-19 2005-03-24 Anwer Basha Substituted diazabicycloakane derivatives
US7399765B2 (en) 2003-09-19 2008-07-15 Abbott Laboratories Substituted diazabicycloalkane derivatives
GB0322140D0 (en) * 2003-09-22 2003-10-22 Pfizer Ltd Combinations
US8580842B2 (en) 2003-09-30 2013-11-12 Abbott Gmbh & Co. Kg Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them
US20050171079A1 (en) 2004-02-04 2005-08-04 Schrimpf Michael R. Amino-substituted tricyclic derivatives and methods of use
JP2007535553A (ja) 2004-04-29 2007-12-06 アボット・ラボラトリーズ アミノ−テトラゾール類縁体および使用方法
US7351833B2 (en) 2004-07-23 2008-04-01 Abbott Laboratories (1S,5S)-3-(5,6-dichloropyridin-3-yl)-3,6-diazabicyclo[3.2.0]heptane benzenesulfonate
US7425556B2 (en) * 2005-12-20 2008-09-16 Astrazeneca Ab Compounds and uses thereof
US20070184490A1 (en) * 2006-01-17 2007-08-09 Marleen Verlinden Neuronal nicotinic receptor ligands and their use
US7728031B2 (en) 2006-02-24 2010-06-01 Abbott Laboratories Octahydro-pyrrolo[3,4-b]pyrrole derivatives
WO2008028903A2 (en) 2006-09-04 2008-03-13 Neurosearch A/S Pharmaceutical combinations of a nicotine receptor modulator and a cognitive enhancer
US20080167286A1 (en) 2006-12-12 2008-07-10 Abbott Laboratories Pharmaceutical compositions and their methods of use
US8486979B2 (en) 2006-12-12 2013-07-16 Abbvie Inc. 1,2,4 oxadiazole compounds and methods of use thereof
US8076350B2 (en) 2006-12-22 2011-12-13 Abbott Laboratories Spirocyclic azaadamantane derivatives and methods of use
UY30846A1 (es) 2006-12-30 2008-07-31 Abbott Gmbh & Amp Derivados de oxindol sustituidos, medicamentos que los comprenden y uso de los mismos
ATE509931T1 (de) 2007-03-23 2011-06-15 Abbott Lab Azaadamantanester- und carbamatderivate sowie anwendungsverfahren dafür
EP2188288A1 (en) 2007-09-11 2010-05-26 Abbott Laboratories Octahydro-pyrrolo[3,4-b]pyrrole n-oxides
PE20091017A1 (es) 2007-10-31 2009-07-16 Janssen Pharmaceutica Nv Diaminas en puente o fusionadas sustituidas con arilo como moduladores de leucotrieno a4 hidrolasa
EP2604611A1 (en) * 2007-11-21 2013-06-19 AbbVie Inc. N-Biaryl substituted diazabicycloalkane derivatives as agonists of the alpha7 and alpha4beta2 nACh Receptor
US8703774B2 (en) 2007-12-07 2014-04-22 AbbVie Deutschland GmbH & Co. KG Carbamate-substituted oxindole derivatives and use thereof for the treatment of vasopressin-dependent diseases
US8703775B2 (en) 2007-12-07 2014-04-22 AbbVie Deutschland GmbH & Co. KG Amidomethyl-substituted oxindole derivatives and the use thereof for the treatment of vasopressin-dependent illnesses
EP2623504A1 (de) 2007-12-07 2013-08-07 Abbott GmbH & Co. KG 5,6-Disubstituierte Oxindol-Derivate und ihre Verwendung zur Herstellung eines Medikaments zur Behandlung von Vasopressin-abhängigen Erkrankungen
US9023854B2 (en) 2007-12-07 2015-05-05 AbbVie Deutschland GmbH & Co. KG 5-halogen-substituted oxindole derivatives and use thereof for treating vasopressin-dependent diseases
ES2380398T3 (es) 2007-12-18 2012-05-11 Actelion Pharmaceuticals Ltd. Derivados 5-aminociclilmetil-oxazolidin-2-ona
US7939527B2 (en) 2008-04-11 2011-05-10 Janssen Pharmaceutica Nv Thiazolopyridin-2-yloxy-phenyl and thiazolopyrazin-2-yloxy-phenyl amines as modulators of leukotriene A4 hydrolase
US8148408B2 (en) 2008-05-09 2012-04-03 Abbott Laboratories Selective substituted pyridine ligands for neuronal nicotinic receptors
EP2411012A4 (en) * 2009-03-24 2012-08-22 Msd Kk NOVEL AMINOPYRIDINE DERIVATIVES HAVING SELECTIVE INHIBITORY ACTION OF AURORA A
US8399465B2 (en) 2009-05-14 2013-03-19 Janssen Pharmaceutica Nv Compounds with two fused bicyclic heteroaryl moieties as modulators of leukotriene A4 hydrolase
US9040568B2 (en) 2009-05-29 2015-05-26 Abbvie Inc. Pharmaceutical compositions for the treatment of pain
WO2010151815A2 (en) 2009-06-25 2010-12-29 Abbott Laboratories 3,9-diazaspiro[5,5]undecane amides and ureas and methods of use thereof
ES2891543T3 (es) 2009-09-04 2022-01-28 Biogen Ma Inc Inhibidores de la tirosina quinasa de Bruton
KR101859409B1 (ko) 2009-10-23 2018-05-18 얀센 파마슈티카 엔.브이. 오렉신 수용체 조절제로서의 이치환된 옥타하이드로피롤로［3,4-ｃ］피롤
US9062044B2 (en) 2009-10-23 2015-06-23 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators
JP5847087B2 (ja) * 2009-10-23 2016-01-20 ヤンセン ファーマシューティカ エヌ．ベー． オレキシン受容体調節因子としての縮合複素環式化合物
US9586962B2 (en) 2011-04-20 2017-03-07 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo [3,4-C] pyrroles as orexin receptor modulators
AR091273A1 (es) 2012-06-08 2015-01-21 Biogen Idec Inc Inhibidores de pirimidinil tirosina quinasa
KR101655787B1 (ko) 2014-05-08 2016-09-22 대우조선해양 주식회사 선박의 하이브리드 공기조화시스템 및 그 방법, 그리고 이를 포함하는 선박 또는 해양구조물
KR20160021679A (ko) 2014-08-18 2016-02-26 대우조선해양 주식회사 극저온 환경의 장비용 히팅장치 및 방법 그리고 이를 구비하는 선박
CN107108597B (zh) 2014-10-31 2020-04-17 英立维尔英国有限公司 多巴胺d3受体拮抗剂化合物
SG11201807597UA (en) 2016-03-10 2018-10-30 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
SG11201900515PA (en) 2016-07-21 2019-02-27 Biogen Ma Inc Succinate forms and compositions of bruton's tyrosine kinase inhibitors
US11266640B2 (en) * 2017-09-20 2022-03-08 Hangzhou Innogate Pharma Co., Ltd. Polycyclic compound acting as IDO inhibitor and/or IDO-HDAC dual inhibitor
GB201809295D0 (en) 2018-06-06 2018-07-25 Institute Of Cancer Res Royal Cancer Hospital Lox inhibitors
RS65638B1 (sr) 2018-11-14 2024-07-31 Janssen Pharmaceutica Nv Unapređene sintetičke metode pravljenja fuzionisanih heterocikličnih jedinjenja kao modulatora receptora oreksina
JP7390401B2 (ja) * 2019-05-30 2023-12-01 シャンハイ インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズ 縮合環化合物、その製造方法及び用途
CN112047878B (zh) * 2020-10-15 2022-04-19 郑州猫眼农业科技有限公司 4-溴-6-氯吡啶-2-羧酸的制备方法
WO2024189472A1 (en) 2023-03-14 2024-09-19 Janssen Pharmaceutica Nv Improved synthetic methods of making substituted pyrimidine intermediates for synthesis of orexin receptor modulators

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0393424B1 (de) * 1989-04-17 1995-09-27 Bayer Ag Verfahren zur Herstellung von 2,7-Diazabicyclo(3.3.0)octanen
NL9201810A (nl) 1992-10-19 1994-05-16 Dsm Nv Werkwijze voor de omzetting van een olefine of een olefinemengsel.
NO301165B1 (no) 1992-12-25 1997-09-22 Daiichi Seiyaku Co Bicykliske aminderivater og antibakterielle midler inneholdende disse
US5817679A (en) * 1993-04-01 1998-10-06 University Of Virginia 7-Azabicyclo 2.2.1!-heptane and -heptene derivatives as cholinergic receptor ligands
US5478939A (en) * 1994-07-20 1995-12-26 American Cyanamid Company (R,R) and (S,S) 2,5-diazabicyclo [2,2,1]heptane derivatives
US5472958A (en) 1994-08-29 1995-12-05 Abbott Laboratories 2-((nitro)phenoxymethyl) heterocyclic compounds that enhance cognitive function
US5585388A (en) 1995-04-07 1996-12-17 Sibia Neurosciences, Inc. Substituted pyridines useful as modulators of acetylcholine receptors
EP0842178B1 (en) * 1995-07-28 2001-03-28 Abbott Laboratories Furopyridine, thienopyridine, pyrrolopyridine and related pyrimidine, pyridazine and triazine compounds useful in controlling chemical synaptic transmission
GB9519558D0 (en) * 1995-09-26 1995-11-29 Merck Sharp & Dohme Therapeutic agents
JPH09172344A (ja) 1995-12-19 1997-06-30 Murata Mfg Co Ltd 圧電共振子
US5733912A (en) 1997-02-19 1998-03-31 Abbott Laboratories 7A-heterocycle substituted hexahydro-1H-pyrrolizine compounds useful in controlling chemical synaptic transmission
DK0984966T3 (da) * 1997-05-30 2003-05-05 Neurosearch As 9-azabicyclo[3.3.1]non-2-en derivater, som er cholinerge ligander på nikotin-ACh receptorer
CA2289574C (en) * 1997-05-30 2007-04-24 Neurosearch A/S 8-azabicyclo(3,2,1)oct-2-ene and octane derivatives as cholinergic ligands at nicotinic ach receptors
GB9722343D0 (en) * 1997-10-22 1997-12-17 British Telecomm Distributed virtual environment
IL135108A0 (en) * 1997-10-27 2001-05-20 Neurosearch As Heteroaryl diazacycloalkanes as cholinergic ligands at nicotinic acetylcholine receptors
US6632823B1 (en) * 1997-12-22 2003-10-14 Merck & Co., Inc. Substituted pyridine compounds useful as modulators of acetylcholine receptors
AU2892999A (en) * 1998-04-02 1999-10-25 R.J. Reynolds Tobacco Company Azatricyclo(3.3.1.1) decane derivatives and pharmaceutical compositions containing them
PA8474101A1 (es) * 1998-06-19 2000-09-29 Pfizer Prod Inc Compuestos de pirrolo [2,3-d] pirimidina
JP2000026408A (ja) 1998-07-02 2000-01-25 Dai Ichi Seiyaku Co Ltd 対掌体的に純粋なピロリジン誘導体、その塩、それらの製造方法
US6804251B1 (en) 1998-11-12 2004-10-12 Broadcom Corporation System and method for multiplexing data from multiple sources
FR2786769B1 (fr) * 1998-12-04 2002-10-25 Synthelabo Derives de 2,5-diazabicyclo[2.2.1]heptane, leur preparation et leur application en therapeutique
ATE253067T1 (de) * 1999-01-29 2003-11-15 Abbott Lab Diazabicyloderivate als nikotin-acetylcholin- rezeptorliganden
WO2000066586A1 (en) * 1999-05-04 2000-11-09 Neurosearch A/S Heteroaryl diazabicycloalkanes, their preparation and use
EP1178982B1 (en) * 1999-05-21 2004-06-30 Abbott Laboratories Heterocyclic substituted aminoazacycles useful as central nervous system agents
JP2003516988A (ja) * 1999-12-14 2003-05-20 ニューロサーチ、アクティーゼルスカブ 新規ヘテロアリール−ジアザビシクロアルカン類

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0181347A2 *

Also Published As

Publication number Publication date
JP2003531210A (ja) 2003-10-21
HK1054375A1 (zh) 2003-11-28
AU2001266559C1 (en) 2005-11-17
TWI323733B (en) 2010-04-21
JP2012041349A (ja) 2012-03-01
IL203035A (en) 2010-12-30
EP2298775A1 (en) 2011-03-23
TW200617013A (en) 2006-06-01
KR20090013833A (ko) 2009-02-05
KR100947187B1 (ko) 2010-03-12
NZ521734A (en) 2004-10-29
PL398491A1 (pl) 2012-06-04
KR20090071654A (ko) 2009-07-01
PL358340A1 (en) 2004-08-09
KR20020093955A (ko) 2002-12-16
NO20025107D0 (no) 2002-10-24
HUP0300602A3 (en) 2005-12-28
KR20090121385A (ko) 2009-11-25
AR030421A1 (es) 2003-08-20
CA2407094A1 (en) 2001-11-01
TWI311137B (en) 2009-06-21
MY168244A (en) 2018-10-15
WO2001081347A2 (en) 2001-11-01
TWI357903B (en) 2012-02-11
MXPA02010594A (es) 2003-05-14
JP4981232B2 (ja) 2012-07-18
CN101935322A (zh) 2011-01-05
BR0107246A (pt) 2002-10-01
CZ302038B6 (cs) 2010-09-15
TW200909432A (en) 2009-03-01
CN100430398C (zh) 2008-11-05
KR100947188B1 (ko) 2010-03-12
BG107303A (bg) 2003-07-31
BG110620A (bg) 2010-07-30
CA2683045A1 (en) 2001-11-01
CA2407094C (en) 2009-11-17
WO2001081347A3 (en) 2002-01-31
TW201141871A (en) 2011-12-01
AU6655901A (en) 2001-11-07
HUP0300602A2 (hu) 2003-06-28
IL177316A0 (en) 2006-12-10
MY137020A (en) 2008-12-31
CN1440410A (zh) 2003-09-03
IL177316A (en) 2010-06-30
PE20011305A1 (es) 2001-12-31
AU2001266559B2 (en) 2005-03-03
SK287658B6 (sk) 2011-05-06
CN102863441A (zh) 2013-01-09
SK16812002A3 (sk) 2003-04-01
IL152231A0 (en) 2003-05-29
EP2295437A1 (en) 2011-03-16
SK287273B6 (sk) 2010-05-07
KR100961406B1 (ko) 2010-06-09
NO20025107L (no) 2002-12-19
BG66151B1 (bg) 2011-08-31
CZ301324B6 (cs) 2010-01-13
KR100899950B1 (ko) 2009-05-28
CZ302072B6 (cs) 2010-09-29
CZ302795B6 (cs) 2011-11-16
MY145722A (en) 2012-03-30
NO324250B1 (no) 2007-09-17
CZ20023765A3 (cs) 2003-02-12

Similar Documents

Publication Publication Date Title
US8119635B2 (en) Diazabicyclic central nervous system active agents
CA2407094C (en) Diazabicyclic central nervous system active agents
AU2001266559A1 (en) Diazabicyclic central nervous system active agents
AU773795B2 (en) Diazabicyclic derivatives as nicotinic acetylcholine receptor ligands
US20040152724A1 (en) Azabicyclic compounds are central nervous system active agents
US20040044029A1 (en) Azabicyclic compounds are central nervous system active agents
HK1154234A (en) Diazabicyclic central nervous system active agents
HK1154235A (en) Diazabicyclic central nervous system active agents

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20021024

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17Q First examination report despatched

Effective date: 20040116

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ABBVIE INC.

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1054375

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20141101