WO1998046609A1 - Furopyridine, thienopyridine, pyrrolopyridine and related pyrimidine, pyridazine and triazine compounds useful in controlling chemical synaptic transmission - Google Patents

Furopyridine, thienopyridine, pyrrolopyridine and related pyrimidine, pyridazine and triazine compounds useful in controlling chemical synaptic transmission Download PDF

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WO1998046609A1
WO1998046609A1 PCT/US1998/007128 US9807128W WO9846609A1 WO 1998046609 A1 WO1998046609 A1 WO 1998046609A1 US 9807128 W US9807128 W US 9807128W WO 9846609 A1 WO9846609 A1 WO 9846609A1
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WIPO (PCT)
Prior art keywords
alkyl
pyridine
furo
substituted
phenyl
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PCT/US1998/007128
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French (fr)
Inventor
Richard L. Elliott
Keith B. Ryther
Mark W. Holladay
James T. Wasciak
Jerome F. Daanen
Nan-Horng Lin
Michael J. Dart
Yun He
Yihong Li
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Abbott Laboratories
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Priority claimed from US08/834,053 external-priority patent/US6001849A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to JP54405598A priority Critical patent/JP2001521523A/en
Priority to EP98913418A priority patent/EP0973777A1/en
Priority to CA002285263A priority patent/CA2285263C/en
Publication of WO1998046609A1 publication Critical patent/WO1998046609A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to furopyridine, thienopyridine, pyrrolopyridine and related pyrimidine, pyridazine and triazine compounds which control chemical synaptic transmission; to therapeutically effective pharmaceutical compositions of these compounds; and to the use of said compositions to selectively control synaptic transmission.
  • Compounds that selectively control chemical synaptic transmission offer therapeutic utility in treating disorders that are associated with dysfunctions in synaptic transmission. 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). EPSPs typically result from a local depolarization of the membrane due to a generalized increased permeability to cations (notably Na + and K + ), whereas EPSPs 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.
  • the nicotinic acetylcholine receptor When the nicotinic acetylcholine receptor is activated, the response is an increased flux of specific extracellular ions (e.g. Na + , K + and Ca " * " " ) through the neuronal membrane.
  • muscarinic acetylcholine receptor activation leads to changes in intracellular systems that contain complex molecules such as G-proteins and inositol phosphates.
  • the biological consequences of 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 nerve terminal 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.
  • 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. Obviously, the more that is understood about chemical synaptic transmission in CNS disorders, the easier it would be to design drugs to treat such disorders. Knowing how specific neurotransmitters act in the CNS allows one to speculate about the disorders that may be treatable with certain CNS-active drugs. For example, dopamine is widely recognized as an important neurotransmitter in the central nervous systems in humans and animals.
  • 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
  • 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
  • Specific agents for treatment of these and related disorders are few in number or non-existent.
  • CNS-active agents of compounds with activity as cholinergic ligands selective for neuronal nicotinic acetylcholine receptors, (i.e., for controlling chemical synaptic transmission) may be found in U.S. Patent 5,472,958, to Gunn et al., issued Dec. 5, 1995, which is incorporated herein by reference.
  • acetylcholine agonists are therapeutically sub-optimal 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).
  • other 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, M.A.H.
  • neurotransmitter controlling agents may be useful include acute and chronic pain. (A. Dray and L. Urban, Annu. Rev. Pharmacology Toxicol. 36: 253-280, (1996).
  • Toyama has disclosed N-BOC-thienopyridine derivatives having use an intermediates for preparation of complex cephalosporin-related antibiotic agents (PCT Patent Application WO 92/18505, published Oct. 29, 1992).
  • Kabi Pharmacia has disclosed bicyclic heteroaryl compounds attached to a quinucUdene moiety useful for treating diseases related to muscarinic receptor function (PCT Patent Application WO 93/23395, published Nov. 25, 1993).
  • Festal et al. have disclosed urea derivatives containing an azaindole moiety having utility as hypolipidemic and antiatheromatous agents (U.S.Patent No. 5,338, 849).
  • Baker et al. have disclosed a class of substituted azetidine, pyrrolidine and piperidine derivatives having selective activity as agonists of 5-HT ⁇ -like receptors (PCT Patent Application WO 96/04274, published Feb. 15, 1996).
  • the present invention provides a compound of formula (I) below, or a pharmaceutically acceptable salt thereof, wherein a monocyclic or bicyclic amine group is directly linked to a substituted or unsubstituted furopyridine, thienopyridine, pyrrolopyridine or related pyrimidine, pyridazine or triazine group.
  • Another aspect of the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier or diluent.
  • the present invention provides a method for selectively controlling synaptic transmission in a mammal.
  • the present invention relates to a compound of formula (I):
  • A is selected from the group consisting of:
  • R 1 is selected from the group consisting of H, allyl and
  • R 2 is selected from the group consisting of H,
  • R is independently selected at each occurrence from the group consisting of
  • NR 3 R 3 wherein R 3 is H or C ⁇ -C3-alkyl; or when substituted at the Y- position can additionally be selected from: NR R 4 , wherein R 3 is H or C1-C3 alkyl and R 4 is hydrogen, Ci-Cs-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-C ⁇ -C6-alkyl-, substituted-phenyl-C ⁇ -C6-alkyl-, heteroaryl-C ⁇ -C6- alkyl-, and substituted-heteroaryl-C ⁇ -C6-alkyl-; C(O)-R 5 > where R 5 is hydrogen, Ci-Cg- alkyl, substituted-C ⁇ -C8-alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted
  • R 8 is Ci-Cs-alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, phenylCi-Cgalkyl-, substituted phenylCi-C ⁇ alkyl-, heteroaryl Ci-C ⁇ alkyl-, CONR 3 R 4 ; phenyl; naphthyl; substituted phenyl; substituted naphthyl; biphenyl; substituted biphenyl; heteroaryl; 5 substituted heteroaryl; phenyl C ⁇ -C6alkyl-; substituted phenylCi-C ⁇ alkyl-; heteroaryl Ci-Cgalkyl-; and substituted heteroarylC ⁇ -C6alkyl-;
  • R 9 is selected from the group consisting of hydrogen, Ci-Csalkyl, substituted Ci-Csalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted heteroaryl, phenylCi-C ⁇ alkyl-, substituted phenylC ⁇ -C6alkyl-, heteroaryl C ⁇ -C6alkyl-, and substituted 15 heteroarylC ⁇ -C6alkyl-;
  • X is -O-, -S- or -NR 3 , wherein R 3 is H or C ⁇ -C3-alkyl;
  • Y 1 , Y 2 and Y 3 are N or CH, with the provisos that at least one of Y 1 ,
  • Y 2 and Y 3 must be N and, 25 when group A is selected from option (b), except for those compounds additionally substituted at Y* 2 above, then Y 2 and Y 3 must be CH; m, on formula (I), is 0, 1, 2 or 3. When m is zero or, at those positions around the 5-6 bicyclic ring system which are not 30 substituted by R, hydrogen is the substituent.
  • the novel compounds of the present invention are also represented by formula (I):
  • R 1 is selected from the group consisting of H and C1-C3- alkyl; and R 2 is H, or when n is 2 or 3 is selected from the group consisting of C ⁇ -C3-alkyl, C ⁇ -C3-alkoxyl, hydroxymethyl, fluoromethyl, methoxymethyl, Br, Cl, F, OH, CN, -O- CO-CH3 and -O-methanesulfonyl.
  • R is independently selected at each occurrence from the group consisting of Ci-G ⁇ -alkyl, bromo, chloro, fluoro, trifluoro-Ci- C4-alkyl, trichloro-C ⁇ -C4-alkyl, COOH, CO2-Ci-C4-alkyl, CN, nitro, amino, NH-CO-Ci- C3-alkyl, and NR 3 R 3 , wherein R 3 is H or C ⁇ -C3-alkyl.
  • the group designated X is selected from the group consisting of -O-, -S- or -NR 3 , wherein R 3 is H or C ⁇ -C3-alkyl.
  • Y 1 , Y 2 and Y 3 are N or CH, with the provisos that at least one of Y 1 , Y 2 and Y 3 must be N and when group A is selected from option (b), then Y 2 and Y 3 must be CH.
  • the invention relates to a compound of formula (HI):
  • A is selected from the group identified above; and R is independently selected at each occurrence from the group consisting of C ⁇ -C4-alkyl, vinyl, bromo, chloro, fluoro, trifluoro-C ⁇ -C4-alkyl, trichloro-C ⁇ -C4-alkyl, COOH, CO2-Ci-C4-alkyl, CN, nitro, amino, hydroxy, NH-CO-C ⁇ -C3-alkyl, and NR R 3 , wherein R 3 is H or C ⁇ -C3-alkyl: and at the Y ⁇ position R can additionally be selected from: NR R 4 , wherein R 3 is H or C1-C3 alkyl and R 4 is hydrogen, Ci-Cg-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Ci-Cg-alkyl-, substituted-
  • R 5 is hydrogen, Ci-Cg-alkyl, substituted-C ⁇ -C8-alkyl, phenyl, substituted-phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Ci-Cg-alkyl-, substituted-phenyl-Ci-C ⁇ -alkyl-, 1 o heteroaryl-Ci-C ⁇ -alkyl-, substituted-heteroaryl-Ci-Cg-alkyl-, and
  • R 6 is selected from the group consisting of H and C ⁇ -C3-alkyl-
  • R 7 is selected from the group consisting of H, C ⁇ -C3-alkyl-, phenyl and substituted-phenyl;
  • R 8 is Ci-Cs-alkyl, phenyl, substituted-phenyl, 15 heteroaryl, substituted-heteroaryl, phenyl-Ci-Cg-alkyl-, substituted-phenyl-Ci-Cg-alkyl-, heteroaryl-Ci-C ⁇ -alkyl-, CONR R 4 ; phenyl; naphthyl; 20 substituted-phenyl; substituted-naphthyl; biphenyl; substituted-biphenyl; heteroaryl; 25 substituted-heteroaryl; phenyl-C i -C ⁇ -alkyl-; substituted-phenyl-Ci- -alkyl-; heteroaryl-Ci-C ⁇ -alkyl-; and substituted-heteroaryl-C i -Cg- alkyl-;
  • R 9 is selected from the group consisting of hydrogen, Ci-Cg-alkyl, substituted-Ci-Cs-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Ci-Cg-alkyl-, substituted-phenyl-C ⁇ -C6-alkyl-, heteroaryl-Ci-C ⁇ -alkyl-, and 35 substituted-heteroaryl-C ⁇ -C6-alkyl-; , wherein m is 1 or 2, and R 9 is as defined above;
  • X is -O-, -S- or -NR 3 , wherein R 3 is H or C ⁇ -C3-alkyl;
  • Y 1 , Y 2 and Y 3 are N or CH, with the provisos that at least one of Y 1 , Y 2 and Y 3 must be N and, when group A is selected from option (b), except for those compounds additionally substituted at Y- 2 above, then Y 2 and Y 3 must be CH methoxymethyl or methoxymethoxy and m is 0, 1 or 2.
  • Certain compounds of this invention may possess one or more asymmetric centers and may exist in optically active forms. Additional asymmetric centers may be present in a substituent group, such as an alkyl group.
  • Compounds of the invention which have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, diastereomeric racemates or mixtures of diastereomeric racemates. It is to be understood that the present invention anticipates and includes within its scope all such isomers and mixtures thereof.
  • the terms "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.
  • C ⁇ -C3-alkyl and “C ⁇ -C4-alkyl” refer to branched or straight-chain, unsubstituted alkyl groups comprising one-to-three or one-to-four carbon atoms, including, but not hmited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl and the like.
  • C ⁇ -C6-alkyl or “Ci-Cs-alkyl” as used herein refer to saturated, straight- or branched-chain hydrocarbon radicals containing between one and six or one and eight carbon atoms, respectively.
  • C1-C3 alkyl radicals include methyl, ethyl, propyl and isopropyl
  • examples of C ⁇ -C6-alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl
  • examples of Ci-Cg-alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, n-heptyl and n-octyl.
  • C ⁇ -C3-alkoxy refers to a C ⁇ -C3-alkyl group, as defined above, containing an oxygen tinker atom.
  • Trichloro-C ⁇ -C4-alkyl refers to a Ci-C ⁇ -alkyl group, as defined above, substituted with three chlorine atoms, including for example, trichloromethyl, 2,2,2-trichloroethyl, 3,3,3-trichloropropyl and 4,4,4-trichlorobutyl.
  • Trifluoro-C ⁇ -C4-alkyl refers to a C ⁇ -C4-alkyl group, as defined above, substituted with three fluorine atoms, including for example, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compounds of Formula (I), as for example, by hydrolysis in blood. T.
  • prodrug ester group refers to any of several ester-forming groups that are hydrolyzed under physiological conditions.
  • Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art.
  • administration refers to systemic use as when taken orally, parenterally, by inhalation spray, by nasal, rectal or buccal routes, or topically as ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or transdermal patches in dosage form unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired.
  • parenteral includes intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection as well as via infusion techniques.
  • salts are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio, effective for their intended use in the treatment of psychological, neurological, cardiovascular and addictive behavior disorders.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in JL Pharmaceutical Sciences, 66: 1-19, 1977.
  • the salts may be prepared in situ during the final isolation and purification of the compounds of Formula (I), or separately by reacting the free base function with a suitable acid.
  • Representative acid addition salts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, methanesulfonate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulfate salts and the like.
  • Representative alkali or alkaline earth metal salts include sodium, calcium, potassium, magnesium salts and the like.
  • Examples of pharmaceutically acceptable, nontoxic amides of the compounds of Formula (I) include amides derived from C ⁇ -C6-alkyl carboxylic acids wherein the alkyl groups are straight- or branched-chain, arortiatic carboxylic acids such as derivatives of benzoic acid and heterocyclic carboxylic acids, including furan-2-carboxylic acid or nicotinic acid.
  • Amides of the compounds of Formula (I) may be prepared according to conventional methods and include amino acid and polypeptide derivatives of the amines of Formula (I).
  • the term, "pharmaceutically acceptable carriers”, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • Some examples of the materials that may serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.
  • antioxidants examples include water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol and the like; and the metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin,
  • a “therapeutically effective amount” of the nicotinic acetylcholinergic agent is meant a sufficient amount of the compound to treat cholinergically related disorders at a reasonable benefit/risk ratio applicable to obtain a desired therapeutic response. 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 judgment.
  • 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; drugs used in combination or coincidentally with the specific compound employed; and like factors well known in the medical arts.
  • Total daily dose of the compounds of this invention administered to a host in single or divided doses may be in amounts as determined by the attending physician, typically, for example, in amounts of from about 0.001 to 100 mg kg body weight daily and preferably 0.01 to 10 mg/kg/day.
  • C ⁇ -C6-alkoxy refers to an Ci-C ⁇ -alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • Examples of C ⁇ -C6-alkoxy include, but are not hmited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
  • heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, such as, for example, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, and the like, the heteroaryl moiety being joined to the rest of the molecule via any of its carbon ring atoms.
  • heteroarylCi-C ⁇ alkyl refers to a C ⁇ -C6-alkyl group as defined herein substituted by replacement of one of the hydrogen atoms thereon with a heteroaryl moiety, as defined above.
  • phenylC ⁇ -C6alkyl refers to a Ci-C ⁇ -alkyl group as defined herein substituted by replacement of one of the hydrogen atoms thereon with a phenyl moiety.
  • substituted Ci-Csalkyl refers to a Ci-Cs-alkyl group as defined herein substituted by independent replacement of one of the hydrogen atoms thereon with Cl, Br, F, CN, CF , OH, CHO, COOH, COO-C ⁇ -C 3 -alkyl, C ⁇ -C6-alkoxy, methoxymethoxy, amino, or C ⁇ -C3-alkyl- amino, except not more than one CHO, COOH, or COO-C ⁇ -C3-alkyl group may be present.
  • substituted biphenyl refers to a biphenyl radical substituted by replacement of one of the hydrogen atoms thereon with F, OH, NO2 or C ⁇ -C3-alkyl.
  • substituted naphthyl refers to a naphthyl substituted by independent replacement of one or two of the hydrogen atoms thereon with Cl, Br, F, CN, CF3, NO 2 , OH, CHO, COOH, COO-C ⁇ -C 3 -alkyl, C ⁇ -C -alkyl, C ⁇ -C 6 -alkoxy, methoxymethyl, methoxymethoxy, amino, or C ⁇ -C3-alkyl-amino, except not more than one CHO, COOH, or COO-C ⁇ -C3-alkyl group may be present.
  • substituted phenyl refers to a phenyl substituted by independent replacement of one or two of the hydrogen atoms thereon with Cl, Br, F, CN, CF 3 , NO 2 , OH, CHO, COOH, COO-C ⁇ -C -alkyl, C ⁇ -C3-alkyl, Ci-C ⁇ -alkoxy, methoxymethyl, methoxymethoxy, amino, or C ⁇ -C3-alkyl-amino, except not more than one CHO, COOH, or COO-C ⁇ -C 3 -alkyl group may be present.
  • substituted phenylCi-Cgalkyl refers to a C ⁇ -C6-alkyl group as defined herein substituted by replacement of one of the hydrogen atoms thereon with a substituted-phenyl moiety, as defined above.
  • substituted heteroaryl refers to a heteroaryl group as defined herein substituted on or two carbon atoms by independent replacement of he hydrogen atoms thereon with Cl, Br, F, CN, CF3, NO2, OH, CHO, COOH, COO-C ⁇ -C3-alkyl, C ⁇ -C3-alkyl, Ci-C ⁇ -alkoxy, methoxymethyl, methoxymethoxy, amino, or C ⁇ -C3-alkyl-amino, except not more than one CHO, COOH, or COO-C ⁇ -C3-alkyl group may be present.
  • substituted heteroaryl Ci-C ⁇ alkyl refers to a Ci-C ⁇ alkyl group as defined herein substituted by replacement of one of the hydrogen atoms thereon with a substituted-heteroaryl moiety, as defined above.
  • R is H, Br, Cl, C ⁇ -C4-alkyl, phenyl or vinyl pyridyl and R 2 is H and ⁇ ⁇ ⁇ 0 is as specified above.
  • compositions comprising one or more of the compounds of formula (I) prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable carriers in the manner described below.
  • compositions suitable for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of a coating 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 preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • the compounds may be incorporated into slow-release or targeted-delivery systems, such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, and additionally (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting
  • 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.
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and others well known in this art. They may contain pacifying agents, and may also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which may be used are polymeric substances and waxes. The active compounds may 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 water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and e
  • these liquid dosage forms 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, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal or vaginal administrations are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are sohd at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are sohd at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical or transdermal administration of a compound of this invention further include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or transdermal patches.
  • Transdermal administration via a transdermal patch is a particularly effective and preferred dosage form of the present invention.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservative, buffers or propellants as may be required. It is known that some agents may require special handling in the preparation of transdermal patch formulations. For example, compounds that are volatile in nature may require admixture with special formulating agents or with special packaging materials to assure proper dosage delivery. In addition, compounds which are very rapidly absorbed through the skin may require formulation with absorption-retarding agents or barriers. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the present compounds may 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 that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used.
  • the present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidylcholines (lecithins), both natural and synthetic. 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.
  • a peripherally acting anti-cholinergic such as N-methylscopolamine, N-methylatropine, propantheline, methantheline, or glycopyrrolate.
  • the compounds of the present invention may be synthesized as shown in reaction schemes 1-23 presented below using the reactions and techniques described in this section.
  • the reactions are performed in a solvent appropriate to the reagents and materials employed are suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the heterocyclic ring and other portions of the molecule must be consistent with the chemical transformation proposed. This will, on occasion, necessitate judgment by the routineer as to the order of synthetic steps, protecting groups required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described, but alternative methods and substituents compatible with the reaction conditions will be readily apparent to skilled practitioners in the art.
  • Compound (4) may be converted into compounds (5), i.e., compounds of formula (I) wherein R 1 is C ⁇ -C3-alkyl by reaction with the appropriate aldehyde under reducing conditions, for example, in the presence of H and a catalyst such as Pd/C or in the presence of NaBH3CN.
  • the process of Scheme 1 is equally applicable to compounds of the series wherein n is 1 or 3, to give compounds analogous to compounds (4) and (5), i.e., compounds of formula (I) wherein A is (a) and n is 1 or 3.
  • the 2-iodo-3-pyridinols of Schemes 1 and 2 may be prepared by direct selective iodination of the corresponding pyridinols (e.g., Koch and Schnatterer, Synthesis, 1990:497).
  • 3-pyridinols with substituents in the 4-position can be prepared by selective lithiation of 3-pyridinol, O-protected with an ortho-directing moiety, e.g. methoxymethyl , diethylcarbamoyl, and the like (see Beak and Snieckus, Ace. Chem. Res., 15:306-312, 1982).
  • 3-hydroxypyridines with substituents in other required positions can be prepared from the conesponding 3-aminopyridines under diazotizing conditions.
  • the 3-aminopyridines can be obtained by reduction of the conesponding 3-nitropyridine or by rearrangement of the 3-carboxylic acid or 3- carboxamide using the Hoffman, Curtius, or Schmidt reanangements which are well-known in the art.
  • 3-hydroxypyridines can be obtained by oxidation of an appropriate 3- lithio or magnesiopyridine with molecular oxygen, oxaziridines, or peroxides (see, for example, Taddei and Ricci, Syn.
  • furo[2,3-c]pyridine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R 1 and R 2 are as described above, X is O, Y 1 is CH, Y 2 is N and Y 3 is CH.
  • the acetylene- substituted starting material (1) or (6) is reacted with an appropriate 4-iodo-3-hydroxypyridine (9), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (10).
  • the requisite 4-iodo-3-hydroxypyridines are generally available using the techniques mentioned above together with selective 4-iodination of 3- hydroxypyridines (cf. Winkle and Ronald, /.
  • furo[2,3-b]pyridine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R 1 and R 2 are as described above, X is O, Y 1 and Y 2 are CH and Y 3 is N.
  • the acetylene-substituted starting material (1) or (6) is reacted with an appropriate 3-iodo-2-hydroxypyridine (11), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (12).
  • the requisite 3-iodo-2-hydroxypyridines are generally available using the techniques mentioned above for synthesis of selectively substituted 3- hydroxypyridines.
  • the requisite 3-iodo-2-hydroxypyridines can be obtained by ortho iodination of the appropriate 2-hydroxypyridine.
  • the reactions of Scheme 4 may be performed with the analogous mercaptopyridine, prepared as described for Scheme 1 above, to give the thieno[2,3-b]pyrimidine compounds of Formula (I), wherein X is a S atom.
  • furo[3,2-d]pyrimidine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R 1 and R 2 are as described above, X is O, Y 1 is N, Y 2 is N and Y 3 is CH.
  • the acetylene-substituted starting material (1) or (6) is reacted with an appropriate 4-iodo-5-hydroxypyrimidine (13), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (14).
  • the requisite 4-iodo-5-hydroxypyrimidine compounds are generally available using the techniques mentioned above for synthesis of selectively substituted 3-hydroxypyridines.
  • the requisite 4-iodo-5-hydroxypyrimidine can be obtained by ortho iodination of the appropriate 5-hydroxypyrimidine.
  • the reactions of Scheme 5 may be performed with the analogous mercaptopyridine, prepared as described for Scheme 1 above, to give the thieno[3,2- djpyrimidine compounds of Formula (I), wherein X is a S atom.
  • the requisite 3-iodo-2-hydroxypyrimidine compounds are generally available using the techniques mentioned above for synthesis of selectively substituted 2-hydroxypyridines.
  • the requisite 3-iodo-2-hydroxypyrimidine can be obtained by ortho iodination of the appropriate 2-hydroxypyrimidine.
  • the reactions of Scheme 5A may be performed with the analogous mercaptopyridine, prepared as described for Scheme 1 above, to give the thieno[2,3- b]pyrimidine compounds of Formula (I), wherein X is a S atom.
  • furo[2,3-c]pyridazine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R 1 and R 2 are as described above, X is O, Y 1 is CH, and Y 2 and Y 3 are N.
  • the acetylene-substituted starting material (1) or (6) is reacted with an appropriate 4-iodo-3-hydroxypyridazine (15), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (16).
  • the requisite 4-iodo-3-hydroxypyridazine compounds are generally available using the techniques mentioned above for synthesis of selectively substituted 3-hydroxypyridines.
  • the requisite 4-iodo-3-hydroxypyridazine can be obtained by ortho iodination of the appropriate 5-hydroxypyridazine.
  • the reactions of Scheme 6 may be performed with the analogous mercaptopyridine, prepared as described for Scheme 1 above, to give the thieno[2,3- c]pyridazine compounds of Formula (I), wherein X is a S atom.
  • furo[3,2-e]triazine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R 1 and R 2 are as described above, X is O, Y 1 is CH, Y 2 is N and Y 3 is N .
  • the acetylene- substituted starting material (1) or (6) is reacted with an appropriate 5-iodo-6-hydroxyrriazine (17), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (18).
  • the requisite 5-iodo-6-hydroxytriazine compounds are generally available using the techniques mentioned above for synthesis of selectively substituted 3- hydroxypyridines. For example, the requisite 5-iodo-6-hydroxyrriazine can be obtained by ortho iodination of the appropriate 5 -hydroxy triazine .
  • this reaction may be performed with the analogous mercaptopyrimidine, prepared as described for Scheme 1 above, to give the thieno[3,2-e]triazine compounds of Formula (I), wherein X is a S atom.
  • pyrrolo[2,3-c]pyridine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R 1 and R 2 are as described above, X is NH, Y 1 and Y 3 are CH and Y 2 is N.
  • a protected aminopyridine compound starting material (22) is reacted with a strong base, such as t-butyllithium, and free iodine to give the iodinated compound (23).
  • Compound (23) is then reacted with compound (1) or (6) in the presence of Pd, Cul and triethylamine at elevated temperature, as described above, followed by N-deprotection under standard conditions, to give the compound (24).
  • pynolo[3,2-d]pyrimidine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R 1 and R 2 are as described above, X is NH, Y 1 and Y 2 are N, and Y 3 is CH .
  • a protected aminopyrimidine compound starting material (28) is reacted with a strong base, such as t-butyllithium, and free iodine to give the iodinated compound (29).
  • Compound (29) is then reacted with compound (1) or (6) in the presence of Pd, Cul and triethylamine at elevated temperature, as described above, then deacylated by standard methods to give the compound (30).
  • pyrrolo[2,3-c]pyridazine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R 1 and R 2 are as described above, X is NH, Y 1 is CH, and Y 2 and Y 3 are N.
  • a protected aminopyridazine compound starting material (31) is reacted with a strong base, such as t-butyllithium, and free iodine to give the iodinated compound (32).
  • Compound (32) is then reacted with compound (1) or (6) in the presence of Pd, Cul and triethylamine at elevated temperature, as described above, then deacylated by standard methods to give the compound (33).
  • Compound (41) is subsequently reacted with, for example, ethynyl magnesium bromide and the intermediate is reacted with triphenylphosphine dibromide to give compound (42).
  • Compound 42 is treated with HCl in a polar organic solvent, such as ethanol, for example to give the 3-substituted pynolizidine compound (43).
  • Compound (43) may be substituted for compounds (1) or (6) in any of Schemes 1-13 above to give the desired compound of Formula (I).
  • Compound (46) is treated with PPh3 and CBr4 to give an intermediate dibromoalkene (not shown), which is then converted to the alkyne (47) by treatment with an alkyllithium compound.
  • Compound (47) may be substituted for compounds (1) or (6) in any of Schemes 1-13 above to give the desired compound of Formula (I).
  • Compound (49) is treated with PPh3 and o CBr4 to give the dibromoalkene (50), which is then converted to the alkyne (51) by treatment with an alkyllithium compound.
  • Compound (51) may be substituted for compounds (1) or (6) in any of Schemes 1-13 above to give the desired compound of Formula (I).
  • compounds of Formula (I) wherein R is C ⁇ -C4-alkyl, Br, Cl, 5 F, CF3 or CCI3 may be conveniently prepared by starting with the appropriately substituted compounds 2, 9, 11, 13, 13A, 15, 17, 20, 23, 26, 29, 32 or 35, which, if necessary, may be prepared by common techniques from the unsubstituted pyridine, pyrimidine or pyrazine starting materials or other commercially available derivatives thereof. Preparation of additional iodohydroxyheterocycles may be carried out by selective electrophilic aromatic 0 substitution reactions upon the conesponding hydroxyheterocycles.
  • compounds of Formula (I) wherein R is NH2 may be prepared. Further treatment of compounds of Formula (I) wherein R is NH2 with NaNO2 and CuCN allows the preparation of compounds of Formula (I) wherein R is CN.
  • amino may be oxidized with H2SO4 and H2O2 to nitro, or carboxamide may be dehydrated to cyano. Cyano groups may be treated with the appropriate alcohol in the presence of a strong acid to prepare compounds of Formula (I) wherein R is COO-Ci- G-j-alkyl.
  • compounds of Formula (I) wherein R is COOH may be N-acylated by the appropriate Ci-C-t-acyl chloride (or acyl hahdes selected from Ci-C8-acyl halide, substituted ClC8-acyl halide, phenyl acyl halide, substituted phenyl-acyl-halide, heteroaryl-acyl halide, substituted heteroaryl-acyl-halide, phenyl-Ci-C6-acyl halide, substituted phenyl-Cl-C6-acyl halide, heteroaryl-acyl halide, substituted heteroaryl-acyl halide or (-O-Ci-C6alkyl)acyl halide to give compounds of Formula (I) wherein R is NH- CO-C ⁇ -C4-alkyl or the acyl derivatives of the groups specified directly above.
  • compounds of Formula (I) wherein R is NH2 may by alkylated or arylated to give the compounds of Formula (I) wherein R is NR-'R 1 or NR6R7
  • bromo- or chloro- substituted compounds may be replaced with alkyl or alkenyl in reactions moderated by transition metals, e.g., palladium or nickel.
  • transition metals e.g., palladium or nickel.
  • Appropriate precursors to compounds 13, 13A, 15, 17, 29, 32 and 35 may also be prepared by ring-closure reactions of appropriately substituted acyclic compounds, such reactions being well known to those skilled in the art.
  • R when substituted at the Y* 2 position, may be selected from: NR R 4 , wherein R 3 is H or C1-C3 alkyl and R 4 is hydrogen, Ci-Cg-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-C ⁇ -C6-alkyl-, substituted-phenyl-C ⁇ -C6-alkyl-, heteroaryl-C ⁇ -C6-alkyl-, and substituted-heteroaryl-C 1 -C6- alkyl-;
  • R 5 is hydrogen, Ci-Cs-alkyl, substituted-Ci-Cs-alkyl, phenyl, substituted-phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted-heteroaryl, phenyl-C ⁇ -C6- alkyl-, substituted-phenyl-C ⁇ -C6-alkyl-, heteroaryl-C ⁇ -C6-alkyl-, substituted-heteroaryl-C ⁇ -C6-alkyl-, and O-C ⁇ -C6-alkyl-, N-R 6 R 7 , wherein R 6 is selected from the group consisting of H and C ⁇ -C3-alkyl-, and R 7 is selected from the group consisting of H, C ⁇ -C3-alkyl-, phenyl and substituted-phenyl;
  • R* may additionally be selected from allyl;
  • R2 for n is 1, 2 or 3 is selected from all the variables previously specified as well as Br, Cl, F, OH, CN, -O-CO-CH3 and -O-methanesulfonyl provided said specifically refened to R2 groups are not alpha to the ring nitrogen atom in group A;
  • R at any position is additionally selected from vinyl and hydroxy.
  • the hydroxy group can then be alkylated by appropriate halides or sulfonates to afford compounds or formula (I) wherein R is C1-C8 alkyl-O-, phenyl-Cl-C6-alkyl-O-, substituted phenyl Cl-C6-alkyl-O-, heteroaryl-Cl-C6-alkyl-O-, substituted heteroaxyl-Cl- C6-alkyl-O-, or acylated by appropriate isocyanates or carbamoyl chlorides to afford compounds of Formula (I) wherein R is OC(O)-NR3R4.
  • the precursor wherein R is hydroxy can alternately be prepared from the compound wherein R is amino by treatment with sodium nitrite followed by heating under acid conditions. It will apparent to those skilled in the art that some of the above transformations will be best carried out following protection of moieties elsewhere in the molecule that may be susceptible to the reaction conditions with a suitable protecting group, followed by removal of the protecting group when no longer needed by conditions well known in the art.
  • intermediate compounds are prepared by reaction of an acetylene compound (la), wherein n is 1 to 3 and R 1 is allyl or Ci-Cg-alkyl or a protecting group such as t-BOC or CBZ, for example, with a 2-iodo-3-hydroxypyridine compound (2a), wherein L is H, F or Cl or R as defined herein for compounds of Formula (I) above, in the presence of Pd, Cul and triethylamine at the elevated temperature (See Kundu, et al., J. Chem. Soc. Chem. Comm., 1992: 41 for analogous preparation of benzofurans) to form the 6-bromofuro[3,2-b]pyridyl compound (3a).
  • Scheme 19 See Kundu, et al., J. Chem. Soc. Chem. Comm., 1992: 41 for analogous preparation of benzofurans
  • an intermediate compound (3a), wherein R 1 is allyl or Ci-C ⁇ -alkyl or a protecting group such as t-BOC or CBZ, for example, is reacted with an unsaturated compound (4a), (6a) or (8a), to give compounds (5a), (7a) or (9a), respectively, which are specific or protected compounds of Formula (I), by treatment with a palladium (II) catalyst under weakly basic conditions at reflux temperature in an organic or aqueous solvent.
  • a reducing agent e.g. hydrogen/catalyst
  • R 1 is a protecting group such as t-BOC or CBZ it must be removed under well-known standard conditions for removing those groups in order to give the desired compound of Formula (I).
  • R 1 is allyl or C ⁇ -C6-alkyl
  • R 1 is allyl, this may be accomplished by reacting the unprotected nitrogen atom with allyl chloride in the presence of a weak base such as triethylamine.
  • R 1 is C ⁇ -C6-alkyl, this may be accomplished by reacting the unprotected nitrogen atom with the appropriate aldehyde in the presence of NaCNBH3, for example.
  • L is chosen from the groups defined under R. Any of the above compounds may be further reduced to form a compound of the invention.
  • an intermediate compound (3a), wherein R 1 is allyl or C ⁇ -C6-alkyl or a protecting group such as t-BOC or CBZ, for example, is reacted with a suitable boronic acid compound (10a) wherein W is selected from the group consisting of: (a) phenyl; (b) naphthyl; (c) substituted-phenyl, as defined herein; (d) substituted-naphthyl, as defined herein; (e) biphenyl; (f) substituted-biphenyl, as defined herein; (g) heteroaryl, as defined herein; (h) substituted-heteroaryl, as defined herein; (i) phenyl-C ⁇ -C6-alkyl-, as defined herein; (j) substituted-phenyl-C ⁇ -C6-alkyl-, as defined herein; (k) heteroaryl-Ci-Cg-alkyl-, as defined herein
  • compound (10a) may be replaced by a WMgX compound and reacted in the presence of Ni(dppp)2Cl2 to give compound (11).
  • R 1 is a protecting group such as t-BOC or CBZ it must be removed under well-known standard conditions for removing those groups in order to give the desired compound of Formula (I).
  • R 1 is allyl or Ci-C ⁇ -alkyl
  • R 1 is allyl, this may be accomplished by reacting the unprotected nitrogen atom with allyl chloride in the presence of a weak base such as triethylamine.
  • R 1 is C ⁇ -C6-alkyl, this may be accomplished by reacting the unprotected nitrogen atom with the appropriate aldehyde in the presence of NaCNBH3, for example.
  • L is equal to R as defined above at the designated position.
  • R 1 is a protecting group such as t-BOC or CBZ it must be removed under well-known standard conditions for removing those groups in order to give the desired compound of Formula (I).
  • R 1 is allyl or C ⁇ -C6- alkyl
  • R 1 is allyl, this may be accomplished by reacting the unprotected nitrogen atom with allyl chloride in the presence of a weak base such as triethylamine.
  • R 1 is Ci- i-alkyl, this may be accomplished by reacting the unprotected nitrogen atom with the appropriate aldehyde in the presence of NaCNBH3, for example.
  • Scheme 22 is shown an alternate process for preparing desired compounds of the invention.
  • the heterocyclic and the pyridine moieties are first joined, and the W group is added according to Schemes 19 and 20, Scheme 22 allows for the placement of the W group before joining.
  • a hydroxypyridine compound is treated with the appropriate reagent, such as a trialkylsilyl or benzyl chloride, to protect the hydroxyl group with a protecting group PG, such as trialkylsilyl or benzyl, respectively, for example to give compound (16a).
  • Compound (16a) may then be reacted with an appropriate reagent, as described in Schemes 19 and 20, to give the compound (17a) having the desired substitution at L and W.
  • Compound (19a) may then be reacted with a reagent R 5 -M, wherein R 5 is as described for Formula (I) above and M is Uthium or a magnesium hahde moiety, under the appropriate anhydrous conditions, with cooling if necessary, for 2-8 hours or until the reaction is complete to give, followed by treatment with aqueous acid to dissociate the metal complexes and give compound (20a).
  • the cyano group of compound (19a) may be reduced by treatment with 1 atm of H2 in the presence of Raney nickel at room temperature for 1-8 hours to give an intermediate amino compound.
  • a ligand-receptor binding assay was carried out as the initial screen.
  • Compounds of the present invention were effective at interacting with neuronal nicotinic acetylcholine receptors as assayed for their ability to displace radioligand from neuronal nicotinic acetylcholine receptors labeled with [ 3 H]-cytisine ([ H]-CYT).
  • Binding of [ 3 H]-CYT to 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 NaCl, 5 mM KC1, 2 mM MgCl2, 2 mM CaC and 50 mM Tris-Cl, pH 7.4 @4°C). After centrifuging at 20,000x g for 15 minutes, the pellets were resuspended in 30 volumes of buffer.
  • Homogenate (containing 125-150 ⁇ g protein) was added to triplicate tubes containing concentrations of test compound 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
  • IMR-32 human neuroblastoma clonal cell line ATCC, Rockville, MD
  • IMR-32 human neuroblastoma clonal cell line ATCC, Rockville, MD
  • Experimental cells were seeded at a density of 500,000 cells/mL into a 24- well tissue culture dish. Plated cells were allowed to proliferate for at least 48 hours before loading with 2 ⁇ Ci/mL of 8 Rb+ (35 Ci/mmol) overnight at 37°C.
  • the 86Rb+ efflux assays were performed according to previously pubhshed protocols (Lukas, 1993) except serum-free Dulbecco's Modified Eagle's Medium was used during the 86Rb+ loading, rinsing, and agonist-induced efflux steps.
  • (S)-nicotine are shown for selected compounds of the invention.
  • the inhibition data (given for other selected compounds) reflect inhibition of the efflux elicited by 100 ⁇ M (S)-nicotine at the indicated concentration.
  • the results (also shown in Table 1) suggest that selected compounds of the present invention either activate or inhibit the initial ion flux aspects of synaptic transmission mediated by neuronal nicotinic acetylcholine receptors. This finding is in agreement with the results of others who have linked dopamine release, which is dependent upon the ion flux in synaptic transmission, to binding at nicotinic receptors (cf., for example, Lippiello and Caldwell, U.S.Patent 5,242,935, issued Sept. 7, 1993; Caldwell and Lippiello, U.S.Patent 5,248,690, issued Sept. 28, 1993; and Wonnacott et al, Prog. Brain Res., 79: 157-163 (1989)).
  • Table 2 shows additional data for examples 53-59 and 134- 136.
  • TLC Thin-layer chromatography
  • E. Merck precoated silica gel plates (60 F-254). Rash chromatography was performed on 200-400 mesh silica gel (E. Merck), and column chromatography was performed on 70-230 mesh silica gel (E. Merck).
  • THF for tetrahydrofuran
  • DMF for N, N- dimethylformamide
  • D2O for deuterium oxide
  • CDCI3 for deuterochloroform
  • DMSO-d6 for deuterodimethylsulfoxide
  • BOC for tert-butyloxycarbonyl
  • CBZ for benzyloxycarbonyl
  • Bn for benzyl
  • Ms for methanesulfonyl
  • PAW for pyridine/acetic acid/water (20:6: 11)
  • DCC for dicyclohexylcarbodiimide
  • DIBALH for d ⁇ sobutylaluminum hydride
  • DIEA for diisopropylethylamine
  • DPPA for diphenylphosphororyl azide
  • DME for 1,2- dimethoxyethane
  • EDC for l-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide
  • N-BOC-(S)-prolinal N-BOC-(S)-proline was reduced to N-BOC-(S)-prolinol by treatment with diborane as described by K.E. Rittle et al. (J. Org. Chem., 47:3016 (1982)).
  • N-t-butyloxycarbonyl- (S)-prolinol was then oxidized to N-t-butyloxycarbonyl-(S)-prolinal by treatment with DMSO and sulfur trioxide-pyridine complex as described by Y. Hamada and T. Shioiri (Chem. Pharm. Bull, 5: 1921 (1982)).
  • triphenylphosphine 13.0 g, 49.5 mmol
  • zinc dust 2.16 g, 33.0 mmol
  • carbon tetrabromide 11.0 g, 33.0 mmol
  • CH2CI2 80 mL
  • N-t-butyloxycarbonyl-(S)- prolinal 3.29 g, 16.5 mmol
  • the reaction was slightly exothermic. After stirring for 1 hour, the reaction mixture was diluted with EtOAc/hexane (1:1) and filtered through basic alumina.
  • reaction mixture was diluted with 1 N HCl, and the aqueous layer was separated.
  • the aqueous solution was adjusted to pH 10 with K2CO3, and the mixture was extracted with CH2C12- The solution was dried over MgSO4 and concentrated.
  • the reaction was stirred at 60 C for 16 hours, then cooled to room temperature.
  • the reaction mixture was diluted with 2 N HCl and extracted with ether.
  • the aqueous layer was adjusted to pH 10 with K2CO3, then extracted with CH2CI2.
  • the extract was washed with 20% NaOH, brine, dried over MgSO4, and the solvent was removed.
  • the residue was repeatedly dissolved in toluene and distilled to azeotiopically remove the DMF.
  • Pentane was added and the solid was coUected by suction filtration (cold pentane wash) to afford 69.1 g of the tetrafluoroborate diazonium salt. This was dissolved in 350 mL of acetic anhydride, warmed to 75 °C (N2 evolution) and stirred for 3 h. The volatUes were removed in vacuo and the dark residue was diluted with Et2 ⁇ and washed with saturated aqueous NaHCO3. The aqueous phase was extracted with Et2 ⁇ . The combined ethereal extracts were washed with brine, dried (MgSO4), and concentrated.
  • step 15a above 1.0 g, 4.8 mmol was added to a solution of 0.5 M ethynylmagnesium bromide (29 mL, 14.3 mmol) in THF at room temperature.
  • the reaction mixture was stirred for 45 minutes, quenched with 15% NaOH solution, and diluted with brine:water (1:1).
  • 2-Iodo-3-pyridinol (902 mg, 4.1 mmol), copper(I) iodide (116 mg, 0.61 mmol), bis(triphenylphosphine)palladium(II) chloride (119 mg, 0.17 mmol) and triethylamine (570 mL, 4.1 mmol) were combined in DMF (4.5 mL) and stirred for one hour.
  • 7a-Ethynyl- hexahydro-lH-pynolizine(460 mg, 3.4 mmol) in DMF (1.2 mL) was added dropwise and the mixture was heated at 60 °C for 18 h.
  • reaction mixture was aUowed to cool to ambient temperature and 2 N aqueous HCl was added.
  • the heterogeneous mixture was washed with Et2 ⁇ (2X), basified with 15% ⁇ aOH solution and extracted with CH2CI2 (2X).
  • the CH2CI2 extracts were combined, dried (MgSO4) concentrated and chromatographed (sihca gel; CHCl3/MeOH, 96:4) to afford an amber oil which solidified upon storage at -20°C (405 mg, 52%): mp 39-41 °C; 1H ⁇ MR (CDCI3, 300 MHz) ⁇ 1.86-
  • N-Boc-R-prolinal (10.25 g, 51.50 mmol) in 150 mL of anhydrous 0 toluene at room temperature was added (triphenylphosphoranyUdene)-acetaldehyde (17.2 g, 56.7 mmol), and the mixture was refluxed for 3 hours under nitrogen. The mixture was concentrated in vacuo. The residue was purified on sihca gel , eluting with 1/4 EtOAc/hexane.
  • Example 18e FoUowing the procedures of Example 18e above, substituting the ejr ⁇ -hexahydro- lH-3-(S)-ethynylpynohzine compound from Example 18d above for the endo-(R) compound of step 18e, the title compound was prepared.
  • Example 15b 7a-Ethynyl-hexahydro-lH-pynotizine from Example 15b (225 mg, 1.66 mol, 6- chloro-2-iodo-3-pyridinol (509 mg, 2.0 mmol), copper(I) iodide (60 mg, 0.30 mmol), bis(triphenylphosphine)paUadium( ⁇ ) chloride (58 mg, 0.08 mmol) and triethylamine (0.280 mL, 2.0 mmol) were combined in a similar fashion as that described in Example 15c.
  • step 25a The compound from step 25a (400 mg, 1.12 mmol) was dissolved in CH2CI2 (3 mL) and TFA (3 mL) was added at ambient temperature. After stirring for 1 hour, the solvent was removed and the residue was dissolved in CH2CI2 and washed with saturated K2CO3 solution, dried (MgSO4) and concentrated.
  • Example 25b The amine from Example 25b (145 mg, 0.57 mmol) was dissolved in an aqueous solution of 37% formaldehyde (excess) and 88% formic acid (excess). The aqueous mixture was heated to 90 °C for 1.5 hours and then aUowed to cool to ambient temperature. The reaction mixture was washed with Et2 ⁇ , basified with 15% NaOH solution and extracted with CH2CI2 (3X).
  • step 26a The compound from step 26a (92 mg, 0.34 mmol) was slunied in Et2 ⁇ and a saturated solution of HCl in Et2 ⁇ was added dropwise. The solvent was removed and the product was recrystallized from MeOH/Et2 ⁇ to afford a white solid (70 mg, 67%): mp 249- 251 °C; 1H NMR (D2O, 300 MHz) ⁇ 2.27-2.37 (m, 2H), 2.47-2.71 (m, 2H), 2.93 (s,
  • N2 was added 18 g (104 mmol) of 5-amino-2-bromopyridine (from step 28a above) dissolved in 35 mL of DME. Then tert-butyl nitrite (14.7 mL, 125 mmol, Aldrich) was added at a rate which kept the temperature below 0 °C. DME (65 mL) and CH2CI2 (60 mL) were then added. After 10 minutes at -10 °C the mixture was warmed to 5 C and stirred for 30 min.
  • Pentane 400 mL was then added to the reaction mixture, the solid was coUected by suction filtration, washed with cold ether, air dried, and dissolved in 125 mL acetic anhydride. The resulting solution was heated to 100 C ⁇ 5 C for 1 hour. The solvent was removed in vacuo, and the residue was suspended in saturated aqueous Na2CO3 ( and extracted with ethyl ether.
  • a 300 mg sample of the compound from step 28f above was dissolved in an aqueous solution of 37 % formaldehyde (4 mL) and 88 % formic acid (2 mL) and heated at reflux for 1 hour.
  • the solution was cooled, dUuted with water, and adjusted to pH 10 with K2CO3.
  • the mixture was extracted with CH2CI2, and the extract was dried and concentrated.
  • the residue was purified by chromatography on sUica gel, eluting with 100:0 to 97:3 CHCl3:MeOH.
  • the product was dissolved in ethanol at ambient temperature and a solution of hydrochloric acid in Et2 ⁇ was added dropwise.
  • 2,3-Dichloro-6-iodo-5-pyridinol (163 mg, 0.56 mmol) from example 25a, copper(I) iodide (20 mg, 0.10 mmol), bis(triphenylphosphine)paUadium(II) chloride (20 mg, 0.030 mmol) and triethylamine (176 mL, 0.67 mmol) were combined and aUowed to stir for 1 hour at ambient temperature. 7a-ethynyl-hexahydro-lH-pynolizine (91 mg, 0.67 mmol) in DMF (1.0 mL) was added to the reaction mixture which was then heated to 60°C for 18 hours.
  • reaction mixture was stined at 60 °C for 16 hours, then cooled to room temperature.
  • the reaction mixture was diluted with ether, then washed with 10% NaOH and brine.
  • the organic extract was dried over MgSO4 and concentrated. The residue was chromatographed
  • 3-Bromo-2-chloro-5-hydroxy-6-iodopyridine (2.0 g, 6.0 mmol)(prepared by treatment of 3-bromo-2-chloro-5-hydroxypyridine (Koch & Schnatterer, Synthesis 1990, 499) with 12 (ibid, p. 497), paUadium (II) bis(triphenylphosphine) chloride (0.21 g, 0.30 mmol), Cul (0.228 g, 1.2 mmol) and triethylamine (1.0 mL) were dissolved in DMF (8 mL).
  • reaction mixture was cooled to room temperature and poured into saturated NaHCO3 and washed with Et2 ⁇ (4X lOOmL). The combined organic extracts were washed with brine/H2 ⁇ (1/1 400mL), dried (MgSO4), and concentrated .
  • Carbon tetrabromide (28.9 g, 87.2 mmol) was added to a 0 °C solution of triphenyphosphine (57.2 g, 218 mmol) in CH2CI2 (200 mL) under a nitrogen atmosphere. The solution was warmed to ambient temperature, stirred for 10 minutes, then a solution of the aldehyde from step 52b in CH2CI2 (20 mL) was added via cannula. After 15 minutes, the reaction mixture was dUuted with 1 : 1 EtOAc/hexane (300 mL) and filtered through a pad of Cehte and sUica gel (1 : 1 EtOAc/hexane wash).
  • 3-Hydroxypyridine (366 mg, 1.65 mmol), copper(I) iodide (47 mg, 0.25 mmol), bis(triphenylphosphine)palladium(II) chloride (58 mg, 0.083 mmol) and triethylamine (242 mL, 1.74 mmol) were combined in DMF (3.0 mL) and allowed to stir for 1 hour.
  • step 52e above 330 mg, 1.05 mmol was dissolved in CH2CI2 (3 mL) and TFA (3 mL) was added at ambient temperature. After stirring for 30 minutes, the solvent was removed and the residue was diluted with CH2CI2 and washed with saturated K2CO3 solution, dried (MgSO4) and concentrated.
  • Phenylbororic acid (0.18 g, 1.48 mmol), paUadium (0) tetrakis(triphenylphosphine) (40 mg) and 2 M aqueous Na2CO3 (1.3 mL) were added to the reaction mixture and refluxed overnight. The solvent was evaporated and the residue was chromatographed (sUica gel; Hexane/EtOAc, 100:5 to 5:1) to afford an oil (0.41 g, 83%). MS (CI/NH3) m/z: 399 (M+H)+; 1H NMR (CDCI3, 300 MHz) ⁇ 1.35, 1.46 (s, 9H), 1.95-2.07 ( , 2H), 2.16
  • Example 55b 2-(2-(R)-pyrrolidinyl)-5-chloro-6-phenyl furor3.2-blpyridine hydrochloride The compound of Example 55a was added to a solution of 4.0 M HCl in dioxane.
  • Example 55a To the compound obtained in Example 55a (0.22 g, 0.55 mmol) was added formic acid (3.0 mL) and formaldehyde (37%, 6 mL). The mixture was heated at 80 °C for two hours. After cooling to room temperature, the solution was basified to pH 9 with saturated o aqueous NaHCO3 followed by extraction with CH2CI2 (3X). The combined organic layers were dried, concentrated and chromatographed (sUica gel; CH2 ⁇ 2/MeOH, 10:0.3 to 10:0.5) to afford an oil (0.11 g, 62%).
  • Example 56b 5-chloro-62-(l -methyl- 2-(R)-pynolidinvD— phenyl furor3,2-blpyridine hydrochloride
  • the compound obtained in Example 56a was dissolved in Et2 ⁇ and 1.0 HCl in Et2 ⁇ was added dropwise. The solvent was evaporated and the salt was triturated in Et2 ⁇ and dried under vacuum, mp 252-254 °C; [ ⁇ ] D 23 +38.79 (c 0.50, MeOH); MS (CI/NH3) 0 m/z: 313 (M+H)+; 1 H NMR (D2O, 300 MHz) ⁇ 2.28-2.40 (m, 2H), 2.50-2.70 (br, 2H),
  • Example 53 replacing the 2-(l-BOC-2(-pynolidinyl)-6- bromofuro[3,2-b]pyridine with the starting material compounds shown in Table 3 and replacing the phenylboronic acid reagent thereof with a R-B(OH)2 reagent shown in Table 3 below, the desired compounds 60-82 having R as described in Table 3 are prepared.
  • the S compounds or the racemic compounds may also readtiy be prepared from the appropriate precursor(s) as shown in the schemes or tables herein.
  • L can be varied as well and is selected from those variables hsted as R in formula I.
  • L at the position shown in Table 3 is prefenably chosen from H, F, Cl or Me. able 3
  • S compound or racemic compounds may also be prepared from the appropriate precursor(s).
  • L is chosen from R as described for formula I for the designated position and is prefenably selected from H, F, Cl or Me.
  • 6-(benzoyl)-2-(l-Boc-2-(R)-pyrrolidinyl)furo[3,2-b]pyridine is dissolved in CH2CI2 (10 mL).
  • the mixture is cooled to 0°C, TFA (10 mL) is added and the reaction is 5 stirred for 45 minutes as it warms to room temperature.
  • the mixture is concentrated in vacuo and taken up in a minimum amount of H2O.
  • the aqueous mixture is basified with 15% NaOH and extracted with CH2CI2 (200 mL), which is dried (MgSO4) and concentrated.
  • the residue is chromatographed (sihca gel) to afford the free amine.
  • the isolated free amine is taken up in a minimum amount of Et2 ⁇ , cooled to 0°C, and treated 0 with HCl in EtOH to afford the hydrochloride salt.
  • Example 93 replacing the 2-(l-Boc-2-(R)-pynolidinyl)- 5 6-cyanofuro[3,2-b]pyridine with the starting material compounds shown in Table 5 and replacing the phenylmagnesium bromide reagent thereof with a R 5 -Mg-Br Grignard reagent shown in Table 5 below, the desired compounds 94-97 having L and R 5 as described in Table 5 are prepared. S or R or racemic compounds may be prepared from the appropriate precursor(s). L is equal to R as described for formula I at that position. R-5 is also selected 0 from the variables as hsted in formula I. Table 5
  • Example 93 Following the procedure of Example 93, replacing the 2-(l-Boc-2-(R)-pyrrolidinyl)- 6-cyano-furo[3,2-b]pyridine with the starting material compounds shown in Table 6 and replacing the phenylmagnesium bromide reagent thereof with a R 5 -Mg-Br Grignard reagent shown in Table 6 below, the desired compounds 112 - 117 having L and R 5 as described in Table 6 are prepared.
  • Example 58 replacing 6-bromo-5-chloro-2-(l-methyl-2- (R)-pyrrohdinyl)furo[3,2-b]pyridine with starting material compounds shown in Table 7, replacing the 4-vinylpyridine starting reagent thereof with the starting reagent compounds shown in Table 7, then hydro genating the product thereof with paUadium or platinum on charcoal the desired compounds 104 - 107 having L and R 9 as described in Table 7 are prepared.
  • S, R or racemic compounds may be prepared from the appropriate precursor(s).
  • L is chosen from R in formula I and is prefenably chosen from H, Cl, F or Me. This reaction is partially described in Scheme 19.
  • Example 108 replacing the 2-(l-methyl-2-(R)- pynohdinyl)-6-(bromo)-furo[3,2-b]pyridine thereof with the starting material compound shown in Table 8 and replacing the 3-pyridinyltributyltin reagent thereof with the reagent shown in Table 8, the desired compounds 109-117 having L and R as described in Table 8 are prepared.
  • L may also be selected from the groups listed for R of formula I at the designated position.
  • the heteroaryl groups (het) shown at position Y-2 of formula I are added as described above using the appropriate tributyltin reagent.
  • R or S or racemic compounds may be prepared from the appropriate precursor and are included within the scope of the invention.
  • the reagents are either readily avaUable or may be prepared from commercially avaUable starting materials by standard synthetic methods.
  • the carbomethoxy group is hydrolyzed with base as additional step in this preparation. **After following the procedures of Example 108, with substitutions as indicated, the following additional steps are necessary: the carbomethoxy group is hydrolyzed with base; the resulting free acid is reduced to the alcohol with LiAlH4, and the resulting alcohol is oxidized to the aldehyde with Swern or Colhns reagents.
  • Example 58 replacing 6-bromo-5-chloro-2-(2-(R)- pynolidinyl)furo[3,2-b]pyridine with starting material compounds shown in Table 9, replacing the vinylpyridine starting reagent thereof with the starting reagent compounds shown Table 9, then optionally hydrogenating the product thereof with palladium on charcoal the desired compounds 118-120 having L and R 9 as described in Table 9 are prepared.
  • L may be selected from the group R of formula I as described herein for the designated position and R ⁇ , in Table 9, is chosen from arylCi-C6alkyl moieties as exemplified below.
  • the R or S or racemic compounds may be prepared from the appropriate precursor(s).
  • L is not selected from a moiety which prevents the regioselective addition to position Y-2 on the compound of formula I.
  • Example 121 Following the procedure of Example 121, replacing the 2-(l-Boc-2-(R)- pyrrolidinyl)-6-cyanofuro[3,2-b]pyridine starting material thereof with the starting materials shown in Table 10 below, and replacing the benzoyl chloride of step 121b with the acylating reagent shown in Table 10, the desired compounds 122-127 having L and R 5 as described in Table 10 are prepared.
  • L may be selected from R as described previously for groups at that position and R, S or racemic compounds may be prepared from the appropriate precursor.
  • the cyano group may be further extended via carbon-carbon homologations to form extended alkyl (branched or unbranched) amines which can be further treated with X(CO)R-5 or other acylating reagents or alkylating reagents to form, for example, -(Ci-C6alkyl)amide compounds within the scope of the invention.
  • X(CO)R-5 or other acylating reagents or alkylating reagents to form, for example, -(Ci-C6alkyl)amide compounds within the scope of the invention.
  • the nitrogen atom on the left hand side of the molecule should be protected during the acylation process.
  • m is selected from 1-6-e.g., C1-C6.
  • Example 121 replacing the 2-(l-Boc-2-(R)- pynohdinyl)-6-(cyano)-furo[3,2-b]pyridine starting material thereof with the starting materials shown in Table 11 below, and replacing the benzoyl chloride of step 121b with the acylating reagent shown in Table 11, the desired compounds 128-132 having L and R 5 as described in Table 11 are prepared.
  • L can be selected from the R group of formula I at the designated position and R ⁇ is selected from, for example, those alkanoyl- or benzoylating reagents as hsted below or from those reagents of like kind which are known, available or readUy prepared.
  • S, R and racemic compounds may be prepared from the appropriate precursor(s).
  • An N-alkyl or suitable protecting group is necessary on the left hand side to permit acylation.
  • 6-Chloro-2-iodo-3-pyridinol (693 mg, 2.71 mmol) from step 1 lc above, copper(I) iodide (77 mg, 0.41 mmol), bis(triphenylphosphine)paUadium(II) chloride (95 mg, 0.14 mmol) and triethylamine (416 mL, 2.98 mmol) were combined in DMF (5.0 mL) and allowed to stir for 1 hour.
  • step 135a above 178 mg, 0.510 mmol was dissolved in 1:1 CH2CI2/TFA (4 mL) and stirred at ambient temperature for 45 min. The solvent was removed in vacuo and the residue was dUuted with saturated aqueous K2CO3 and extracted with CH2CI2 (3X). The combined organic extracts were dried (Na2SO4) and concentrated.
  • the diazonium salt from step 136c above (83.6 g) was suspended in acetic anhydride (500 mL) and quickly warmed to 110 °C ⁇ 5 °C until nitrogen evolution became minimal (approximately 1 hour).
  • the solvent was removed in vacuo with a rotary evaporator (bath temperature 70 °C) and the residue was dUuted with Et2 ⁇ (1 L) and saturated aqueous Na2CO3 (300 mL).
  • the layers were separated and the aqueous phase was extracted with Et2 ⁇ (4 x 500 mL).
  • the combined ethereal extracts were dried (MgSO4) and concentrated.
  • step 136g above The compound from step 136g above (245 mg, 0.737 mmol) was dissolved in 1:1 CH2CI2/TFA (6 mL) and stirred at ambient temperature for 30 minutes. The solvent was removed in vacuo and the residue was partitioned between CH2CI2 and saturated aqueous 0 K2CO3. The organic extract was dried (Na2SO4) and concentrated.
  • the prefened compounds are those designated as Examples 15, 23, 26, 55 and 58 which are the most potent binders to the nicotinic acetylcholine receptor.
  • the prefened use of compounds of the invention is as a nicotinic acethycholine receptor modulator as described herein.
  • the prefened compounds for the most part, have a chlorine at the 5- position of the moiety and, thus, the preferred class of compounds is directed thereto.

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Abstract

Novel heterocyclic ether compounds having formula (I) wherein A, m, R, X, Y?1, Y2 and Y3¿ are specifically defined, which are useful in selectively controlling chemical synaptic transmission; therapeutically-effective pharmaceutical compositions thereof; and use of said compositions to selectively control synaptic transmission in mammals.

Description

Furopyridine, Thienopyridine, Pyrrolopyridine and Related Pyrimidine, Pyridazine and Triazine Compounds Useful in Controlling Chemical
Synaptic Transmission
This application is a Continuation-in Part ("OP") application which claims priority to United States Serial Number 08/679,237 filed July 23, 1996 which is a non-provisional application which claims priority to United States Serial Number 60/001,619 filed July 28, 1995.
TECHNICAL FIELD
This invention relates to furopyridine, thienopyridine, pyrrolopyridine and related pyrimidine, pyridazine and triazine compounds which control chemical synaptic transmission; to therapeutically effective pharmaceutical compositions of these compounds; and to the use of said compositions to selectively control synaptic transmission.
BACKGROUND OF THE INVENTION
Compounds that selectively control chemical synaptic transmission offer therapeutic utility in treating disorders that are associated with dysfunctions in synaptic transmission. 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.
An explanation of the processes involved in chemical synaptic transmission will help to illustrate more fully the potential applications of the invention. (For a fuller explanation of chemical synaptic transmission refer to Hoffman et al., "Neurorransmission: The autonomic and somatic motor nervous systems." In: Goodman and Gilman's. The Pharmacological Basis of Therapeutics, 9th ed., J.G. Hardman, L.E. Limbird, P.B. Molinoff, R.W. Ruddon, and A. Goodman Gilman, eds., Pergamon Press, New York, 1996, pp. 105-139).
Typically, chemical synaptic transmission begins with a stimulus that depolarizes the transmembrane potential of the synaptic junction above the threshold that elicits an all-or-none action potential in a nerve axon. The action potential propagates to the nerve terminal where ion fluxes activate a mobilization process leading to neurotransmitter secretion and "transmission" to the postsynaptic cell. Those cells which receive communication from the central and peripheral nervous systems in the form of neurotransmitters are referred to as "excitable cells." 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). EPSPs typically result from a local depolarization of the membrane due to a generalized increased permeability to cations (notably Na+ and K+), whereas EPSPs 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"). For example, the neurotransmitter acetylcholine excites at skeletal muscle junctions by opening permeability channels for Na+ and K+. At other synapses, such as cardiac cells, 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. Na+, K+ and Ca"*" ") through the neuronal membrane. In contrast, muscarinic acetylcholine receptor activation leads to changes in intracellular systems that contain complex molecules such as G-proteins and inositol phosphates. Thus, the biological consequences of nicotinic acetylcholine receptor activation are distinct from those of muscarinic receptor activation. In an analogous manner, inhibition of nicotinic acetylcholine receptors results in still other biological effects, which are distinct and different from those arising from muscarinic receptor inhibition.
As indicated above, the two principal sites to which drug compounds that affect chemical synaptic transmission may be directed are the presynaptic nerve terminal 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. Classic examples of 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.
In the 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. Obviously, the more that is understood about chemical synaptic transmission in CNS disorders, the easier it would be to design drugs to treat such disorders. Knowing how specific neurotransmitters act in the CNS allows one to speculate about the disorders that may be treatable with certain CNS-active drugs. For example, 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", In: Psychopharmacology: The Fourth Generation of Progress. F.E. Bloom and D.J. Kupfer, Eds., Raven Press, NY, 1995, pp 227-243). Patients with Parkinson's disease have a primary loss of dopamine containing neurons of the nigrostriatal pathway, which results in profound loss of motor control. Therapeutic strategies to replace the dopamine deficiency with dopamine mimetics, as well as administering pharmacologic agents that modify dopamine release and other neurotransmitters have been found to have therapeutic benefit ("Parkinson's Disease", In: Psychopharmacology: The Fourth Generation of Progress, op. cit, pp 1479-1484).
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. For example, dementia, such as is seen with Alzheimer's disease or Parkinsonism, remains 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). Specific agents for treatment of these and related disorders are few in number or non-existent. A more complete discussion of the possible utility as CNS-active agents of compounds with activity as cholinergic ligands selective for neuronal nicotinic acetylcholine receptors, (i.e., for controlling chemical synaptic transmission) may be found in U.S. Patent 5,472,958, to Gunn et al., issued Dec. 5, 1995, which is incorporated herein by reference.
Existing acetylcholine agonists are therapeutically sub-optimal in treating the conditions discussed above. For example, 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). In addition, other 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, M.A.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. Becker, ed.; Taylor & Francis: New York, 1988; pp 333-336).
Additional conditions for which neurotransmitter controlling agents may be useful include acute and chronic pain. (A. Dray and L. Urban, Annu. Rev. Pharmacology Toxicol. 36: 253-280, (1996).
A 6-bromo-2-(l-piperidinyl)thieno[2,3-b]pyridine of indeterminate use was disclosed by Meth-Cohn et al., J. Chem. Soc, Perkin Trans., 1:2509-17 (1981). Ciba- Geigy and Schenker et al. have disclosed various (2-benzofuranyl)-substituted tetrahydro pyridines and pyridines useful in treating mental depression (GB Patent No. 1,510,977, published May 17, 1978; and U.S. Patents No. 4,210,655 and 4,600,719). Toyama has disclosed N-BOC-thienopyridine derivatives having use an intermediates for preparation of complex cephalosporin-related antibiotic agents (PCT Patent Application WO 92/18505, published Oct. 29, 1992). Kabi Pharmacia has disclosed bicyclic heteroaryl compounds attached to a quinucUdene moiety useful for treating diseases related to muscarinic receptor function (PCT Patent Application WO 93/23395, published Nov. 25, 1993). Festal et al. have disclosed urea derivatives containing an azaindole moiety having utility as hypolipidemic and antiatheromatous agents (U.S.Patent No. 5,338, 849). Baker et al. have disclosed a class of substituted azetidine, pyrrolidine and piperidine derivatives having selective activity as agonists of 5-HTι-like receptors (PCT Patent Application WO 96/04274, published Feb. 15, 1996).
SUMMARY OF THE INVENTION It has been found, in accordance with the present invention, that certain furopyridine, thienopyridine, pyrrolopyridine and related pyrimidine, pyridazine and triazine compounds are selective and potent cholinergic compounds useful in selectively controlling synaptic transmission. In its principal aspect, the present invention provides a compound of formula (I) below, or a pharmaceutically acceptable salt thereof, wherein a monocyclic or bicyclic amine group is directly linked to a substituted or unsubstituted furopyridine, thienopyridine, pyrrolopyridine or related pyrimidine, pyridazine or triazine group. Another aspect of the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier or diluent.
In yet another aspect, the present invention provides a method for selectively controlling synaptic transmission in a mammal. The present invention relates to a compound of formula (I):
Figure imgf000007_0001
(I) or a pharmaceutically acceptable salt or pro-drug thereof wherein:
A is selected from the group consisting of:
Figure imgf000007_0002
wherein * denotes a chiral center, n is 1, 2 or 3, R1 is selected from the group consisting of H, allyl and
Cι-C -alkyl; R2 is selected from the group consisting of H,
Cι-C3-alkyl, Cι-C3-alkoxy, hydroxymethyl, fluoromethyl, methoxymethyl, and R2, when substituted at a position other than alpha to the ring nitrogen atom, is selected from Br, Cl, F, OH, CN, -O-CO- CH3 and-O-methanesulfonyl;
(b)
(c)
Figure imgf000008_0001
wherein p and q are independently 1 or 2;
( )
Figure imgf000008_0002
wherein p and q are independently 1 or 2;
(e)
Figure imgf000008_0003
(f)
R1
I
15
Figure imgf000008_0004
wherein, in the case of (e) and (f) R s as described above; R is independently selected at each occurrence from the group consisting of
Cι-C4-alkyl, vinyl, bromo, chloro, fluoro, trifluoro-Cι-C4-alkyl, trichloro-Cι-C4-alkyl, COOH,
CO2-Ci-C4-alkyl, CN, nitro, amino, hydroxy,
NH-CO-Cι-C3-alkyl, and
NR3R3, wherein R3 is H or Cι-C3-alkyl; or when substituted at the Y- position can additionally be selected from: NR R4, wherein R3 is H or C1-C3 alkyl and R4 is hydrogen, Ci-Cs-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6- alkyl-, and substituted-heteroaryl-Cι-C6-alkyl-; C(O)-R5> where R5 is hydrogen, Ci-Cg- alkyl, substituted-Cι-C8-alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted heteroaryl, phenyl Cι-C6alkyl-, substituted phenylCi-Cβalkyl-, heteroaryl Cι-C6alkyl-, substituted heteroaryl C1-C6 alkyl-, and Ci-C6alkoxy-, NR6R7, wherein R6 is selected from the group consisting of H and Cι-C3-alkyl-, and R7 is selected from the group consisting of H,
Cι-C3-alkyl-, phenyl and substituted phenyl;
OR8, wherein R8 is Ci-Cs-alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, phenylCi-Cgalkyl-, substituted phenylCi-Cδalkyl-, heteroaryl Ci-Cβalkyl-, CONR3R4; phenyl; naphthyl; substituted phenyl; substituted naphthyl; biphenyl; substituted biphenyl; heteroaryl; 5 substituted heteroaryl; phenyl Cι-C6alkyl-; substituted phenylCi-C^alkyl-; heteroaryl Ci-Cgalkyl-; and substituted heteroarylCι-C6alkyl-;
1 o = — R9 , wherein R9 is selected from the group consisting of hydrogen, Ci-Csalkyl, substituted Ci-Csalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted heteroaryl, phenylCi-Cόalkyl-, substituted phenylCι-C6alkyl-, heteroaryl Cι-C6alkyl-, and substituted 15 heteroarylCι-C6alkyl-;
^ , R9 rm , wherein m is 1 or 2, and R9 is as defined above;
-CH2-NH-CO-R-5, wherein R5 is as defined above; and -CH2-CH2-CO-O-Cι-C6-alkyl;
20
X is -O-, -S- or -NR3, wherein R3 is H or Cι-C3-alkyl;
Y1, Y2 and Y3 are N or CH, with the provisos that at least one of Y1,
Y2 and Y3 must be N and, 25 when group A is selected from option (b), except for those compounds additionally substituted at Y*2 above, then Y2 and Y3 must be CH; m, on formula (I), is 0, 1, 2 or 3. When m is zero or, at those positions around the 5-6 bicyclic ring system which are not 30 substituted by R, hydrogen is the substituent. The novel compounds of the present invention are also represented by formula (I):
Figure imgf000011_0001
(I) or a pharmaceutically acceptable salt or pro-drug thereof wherein the group designated A is selected from the group consisting of (a)-(f) as above: the asterisk denotes a chiral center; m is 0, 1 or 2; n is 1, 2 or 3, and p and q are independently 1 or 2. The group R1 is selected from the group consisting of H and C1-C3- alkyl; and R2 is H, or when n is 2 or 3 is selected from the group consisting of Cι-C3-alkyl, Cι-C3-alkoxyl, hydroxymethyl, fluoromethyl, methoxymethyl, Br, Cl, F, OH, CN, -O- CO-CH3 and -O-methanesulfonyl.
In the generic chemical structure shown above, R is independently selected at each occurrence from the group consisting of Ci-Gφ-alkyl, bromo, chloro, fluoro, trifluoro-Ci- C4-alkyl, trichloro-Cι-C4-alkyl, COOH, CO2-Ci-C4-alkyl, CN, nitro, amino, NH-CO-Ci- C3-alkyl, and NR3R3, wherein R3 is H or Cι-C3-alkyl. The group designated X is selected from the group consisting of -O-, -S- or -NR3, wherein R3 is H or Cι-C3-alkyl.
Y1, Y2 and Y3 are N or CH, with the provisos that at least one of Y1, Y2 and Y3 must be N and when group A is selected from option (b), then Y2 and Y3 must be CH. In yet another aspect of the invention, the invention relates to a compound of formula (HI):
Figure imgf000011_0002
(πi) or a pharmaceutically acceptable salt or pro-drug thereof wherein:
A is selected from the group identified above; and R is independently selected at each occurrence from the group consisting of Cι-C4-alkyl, vinyl, bromo, chloro, fluoro, trifluoro-Cι-C4-alkyl, trichloro-Cι-C4-alkyl, COOH, CO2-Ci-C4-alkyl, CN, nitro, amino, hydroxy, NH-CO-Cι-C3-alkyl, and NR R3, wherein R3 is H or Cι-C3-alkyl: and at the Y^ position R can additionally be selected from: NR R4, wherein R3 is H or C1-C3 alkyl and R4 is hydrogen, Ci-Cg-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Ci-Cg-alkyl-, substituted-phenyl-Cι-C6-alkyl-, 5 heteroaryl-Cι-C6- alkyl-, and substituted-heteroaryl-Ci-Cg-alkyl-;
C(O)-R5- where R5 is hydrogen, Ci-Cg-alkyl, substituted-Cι-C8-alkyl, phenyl, substituted-phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Ci-Cg-alkyl-, substituted-phenyl-Ci-Cβ-alkyl-, 1 o heteroaryl-Ci-Cό-alkyl-, substituted-heteroaryl-Ci-Cg-alkyl-, and
O-Cι-C6-alkyl-, N-R6R7, wherein R6 is selected from the group consisting of H and Cι-C3-alkyl-, and R7 is selected from the group consisting of H, Cι-C3-alkyl-, phenyl and substituted-phenyl;
OR8, wherein R8 is Ci-Cs-alkyl, phenyl, substituted-phenyl, 15 heteroaryl, substituted-heteroaryl, phenyl-Ci-Cg-alkyl-, substituted-phenyl-Ci-Cg-alkyl-, heteroaryl-Ci-Cβ-alkyl-, CONR R4; phenyl; naphthyl; 20 substituted-phenyl; substituted-naphthyl; biphenyl; substituted-biphenyl; heteroaryl; 25 substituted-heteroaryl; phenyl-C i -Cβ-alkyl-; substituted-phenyl-Ci- -alkyl-; heteroaryl-Ci-Cβ-alkyl-; and substituted-heteroaryl-C i -Cg- alkyl-;
30 = — R9 , wherein R9 is selected from the group consisting of hydrogen, Ci-Cg-alkyl, substituted-Ci-Cs-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Ci-Cg-alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Ci-Cό-alkyl-, and 35 substituted-heteroaryl-Cι-C6-alkyl-;
Figure imgf000013_0001
, wherein m is 1 or 2, and R9 is as defined above;
-CH2-NH-CO-R-5, wherein R5 is as defined above; and -CH2-CH2-CO-O-Cι-C6-alkyl;
X is -O-, -S- or -NR3, wherein R3 is H or Cι-C3-alkyl;
Y1, Y2 and Y3 are N or CH, with the provisos that at least one of Y1, Y2 and Y3 must be N and, when group A is selected from option (b), except for those compounds additionally substituted at Y-2 above, then Y2 and Y3 must be CH methoxymethyl or methoxymethoxy and m is 0, 1 or 2.
DETAILED DESCRIPTION OF THE INVENTION
Certain compounds of this invention may possess one or more asymmetric centers and may exist in optically active forms. Additional asymmetric centers may be present in a substituent group, such as an alkyl group. Compounds of the invention which have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, diastereomeric racemates or mixtures of diastereomeric racemates. It is to be understood that the present invention anticipates and includes within its scope all such isomers and mixtures thereof. The terms "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.
"Cι-C3-alkyl" and "Cι-C4-alkyl" refer to branched or straight-chain, unsubstituted alkyl groups comprising one-to-three or one-to-four carbon atoms, including, but not hmited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl and the like. "Cι-C6-alkyl" or "Ci-Cs-alkyl" as used herein refer to saturated, straight- or branched-chain hydrocarbon radicals containing between one and six or one and eight carbon atoms, respectively. Examples of C1-C3 alkyl radicals include methyl, ethyl, propyl and isopropyl, examples of Cι-C6-alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, and examples of Ci-Cg-alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, n-heptyl and n-octyl. "Cι-C3-alkoxy" refers to a Cι-C3-alkyl group, as defined above, containing an oxygen tinker atom.
"Trichloro-Cι-C4-alkyl" refers to a Ci-Cψ-alkyl group, as defined above, substituted with three chlorine atoms, including for example, trichloromethyl, 2,2,2-trichloroethyl, 3,3,3-trichloropropyl and 4,4,4-trichlorobutyl.
"Trifluoro-Cι-C4-alkyl refers to a Cι-C4-alkyl group, as defined above, substituted with three fluorine atoms, including for example, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl.
The term, "prodrug", refers to compounds that are rapidly transformed in vivo to yield the parent compounds of Formula (I), as for example, by hydrolysis in blood. T.
Higuchi and V. Stella provide a thorough discussion of the prodrug concept in Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, American Chemical Society (1975). Examples of esters useful as prodrugs for compounds containing carboxyl groups may be found on pages 14-21 of Bioreversible Carriers in Drug Design: Theory and Application, edited by E.B. Roche, Pergamon Press (1987).
The term, "prodrug ester group", refers to any of several ester-forming groups that are hydrolyzed under physiological conditions. Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art. The term, "administration", of the cholinergic agent or composition, as used herein, refers to systemic use as when taken orally, parenterally, by inhalation spray, by nasal, rectal or buccal routes, or topically as ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or transdermal patches in dosage form unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired.
The term "parenteral", as used herein, includes intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection as well as via infusion techniques.
By "pharmaceutically acceptable", it is meant those salts, amides and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio, effective for their intended use in the treatment of psychological, neurological, cardiovascular and addictive behavior disorders. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in JL Pharmaceutical Sciences, 66: 1-19, 1977. The salts may be prepared in situ during the final isolation and purification of the compounds of Formula (I), or separately by reacting the free base function with a suitable acid. Representative acid addition salts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, methanesulfonate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulfate salts and the like. Representative alkali or alkaline earth metal salts include sodium, calcium, potassium, magnesium salts and the like. Examples of pharmaceutically acceptable, nontoxic amides of the compounds of Formula (I) include amides derived from Cι-C6-alkyl carboxylic acids wherein the alkyl groups are straight- or branched-chain, arortiatic carboxylic acids such as derivatives of benzoic acid and heterocyclic carboxylic acids, including furan-2-carboxylic acid or nicotinic acid. Amides of the compounds of Formula (I) may be prepared according to conventional methods and include amino acid and polypeptide derivatives of the amines of Formula (I).
As used herein, the term, "pharmaceutically acceptable carriers", means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of the materials that may serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator. Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol and the like; and the metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like. By a "therapeutically effective amount" of the nicotinic acetylcholinergic agent, is meant a sufficient amount of the compound to treat cholinergically related disorders at a reasonable benefit/risk ratio applicable to obtain a desired therapeutic response. 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 judgment. 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; drugs used in combination or coincidentally with the specific compound employed; and like factors well known in the medical arts. Total daily dose of the compounds of this invention administered to a host in single or divided doses may be in amounts as determined by the attending physician, typically, for example, in amounts of from about 0.001 to 100 mg kg body weight daily and preferably 0.01 to 10 mg/kg/day. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The term "Cι-C6-alkoxy" as used herein refers to an Ci-Cβ-alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of Cι-C6-alkoxy include, but are not hmited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
The term "heteroaryl", as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, such as, for example, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, and the like, the heteroaryl moiety being joined to the rest of the molecule via any of its carbon ring atoms. The term "heteroarylCi-Cβalkyl" as used herein refers to a Cι-C6-alkyl group as defined herein substituted by replacement of one of the hydrogen atoms thereon with a heteroaryl moiety, as defined above.
The term "phenylCι-C6alkyl" as used herein refers to a Ci-Cβ-alkyl group as defined herein substituted by replacement of one of the hydrogen atoms thereon with a phenyl moiety.
The term "substituted Ci-Csalkyl" as used herein refers to a Ci-Cs-alkyl group as defined herein substituted by independent replacement of one of the hydrogen atoms thereon with Cl, Br, F, CN, CF , OH, CHO, COOH, COO-Cι-C3-alkyl, Cι-C6-alkoxy, methoxymethoxy, amino, or Cι-C3-alkyl- amino, except not more than one CHO, COOH, or COO-Cι-C3-alkyl group may be present. The term "substituted biphenyl" as used herein refers to a biphenyl radical substituted by replacement of one of the hydrogen atoms thereon with F, OH, NO2 or Cι-C3-alkyl.
The term "substituted naphthyl" as used herein refers to a naphthyl substituted by independent replacement of one or two of the hydrogen atoms thereon with Cl, Br, F, CN, CF3, NO2, OH, CHO, COOH, COO-Cι-C3-alkyl, Cι-C -alkyl, Cι-C6-alkoxy, methoxymethyl, methoxymethoxy, amino, or Cι-C3-alkyl-amino, except not more than one CHO, COOH, or COO-Cι-C3-alkyl group may be present.
The term "substituted phenyl" as used herein refers to a phenyl substituted by independent replacement of one or two of the hydrogen atoms thereon with Cl, Br, F, CN, CF3, NO2, OH, CHO, COOH, COO-Cι-C -alkyl, Cι-C3-alkyl, Ci-Cό-alkoxy, methoxymethyl, methoxymethoxy, amino, or Cι-C3-alkyl-amino, except not more than one CHO, COOH, or COO-Cι-C3-alkyl group may be present.
The term "substituted phenylCi-Cgalkyl" as used herein refers to a Cι-C6-alkyl group as defined herein substituted by replacement of one of the hydrogen atoms thereon with a substituted-phenyl moiety, as defined above.
The term "substituted heteroaryl" as used herein refers to a heteroaryl group as defined herein substituted on or two carbon atoms by independent replacement of he hydrogen atoms thereon with Cl, Br, F, CN, CF3, NO2, OH, CHO, COOH, COO-Cι-C3-alkyl, Cι-C3-alkyl, Ci-Cό-alkoxy, methoxymethyl, methoxymethoxy, amino, or Cι-C3-alkyl-amino, except not more than one CHO, COOH, or COO-Cι-C3-alkyl group may be present.
The term "substituted heteroaryl Ci-Cβalkyl" as used herein refers to a Ci-Cβalkyl group as defined herein substituted by replacement of one of the hydrogen atoms thereon with a substituted-heteroaryl moiety, as defined above.
Examples of compounds falling within the scope of the present invention precede the appended claims. If one specific enantiomer is shown or described, the other enantiomer may readily be made from the appropriate chiral precursor or can be resolved from a racemic mixture. In a preferred embodiment of the present invention, there are provided compounds of formula (II)
Figure imgf000018_0001
II wherein A is selected from the group consisting of
Figure imgf000018_0002
R1
I
Figure imgf000018_0003
and the other variables as recited above for X and Rm.
In a particularly preferred embodiment of the present invention there is provided a compound of formula (II) above wherein A is selected from
Figure imgf000018_0004
wherein R is H, Br, Cl, Cι-C4-alkyl, phenyl or vinyl pyridyl and R2 is H and \~\0 is as specified above.
Further included within the scope of the present invention are pharmaceutical compositions comprising one or more of the compounds of formula (I) prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable carriers in the manner described below.
Compositions suitable for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
If desired, and for more effective distribution, the compounds may be incorporated into slow-release or targeted-delivery systems, such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water, or some other sterile injectable medium immediately before use.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, and additionally (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, sohd polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
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.
Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and others well known in this art. They may contain pacifying agents, and may also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which may be used are polymeric substances and waxes. The active compounds may 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. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, these liquid dosage forms may also include 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, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal or vaginal administrations are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are sohd at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical or transdermal administration of a compound of this invention further include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or transdermal patches. Transdermal administration via a transdermal patch is a particularly effective and preferred dosage form of the present invention. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservative, buffers or propellants as may be required. It is known that some agents may require special handling in the preparation of transdermal patch formulations. For example, compounds that are volatile in nature may require admixture with special formulating agents or with special packaging materials to assure proper dosage delivery. In addition, compounds which are very rapidly absorbed through the skin may require formulation with absorption-retarding agents or barriers. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The present compounds may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidylcholines (lecithins), both natural and synthetic. 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.
In order to reduce unwanted peripherally mediated side-effects, it is advantageous, but not essential, to incorporate into the composition a peripherally acting anti-cholinergic such as N-methylscopolamine, N-methylatropine, propantheline, methantheline, or glycopyrrolate.
The compounds of the present invention may be synthesized as shown in reaction schemes 1-23 presented below using the reactions and techniques described in this section. The reactions are performed in a solvent appropriate to the reagents and materials employed are suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the heterocyclic ring and other portions of the molecule must be consistent with the chemical transformation proposed. This will, on occasion, necessitate judgment by the routineer as to the order of synthetic steps, protecting groups required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described, but alternative methods and substituents compatible with the reaction conditions will be readily apparent to skilled practitioners in the art. The use of nitrogen-protecting groups is well known in the art for protecting amino groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf, for example, T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons, New York (1991). Scheme 1
Figure imgf000022_0001
In accordance with Scheme 1 are prepared furo[3,2-b]pyridine compounds of Formula (I) wherein A is selected from group (a), R, R1 and R2 are as described above, X is O, Y1 is N and Y2 and Y3 are CH. The process may be illustrated with the pyrrolidine series (n=2) thereof, in which an N-protected 2-acetylenylpyrrolidine starting material (1), wherein P is a N-protecting group, such as for example, BOC or CBZ, (which may be prepared from the corresponding irnino-2-carboxylic acids according to known methods (Garvey, et al., J. Med. Chem., 35: 1550-1557, 1992)) is reacted with an appropriate 2- iodo-3-hydroxypyridine (2), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (3). (See Kundu, et al., J. Chem. Soc. Chem. Comm., 1992: 41 for analogous preparation of benzofurans). The protecting group P may then be removed by standard methods to give compound (4), i.e., compounds of formula (I) wherein R1 is H. Compound (4) may be converted into compounds (5), i.e., compounds of formula (I) wherein R1 is Cι-C3-alkyl by reaction with the appropriate aldehyde under reducing conditions, for example, in the presence of H and a catalyst such as Pd/C or in the presence of NaBH3CN. The process of Scheme 1 is equally applicable to compounds of the series wherein n is 1 or 3, to give compounds analogous to compounds (4) and (5), i.e., compounds of formula (I) wherein A is (a) and n is 1 or 3.
Alternately, for compounds of Formula (I) wherein X is S, compounds are prepared by appropriate modifications of the above schemes for X = O. The appropriate precursor o- halo-hydroxyheterocycles are converted to the corresponding o-halo-mercaptoheterocycles by reaction with a diakylthiocarbamyl chloride, for example diethyl thiocarbamyl chloride, followed by heating to effect reanangement to the thiocarbamate, followed by hydrolysis (Kwart and Evans, J. Org. Chem., 31: 410, 1966; Newman and Karnes, Org. Syn., 51: 139, 1971). The resultant o-halo-mercaptoheterocycles are then allowed to react with the acetylene compound (1) under copper catalysis (optionally in the presence of palladium) at elevated temperature to afford thieno-fused heterocycles (cf. Make and Castro, J. Am. Chem. Soc, 89. 6770, 1967). Such reactions may be applied to give the desired starting materials wherein O is replaced by S for the compounds described in the following schemes, also.
Scheme 2
Figure imgf000023_0001
In accordance with Scheme 2 are prepared furo[3,2-b]pyridine compounds of Formula (I) wherein A is selected from group (b), R2 is as described above, X is O, Y1 is N and Y2 and Y3 are CH. The process may be illustrated with the pynolidine series (n=2) thereof, in which a l-(3-propynyl)pyrrolidine starting material (6) (which may be prepared by reaction of the appropriately substituted pynolidine with 3-bromopropyne under basic conditions; see, for example, Biehl and DiPieno, J. Am. Chem. Soc, 80:4609-4614. 1958). The compound (6) is reacted with an appropriate 2-iodo-3-pyridinol (2), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (7). The process of Scheme 2 is equally applicable to compounds of the series wherein n is 1 or 3, to give compounds analogous to compound (7), i.e., compounds of formula (I) wherein A is (b) and n is 1 or 3.
The 2-iodo-3-pyridinols of Schemes 1 and 2 may be prepared by direct selective iodination of the corresponding pyridinols (e.g., Koch and Schnatterer, Synthesis, 1990:497). Alternately, 3-pyridinols with substituents in the 4-position can be prepared by selective lithiation of 3-pyridinol, O-protected with an ortho-directing moiety, e.g. methoxymethyl , diethylcarbamoyl, and the like (see Beak and Snieckus, Ace. Chem. Res., 15:306-312, 1982). Alternately, 3-hydroxypyridines with substituents in other required positions can be prepared from the conesponding 3-aminopyridines under diazotizing conditions. Where appropriate, the 3-aminopyridines can be obtained by reduction of the conesponding 3-nitropyridine or by rearrangement of the 3-carboxylic acid or 3- carboxamide using the Hoffman, Curtius, or Schmidt reanangements which are well-known in the art. In addition, 3-hydroxypyridines can be obtained by oxidation of an appropriate 3- lithio or magnesiopyridine with molecular oxygen, oxaziridines, or peroxides (see, for example, Taddei and Ricci, Syn. Comm., 1986:633-635), or alternately peroxide oxidation of a pyridyl-3-dialkylborate, which can be obtained by reaction of a trialkyl borate with the appropriate 3-lithio- or magnesiopyridine (cf. Lawesson and Yang, J. Am. Chem. Soc, 81:4320, 1959, and/or Hawthorne, J. Org. Chem., 22: 1001, 1957).
In an alternate procedure, the reactions of Scheme 2 may be performed with the analogous mercaptopyridine, prepared as described for Scheme 1 above, to give the thieno[3,2-b]pyrimidine compounds of Formula (I), wherein X is a S atom.
Scheme 3
Figure imgf000024_0001
9 10
In accordance with Scheme 3 are prepared furo[2,3-c]pyridine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R1 and R2 are as described above, X is O, Y1 is CH, Y2 is N and Y3 is CH. The acetylene- substituted starting material (1) or (6) is reacted with an appropriate 4-iodo-3-hydroxypyridine (9), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (10). The requisite 4-iodo-3-hydroxypyridines are generally available using the techniques mentioned above together with selective 4-iodination of 3- hydroxypyridines (cf. Winkle and Ronald, /. Org. Chem., 47:2101, 1982). In a further alternate procedure, the reactions of Scheme 3 may be performed with the analogous mercaptopyridine, prepared as described for Scheme 1 above, to give the thieno[2,3- c]pyrimidine compounds of Formula (I), wherein X is a S atom.
Scheme 4
Figure imgf000024_0002
In accordance with Scheme 4 are prepared furo[2,3-b]pyridine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R1 and R2 are as described above, X is O, Y1 and Y2 are CH and Y3 is N. The acetylene-substituted starting material (1) or (6) is reacted with an appropriate 3-iodo-2-hydroxypyridine (11), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (12). The requisite 3-iodo-2-hydroxypyridines are generally available using the techniques mentioned above for synthesis of selectively substituted 3- hydroxypyridines. For example, the requisite 3-iodo-2-hydroxypyridines can be obtained by ortho iodination of the appropriate 2-hydroxypyridine. In a further alternate procedure, the reactions of Scheme 4 may be performed with the analogous mercaptopyridine, prepared as described for Scheme 1 above, to give the thieno[2,3-b]pyrimidine compounds of Formula (I), wherein X is a S atom.
Scheme 5
Figure imgf000025_0001
13 14
In accordance with Scheme 5 are prepared furo[3,2-d]pyrimidine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R1 and R2 are as described above, X is O, Y1 is N, Y2 is N and Y3 is CH. The acetylene-substituted starting material (1) or (6) is reacted with an appropriate 4-iodo-5-hydroxypyrimidine (13), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (14). The requisite 4-iodo-5-hydroxypyrimidine compounds are generally available using the techniques mentioned above for synthesis of selectively substituted 3-hydroxypyridines. For example, the requisite 4-iodo-5-hydroxypyrimidine can be obtained by ortho iodination of the appropriate 5-hydroxypyrimidine. In a further alternate procedure, the reactions of Scheme 5 may be performed with the analogous mercaptopyridine, prepared as described for Scheme 1 above, to give the thieno[3,2- djpyrimidine compounds of Formula (I), wherein X is a S atom.
Scheme 5A
Figure imgf000025_0002
13A 14A In accordance with Scheme 5A are prepared furo[2,3-b]pyrimidine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R1 and R2 are as described above, X is O, Y1 is N, Y2 is N and Y3 is CH. The acetylene-substituted starting material (1) or (6) is reacted with an appropriate 3-iodo-2-hydroxypyrimidine (13A), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (14A). The requisite 3-iodo-2-hydroxypyrimidine compounds are generally available using the techniques mentioned above for synthesis of selectively substituted 2-hydroxypyridines. For example, the requisite 3-iodo-2-hydroxypyrimidine can be obtained by ortho iodination of the appropriate 2-hydroxypyrimidine. In a further alternate procedure, the reactions of Scheme 5A may be performed with the analogous mercaptopyridine, prepared as described for Scheme 1 above, to give the thieno[2,3- b]pyrimidine compounds of Formula (I), wherein X is a S atom.
Scheme 6
Figure imgf000026_0001
15 16
In accordance with Scheme 6 are prepared furo[2,3-c]pyridazine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R1 and R2 are as described above, X is O, Y1 is CH, and Y2 and Y3 are N. The acetylene-substituted starting material (1) or (6) is reacted with an appropriate 4-iodo-3-hydroxypyridazine (15), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (16). The requisite 4-iodo-3-hydroxypyridazine compounds are generally available using the techniques mentioned above for synthesis of selectively substituted 3-hydroxypyridines. For example, the requisite 4-iodo-3-hydroxypyridazine can be obtained by ortho iodination of the appropriate 5-hydroxypyridazine. In a further alternate procedure, the reactions of Scheme 6 may be performed with the analogous mercaptopyridine, prepared as described for Scheme 1 above, to give the thieno[2,3- c]pyridazine compounds of Formula (I), wherein X is a S atom. Scheme 7 R
Figure imgf000027_0001
17 18
In accordance with Scheme 7 are prepared furo[3,2-e]triazine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R1 and R2 are as described above, X is O, Y1 is CH, Y2 is N and Y3 is N . The acetylene- substituted starting material (1) or (6) is reacted with an appropriate 5-iodo-6-hydroxyrriazine (17), wherein R is as described above, in the presence of Pd, Cul and triethylamine at elevated temperature, to give the compound (18). The requisite 5-iodo-6-hydroxytriazine compounds are generally available using the techniques mentioned above for synthesis of selectively substituted 3- hydroxypyridines. For example, the requisite 5-iodo-6-hydroxyrriazine can be obtained by ortho iodination of the appropriate 5 -hydroxy triazine .
Alternately, this reaction may be performed with the analogous mercaptopyrimidine, prepared as described for Scheme 1 above, to give the thieno[3,2-e]triazine compounds of Formula (I), wherein X is a S atom.
Scheme 8
Figure imgf000027_0002
In accordance with Scheme 8 are prepared pyrrolo[3,2-b]pyridine compounds of
Formula (I) wherein A is selected from (a) or (b) above, R, R1 and R2 are as described above, X is NH, Y1 is N and Y2 and Y3 are CH. A starting material amino-nitro pyridine (19) is reacted with NaNO2 and HI to replace the amino group with an iodo group, then with iron and acetic acid to reduce the nitro group to an amino group and give the compound (20). Compound 20 is then reacted with compound 1 or 6 in the presence of Pd, Cul and triethylamine at elevated temperature, as described above, to give the compound (21). Scheme 9
Figure imgf000028_0001
In accordance with Scheme 9 are prepared pyrrolo[2,3-c]pyridine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R1 and R2 are as described above, X is NH, Y1 and Y3 are CH and Y2 is N. A protected aminopyridine compound starting material (22) is reacted with a strong base, such as t-butyllithium, and free iodine to give the iodinated compound (23). Compound (23) is then reacted with compound (1) or (6) in the presence of Pd, Cul and triethylamine at elevated temperature, as described above, followed by N-deprotection under standard conditions, to give the compound (24).
Scheme T O
Figure imgf000028_0002
In accordance with Scheme 10 are prepared pynolo[2,3-b]pyridine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R1 and R2 are as described above, X is NH, Y1 and Y2 are CH and Y3 is N. A protected aminopyridine compound starting material (25) is reacted with a strong base, such as t-butyllithium, and free iodine to give the iodinated compound (26). Compound (26) is then reacted with compound (1) or (6) in the presence of Pd, Cul and triethylamine at elevated temperature, as described above, then deacylated by standard methods to give the compound (27). Sςh iηe ll
Figure imgf000029_0001
In accordance with Scheme 11 are prepared pynolo[3,2-d]pyrimidine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R1 and R2 are as described above, X is NH, Y1 and Y2 are N, and Y3 is CH . A protected aminopyrimidine compound starting material (28) is reacted with a strong base, such as t-butyllithium, and free iodine to give the iodinated compound (29). Compound (29) is then reacted with compound (1) or (6) in the presence of Pd, Cul and triethylamine at elevated temperature, as described above, then deacylated by standard methods to give the compound (30).
Scheme 12
Figure imgf000029_0002
In accordance with Scheme 12 are prepared pyrrolo[2,3-c]pyridazine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R1 and R2 are as described above, X is NH, Y1 is CH, and Y2 and Y3 are N. A protected aminopyridazine compound starting material (31) is reacted with a strong base, such as t-butyllithium, and free iodine to give the iodinated compound (32). Compound (32) is then reacted with compound (1) or (6) in the presence of Pd, Cul and triethylamine at elevated temperature, as described above, then deacylated by standard methods to give the compound (33).
Scheme 13
Figure imgf000030_0001
In accordance with Scheme 13 are prepared pynolo [3, 2-e] triazine compounds of Formula (I) wherein A is selected from (a) or (b) above, R, R1 and R2 are as described above, X is NH, Y1 is CH, and Y2 and Y3 are N. A protected aminotiϊazine compound starting material (34) is reacted with a strong base, such as t-butyllithium, and free iodine to give the iodinated compound (35). Compound (35) is then reacted with compound (1) or (6) in the presence of Pd, Cul and triethylamine at elevated temperature, as described above, then deacylated by standard methods to give the compound (36).
Scheme 14
Figure imgf000030_0002
37 38
In accordance with Scheme 14 is prepared the 7a-ethynyl- lH-hexahydropyrrolizine starting material for compounds of Formula (I) wherein A is selected from option (c). The starting material pynolizidinium compound (prepared according to the procedure of Miyano et al., Synthesis, 1978:701-2) is reacted with the ethynyl magnesium bromide under appropriate Grignard conditions to give the compound (38). Compound 38 may be substituted for compounds (1) or (6) in any of Schemes 1-13 above to give the desired compound of Formula (I). Sc eme 15
Figure imgf000031_0001
In accordance with Scheme 15 is prepared the 3-ethynyl-lH-hexahydropynolizine starting material (43) for compounds of Formula (I) wherein A is selected from option (d). The protected prolinol (39) is converted to the aldehyde compound (40) by reaction with triethylamine and pyridine-»sulfur trioxide complex in DMSO. Compound (40) is reacted with (triphenylphosporanylidene)acetaldehyde, followed by reduction of the intermediate with H2 over a Pd/C catalyst to give the extended aldehyde compound (41). Compound (41) is subsequently reacted with, for example, ethynyl magnesium bromide and the intermediate is reacted with triphenylphosphine dibromide to give compound (42). Compound 42 is treated with HCl in a polar organic solvent, such as ethanol, for example to give the 3-substituted pynolizidine compound (43). Compound (43) may be substituted for compounds (1) or (6) in any of Schemes 1-13 above to give the desired compound of Formula (I).
Scheme 16
1. LiAIH4 2. pyridine-S03
Figure imgf000032_0001
44 45
Figure imgf000032_0002
Boc
46 47
In accordance with Scheme 16 is prepared the ethynyl substituted 2- azabicyclo[2.2.1]heptane starting material for compounds of Formula (I) wherein A is selected from option (e). Compound (44) (prepared according to the procedure of Stella et al., Tetrahedron Lett., 21:2603 (1990)) is deprotected by hydrogenolysis over Pd/C, then reprotected by treatment with di-t-butyldicarbonate to give the BOC-protected compound (45). Compound (45) is reduced with L1AIH4 to an intermediate alcohol, which is then oxidized to obtain the aldehyde (46). Compound (46) is treated with PPh3 and CBr4 to give an intermediate dibromoalkene (not shown), which is then converted to the alkyne (47) by treatment with an alkyllithium compound. Compound (47) may be substituted for compounds (1) or (6) in any of Schemes 1-13 above to give the desired compound of Formula (I).
Figure imgf000033_0001
exo
Figure imgf000033_0002
In accordance with Scheme 17 is prepared the ethynyl substituted 7- 5 azabicyclo[2.2.1]heptane starting material for compounds of Formula (I) wherein A is selected from option (f). Compound (48) (prepared according to the procedure of Hernandez et al., J. Org. Chem., 60:2683-2691 (1995)) is reduced with LiAlH4 to an intermediate alcohol, which is then oxidized under Swern (DMSO, oxalyl chloride, NEt3) or similar conditions to obtain the aldehyde (49). Compound (49) is treated with PPh3 and o CBr4 to give the dibromoalkene (50), which is then converted to the alkyne (51) by treatment with an alkyllithium compound. Compound (51) may be substituted for compounds (1) or (6) in any of Schemes 1-13 above to give the desired compound of Formula (I).
It should be noted that compounds of Formula (I) wherein R is Cι-C4-alkyl, Br, Cl, 5 F, CF3 or CCI3 may be conveniently prepared by starting with the appropriately substituted compounds 2, 9, 11, 13, 13A, 15, 17, 20, 23, 26, 29, 32 or 35, which, if necessary, may be prepared by common techniques from the unsubstituted pyridine, pyrimidine or pyrazine starting materials or other commercially available derivatives thereof. Preparation of additional iodohydroxyheterocycles may be carried out by selective electrophilic aromatic 0 substitution reactions upon the conesponding hydroxyheterocycles. In the above selective electrophilic substitution reactions, occasionally it may be necessary or desirable to achieve the desired position of substitution by blocking a more readily substituted position with a blocking and/or directing group, e.g. chloro or nitro, which can subsequently (either prior or subsequent to cycloaddition to acetylenes, e.g. 1, 6, 38, 43, 47 and 57) be removed by, 5 respectively, reduction or a reduction/diazotization/reduction sequence. Alternately, a bromo- or chloro-substituent on an intermediate substituted pyridine or a fully assembled furopyridine or related heterocycle which has been constructed by way of the methods described above can be converted to other substituents. For example, by treating a compound of Formula (I) wherein R is Br with NH3, optionally with catalysis by copper salts, under heat and pressure, compounds of Formula (I) wherein R is NH2 may be prepared. Further treatment of compounds of Formula (I) wherein R is NH2 with NaNO2 and CuCN allows the preparation of compounds of Formula (I) wherein R is CN. As a further example, amino may be oxidized with H2SO4 and H2O2 to nitro, or carboxamide may be dehydrated to cyano. Cyano groups may be treated with the appropriate alcohol in the presence of a strong acid to prepare compounds of Formula (I) wherein R is COO-Ci- G-j-alkyl. Further hydrolysis of these esters with mild base gives the compounds of Formula (I) wherein R is COOH. Or compounds of Formula (I) wherein R is NH2 may be N-acylated by the appropriate Ci-C-t-acyl chloride (or acyl hahdes selected from Ci-C8-acyl halide, substituted ClC8-acyl halide, phenyl acyl halide, substituted phenyl-acyl-halide, heteroaryl-acyl halide, substituted heteroaryl-acyl-halide, phenyl-Ci-C6-acyl halide, substituted phenyl-Cl-C6-acyl halide, heteroaryl-acyl halide, substituted heteroaryl-acyl halide or (-O-Ci-C6alkyl)acyl halide to give compounds of Formula (I) wherein R is NH- CO-Cι-C4-alkyl or the acyl derivatives of the groups specified directly above. Further, compounds of Formula (I) wherein R is NH2 may by alkylated or arylated to give the compounds of Formula (I) wherein R is NR-'R1 or NR6R7 Also, bromo- or chloro- substituted compounds may be replaced with alkyl or alkenyl in reactions moderated by transition metals, e.g., palladium or nickel. Such alternate procedures as may be required are well known to those skilled in the art, and such alternate substituents are considered to be within the scope of the invention. Appropriate precursors to compounds 13, 13A, 15, 17, 29, 32 and 35 may also be prepared by ring-closure reactions of appropriately substituted acyclic compounds, such reactions being well known to those skilled in the art. In addition to the syntheses and synthetic schemes described above, the schemes and discussion presented below are directed to preparation of compounds of formula I wherein R, when substituted at the Y*2 position, may be selected from: NR R4, wherein R3 is H or C1-C3 alkyl and R4 is hydrogen, Ci-Cg-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6-alkyl-, and substituted-heteroaryl-C 1 -C6- alkyl-;
C(O)-R5 ' where R5 is hydrogen, Ci-Cs-alkyl, substituted-Ci-Cs-alkyl, phenyl, substituted-phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6- alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6-alkyl-, substituted-heteroaryl-C ι-C6-alkyl-, and O-Cι-C6-alkyl-, N-R6R7, wherein R6 is selected from the group consisting of H and Cι-C3-alkyl-, and R7 is selected from the group consisting of H, Cι-C3-alkyl-, phenyl and substituted-phenyl;
OR8, wherein R8 is Ci-Cs-alkyl, phenyl, substituted-phenyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6-alkyl-, CONR3R4; phenyl; naphthyl; substituted-phenyl; substituted-naphthyl; biphenyl; substituted-biphenyl; heteroaryl; substituted-heteroaryl; phenyl-Cι-C6-alkyl-; substituted-phenyl-Ci- -alkyl-; heteroaryl-Ci-Cό-alkyl-; and substituted-heteroaryl-C i -C6- alkyl-; = — R9 , wherein R9 is selected from the group consisting of hydrogen,
Ci-Cg-alkyl, substituted-Ci-Cs-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6-alkyl-, and substituted-heteroaryl-Cι-C6-alkyl-;
Figure imgf000035_0001
-CH2-NH-CO-R-\ wherein R5 is as defined above; and -CH2-CH2-CO-O-Cι-C6-alkyl.
In addition to the groups or variables recited for a compound of formula I in the preceding section with respect to A, Rl, R2 and R, in a compound of formula I, R* may additionally be selected from allyl; R2 for n is 1, 2 or 3 is selected from all the variables previously specified as well as Br, Cl, F, OH, CN, -O-CO-CH3 and -O-methanesulfonyl provided said specifically refened to R2 groups are not alpha to the ring nitrogen atom in group A; R at any position is additionally selected from vinyl and hydroxy.
Treatment of compounds of formula (I) wherein R is Br with alkoxides, e.g. those derived from C1-C alcohols or benzyl alcohol, for example, at elevated temperature allows preparation of of compounds of Formula (I) wherein R is C1-C6 alkyl-O- or benzyl-O-. Removal of the benzyl group by catalytic hydrogeno lysis or treatment with acid, for example, hydrogen bromide in acetic acid, provides compound of formula (I) wherein R is hydroxy. The hydroxy group can then be alkylated by appropriate halides or sulfonates to afford compounds or formula (I) wherein R is C1-C8 alkyl-O-, phenyl-Cl-C6-alkyl-O-, substituted phenyl Cl-C6-alkyl-O-, heteroaryl-Cl-C6-alkyl-O-, substituted heteroaxyl-Cl- C6-alkyl-O-, or acylated by appropriate isocyanates or carbamoyl chlorides to afford compounds of Formula (I) wherein R is OC(O)-NR3R4. The precursor wherein R is hydroxy can alternately be prepared from the compound wherein R is amino by treatment with sodium nitrite followed by heating under acid conditions. It will apparent to those skilled in the art that some of the above transformations will be best carried out following protection of moieties elsewhere in the molecule that may be susceptible to the reaction conditions with a suitable protecting group, followed by removal of the protecting group when no longer needed by conditions well known in the art.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared. The groups n, R1 are as defined above unless otherwise noted.
Scheme 18
Figure imgf000036_0001
In accordance with Scheme 18 intermediate compounds are prepared by reaction of an acetylene compound (la), wherein n is 1 to 3 and R1 is allyl or Ci-Cg-alkyl or a protecting group such as t-BOC or CBZ, for example, with a 2-iodo-3-hydroxypyridine compound (2a), wherein L is H, F or Cl or R as defined herein for compounds of Formula (I) above, in the presence of Pd, Cul and triethylamine at the elevated temperature (See Kundu, et al., J. Chem. Soc. Chem. Comm., 1992: 41 for analogous preparation of benzofurans) to form the 6-bromofuro[3,2-b]pyridyl compound (3a). Scheme 19
Figure imgf000037_0001
In accordance with Scheme 19 an intermediate compound (3a), wherein R1 is allyl or Ci-Cό-alkyl or a protecting group such as t-BOC or CBZ, for example, is reacted with an unsaturated compound (4a), (6a) or (8a), to give compounds (5a), (7a) or (9a), respectively, which are specific or protected compounds of Formula (I), by treatment with a palladium (II) catalyst under weakly basic conditions at reflux temperature in an organic or aqueous solvent. Compound (4a) may be prepared by reacting a compound R9-CHO, wherein R9 is selected from the group consisting of hydrogen, Ci-Cg-alkyl, substituted-Ci-Cs-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6-alkyl-, and substituted-heteroaryl-Cι-C6-alkyl-, with (phenyl)3P=CH2 in refluxing toluene. Of course, these compounds may further be treated with a reducing agent (e.g. hydrogen/catalyst) to form the saturated derivatives (R= heteroarylCι-C6alkyl.
Compound (6a) may be prepared by reacting a compound R9-CHO, wherein R9 is as described above, with (Ph)3P=CH-CHO in refluxing toluene to give R9-CH=CH-CHO, then reacting R9-CH=CH-CHO with (Ph)3P=CH2 in refluxing toluene. Compound (8a) may be prepared by reacting R9-CHO, wherein R9 is as described above, with CBr4 and P(Ph)3 to give R9-CH=CBr2, then reacting R9-CH=CBr2 with 2 equivalents of n-butyllithium followed by treatment with H+. In the cases wherein R1 is a protecting group such as t-BOC or CBZ it must be removed under well-known standard conditions for removing those groups in order to give the desired compound of Formula (I). In some cases wherein R1 is allyl or Cι-C6-alkyl, it may be desirable to place this grouping in the compound after the protecting R1 group has been removed. When R1 is allyl, this may be accomplished by reacting the unprotected nitrogen atom with allyl chloride in the presence of a weak base such as triethylamine. When R1 is Cι-C6-alkyl, this may be accomplished by reacting the unprotected nitrogen atom with the appropriate aldehyde in the presence of NaCNBH3, for example. L is chosen from the groups defined under R. Any of the above compounds may be further reduced to form a compound of the invention.
Scheme 20
Figure imgf000038_0001
In accordance with Scheme 20 an intermediate compound (3a), wherein R1 is allyl or Cι-C6-alkyl or a protecting group such as t-BOC or CBZ, for example, is reacted with a suitable boronic acid compound (10a) wherein W is selected from the group consisting of: (a) phenyl; (b) naphthyl; (c) substituted-phenyl, as defined herein; (d) substituted-naphthyl, as defined herein; (e) biphenyl; (f) substituted-biphenyl, as defined herein; (g) heteroaryl, as defined herein; (h) substituted-heteroaryl, as defined herein; (i) phenyl-Cι-C6-alkyl-, as defined herein; (j) substituted-phenyl-Cι-C6-alkyl-, as defined herein; (k) heteroaryl-Ci-Cg-alkyl-, as defined herein; and (1) substituted-heteroaryl-Cι-C6-alkyl-, as defined herein; for Formula (I) above, in the presence of Pd(0) under the conditions of the Suzuki reaction, for example in the presence of a weak base such as NaHCO3 and in an aprotic solvent, such as toluene, benzene or methylene chloride at reflux temperatures to give a compound (11a), wherein R3 is as described above, to produce specific compounds of Formula (I). In an alternate method, compound (10a) may be replaced by a WMgX compound and reacted in the presence of Ni(dppp)2Cl2 to give compound (11). In the cases wherein R1 is a protecting group such as t-BOC or CBZ it must be removed under well-known standard conditions for removing those groups in order to give the desired compound of Formula (I). In some cases wherein R1 is allyl or Ci-Cό-alkyl, it may be desirable to place this grouping in the compound after the protecting R1 group has been removed. When R1 is allyl, this may be accomplished by reacting the unprotected nitrogen atom with allyl chloride in the presence of a weak base such as triethylamine. When R1 is Cι-C6-alkyl, this may be accomplished by reacting the unprotected nitrogen atom with the appropriate aldehyde in the presence of NaCNBH3, for example. L is equal to R as defined above at the designated position.
Scheme 21
1 1 a + Pheny
Figure imgf000039_0001
Figure imgf000039_0002
In accordance with Scheme 21 are prepared compounds of Formula (I) wherein L is vinyl, phenyl or substituted phenyl. Reaction of a starting material compound (11a) wherein L is chloro with phenylboronic acid (12a) in the presence of Pd(0) under the conditions of the Suzuki reaction, for example in the presence of a weak base such as NaHCO3 and in an aprotic solvent, such as toluene, benzene or methylene chloride at reflux temperatures gives the compound 13a. Reaction of a starting material compound (11a) wherein L is chloro with vinyl-Sn(n-Bu)3 (14a) in the presence of Pd(0) under Stille reaction conditions to give the compound (15a). In the cases wherein R1 is a protecting group such as t-BOC or CBZ it must be removed under well-known standard conditions for removing those groups in order to give the desired compound of Formula (I). In some cases wherein R1 is allyl or Cι-C6- alkyl, it may be desirable to place this grouping in the compound after the protecting R1 group has been removed. When R1 is allyl, this may be accomplished by reacting the unprotected nitrogen atom with allyl chloride in the presence of a weak base such as triethylamine. When R1 is Ci- i-alkyl, this may be accomplished by reacting the unprotected nitrogen atom with the appropriate aldehyde in the presence of NaCNBH3, for example. Sc me 22
Figure imgf000040_0001
1 6a
Figure imgf000040_0002
Figure imgf000040_0003
In Scheme 22 is shown an alternate process for preparing desired compounds of the invention. Whereas in Schemes 19 and 20, the heterocyclic and the pyridine moieties are first joined, and the W group is added according to Schemes 19 and 20, Scheme 22 allows for the placement of the W group before joining. Accordingly a hydroxypyridine compound is treated with the appropriate reagent, such as a trialkylsilyl or benzyl chloride, to protect the hydroxyl group with a protecting group PG, such as trialkylsilyl or benzyl, respectively, for example to give compound (16a). Compound (16a) may then be reacted with an appropriate reagent, as described in Schemes 19 and 20, to give the compound (17a) having the desired substitution at L and W. L is chosen from R as designated previously at that position on the ring and W is as defined previously. Subsequent iodination followed by deprotection by standard methods gives (18a), which is then coupled with compound (1) according to the method of Scheme 18 to give the desired compound of Formula (I). Scheme 23
Figure imgf000041_0001
In accordance with Scheme 23 are prepared additional compounds of Formula (I). Compound (3a) is first reacted with Zn(CN)2 and tetrakis(triphenylphosphine)palladium(0) under anhydrous conditions in DMF or a similar solvent at room temperature to 120°C for 12-24 hours, to give the cyano intermediate compound (19a) with L selected from R as defined above. Compound (19a) may then be reacted with a reagent R5-M, wherein R5 is as described for Formula (I) above and M is Uthium or a magnesium hahde moiety, under the appropriate anhydrous conditions, with cooling if necessary, for 2-8 hours or until the reaction is complete to give, followed by treatment with aqueous acid to dissociate the metal complexes and give compound (20a). Alternately, the cyano group of compound (19a) may be reduced by treatment with 1 atm of H2 in the presence of Raney nickel at room temperature for 1-8 hours to give an intermediate amino compound. The intermediate amino compound may then be treated with a suitable acylating reagent, for example ethyl formate, an acyl chloride R5-C(=0)CI wherein R5 is, for example, Ci-Cs-alkyl, substituted-Ci-Cs-alkyl, phenyl, substituted-phenyl, heteroaryl, substituted-heteroaryl, aryl-Cι-C6-alkyl-, substituted-aryl-Cι-C6-alkyl-, heteroaryl- Ci-Cό-alkyl-, or substituted-heteroaryl-C ι-C6-alkyl-, a Cι-C6-alkyl dicarbonate; or is treated with an appropriate carbamylating reagent, for example KOCN or an isocyanate R^NCO wherein R7 is selected from Ci-C3alkyl, phenyl or substituted phenyl or Cl-CO-N-R6R7, for example, wherein R6 may be Cι-C3-alkyl-, and R7 may be Cι-C3-alkyl-, phenyl or substituted-phenyl. In Vitro Determination of Neuronal Nicotinic Acetylcholine Receptor Binding Potencies
For the purpose of identifying compounds as nicotinic acetylcholinergic agents which are capable of interacting with neuronal nicotinic acetylcholine receptors in the brain, a ligand-receptor binding assay was carried out as the initial screen. Compounds of the present invention were effective at interacting with neuronal nicotinic acetylcholine receptors as assayed for their ability to displace radioligand from neuronal nicotinic acetylcholine receptors labeled with [3H]-cytisine ([ H]-CYT).
A. Protocol For Determination of Nicotinic Acetylcholine Receptor Binding Potencies of Ligands
Binding of [3H]-CYT to 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 NaCl, 5 mM KC1, 2 mM MgCl2, 2 mM CaC and 50 mM Tris-Cl, pH 7.4 @4°C). After centrifuging at 20,000x g for 15 minutes, the pellets were resuspended in 30 volumes of buffer. Homogenate (containing 125-150 μg protein) was added to triplicate tubes containing concentrations of test compound and [3H]-CYT (1.25 nM) in a final volume of 500 μL. Samples were incubated for 60 minutes at 4°C, then rapidly filtered through
Whatman GF/B filters presoaked in 0.5% polyethylimine using 3 x 4 mL of ice-cold buffer. The filters were counted in 4 mL of Ecolume® (ICN). Nonspecific binding was determined in the presence of 10 μM (-)-nicotϊne and values were expressed as a percentage of total binding. IC50 values were determined with the RS-1 (BBN) nonlinear least squares curve- fitting program and IC50 values were converted to Ki values using the Cheng and Prusoff conection (Ki=IC5o (l+[ligand]/Kd of ligand). The results (shown in Table 1) suggest that the compounds of the present invention have high affinity for the neuronal nicotinic acetylcholine receptor.
The ability of the compounds of the invention to interact with nicotinic acetylcholine receptors and thereby to activate or inhibit synaptic transmission can be demonstrated in vitro using the following protocol.
B. Protocols for the Determination of Functional Effects of Nicotinic Acetylcholine Receptor Ligands on Synaptic Transmission
Cells of the IMR-32 human neuroblastoma clonal cell line (ATCC, Rockville, MD) were maintained in a log phase of growth according to established procedures (Lukas, R.J., J. Pharmacol. Exp. Ther., 265: 294-302, 1993). Experimental cells were seeded at a density of 500,000 cells/mL into a 24- well tissue culture dish. Plated cells were allowed to proliferate for at least 48 hours before loading with 2 μCi/mL of 8 Rb+ (35 Ci/mmol) overnight at 37°C. The 86Rb+ efflux assays were performed according to previously pubhshed protocols (Lukas, 1993) except serum-free Dulbecco's Modified Eagle's Medium was used during the 86Rb+ loading, rinsing, and agonist-induced efflux steps.
Cells of the K177 cell line, resulting from stable transfection of the human embryonic kidney (HEK) 293 cell line with the cDNA of the α4 and β2 nicotinic acetylcholine subunits (Gopalakrishnan, et al, J. Pharmacol. Expt. Ther. 1996, 276, 289- 297), were maintained in a log phase of growth according to established procedures
(Gopalakrishnan, et al., loc cit.). The cells were plated onto poly-lysine coated 24-well Costar plates (Cambridge, MA) at a density of 250,000 cells/well. When confluent, the cells were loaded with 86R + ancj agonist-induced efflux was assessed as reported above for IMR-32 cells. Maximal responses (reported as percent relative to the response elicited by 100 μM
(S)-nicotine) are shown for selected compounds of the invention. The inhibition data (given for other selected compounds) reflect inhibition of the efflux elicited by 100 μM (S)-nicotine at the indicated concentration. The results (also shown in Table 1) suggest that selected compounds of the present invention either activate or inhibit the initial ion flux aspects of synaptic transmission mediated by neuronal nicotinic acetylcholine receptors. This finding is in agreement with the results of others who have linked dopamine release, which is dependent upon the ion flux in synaptic transmission, to binding at nicotinic receptors (cf., for example, Lippiello and Caldwell, U.S.Patent 5,242,935, issued Sept. 7, 1993; Caldwell and Lippiello, U.S.Patent 5,248,690, issued Sept. 28, 1993; and Wonnacott et al, Prog. Brain Res., 79: 157-163 (1989)).
Table 1
Binding to Neuronal Nicotinic Acetylcholine Receptors and Activation or Inhibition of Neuronal Nicotinic
Acetylcholine in K177 or IMR-32 Cells
Figure imgf000043_0001
Figure imgf000044_0001
In addition to the data presented above which demonstrates that the compounds of the invention are effective binders to the nicotinic acetylcholine receptor and are functional ligands, the following table (Table 2) shows additional data for examples 53-59 and 134- 136. Table 2
Binding to Neuronal Nicotinic Acetylcholine Receptors and Activation of Neuronal Nicotinic
Acetylcholine Receptors in EMR-32 Cells
Figure imgf000045_0001
As can be seen from Tables 1 and 2, compound 55 exhibited potent in vitro binding. The following examples will serve to further illustrate preparation of the novel compounds of the invention. They are not to be read as limiting the scope of the invention as it is defined by the appended claims.
Thin-layer chromatography (TLC) was performed on 0.25 mm E. Merck precoated silica gel plates (60 F-254). Rash chromatography was performed on 200-400 mesh silica gel (E. Merck), and column chromatography was performed on 70-230 mesh silica gel (E. Merck). The following abbreviations are used: THF for tetrahydrofuran, DMF for N, N- dimethylformamide, D2O for deuterium oxide, CDCI3 for deuterochloroform, DMSO-d6 for deuterodimethylsulfoxide, BOC for tert-butyloxycarbonyl, CBZ for benzyloxycarbonyl, Bn for benzyl, Ms for methanesulfonyl, PAW for pyridine/acetic acid/water (20:6: 11), DCC for dicyclohexylcarbodiimide, DIBALH for dϋsobutylaluminum hydride, DIEA for diisopropylethylamine, DPPA for diphenylphosphororyl azide, DME for 1,2- dimethoxyethane, EDC for l-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride, EtOH for ethanol, Et2θ for diethyl ether, EBCF for isobutyl chloroformate, HOAc for acetic acid, HOBT for 1-hydroxybenzotriazole, LAH for lithium aluminum hydride, MeOH for methanol, NH4OAC for ammonium acetate, dppp for 1 ,3-bis(diphenylphosphino)propane; NMM for N-methylmorpholine, TEA for triethylamine, THF for tetrahydrofuran. Exam le i
Preparation of 2-(l-methyl-2-(S)-pynolidinyl)furor3.2-blpyridine dihydrochloride
la. N-BOC-(S)-prolinal N-BOC-(S)-proline was reduced to N-BOC-(S)-prolinol by treatment with diborane as described by K.E. Rittle et al. (J. Org. Chem., 47:3016 (1982)). N-t-butyloxycarbonyl- (S)-prolinol was then oxidized to N-t-butyloxycarbonyl-(S)-prolinal by treatment with DMSO and sulfur trioxide-pyridine complex as described by Y. Hamada and T. Shioiri (Chem. Pharm. Bull, 5: 1921 (1982)). 1 b. 2(S -(2,2-Dibromoethenyl)-N-t-butyloxycarbonylpynolidine
At room temperature and under nitrogen, triphenylphosphine (13.0 g, 49.5 mmol), zinc dust (2.16 g, 33.0 mmol) and carbon tetrabromide (11.0 g, 33.0 mmol) were added to CH2CI2 (80 mL). After stirring for 5 minutes, a solution of N-t-butyloxycarbonyl-(S)- prolinal (3.29 g, 16.5 mmol) in CH2CI2 (25 mL) was added. The reaction was slightly exothermic. After stirring for 1 hour, the reaction mixture was diluted with EtOAc/hexane (1:1) and filtered through basic alumina. The filter cake was then washed with a mixture of CH2Cl2/EtOAc/hexane (1:1:1). The filtrate was concentrated in vacuo, and the residue was taken up in EtOAc/hexane (1:1). The resulting precipitate was filtered, and the filtrate was concentrated. The residual oil was subjected to flash chromatography using EtOAc/hexane (1:6.5 to 1:5) as the eluant. The resultant pure sohd product was isolated in 91% yield (5.31 g): mp 65-66 °C; [α]D 23 +20.1 (c 1.10, MeOH); 1H NMR (DMSO-d6, 70 °C, 300 MHz) δ 6.57 (d, J=8.1 Hz, IH), 4.26 (ddd, J=7.9, 7.9, 4.9 Hz, IH), 3.30 (m, 2H), 2.11 (m, IH), 1.72-1.92 (m, 2H), 1.65 (m, IH), 1.40 (s, 9H); MS m/e 354 (M+H)+; Anal. Calcd for CnHι7Br Nθ2: C, 37.21; H, 4.83; N, 3.95. Found: C, 37.45; H, 4.85; N, 3.97. lc. l-BOC-2-(S -ethvnylpynolidine
A solution of the compound of step lb above (27.1 g, 76.3 mmol) and THF (550 mL) was cooled to -75 C. Under a nitrogen atmosphere, a 2.5 M solution of n-butyllithium in hexane (62.6 mL, 156 mmol) was added dropwise over a 15 minute period. After stirring for 1 hour, saturated aqueous sodium bicarbonate was added dropwise to the reaction flask. The dry ice bath was removed and an additional portion of saturated aqueous sodium bicarbonate was added. The mixture was extracted with EtOAc (3X) and the combined organic phases dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with Et2O/hexane (1:6 to 1:5) to give 11.5 g (77% yield) of the title compound (lc) as an oil: [α]D 23 -92.1 (c 2.20, MeOH); 1H NMR (CDCI3, 300 MHz) δ 4.45 (m, IH), 3.53-3.24 (m, 2H), 2.25-1.85 (m, 5H), 1.48 (s, 9H); MS (Cl) m/e 196 (M+H)+. Id. 2-(l-BOC-2-(SVpyrrolidinyl)furor3.2-blpyridine
A 2.34 g (12 mmol) sample of the compound from step lc above was dissolved in 15 mL of DMF, and (Ph3P)2PdCl2 (0.6 mmol), Cul (0.74 mmol) and triethylamine (14.25 mmol) were added. The mixture was stirred at room temperature for 1 hour, then 3.14 g (14.4 mmol) of 2-iodo-3-hydroxypyridine (Lancaster Chem. Co.) was added. The reaction mixture was stirred at 60 C for 16 hours. The solution was cooled, diluted with toluene, and the volatiles were removed under reduced pressure. The residue was dissolved in 1 N HCl, and this solution was extracted with ether. The acidic aqueous layer was adjusted to pH 10 with K2CO3, and this solution was extracted with CH2CI2. The CH2CI2 extract was washed with 20% NaOH, dried over MgSO4, and evaporated. The residue was chromatographed on silica gel, eluting with 100:0 to 95:5 CHCl3:MeOH to give 980 mg of title compound: 1H NMR (CDCI3, 300 MHz) δ 1.32 (s, 9H), 1.90-2.20 (m, 4H), 2.95- 3.15 (m, 2H), 5.05 (m, IH), 6.68 (s, IH), 7.15 (br s, IH), 7.67 (d, IH, J=8 Hz), 8.48 (d, IH, J=3 Hz); MS m/z: 289 (M+H)+. le. 2-(l-methyl-2-(S -pynolidinyl)furo[3.2-blpyridine dihydrochloride
A 147 mg sample of the compound from step Id above was dissolved in 4 mL of HCHO and 2 mL of 88% formic acid and heated at reflux for 25 minutes. The solution was cooled, diluted with water, and adjusted to pH 10 with K2CO3. The mixture was extracted with CH2CI2, and the extract dried and concentrated. The residue was purified by chromatography on sihca gel, eluting with 100:0 to 90:10 CHCl3:MeOH. The product was dissolved in ethanol, and a solution of HCl in Et2θ was added dropwise. The resultant white precipitate was then collected by evaporation of solvent and triturated with three portions of Et2θ to give the title compound (200 mg): 1H NMR (CDCI3, 300 MHz) δ
2.35-2.37 (m, 2H), 2.58-2.67 (m, 3H), 3.00 (br s, 3H), 3.40 (br s, IH), 3.90 (br s, IH), 7.45 (s, IH), 7.70 (dd, IH, J=5, 8.5 Hz), 8.33 (d, IH, J=8.5 Hz), 8.64 (dd, IH, J=5, 1 Hz). MS m/z: 203 (M+H)+; Anal. Calcd for Ci2Hι4N2O-2.0 HCKI.2 H2O-0.1 EtOH: C, 51.99; H, 6.08; N, 9.94. Found: C, 51.59; H, 6.03; N, 9.68.
Example 2 Preparation of 2-(2-(S)-pynolidinyl)furor3-2-blpyridine dihydrochloride
A 980 mg sample of 2-(l-BOC-2-(S)-pynohdinyl)furo[3,2-b]pyridine, from Example Id above, was dissolved in a solution of TFA in CH2CI2 at 0 C and stined under
N2 while warming to room temperature. The reaction mixture was diluted with 1 N HCl, and the aqueous layer was separated. The aqueous solution was adjusted to pH 10 with K2CO3, and the mixture was extracted with CH2C12- The solution was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel and treated with HCl in Et2θ as described in Example le to obtain 280 mg of title compound: 1H NMR (CDCI3, 300 MHz) δ 2.17-2.52 (m, 3H), 2.65 (m, IH), 3.57 (dt, 2 H, J=1.5, 7.5 Hz), 5.15 (t, IH, J=8 Hz), 7.44 (s, IH), 7.84 (dd, IH, J=6, 8.5 Hz), 8.5 (dt, IH, J=l, 8.5 Hz), 8.70 (dd, IH, J= 1, 6 Hz). MS m/z: 189 (M+H)+, 206 (M+NH4)+; Anal. Calcd for CΠHI2N2O-2.0 HCl: C, 50.59; H, 5.40; N, 10.73. Found: C, 50.52; H, 5.26; N, 10.50.
Example 3
Preparation of 2-(2-(R)-pyrrohdinyl)furor3.2-blpyridine dihydrochloride 3a. l-BOC-2-(R -ethvnylpynolidine The title compound was prepared from N-BOC-(R)-proline according to the procedures of Examples la-c above. [α]o23 +113.0 (c 0.94, MeOH). 3b. 2-(l-BOC-2-(R -pynolidinyl)furol3.2-blpyridine
A 3.14 g (14.4 mmol) sample of 2-iodo-3-hydroxypyridine (Lancaster Chem. Co.) was dissolved in 5 mL of DMF, and (Ph3P)2PdCl2 (0.34 g, 0.50 mmol), Cul (0.371 g, 1.98 mmol) and triethylamine (1.80 mL, 13.2 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 2.15 g ( 11.0 mmol) of the compound from step 3a above, dissolved in 5 mL of DMF, was added carefully. The mixture was stined at 60 C for 16 hours, then cooled to room temperature. The reaction mixture was diluted with ether and filtered. The solution was washed with 10% NaOH, 50% brine, dried over MgSO4, and the solvent was removed. The residue was chromato graphed on sihca gel, eluting with 100:0 to 60:40 hexane:EtOAc to give 620 mg of title compound: 1H NMR (CDCI3, 300 MHz) δ 1.73 (s, 9H), 1.85-2.30 (m, 4H), 3.05-3.22 (m, 2H), 4.42 (m, IH), 6.78 (s, IH), 7.16 (dd, IH), 7.68 (dd, IH), 8.48 (dd, IH); MS m/z: 289 (M+H)+. 3c. 2-(2-(R)-pynolidinyl)furor3-2-b1pyridine dihydrochloride A 614 mg (2.13 mmol) sample of 2-(l-BOC-2-(R)-pynolidinyl)furo[3,2-b]pyridine, from step 3b above, was dissolved in 3 mL of CH2CI2, and the solution was cooled to 0
C. To this solution was added 3 mL of TFA, and the reaction mixture was stirred at 0 C for 2 hours. The reaction was quenched with saturated aqueous K2CO3 solution, and the mixture was extracted with CH2CI2. The organic extract was dried over MgSO4, and the solvent was removed. The residue was purified by chromatography on silica gel and treated with HCl in Et2θ as described in Example le above to obtain the title compound: 1H NMR (D2O, 300 MHz) δ 2.17-2.69 (m, 4H), 3.52-3.59 (m, 2 H), 5.14 (t, IH, J=5.5 Hz), 7.42 (t, IH, J=l Hz), 7.80 (dd, IH, J=5.6, 8.5 Hz), 8.5 (dt, IH, J=l, 8.5 Hz), 8.70 (dd, IH, J= 1, 5.5 Hz); MS m/z: 189 (M+H)+, 206 (M+NH4)+; Anal. Calcd for CιιHi2N O«2.0 HCWλ5 H2O: C, 48.90; H, 5.60; N, 10.90. Found: C, 48.75; H, 5.74; N, 10.11. Example 4
Preparation 2-(l-methyl-2-(R -pyrrohdinyl furor3-2-b1pyridine dihydrochloride
A 140 mg sample of the compound from Example 3 above was dissolved in 8 mL of 37% aqueous formaldehyde and 4 mL of 88% formic acid and heated at reflux for 1 hour. The solution was poured into saturated aqueous K2CO3 solution, and the mixture was extracted with CH2CI2. The organic extract was dried, concentrated and purified by chromatography on sihca gel, eluting with 100:0 to 95:5 CHCl3:MeOH. The product was dissolved in ethanol, and a solution of HCl in Et2θ was added dropwise at ambient temperature. The resultant white precipitate was then collected by evaporation of solvent and triturated with three portions of Et2θ to give the title compound (60 mg): 1H NMR (D2O,
300 MHz) δ 2.35 (br, 2H), 2.53-2.70 (m, 3H), 3.00 (br s, 3H), 3.40 (br s, IH), 3. 90 (br s, IH), 7.38 (s, IH), 7.60 (dd, IH), 8.33 (d, IH), 8.64 (dd, IH); MS m/z: 203 (M+H)+, 220 (M+NH4)+; Anal. Calcd for Cι2Hi4N2O»2.0 HCl- 1.0 H2O: C, 49.16; H, 6.19; N, 9.55. Found: C, 49.03; H, 6.08; N, 9.13.
Figure imgf000049_0001
Preparation 5-methyl-2-(2-(S)-pyτrohdinyl furor3.2-blpyridine dihydrochloride
5a. 2-(l-BOC-2-(S -pynolidinvD-5-methylfurof3.2-blpyridine
A 3.10 g (13.2 mmol) sample of 6-iodo-2-picoline-5-ol (Aldrich Chem. Co.) was dissolved in 5 mL of DMF, and (Ph3P)2PdCl2 (0.38 g, 0.50 mmol), Cul (0.377 g, 1.98 mmol) and triethylamine (1.80 mL, 13.2 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 2.15 g (11 mmol) of l-BOC-2-(S)- ethynylpynolidine, from Example lc above, dissolved in 1 mL of DMF, was added carefully. The reaction was stirred at 60 C for 16 hours, then cooled to room temperature. The reaction mixture was diluted with 2 N HCl and extracted with ether. The aqueous layer was adjusted to pH 10 with K2CO3, then extracted with CH2CI2. The extract was washed with 20% NaOH, brine, dried over MgSO4, and the solvent was removed. The residue was repeatedly dissolved in toluene and distilled to azeotiopically remove the DMF. The residue was chromatographed on sihca gel, eluting with 100:0 to 50:50 hexane:EtOAc to give 521 mg of title compound: 1H NMR (CDCI3, 300 MHz) δ 1.33 and 1.47 (2 s, 9H), 1.90-2.30 (m, 4H), 2.63 (s, 3H), 3.45-3.65 (m, 2H), 4.95 and 5.10 (2 s, IH), 5.58 (s, IH), 7.02 (d, IH), 7.55 (d, IH); MS m/z: 303 (M+H)+. 5b. 5-methyl-2-(2-(S)-pyrrolidinyl)furor3.2-b1pyridine dihydrochloride
To a 530 mg sample of the compound from step 5a above in 4 mL of CH2CI2 at 0
C was added 4 mL of TFA. The reaction mixture was stirred for 16 hours, then diluted with saturated aqueous Na2CO3, and extracted with CH2CI2. The organic extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on sihca gel, eluting with 100:0 to 90:10 CHCl3:EtOH. The residue was treated with HCl/ether, and the salt was recrystallized from ethanol/EtOAc to give 158 mg of title compound: ^H NMR (DMSO, 300 MHz) δ 2.0-2.5 (m, 4H), 2.55 (s, 3H), 3.34 (m, 3H), 4.93 (m, IH), 7.24 (s, IH), 7.27 (d, IH), 7.97 (d, IH); MS m/z: 203 (M+H)+, 220 (M+NH4)+; Anal. Calcd for Ci2Hι4N2O-»2.0 HC1-0.5 H2O: C, 50.72; H, 6.03; N, 9.86. Found: C, 50.53; H, 6.06; N, 9.62.
Example 6
Preparation of 2-(l-methyl-2-(S)-pmolidinyl)-5-methylfuroF3.2-b1pyridine dihydrochloride
A 315 mg (1.04 mmol) sample of 2-(2-(S)-pynolidinyl)-5-methylfuro[3,2- bjpyridine dihydrochloride, from Example 5b above, was dissolved in 5 mL of 88% formic acid and 10 mL of 37% aqueous formaldehyde and heated at reflux for 0.5 hours. The reaction mixture was cooled, diluted with 2 N HCl and extracted with ether. The aqueous solution was adjusted to pH 10 with K2CO3 and extracted with CH2CI2. The CH2CI2 extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on sihca gel, eluting with 100:0 to 95:5 CHCl3:EtOH The residue was converted to the salt by treatment with HCl/ether, and the salt was recrystallized from
EtOH/EtOAc to give 332 mg of title compound: ^ NMR (DMSO, 300 MHz) δ 2.13-2.23 (m, 2H), 2.35-2.60 (m, 3H), 2.71 (s, 3H), 2.88 (s, 2H), 3.33 (br s, IH), 3.70 (br s, IH), 4.88 (m, IH), 7.54 (d, IH, J=8.8 Hz), 7.61 (s, IH), 8.36 (d, IH, J=8.5 Hz); MS m/z: 217 (M+H)+, 234 (M+NH4)+; Anal. Calcd for Cι3Hι6N2O-»2.0 HC .O H2O: C, 50.82; H, 6.55; N, 9.12. Found: C, 50.47; H, 6.77; N, 8.92.
Example 7
Preparation of 6-chloro-2-(2-(S -pynolidinyl)-furor3.2-b1pyridine dihydrochloride
7a. 5-chloro-2-iodo-3-pyridinol
A 20.3 g (0.157 mol) sample of 5-chloro-3-pyridinol (Aldrich Chemical Co.) and 35 g (0.33 mol) of Na2CO3 were dissolved in 220 mL of H2O. To this solution was added 39.9 g of I2, and the reaction mixture was stirred for 45 minutes. The mixture was then poured slowly into 2 N HCl, and the acidity was adjusted to pH 3. The product was collected by filtration and crystaUized from EtOH/ether, affording 23.35 g of title compound: lH NMR (CDCI3, 300 MHz) δ 5.45 (s, IH), 8.0 (d, IH); MS m/z: 256 (M+H)+, 273
(M+NH4)+.
7b. 2-(l-BOC-2-(S -pyrrolidinyl -6-chlorofuror3.2-b1pyridine
A 5.63 g (22.0 mmol) sample of 5-chloro-2-iodo-3-pyridinol, from step 7a above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.38 g, 0.50 mmol), Cul (0.377 g,
1.98 mmol) and triethylamine (1.90 mL, 13.6 mmol) were added. The mixture was stined under N2 at room temperature for 1 hour, then 2.15 g (11.0 mmol) of l-BOC-2-(S)- ethynylpynolidine, from Example lc above, dissolved in 5 mL of DMF, was added carefully. The reaction was stirred at 60 C for 16 hours, then cooled to room temperature. The reaction mixture was diluted with ether, then washed with 10% NaOH and brine, then dried over MgSO4. The solvent was removed, and the residue was chromatographed on sihca gel, eluting with 100:0 to 60:40 hexane:EtOAc to give 2.04 g of title compound: 1H NMR (CDCI3, 300 MHz) δ 1.3, 1.45 (2 s, 9H), 1.94-2.3 (m, 4H), 3.45-3.65 (m, 2H), 4.97-5.1 (m, IH), 6.66 (s, IH), 7.70 (s, IH), 8.47 (s, IH); MS m/z: 323 (M+H)+. 7c. 6-chloro-2-(2-(S)-pyrrolidinyl)-furor3.2-blpyridine dihydrochloride
To a 2 g sample of the compound from step 7b above in 10 mL of CH2CI2 at 0 C was added 10 mL of TFA, and the reaction mixture was stirred for 1 hour, poured into saturated aqueous Na2CO3 and extracted with CH2CI2. The organic extract was dried over
MgSO4, and the solvent was removed. The residue was chromatographed on sihca gel, eluting with 99:1 to 95:5 CHCl3:MeOH. The product was treated with HCl/ether, and the salt was recrystallized from EtOH/EtOAc to give 1.2 g of title compound: 1H NMR (D2O, 300 MHz) δ 2.18-2.50 (m, 3H), 2.54-2.65 (m, IH), 3.51-3.36 (m, 2H), 5.06 (t, IH, J=8 Hz), 7.26 (d, IH, J=0.7 Hz), 8.24 (dd, IH, J=0.7, 1.8 Hz), 8.60 (d, IH, J=1.8 Hz); MS m/z: 223 (M+H)+, 240 (M+NI +; Anal. Calcd for CnHnN2OCl-2.0 HCl: C, 44.69; H, 4.43; N, 9.47. Found: C, 44.57; H, 4.31; N, 9.33.
Exapi ie 8
Preparation of 6-chloro-2-( 1 -methyl-2-(S)-pyrrolidinyl)-furor3.2-b1pyridine dihydrochloride
A 315 mg (1.04 mmol) sample of 6-chloro-2-(2-(S)-pynolidinyl)-furo[3,2- bjpyridine dihydrochloride, from Example 7c above, was dissolved in 3 mL of 88% formic acid and 6 mL of 37% aqueous formaldehyde and heated at reflux for 0.5 hour. The reaction mixture was cooled, poured into saturated K2CO3, and the mixture was extracted with CH2CI2. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 95:5 CHCl3:MeOH. The residue was converted to the salt by treatment with HCl/ether, and the salt was recrystallized from ethanol/EtOAc to give 159 mg of title compound: 1H NMR (D2O, 300 MHz) 5 2.31- 2.39 (m, 2H), 2.52-2.70 (m, 3H), 2.96 (br s, 3H), 3.55 (br s, IH), 3.88 (br s, IH), 7.33 (s, IH), 8.13 (dd, IH), 8.56 (d, IH); MS m/z: 237 (M+H)+, 254 (M+NH4)+; Anal. Calcd for Ci2Hι N2OCl-»2HCl: C, 46.55; H, 4.88; N, 9.05. Found: C, 50.75; H, 5.12; N, 9.69.
Example 9
Preparation of 2-(2-(S -pyrrolidinyl furor2,3-clpyridine dihydrochloride
9a. 4-iodo-3-methoxymethoxypyridine
The title compound was prepared according to the procedure of Winkle and Ronald, /. Org. Chem., 47:2101-2106 (1982). 9b. 3-hydroxy-4-iodopyridine A 1.48 g (5.3 mmol) sample of 4-iodo-3-methoxymethoxypyridine, from step 9a above, was suspended in 10 mL of 50% aqueous acetic acid and 4 drops of concentrated H2SO4, and the mixture was heated at reflux for 20 minutes. The solution was cooled, adjusted to pH 3 with sohd Na2CO3, diluted with water, and extracted with EtOAc. The organic extract was dried over MgSO4, and the solvent was removed to give 0.86 g of the title compound: MS m/z: 223 (M+H)+, 239 (M+NH4)+. 9c. 2-(l-BOC-2-(S -pynohdinvnfuror2.3-clpyridine
A 829 mg (3.7 mmol) sample of 3-hydroxy-4-iodopyridine, from step 9b above, 130 mg (0.18 mmol) of (Ph3P)2PdCl2, 170 mg (0.74 mmol) of Cul, and 0.6 mL of triethylamine were combined in 10 mL of DMF at ambient temperature and stined for 3 hours. To this mixture was added a solution of l-BOC-2-(S)-ethynylpynolidine (1.5 g, 7.7 mmol, from Example lc above) in 5 mL of DMF, and the reaction mixture was stirred at 60 C for 16 hours. The reaction mixture was cooled to room temperature and diluted with ether. The ether layer was filtered, washed with 10% NaOH then 50% brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on sihca gel, eluting with 100:0 to 50:50 hexane:EtOAc to give the title compound. 9d. 2-(2-(S)-pynolidinyl)furo[2.3-clpyridine dihydrochloride
To a 700 mg sample of the compound from step 9c above in 5 mL of CH2CI2 at 0
C was added 5 mL of TFA. The reaction mixture was stirred for 1 hour at 0 °C then poured into saturated Na2CO3, and the layers were separated. The aqueous layer was extracted with CH2CI2. The combined organic layers were dried over MgSO4 and concentrated, and the residue was chromatographed on sihca gel, eluting with 100:0 to 95:5 CHCl3:MeOH. The product was converted to the salt by treatment with HCl/ether, which was recrystallized from ethanol/EtOAc: 1H NMR (D O, 300 MHz) δ 2.19-2.52 (m, 3H), 2.64 (m, IH), 3.53-3.58 (m, 2H), 5.13 (t, IH, J=8 Hz), 7.34 (s, IH), 8.05 (dd, IH, J=0.8, 5.8 Hz), 8.49 (d, IH, J=5.8 Hz), 9.07 (s, IH); MS m/z: 189 (M+H)+, 206 (M+NH4)+; Anal. Calcd for CnHι2N2θ-»2.0 HC1-H2O: C, 47.33; H, 5.78; N, 10.03. Found: C, 47.32; H, 5.83; N, 9.90.
Example 10
Preparation of 2-(l-methyl-2-(S)-pyrrolidinyl)furor2.3-c1pyridine dihydrochloride
A 120 mg sample of the compound from Example 9 above was dissolved in 4 mL of formic acid and 2 mL of formalin, and the reaction mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature and poured into saturated K2CO3 solution. The resulting mixture was extracted with CH2CI2, the extract was dried, and the solvent was removed. The residue was chromatographed on silica gel, and the compound was converted to the salt by treatment with HCl/ether: 1H NMR (D2O, 300
MHz) δ 2.30-2.40 (m, 3H), 2.50-2.74 (m, IH), 2.98 (s, 3H), 3.45 (br d, IH), 3.85 (br s, IH), 4.97 (t, IH), 7.47 (s, IH), 8.08 (d, IH), 8.51 (d, IH), 9.10 (s, IH); MS m/z: 203 (M+H)+; Anal. Calcd for Ci2Hι4N2O-»2 HC1»0.5H O: C, 50.70; H, 6.03; N, 9.86. Found: C, 50.69; H, 6.09; N, 9.61.
Sample 11
Preparation of 5-chloro-2-(2-(S)-pyrrohdinyl)-furor3,2-b1pyridine hydrochloride
1 1 a. 5-acetoxy-2-chloropyridine To a solution of 5-amino-2-chloropyridine (40.0 g, 0.311 mol) in 180 mL of 3: 1
1 ,2-dimethoxyethane/CH2Cl2 at -10 °C was slowly added boron trifluoride diethyl etherate (76.5 mL, 0.662 mol). Then a solution of tert-butyl nitrite (44.4 mL, 0.373 mol) in 40 mL of 1,2-dimethoxyethane was slowly added over 15 min such that the reaction temperature remained below -5 °C. The mixture was stirred for 10 min at -10 °C then warmed to 0 °C and stined for an additional 30 min. Pentane was added and the solid was coUected by suction filtration (cold pentane wash) to afford 69.1 g of the tetrafluoroborate diazonium salt. This was dissolved in 350 mL of acetic anhydride, warmed to 75 °C (N2 evolution) and stirred for 3 h. The volatUes were removed in vacuo and the dark residue was diluted with Et2θ and washed with saturated aqueous NaHCO3. The aqueous phase was extracted with Et2θ. The combined ethereal extracts were washed with brine, dried (MgSO4), and concentrated. Purification by chromatography (sihca gel; hexane/EtOAc 90:10 to 70:30) afforded the title compound as a white soUd (29.4 g, 55%): mp 45 °C; lH NMR (CDCI3, 300 MHz) δ 2.35 (s, 3H) 7.35 (d, J=8.5 Hz, IH), 7.48 (dd, J=2.9, 8.5 Hz, IH), 8.21 (d, J=2.9 Hz, IH); MS (CI/NH3) m/z: 172, 174 (M+H)+; 189, 191 (M+NH4)+. l ib. 2-chloro-5-hvdroxypyridine 5-Acetoxy-2-chloropyridine (11.1 g, 64.7 mmol) from step 1 la was dissolved in
MeOH at ambient temperature and sohd potassium carbonate (4.47 g, 32.4 mmol) was added. After stirring for 2 h, the volatUes were removed in vacuo and the residue was diluted with Et2θ and H2O. The aqueous phase was neutralized to pH 7 by the addition of 1 N aqueous HCl. The layers were separated and the aqueous phase was extracted twice with Et2θ. The combined organic extracts were dried (MgSO4) and concentrated to provide the title compound as a white solid (8.03 g, 96%): mp 155 °C; -Η ΝMR (CD3OD, 300 MHz) δ 7.20-7.28 (m, 2H), 7.88 (m, IH); MS (CI/ΝH3) m/z: 130,132 (M+H)+; 147,149 (M+NH4)+. l ie. 6-chloro-2-iodo-3-pyridinol To a solution of 2-chloro-5-hydroxypyridine (5 g, from step 1 lb) and 8.6 g of
Na2CO3 in 100 mL of water was added 9.8 g of I2. The mixture was stirred until the iodine color disappeared. The reaction mixture was then adjusted to pH 5 and extracted with EtOAc. The extract was dried over MgSO4, and the solvent was removed. The residue was recrystaUized from MeOH to afford 5.4 g of the title compound: 1H NMR (CD3OD, 300 MHz) δ 7.09 (d, IH, J=8.5 Hz), 7.20 (d, IH, J=8.5 Hz); MS m/z: 256 (M+H)+, 273 (M+NH4)+. 1 Id. 2-(l-BOC-2-(S)-pyτrolidinyl -5-chlorofuror3.2-blpyridine
A 3.07 g (12.0 mmol) sample of 6-chloro-2-iodo-3-pyridinol, from step 1 lc above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.38 g, 0.50 mmol), Cul (0.380 g, 1.98 mmol) and triethylamine (1.7 mL, 12 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 1.95 g (10.0 mmol) of l-BOC-2-(S)- ethynylpyrrolidine, from Example la above, dissolved in 5 mL of DMF, was added carefully. The reaction mixture was stirred at 60 C for 16 hours, cooled to room temperature, diluted with ether, washed with 50% brine and dried over MgSO4, then the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 50:50 hexane:EtOAc to give 1.54 g of title compound: 1H NMR (DMSO, 300 MHz, 130 °C) δ 1.37 (two s, 9H), 1.89-2.07 (m, 3H), 2.37 (m, IH), 3.40-3.54 (m, IH), 4.98 (m, IH), 6.72 (s, IH), 7.26-7.29 (d, IH, J=8.6 Hz), 7.93-7.96 (d, IH, J=8.6 Hz); MS m/z: 323 (M+H)+. 1 le. 5-chloro-2-(2-(S)-pyrtolidinyl)-furor3-2-blpyridine hydrochloride
A 1.5 g sample of the compound from step 1 Id above was dissolved in 10 mL of CH2CI2 and cooled to 0 C. The solution was stirred under N2, 10 mL of TFA was added, and the reaction mixture was stirred for 1 hr. The reaction mixture was poured into saturated K2CO3, and the mixture was extracted with CH2CI2. The solution was dried over
MgSO4, and the solvent was removed. The residue was chromatographed on sihca gel, eluting with 99: 1 to 95:5 CHCl3:MeOH. The residue was converted to the salt by treatment with HCl/ether to give 0.78 g of title compound: -1H NMR (D2O, 300 MHz) δ 2.22-2.65 (m, 4H), 3.52-3.57 (m, 2H), 5.06 (t, IH, J=8 Hz), 7.15 (d, IH), 7.48 (d, IH, J=8.6 Hz), 8.1 (d, IH, J=8.6 Hz); MS m/z: 223 (M+H)+, 240 (M+NH4)+; Anal. Calcd for
C11H11N2OC .O HCl: C, 50.99; H, 4.67 N, 10.81. Found: C, 51.21; H, 4.79; N, 10.55.
Example 12 Preparation of 5-chloro-2-(l-methyl-2-(S)-pyrtolidinyl)-furoF3.2-blpyridine hydrochloride
A 660 mg (1.04 mmol) sample of 2-(2-(S)-pyrrolidinyl)-5-chlorofuro[3,2- bjpyridine dihydrochloride, from Example 1 le above, was dissolved in 5 mL of 88% formic acid and 10 mL of 37% aqueous formaldehyde and heated at reflux for 1 hour. The reaction mixture was cooled, poured into saturated K2CO3, and the mixture was extracted with CH2CI2. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on sUica gel, eluting with 100:0 to 95:5 CHCl3:MeOH. The residue was converted to the salt by treatment with HCl/ether to give 540 mg of title compound: *H NMR (D2O, 300 MHz) δ 2.28-2.38 (m, 2H), 2.49-2.72 (m, 2H), 2.92 (br s, 3H), 3.41 (m, IH), 3.80 (m, IH), 4.84 (m, IH), 7.50 (d, IH, J=8.8 Hz), 8.0 (d, IH, J=8.8 Hz), 8.56 (d, IH); MS m/z: 237 (M+H)+; Anal. Calcd for C12H13N2OCM.O HCl: C, 52.07; H, 5.13; N, 10.12. Found: C, 51.85; H, 5.46; N, 9.78.
Example 13 Preparation of 5-chloro-2-(2-(S )-pyrrolidinyl)-furol2.3-blpyridine hydrochloride
13a. 5-chloro-3-iodo-2-pyridinol
A 6.48 g sample of 5-chloro-2-pyridinol (Aldrich) and 10.8 g of Na2CO3 were dissolved in 250 mL of water. To this solution was added 12.73 g of I2, and the mixture was stirred untU the iodine color disappeared. The reaction mixture was then adjusted to pH 7 and extracted with EtOAc. The extract was dried over MgSO4, and the solvent was removed. The residue was recrystallized from ethanol water to afford 4 g of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ 7.71 (d,lH), 8.18 (d, IH); MS m/z: 256
(M+H)+, 273 (M+NH4)+.
13b. 2-(l-BOC-2-(SVpyτrolidinvn-5-chlorofuror2.3-blpyridine
A 3.07 g (12 mmol) sample of 5-chloro-3-iodo-2-pyridinol, from step 13a above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.39 g, 0.5 mmol), Cul (0.38 g, 1.98 mmol) and triethylamine (1.7 mL, 12 mmol) were added. The mixture was stined under N2 at room temperature for 1 hour, then 1.95 g (10 mmol) of l-BOC-2-(S)-ethynylpyrroUdine, from Example lc above, dissolved in 5 mL of DMF, was added carefuUy. The reaction mixture was stirred at 60 C for 16 hours, cooled to room temperature, dUuted with ether and washed with 50% brine. The organic layer was dried over MgSO4 and concentrated.
The residue was chromatographed on sihca gel, eluting with 100:0 to 50:50 hexane:EtOAc to give 1.55 g of title compound: MS m/z: 323 (M+H)+.
13c. 5-chloro-2-(2-(S pyrrolidinyl)-furor2-3-blpyridine hydrochloride
A 0.56 g sample of the compound from step 13b above was dissolved in 3 mL of CH2CI2 and cooled to 0 C. The solution was stirred under N2, 3 mL of TFA was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was poured into saturated K2CO3, and the mixture was extracted with CH2O2. The solution was dried over
MgSO4, and the solvent was removed. The residue was chromatographed on sihca gel, eluting with 99:1 to 95:5 CHCl3:MeOH. The product was converted to the salt by treatment with HCl/ether to give 0.36 g of title compound: 1H NMR (D2O, 300 MHz) δ 2.22-2.60 (m, 4H), 3.50-3.56 (m, 2H), 5.01 (t, IH, J=8.1 Hz), 7.10 (s, IH, ), 7.82 (d, IH, J=2.3 Hz), 8.33 (d, IH, J=2.3 Hz); MS m/z: 223 (M+H)+, 240 (M+NI +; Anal. Calcd for C11H11N2OCM.O HCl: C, 50.99; H, 4.67 N, 10.81. Found: C, 51.06; H, 4.64; N, 10.65.
Example 14
Preparation of 5-chloro-2-(l-methyl-2-(S)-pynolidinyl -furor2.3-b1pyridine dihydrochloride
A 200 mg (0.80 mmol) sample of 5-chloro-2-(2-(S)-pyrrolidinyl)-furo[2,3- bjpyridine dihydrochloride, from Example 13c above, was dissolved in 4 mL of 88% formic acid and 8 mL of 37% aqueous formaldehyde and heated at reflux for 1 hour. The reaction mixture was cooled, poured into saturated K2CO3, and the mixture was extracted with CH2CI2. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on sUica gel, eluting with 100:0 to 95:5 CHCl3:MeOH. The product was converted to the salt by treatment with HCl ether to give 140 mg of title compound: 1H NMR (D2O, 300 MHz) δ 2.29-2.38 (m, 2H), 2.49-2.68 (m, 2H), 2.95 (br s, 3H), 3.44 (m, IH), 3.84 (m, IH), 4.84 (m, IH), 7.22 (s, 1H), 8.22 (d, IH, J=2.3 Hz), 8.36 (d, IH, J=2.4); MS m/z: 237 (M+H)+, 254 (M+NH4)+; Anal. Calcd for C12H13N2OCM.O HCM).3 H2O: C, 51.74; H, 5.28; N, 9.73. Found: C, 51.74; H, 5.28; N, 10.16.
Example 15
Preparation of 2-(Hexahvdro-lH-7a-pyτrohzinyl)furo[3.2-b1pyridine hydrochloride
15a. 1,2,3.5,6-7-Hexahydropyιτolizinium perchlorate
The title compound was prepared using the procedures of Miyano et al., Synthesis , 1978: 701-702, and J. Heterocyclic Chem., 19:1465-1468 (1982). 15b. 7a-Ethynyl-hexahydro- 1 H-pynolizine
The compound from step 15a above (1.0 g, 4.8 mmol) was added to a solution of 0.5 M ethynylmagnesium bromide (29 mL, 14.3 mmol) in THF at room temperature. The reaction mixture was stirred for 45 minutes, quenched with 15% NaOH solution, and diluted with brine:water (1:1). The aqueous phase was extracted with CH2CI2, and the organic phases were combined, dried (MgSO4), concentrated and chromatographed (sihca gel; CHCl /MeOH, 90:10) to afford an amber oil (463 mg, 71%): *H NMR (CDCI3, 300 MHz) δ 1.75-2.06 (m, 6H), 2.14-2.23 (m, 2H), 2.33 (s, IH), 2.53-2.62 (m, 2H), 3.22- 3.28 (m, 2H); MS (CI NH3) m/z: 136 (M + H)+.
15c. 2-(Hexahvdro-lH-7a-pyrrolizinyl)furor3.2-blpyridine
2-Iodo-3-pyridinol (902 mg, 4.1 mmol), copper(I) iodide (116 mg, 0.61 mmol), bis(triphenylphosphine)palladium(II) chloride (119 mg, 0.17 mmol) and triethylamine (570 mL, 4.1 mmol) were combined in DMF (4.5 mL) and stirred for one hour. 7a-Ethynyl- hexahydro-lH-pynolizine(460 mg, 3.4 mmol) in DMF (1.2 mL) was added dropwise and the mixture was heated at 60 °C for 18 h. The reaction mixture was aUowed to cool to ambient temperature and 2 N aqueous HCl was added. The heterogeneous mixture was washed with Et2θ (2X), basified with 15% ΝaOH solution and extracted with CH2CI2 (2X). The CH2CI2 extracts were combined, dried (MgSO4) concentrated and chromatographed (sihca gel; CHCl3/MeOH, 96:4) to afford an amber oil which solidified upon storage at -20°C (405 mg, 52%): mp 39-41 °C; 1H ΝMR (CDCI3, 300 MHz) δ 1.86-
1.97 (m, 6H), 2.24-2.34 (m, 2H), 2.68-2.76 (m, 2H), 3.21-3.28 (m, 2H), 6.77 (s, IH), 7.12 (dd, J=8.5, 5 Hz, IH), 7.65 (d, J=8.5 Hz, IH), 8.46 (d, J=5 Hz, IH); MS (CI/ΝH3) m/z: 229 (M + H)+. 15d. 2-(Hexahvdro-lH-7a-pyrrolizinyl)furor3.2-b1pyridine hydrochloride
The free base (395 mg, 1.73 mmol), from step 15c above, was dissolved in THF (30 mL) and a saturated solution of HCl in Et2θ was added until precipitation ceased. The solvent was decanted and the remaining light yeUow solid triturated with THF (2X). The product was recrystaUized from MeOH/Et2θ to afford a light yeUow powder, (349 mg,
76%): mp 201-203 °C dec; 1H NMR (DMSO, 300 MHz) δ 2.09-2.37 (m, 6H), 2.62-2.73
(m, 2H), 3.23-3.40 (m, 2H), 3.57-3.70 (m, 2H), 7.40 (dd, J=8, 5 Hz, IH), 7.53 (s, IH), 8.05 (dd, J=8, 1 Hz, IH), 8.56 (dd, J=5, 1 Hz, IH), 11.35 (br s); MS (CI/NH3) m/z: 229 (M +H)+; Anal. Calcd for C14H16N2O.I.IHCI: C, 62.81; H, 6.51; N, 10.42. Found: C, 62.65; H, 6.42; N, 10.44.
Example 16
Preparation of 2-(Hexahydro- lH-7a-pynolizinyl)-5-methylfuror3.2-b1pyridine dihydrochloride
16a. 2-(Hexahvdro- 1 H-7a-pynolizinyl)-5-methylfurol3.2-blpyridine
The acetylene compound 7a-ethynyl-hexahydro-lH-pynolizine (450 mg, 3.33 mmol), 2-iodo-6-methyl-3-pyridinol (939 mg, 4.0 mmol)(Aldrich), copper(I) iodide (114 mg, 0.6 mmol), bis(triphenylphosphine)paUadium(II) chloride (117 mg, 0.17 mmol) and triethylamine (560 mL, 4.0 mmol) were combined in a similar fashion as that described for Example Id. The residue was chromatographed (sihca gel; CHCl3/MeOH, 96:4) to afford a yellow solid (403 mg, 50%): !H NMR (CDCI3) δ 1.85-1.95 (m, 6H), 2.25-2.30 (m, 2H),
2.62 (s, 3H), 2.67-2.75 (m, 2H), 3.19-3.26 (m, 2H), 6.68 (s, IH), 6.98 (d, J=8 Hz, IH), 7.54 (d, J=8 Hz, IH); MS (CI/NH3) m/z: 243 (M + H)+. 16b. 2-(Hexahvdro-lH-7a-pynolizinyl)-5-methylfuror3.2-b1pyridine dihydrochloride
A sample of the compound from step 16a (395 mg, 1.63 mmol) (395 mg, 1.63 mmol) was dissolved in CH2CI2 (20 mL) and a saturated solution of HCl in Et2θ was added dropwise. The solvent was removed to afford a yellow oU/solid (390 mg, 72%): 1H NMR (D2O, 300 MHz) δ 2.30-2.48 (m, 6H), 2.75-2.84 (m, 5H), 3.35-3.45 (m, 2H), 3.77-3.85 (m, 2H), 7.39 (s, IH), 7.62 (d, J=9 Hz, IH), 8.31 (d, J=9 Hz, IH); MS
(CI/NH3) m/z: 243 (M + H)+; Anal. Calcd for C15H18N2O.2.O HCl- 1.0 H2O: C, 54.06;
H, 6.65; N, 8.41. Found: C, 54.00; H, 6.33; N, 8.11. Example 17
Preparation of 2-(Hexahvdro-lH-7a-pyτrolizinyl)furor2.3-c1pyridine dihydrochloride
17a. 2-(Hexahvdro- lH-7a-pynolizinyl)furol2.3-c1pyridine 5 The acetylene compound 7a-ethynyl-hexahydro-lH-pyrrolizine (225 mg, 1.66 mmol), 4-iodo-3-pyridinol (441 mg, 2.0 mmol) from Example 9b, copper(I) iodide (60 mg, 0.30 mmol), bis(triphenylphosphine)-palladium(II) chloride (58 mg, 0.08 mmol) and triethylamine (280 mL, 2.0 mmol) were combined in a similar fashion as that described in Example 15c. The crude product was chromatographed (sihca gel; CHCl3/MeOH, 98:2 to o 95:5) to afford a turbid yellow oil (185 mg, 49%): lH NMR (CDCI3, 300 MHz) δ 1.83-
1.97 (m, 6H), 2.24-2.31 (m, 2H), 2.67-2.75 (m, 2H), 3.19-3.26 (m, 2H), 6.62 (s, IH), 7.42 (d, J=5 Hz, IH), 8.35 (d, J=5 Hz, IH), 8.77 (s, IH); MS (CI/NH3) m/z: 229 (M +
H)+
17b. 2-(Hexahydro- lH-7a-pynolizinyl)furor2.3-c1pyridine dihydrochloride 5 A sample of the compound from step 17a (173 mg, 0.76 mmol) was dissolved in
CH2CI2 (10 mL) and a saturated solution of HCl in Et2θ was added untU precipitation ceased. The solvent was removed and the product was recrystallized from MeOH/Et2θ to afford a tight yellow solid (226 mg, 98%): mp 235-238 °C; 1H NMR (D2O, 300 MHz) δ
2.30-2.49 (m, 6H), 2.76-2.85 (m, 2H), 3.35-3.45 (m, 2H), 3.77-3.86 (m, 2H), 7.41 (s, 0 IH), 8.04 (d, J=6 Hz, IH), 8.49 (d, J=6 Hz, IH), 9.05 (s, IH); MS (CI/NH3) m/z: 229 (M + H)+; Anal. Calcd for Ci4Hl6N2O-2.0 HC1-0.8 H2O: C, 53.28; H, 6.26; N, 8.88. Found: C, 53.61; H, 6.49; N, 8.35.
Example 18 5 Preparation of enύfo-2-(Hexahvdro- lH-3-(R)-pyrrolizinyl furor3.2-blpyridine dihydrochloride
Figure imgf000059_0001
18a. 3-(N-BOC-2-(R)-pyrrolidinyl propenal
To a solution of N-Boc-R-prolinal (10.25 g, 51.50 mmol) in 150 mL of anhydrous 0 toluene at room temperature was added (triphenylphosphoranyUdene)-acetaldehyde (17.2 g, 56.7 mmol), and the mixture was refluxed for 3 hours under nitrogen. The mixture was concentrated in vacuo. The residue was purified on sihca gel, eluting with 1/4 EtOAc/hexane. The title compound was obtained as an amber oU in 53% yield (6.13g): 1H NMR (CDCI3, 300 MHz) δ 1.42 (s (major isomer), 9H), 1.49 (s (minor isomer), 9H), 1.73-1.90 (m, 3H), 2.06-2.24 (m, IH), 3.37-3.54 (m, IH), 4.41-4.52 (m (minor isomer), IH), 4.58-4.68 (m (minor isomer), IH), 6.11 (dd, 3.0 Hz, 8.0 Hz, IH), 6.63-6.82 (m, IH), 9.57 (s (minor isomer), IH), 9.59 (s (major isomer), IH); MS(DCI) (M+H)+: 226, (M+NH4)+: 243. 18b. 3-(N-BOC-2-(R)-pyτrolidinvnpropanal
To a solution of the propenal compound from step 18a (27.20 mmol, 8.02 g) was added 100 mL of EtOAc and 0.5 g of 10% Pd/C. The mixture was agitated under 4 atmosphere of H2 for 16 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified on sihca gel, eluting with 1/4 EtOAc/hexane. The title compound was obtained in 97% yield as a yeUow oU (5.99g): 1H NMR (CDCI3, 300 MHz) δ 1.48 (s, 9H), 1.60 (m, IH), 1.69-2.01 (m, 5H), 2.39-2.52 (m, 2H), 3.21-3.36 (m, 2H), 3.73-3.94 (m, IH), 7.27 (s, IH); MS (DCI) m/z: 228 (M+H)+, 245 (M+NH4)+. 18c. 5-(N-BOC-2-(RVpyτrolidinylV3-hvdroxy-l-pentyne
A solution of the propanal compound from step 18b above (26.40 mmol, 5.99 g) in 100 mL of anhydrous THF under a nitrogen atmosphere was cooled to -78 C. To this solution was added ethynyl magnesium bromide (0.5 M in THF/79.20 mL), and the mixture was stirred at -78 °C for one hour. The mixture was then warmed to room temperature and stined for 1.5 hours. The reaction was quenched by pouring it into 200 mL of saturated NH4CI. The mixture was extracted with CH2CI2, and the extracts were dried over Na2SO4 and concentrated under vacuum. The residue was purified on sihca gel, eluting with EtOAc/hexane (1/3). The title compound was obtained in 90% yield as a light yeUow oU (5.99 g): ^ NMR (CDCI3, 300 MHz) δ 1.47 (s, 9H), 1.58-2.00 (m, 8H), 2.41-2.49 (br s, IH), 3.24-3.37 (m, 3H), 3.66-4.01 (br d, IH), 4.31-4.51 (m, IH); MS (DCI) m/z: 254 (M+H)+; 271 (M+NH )+- 18d. erafo-hexahydro- lH-3-(R)-ethvnylpynolizine and exo-hexahvdro- lH-3-(S)- ethynylpynolizine
To a solution of the alcohol compound from step 18c above (17.30 mmol, 4.38 g) in CH2CI2 (30 mL) at room temperature was added triphenylphosphine dibromide (21.60 mmol, 9.12g), and the mixture was stined for 16 hours. Next, 5 mL of TFA was added followed by stirring for another 4 hours at room temperature. The mixture was then concentrated under vacuum. The residue was purified by chromatography on sUica gel, eluting with 10% MeOH/CH2θ2 containing 1% NH4OH, to separate the exo and endo products The combined yield for the reaction was 64%. endo-(R)- compound: r l23n -42.76 (c 0.14, H2O); 1H NMR (CDC13, 300 MHz) δ 1.32-1.48 (m, 2H), 1.69-1.74 (m, 4H), 1.75-2.04 (m, 2H), 2.38 (m, IH), 2.75 (d, J=2.0 Hz, IH), 2.67 (m, IH), 3.07 (m, IH), 3.36 (m, IH), 3.60 (m, IH); MS (DCI) m/z: 136 (M+H)+, 153 (M+NH4)+; Anal. Calcd for C9Hι3N-0.20 H2O: Q77.87; H, 9.73; N, 10.09. Found: C, 78.15; H, 9.87; N, 10.17. exo-(S)- compound: [α]23 D +51.14 (c 0.37, H2O); lH NMR (CDCI3, 300 MHz) δ 1.42 (m, IH), 1.62 (m, IH), 1.88 (m, IH), 1.89-2.19 (m, 5H), 2.22 (d, J=2.0 Hz, IH), 2.90 (m, IH), 3.07 (m, IH), 3.53 (m, IH), 3.88 (m, IH); MS (DCI) m/z: 136 (M+H)+, 153 (M+NH4)+; Anal. Calcd for C-^HπN-O.lO H2O: C.78.89; H, 9.71; N, 10.22. Found: C, 78.88; H, 9.59; N, 10.05.
18e. enc.o-2-(hexahvdro- lH-3-(R)-pynolizinyl)furor3.2-b1pyridine dihydrochloride
To DMF (5.0 mL) in a flask purged with nitrogen was added 2-iodo-3- hydroxypyridine (1.20 mmol, 0.2652 g)(Aldrich), bis(triphenylphosphine)-palladium(II) chloride (0.05 mmol, 35 mg), copper(I)iodide (0.20 mmol, 38.1 mg), and triethylamine ( 1.2 mmol, 0.1214 g), and the mixture was stirred for one hour at room temperature. The endo-(R)-acetylene compound from step 18d above (1.0 mmol, 0.134 g in 5.0 mL of DMF) was then added and the mixture was heated at 60 C for 16 hours. The mixture was cooled and poured into 2 N HCl (100 mL), and the mixture was extracted with CH2CI2 (2x75 mL). The aqueous layer was basified with sohd K2CO3 and extracted with CH2CI2, and the extract was dried over MgSO4 and concentrated under vacuum. The residue was purified on sihca gel, eluting with 10% MeOH in CH2 2. The title compound was obtained by treating the base with a saturated solution of HCl/EtOH at 0 °C: [α]ϋ23 +26.21 (c 0.12, MeOH); lH NMR (CDCI3, 300 MHz) δ 1.96-2.13 (m, 2H), 2.15-2.40 (m, 3H), 2.51- 2.78 (m, 3H), 3.57-3.69 (m, 2H), 4.45-4.57 (m, IH), 4.96-5.08 (m, IH), 7.65 (bs, IH), 7.95-8.07 (m, IH), 8.28-8.37 (m, IH), 8.51-8.71 (d, J=10,0 Hz, IH); MS (DCI) m/z: 229 (M+H)+, 246 (M+NH4)+; Anal. Calcd for Cι4Hι6N2O-2.2 HCl- 1.1 H2O: C, 51.21; H, 6.26; N, 8.53. Found: C, 51.27; H, 6.05; N, 8.31.
Example 19
Preparation of exo-2-(Hexahvdro-lH-3-(S)-pynolizinyl)furor3.2-b1pyridine dihydrochloride
Figure imgf000062_0001
FoUowing the procedures of Example 18e above, substituting the ejrø-hexahydro- lH-3-(S)-ethynylpynohzine compound from Example 18d above for the endo-(R) compound of step 18e, the title compound was prepared. [α]o23 -21.28 (c 0.10, MeOH); lH NMR (CDC1 , 300 MHz) δ 1.78-2.00 (m, 2H), 2.06-2.24 (m, 2H), 2.36-2.52 (m, 2H), 2.53-2.78 (m, 2H), 2.90-3.03 (m, IH), 3.21-3.30 (m, IH), 4.42-4.53 (m, IH), 5.17-5.29 (m, IH), 7.61 (s, IH), 7.89 (dd, J=9.0 Hz, J=11.0 Hz, IH), 8.62 (d, J=12.0 Hz, IH), 8.27-8.38 (m, IH); MS (DCI) m/z: 229 (M+H)+, 246 (M+NH4)+; Anal. Calcd for Ci4Hι6N2O-2.40 HC1-0.50 H2O: C, 51.87; H, 6.02; N, 8.49. Found: C, 51.87; H, 5.71; N, 8.49.
Example 20
Preparation of exo-2-(Hexahydro- lH-3-(R)-pynolizinyl)furor3-2-blpyridine dihydrochloride
Figure imgf000062_0002
FoUowing the procedures of Example 18, substituting (S)-prohnal for the (R)- starting material of step 18a therein, and carrying the reactions forward as in steps 18b, c, and d, then separating the exo-(R)- and endo-(S)-isomers and canying the exo-(R)- compound forward according to the procedures of step 18e, the title compound was prepared. The MS and NMR data were simtiar to the compound of Example 18e. [OC]D23 24.68 (c 0.16, MeOH). Example 21
Preparation of en o-2-(Hexahydro-lH-3-(S -pyrrolizinyl)furor3.2-b1pyridine dihydrochloride
Figure imgf000063_0001
FoUowing the procedures of Example 18e above, substituting the endo-hexahydro- lH-3-(S)-ethynylpyrrohzine compound from Example 20 above for the endo-(R) compound of step 18e, the title compound was prepared. The MS and NMR data were similar to the compound of Example 18e. [α]D 23 +31.01 (c 0.21, MeOH).
Example 22
Preparation of l-Pvnolidinylmethyl-(2-furor3,2-blpyridine
To DMF (20.0 mL) in a flask purged with nitrogen were added 2-iodo-3- hydroxypyridine (18.60 mmol, 4.11 g)(Aldrich) , bis(triphenylphosphine)-paUadium(II) chloride (0.80 mmol, 0.544 g), copper(I) iodide (3.10 mmol, 0.590 g), and triethylamine (18.60 mmol, 2.59 g), and the mixture was stirred for one hour at room temperature. To this solution was then added N-(3-propynylpyrrolidine (15.50 mmol, 1.68 g, prepared according to Biehl and DiPierro, J. Am. Chem. Soc, 80, 4609-4614, 1958), in DMF (10.0 mL), and the mixture was heated at 60 C for 16 hours. The mixture was cooled, poured into 4 N HCl (100 mL) and extracted with CH2CI2. The aqueous phase was then basified with 15% NaOH and extracted with CH2CI2. The extract was dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography, eluting with 10% MeOH/CH2Cl2 to give the title compound in 72% yield: 1H NMR (300 MHz): δ 2.25 (bs, 4H), 3.64 (bs, 4H), 4.88 (s, 2H), 7.57 (s, IH), 7.90 (dd, J=5.37, 13.67 Hz, IH), 8.56 (d, J=8.30 Hz, IH), 8.80 (d, J=5.86 Hz, IH). MS (DCI): (M+H)+, 203; (M+NH4)+, 220. Anal. Calcd for Ci2Hι4N O-2.0 HCl-0.1 H2O: C, 52.03; H, 5.89; N.10.11. Found C, 51.72; H, 6.12; N, 10.05 Example 23
Preparation of 5-Chloro-2-(hexahydro- lH-7a-pynolizinv furor3.2-b1pyridine hydrochloride
5 23a. 5-Chloro-2-(hexahvdro- lH-7a-pynoUzinyl furor3.2-blpyridine
7a-Ethynyl-hexahydro-lH-pynotizine from Example 15b (225 mg, 1.66 mol, 6- chloro-2-iodo-3-pyridinol (509 mg, 2.0 mmol), copper(I) iodide (60 mg, 0.30 mmol), bis(triphenylphosphine)paUadium(π) chloride (58 mg, 0.08 mmol) and triethylamine (0.280 mL, 2.0 mmol) were combined in a similar fashion as that described in Example 15c. The o crude product was chromatographed (sUica gel; CHCl3/MeOH, 97.5:2.5) to afford a waxy tan solid (335 mg, 77%): lH NMR (CDCI3, 300 MHz) δ 1.88-1.97 (m, 6H), 2.21-2.33
(m, 2H), 2.67-2.79 (m, 2H), 3.19-3.26 (m, 2H), 6.70 (s, IH), 7.14 (d, J=8.5 Hz, IH), 7.61 (d, J=8.5 Hz, IH); MS (CI/NH3) m/z: 263 (M + H)+.
5 23b. 5-Chloro-2-(hexahydro- lH-7a-pyrrolizinyl)furor3.2-b1pyridine hydrochloride
The compound from step 23a (325 mg, 1.24 mmol) was dissolved in CH2CI2 (10 mL) and a saturated solution of HCl in Et2θ was added dropwise. The solvent was removed and the product recrystallized from MeOH/Et2θ to afford a white sohd (223 mg, 58%): mp 233-235 °C; -1H NMR (D2O, 300 MHz) δ 2.32-2.45 (m, 6H), 2.75-2.83 (m, 2H), 3.31- 0 3.43 ( , 2H), 3.75-3.83 (m, 2H), 7.23 (s, IH), 7.49 (d, J=9 Hz, IH), 8.01 (d, J=9 Hz, IH); MS (CI/NH3) m/z: 263 (M + H)+; Anal. Calcd for Ci4Hi5ClN2θ-1.2 HCl: C,
54.86; H, 5.33; N, 9.14. Found: C, 54.61; H, 5.36; N, 8.98.
Example 24 5 Preparation of 2-(Hexahvdro-lH-7a-pynolizinyl)thienor3.2-blpyridine hydrochloride
24a. 2-(Hexahydro-lH-7a-p\ττolizinyl)thieno[~3.2-b1pyτidine
Thieno[3,2-b]pyridine (200 mg, 1.48 mmol) prepared according to S. Gronowitz et al., Acta Chemica Scandinavica B 1975, 29: 233-238 was dissolved in THF (6 mL) and 0 nBuLi in hexanes (2.5 M, 0.6 mL, 1.5 mmol) was added at 0 °C. After 10 minutes of stirring, 1,2,3,5, 6,7-hexahydropyrrolizinium perchlorate from Example 15a (155 mg, 0.74 mmol) was added. The slurry was allowed to graduaUy warm to ambient temperature and stir for an additional two hours. The reaction mixture was partitioned between 2 N aqueous HCl and Et2O. The phases were separated and the aqueous phase was basified with 15% 5 ΝaOH solution and then extracted with CH2CI2 (3X). The CH2CI2 extracts were combined, dried (MgSO4) and concentrated. The residue was chromatographed (sihca gel; CHCl3/MeOH, 100:0 to 99: 1) to afford a yellow solid (115 mg, 63%): mp 94-96 °C; 1H NMR (CDCI3, 300 MHz) δ 1.80-1.96 (m, 4H), 2.00-2.09 (m, 2H), 2.18-2.26 (m, 2H),
2.64-2.72 (m, 2H), 3.23-3.30 (m, 2H), 7.13 (dd, J=8, 4 Hz, IH), 7.23 (s, IH), 8.05 (dd, J=8, 1.5 Hz, IH), 8.58 (dd, J=4, 1.5 Hz, IH); MS (CI/NH3) m/z: 245 (M + H)+.
24b. 2-(Hexahydro-lH-7a-pynolizinyl)thienol3.2-b1pyridine hydrochloride The compound from step 24a (104 mg, 0.43 mmol) was dissolved in CH2CI2 (3 mL) and a saturated solution of HCl in Et2θ was added dropwise. The solvent was removed and the product was dried in vacuo to afford a hygroscopic yeUow sohd (124 mg, 93%): !H NMR (D2O, 300 MHz) δ 2.30-2.48 (m, 4H), 2.51-2.60 (m, 2H), 2.77-2.86 (m, 2H),
3.36-3.44 (m, 2H), 3.79-3.88 (m, 2H), 7.67 (dd, J=8, 5 Hz, IH), 7.84 (s, IH), 8.70 (dd, J=8, 1 Hz, IH), 8.75 (dd, J=5, 1 Hz, IH); MS (CI/NH3) m/z: 245 (M + H)+; Anal. Calcd for C14H16N2S-1.8 HCl: C, 54.25; H, 5.79; N, 9.04. Found: C, 54.25; H, 5.81; N, 8.75.
Example 25 Preparation of 5.6-Dichloro-2-(2-(S)-pynolidinyl)furor3.2-blpyridine hydrochloride
5.6-dichloro-2-(l-t-butyloxycarbonyl-2-(S)-pynolidinyl)furor3-2-blpyridine
5,6-Dichloro-2-iodo-3-pyridinol (750 mg, 2.6 mmol)(prepared by treatment of 5,6- dichloro-3-hydroxypyridine (Koch & Schnatterer, Synthesis 1990, 499) with 12 (ibid, p. 497), copper(I) iodide (89 mg, 0.47 mmol), bis(triphenylphosphine)palladium(II) chloride (91 mg, 0.13 mmol) and triethylamine (433 mL, 3.1 mmol) were combined in DMF (3.0 mL) and aUowed to stir for 1 hour. l-t-Butyloxycarbonyl-2-(S)-ethynylpynohdine (610 mg, 3.1 mmol) in DMF (1 mL) was added and the reaction mixture was heated to 60 °C for 16 hours. After coohng to ambient temperature, the reaction mixture was poured over Et- 2θ/saturated K2CO3 solution and the phases separated. The organic phase was washed with brine:water (1:1) (4X), dried (MgSO4), concentrated and chromatographed (siUca gel; EtOAc/hexane, 1:6) to afford an amber oil (408 mg, 44%): 1H NMR (CDCI3, 300 MHz) δ
1.32 and 1.45 (two br s, 9H), 1.95-2.40 (m, 4H), 3.45-3.74 (m, 2H), 5.02 (m, IH), 6.62 (s, IH), 7.81 (s, IH); MS (CI/NH3) m/z: 357 (M + H)+. 25b. 5.6-Dichloro-2-(2-(S -pyrrolidinyl furor3.2-b1pyridine
The compound from step 25a (400 mg, 1.12 mmol) was dissolved in CH2CI2 (3 mL) and TFA (3 mL) was added at ambient temperature. After stirring for 1 hour, the solvent was removed and the residue was dissolved in CH2CI2 and washed with saturated K2CO3 solution, dried (MgSO4) and concentrated. The crude product was chromatographed (sihca gel; CHCl3/MeOH, 98:2) to afford a solid (206 mg, 71 %): mp 98- 100 °C; !H NMR (CDCI3, 300 MHz) δ 1.81-2.05 (m, 3H), 2.22 (m, IH), 3.04-3.20 (m, 2H), 4.40 (m, IH), 6.70 (s, IH), 7.80 (s, IH); MS (CI/NH3) m/z: 257 (M + H)+.
25c 5.6-Dichloro-2-(2-(S)-pyrrolidinyl)furor3,2-b1pyridine hydrochloride
The compound from step 25b above (54 mg, 0.21 mmol) was slunied in Et2θ and a saturated solution of HCl in Et2θ was added dropwise. The solvent was removed and the product was recrystallized from MeOH/Et2θ to afford a white sohd (48 mg, 78%): [αb20 +5.3 (c 0.51, MeOH); lH NMR (D2O, 300 MHz) δ 2.18-2.65 (m, 4H), 3.51-3.56 (m,
2H), 5.05 (dd, J=8, 8 Hz, IH), 7.16 (d, J=l Hz, IH), 8.24 (d, J=l Hz, IH); MS (CI/NH3) m/z: 257 (M + H)+; Anal. Calcd for Cl ι Hi()Cl2N2θ-HCl: C, 45.00; H, 3.78; N, 9.54. Found: C, 45.08; H, 3.59; N, 9.40.
Example 26
Preparation of 5.6-Dichloro-2-(l-methyl-2-(S -pyrrohdinyl)furo[3.2-blpyridine hydrochloride
26a. 5.6-Dichloro-2-(l-methyl-2-(S)-pyrrolidinyl)furor3.2-blpyridine
The amine from Example 25b (145 mg, 0.57 mmol) was dissolved in an aqueous solution of 37% formaldehyde (excess) and 88% formic acid (excess). The aqueous mixture was heated to 90 °C for 1.5 hours and then aUowed to cool to ambient temperature. The reaction mixture was washed with Et2θ, basified with 15% NaOH solution and extracted with CH2CI2 (3X). The organic phases were combined, dried (MgSO4), concentrated and chromatographed (sUica gel; CHCl3/MeOH, 98:2) to afford a white sohd (97 mg, 62%): mp 58-60 °C; 1H NMR (CDCI3, 300 MHz) δ 1.89 (m, IH), 2.00-2.17 (m, 2H), 2.24 (m,
IH), 2.33 (s, 3H), 2.39 (m, IH), 3.26 (m, IH), 3.43 (m, IH), 6.74 (s, IH), 7.83 (s, IH); MS (CI/NH3) m/z: 271 (M + H)+.
26b. 5.6-Dichloro-2-(l-methyl-2-(S)-pyrrolidinyl)furor3.2-blpyridine hydrochloride
The compound from step 26a (92 mg, 0.34 mmol) was slunied in Et2θ and a saturated solution of HCl in Et2θ was added dropwise. The solvent was removed and the product was recrystallized from MeOH/Et2θ to afford a white solid (70 mg, 67%): mp 249- 251 °C; 1H NMR (D2O, 300 MHz) δ 2.27-2.37 (m, 2H), 2.47-2.71 (m, 2H), 2.93 (s,
3H), 3.38 (m, IH), 3.79 (m, IH), 4.82 (m, partially buried under H2O peak, IH), 7.27 (s, IH), 8.26 (s, IH); MS (CI/NH3) m/z: 271 (M + H)+; Anal. Calcd for C12H12CI2N2O.I.2 HCl: C, 45.77; H, 4.23; N, 8.82; Found: C, 45.61; H, 4.36; N, 8.90. Example 27
Preparation of 2-(Hexahvdro- lH-7a-pyrrolizinyl)-4-methylthienor3,2-blpyridine dihydrochloride
5 27a. 2-(Hexahvdro-lH-7a-pynohzinyl)-4-methylthieno|3.2-b1pyridine
5-Methylthieno[3,2-b]pyridine(285 mg, 1.91 mmol, prepared according to Gronowitz et al., Acta Chemica Scandinavica B, 29:233-238 (1975)), diisopropylamine (270 uL, 1.91 mmol) and nBuLi (2.5 M in hexanes, 765 uL, 1.91 mmol) were combined in THF (8 mL). After 20 minutes of stirring, 1,2,3,5,6,7-hexahydro-pyrrolizinium perchlorate from o Example 15a (200 mg, 0.95 mmol) was added. The mixture was allowed to warm to ambient temperature and 2 N aqueous HCl was added. The reaction mixture was washed with Et2θ and the aqueous phase was basified with 15% ΝaOH solution and extracted with CH2CI2 (3X). The organic phases were combined, dried (MgSO4), concentrated and chromatographed (silica gel; CHCl3/MeOH, 99:1) to afford a sohd (79 mg, 32%): 1H 5 ΝMR (CDCI3, 300 MHz) δ 1.80-1.94 (m, 4H), 1.98-2.07 (m, 2H), 2.16-2.24 (m, 2H),
2.64 (s, 3H), 2.64-2.71 (m, 2H), 3.22-3.28 (m, 2H), 7.02 (d, J=8 Hz, IH), 7.16 (s, IH), 7.92 (d, J=8 Hz, IH); MS (CI/ΝH3) m/z: 259 (M + H)+.
27b. 2-(Hexahydro-lH-7a-pyrroUzinyl -4-methylthienor3.2-blpyridine dihydrochloride The compound from step 27a (73 mg, 0.28 mmol) was dissolved in CH2CI2 and 0 treated with a saturated solution of HCl in Et2θ to afford a hygroscopic foam-like sohd (100 mg, quantitative): mp 233-235 °C; l NMR (D2O, 300 MHz) δ 2.28-2.49 (m, 4H), 2.55-
2.64 (m, 2H), 2.77-2.86 (m, 2H), 2.89 (s, 3H), 3.38-3.47 (m, 2H), 3.82-3.90 (m, 2H), 7.78 (d, J=8.5 Hz, IH), 7.90 (s, IH), 8.90 (d, J=8.5 Hz, IH); MS (CI/NH3) m/z: 259 (M + H)+; Anal. Calcd for Ci5Hl8N2S«1.3 HC1-0.9 H2O: C, 50.26; H, 6.21; N, 7.81. 5 Found: C, 50.68; H, 6.40; N, 7.41.
Example 28
Preparation of 5-bromo-2-(2-(SVpynolidinyl -furor3,2-b1pyridine hydrochloride
0 28a. 5-amino-2-bromopyridine
A mixture of 2-bromo-5-nitropyridine (30.75 g, 151.5 mmol), water (250 mL), and acetic acid (110 mL) was heated to 45 C. Iron powder (24.5 g, 439 mmol) was added at a rate which kept the temperature below 53 C, then the mixture was stirred at 48 °C ± 5 °C. The mixture was cooled to room temperature and filtered through diatomaceous earth. The 5 filter cake was washed with EtOAc, and the aqueous mixture was extracted with EtOAc. The combined organic fractions were washed with saturated Na2CO3 and brine, dried over MgSO4, and the solvent was removed in vacuo. The residue was chromatographed on stiica gel, eluting with 100:0 to 50:50 hexane:EtOAc to give 20.4 g of the title compound: 1H NMR (CDC1 300 MHz) δ 6.86-6.90 (dd, IH, J=8.5, 2.4 Hz) 7.21-7.23 (d, IH, J=8.2 Hz) 7.85-7.86 (d, IH, J=3 Hz); MS m/z: 173 (M+H)+, 190 (M+NH4)+. 28b. 5-acetoxy-2-bromopyridine To 25.6 mL of boron trifluoride etherate (208 mmol, Aldrich) cooled to -15 C under
N2 was added 18 g (104 mmol) of 5-amino-2-bromopyridine (from step 28a above) dissolved in 35 mL of DME. Then tert-butyl nitrite (14.7 mL, 125 mmol, Aldrich) was added at a rate which kept the temperature below 0 °C. DME (65 mL) and CH2CI2 (60 mL) were then added. After 10 minutes at -10 °C the mixture was warmed to 5 C and stirred for 30 min. Pentane (400 mL) was then added to the reaction mixture, the solid was coUected by suction filtration, washed with cold ether, air dried, and dissolved in 125 mL acetic anhydride. The resulting solution was heated to 100 C ± 5 C for 1 hour. The solvent was removed in vacuo, and the residue was suspended in saturated aqueous Na2CO3( and extracted with ethyl ether. The ether solution was dried over MgSO4, the solvent was removed in vacuo, and the residue was chromatographed on sihca gel, eluting with 100:0 to 60:40 hexane:EtOAc to give 13.6 g of the title compound: *H NMR (CDCI3 300 MHz) δ 2.35 (s, 3H) 7.36-7.39 (dd, IH), 7.49-7.52 (d, IH), 8.19-8.21 (d, IH) MS m/z: 216 (M+H)+, 233 (M+NH4)+.
28c 2-bromo-5-hydroxypyridine 5-Acetoxy-2-bromopyridine (12.8 g, 60 mmol, from step 28b) was dissolved in
15% aqueous NaOH (50 mL) at 0 C, and the solution was warmed to room temperature and stirred for 60 minutes. After complete consumption of the starting material the solution was neutralized by addition of 1 N HCl. The aqueous mixture was extracted with EtOAc (3 X 200 mL). The organic extracts were washed with brine (4 X 50 mL), water (2 X 50 mL), dried (MgSO4), and the solvent was evaporated to yield 9.8 g of the title compound: 1H
NMR (CDCI3, 300 MHz) δ 7.12-7.16 (dd, IH, J=3.2 Hz),7.36-7.39 (d, IH, J=8.5Hz), 8.04-8.05 (d, IH, J=2.4 Hz); MS m/z: 174 (M+H)+. 28d. 6-bromo-2-iodo-3-pyridinol
A 4.125 g sample of 2-bromo-5-hydroxypyridine (from step 28c) and 5.28 g of Na2CO3 were dissolved in 75 mL of water. To this solution was added 6.02 g of I2, and the mixture was stirred until the iodine color disappeared. The reaction mixture was then adjusted to pH 5, and extracted with EtOAc. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on sihca gel, eluting with 97:3 CHCl3:MeOH to give 4.3 g of the title compound: 1H NMR (CDCI3, 300 MHz) δ 7.08- 7.11 (d, IH, J=8.5 Hz), 7.29-7.32 (d, IH, J=8.5 Hz); MS m/z: 300 (M+H)+, 317 (M+NH4)+. 28e 2-( l-BOC-2-(S)-ρyrrolidinyl)-5-bromofuror3.2-blpyτidine
A 1.84 g (6.10 mmol) sample of 6-bromo-2-iodo-3-pyridinol, from step 28d above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.30 g, 0.4 mmol), Cul (0.3 g, 1.6 mmol) and triethylamine (1.2 mL, 8.5 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 1.3 g (6.7 mmol) of l-BOC-2-(S)- ethynylpyrrolidine, from Example lc above, dissolved in 5 mL of DMF, was added carefully. The reaction was stirred at 80 C for 16 hours, then cooled to room temperature. The reaction mixture was diluted with ether, then washed with 50% brine, and the extract was dried over MgSO4. The solvent was removed, and the residue was chromatographed on silica gel, eluting with 100:0 to 60:40 hexane:EtOAc to give 1.4 g of title compound: 1H NMR (CDCI3, 300 MHz) δ 1.31(s, 9H), 1.89-2.06 (m, 3H), 2.27-2.34 (m, IH), 3.43-3.5 (m, 2H), 4.96-5.0 (m, IH), 6.72 (s, IH), 7.38-7.41 (d, IH, J =8.6 Hz), 7.83-7.86 (d, IH, J =8.6 Hz); MS m/z: 367 (M+H)+ 28f. 2-(2-(S)-pyrroUdinyl)-5-bromofuror3.2-blpyridine hydrochloride To a solution of the product from step 28e above (1.2 g) in 10 mL of CH2CI2 at 0
C was added 10 mL of TFA. The reaction mixture was stirred for 1 hour, the mixture was poured into saturated K2CO3, and the aqueous solution was extracted with CH2CI2. The organic extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on sUica gel, eluting with 99:1 to 95:5 CHCl3:MeOH. The residue was converted to the salt by treatment with HCl/ether to give 0.6 g of the title compound: 1H
NMR (D2O, 300 MHz) δ 2.30-2.63 (m, 4H), 3.51-3.56 (m, 2H), 5.02-5.07 (t, IH, J=7.7 Hz), 7.15 (s, IH,), 7.61-7.64 (d, IH, J=8.8 Hz), 7.91-7.95 (d, IH, J=8.8 Hz); MS m/z: 267 (M+H)+, 282 (M+NH4)+; Anal. Calcd for CιιHnN2OCl-1.0 HCl: C, 43.52; H, 3.98 N, 9.23. Found: C, 43.53; H, 4.08; N, 9.13. 28g 2-(l-methyl-2-(S)-pynohdinyl)-5-Br-furor3-2-blpyridine dihydrochloride
A 300 mg sample of the compound from step 28f above was dissolved in an aqueous solution of 37 % formaldehyde (4 mL) and 88 % formic acid (2 mL) and heated at reflux for 1 hour. The solution was cooled, dUuted with water, and adjusted to pH 10 with K2CO3. The mixture was extracted with CH2CI2, and the extract was dried and concentrated. The residue was purified by chromatography on sUica gel, eluting with 100:0 to 97:3 CHCl3:MeOH. The product was dissolved in ethanol at ambient temperature and a solution of hydrochloric acid in Et2θ was added dropwise. The resultant white precipitate was then coUected by evaporation of solvent and triturated with three portions of Et2θ to give the title compound (163 mg, 43 %): l NMR (D2O, 300 MHz) δ 2.28-2.39 (m 2H), 2.49-2.72 (m, 2H), 2.95 (s, 3H), 3.38 (m, IH), 3.80 (m, IH), 4.85 (m, IH), 7.27 (s, IH), 7.96 (d, IH, J=1.02 Hz), 7.96 (d, IH, J=1.02 Hz); MS m/z: 281 (M+H)+; Anal. Calcd for Ci2Hi3N2OBr-1.0 HCl: C, 45.38; H, 4.44 N, 8.82. Found: C, 45.11; H, 4.17; N, 8.52.
Example 29 Preparation of 5-methyl-2-(2-(R -pynolidinyl)-furor3.2-b1pyridine hydrochloride
The title compound was prepared from l-Boc-2(R)-ethynylpyrrolidine according to the procedures of Example 5 above: [α]o23 +16.5° (c 1.0, MeOH); Anal. Calcd for Cι2Hι4N2O-2.0 HC1-0.2 H2O-0.2 ethanol: C, 51.39; H, 6.19; N, 9.67. Found: C, 51.63; H, 6.49; N, 9.33.
Example 30
Preparation of 5-methyl-2-(l-methyl-2-(R -pyτrolidinyl)-furor3.2-blpyridine dihydrochloride
The title compound was prepared from l-Boc-2(R)-ethynylpynolidine according to the procedures of Example 6 above: Anal. Calcd for Ci3H 6N2θ-2.0 HC1-0.4 H2O: C, 52.68; H, 6.39; N, 9.145. Found: C, 52.70; H, 6.27; N, 9.32.
Example 31
Preparation of 6-chloro-2-(2-(R')-pynolidinyl)-furor3.2-blpyridine hydrochloride
The title compound was prepared from l-Boc-2(R)-ethynylpyrrohdine according to the procedures of Example 13 above: Anal. Calcd for CnHnN2OCl-1.0 HCl: C, 50.99; H, 4.67 N, 10.81. Found: C, 50.91; H, 4.75; N, 10.86.
Example 32
Preparation of 5-chloro-2-(l -methyl- 2-(R)-pyrrohdinyl)-furor3.2-blpyridine hydrochloride
The title compound was prepared from l-Boc-2(R)-ethynylpynohdine according to the procedures of Example 12 above: Anal. Calcd for C12H13N2OCM.8 HCl: C, 47.67; H, 4.93; N, 9.27. Found: C, 47.49; H, 5.08; N, 8.97. Example 33
Preparation of 5-bromo-2-(2-(R)-pyrrolidinyl)-furor3.2-b1pyridine hydrochloride
The title compound was prepared from l-Boc-2(R)-ethynylpyrrohdine according to the procedures of Examples 28 above: Anal. Calcd for C11H11N2OOLO HCl: C, 43.52; H, 3.98 N, 9.23. Found: C, 43.40; H, 4.05; N, 8.98
Example 34
Preparation of 2-(2-(R)-pynolidinyl furor2.3-clpyridine dihydrochloride
The title compound was prepared from l-Boc-2(R)-ethynylpyrrolidine according to the procedures of Example 9 above: Anal. Calcd for CnHi2N2O-2 HCl: C, 50.58; H, 5.40; N, 10.73. Found: C, 50.38; H, 5.37; N, 10.51.
Exampl 35
Preparation of 5-chloro-2-(2-(R)-pynolidinyl')-furor3.2-blpyridine hydrochloride
The title compound was prepared from l-Boc-2(R)-ethynylpynoUdine according to the procedures of Example 11 above: Anal. Calcd for Cl l Hi 1N2OO2 HCl: C, 50.99; H, 4.67; N, 10.81. Found: C, 50.90; H, 4.75; N, 10.86.
Example 36
Preparation of 2-(2-(S)-pyτrolidinyl)furor2.3-blpyridine hydrochloride
36a. 2-(l-BOC-2-(S)-pyrrolidinyl)furor2.3-b1pyridine
The compound from step 13b above (0.23 g, 0.7 mmol), triethylamine (0.2 mL, 1.4 mmol), and 10% Pd on C (Aldrich, 50 mg) were stirred in 20 mL of EtOH under H2 (1 atm) for 4 hours. The mixture was filtered, concentrated and the crude product was purified by flash chromatography on sihca gel eluting with hexane/EtOAc (9:1 to 7:3) to provide 140 mg (68%) of the titie compound: 1H NMR (DMSO, 120° C, 300 MHz) δ 1.33 (s, 9H),
1.93-2.10 (m, 3H), 2.32 (m, IH), 3.46-3.53 (m, 2H), 5.0 (m, IH), 7.28 (dd, IH, J= 6.7, 2.8 Hz), 8.0 (dd, IH, J=6.0, 1.7 Hz), 8.22 (dd, J=4.0, 1.4 IH); MS m/z: 289 (M+H)+, 306 (M+NH4)+.
36b. 2-(2-(S)-pyrrolidinyl)furor2,3-b1pyridine hydrochloride The compound from step 36a above (0.13 g, 0.45 mmol) was dissolved in 3 mL of
CH2CI2 at 0 °C and 3 mL of TFA was added. The reaction mixture was stirred for 1 hour, poured into saturated aqueous K2CO3, and extracted with CH2CI2. The organic extract was dried over Mgθ4, and the solvent was removed. The residue was chromatographed on sihca gel, eluting with 99: 1 to 95:5 CHCl3:MeOH. The residue was treated with a solution of HCl in Et2θ to give 40 mg (42 %) of title compound: l NMR (D2O, 300 MHz) δ 2.15-2.62 (m, 4H), 3.48-3.75 (m, 2H), 5.01 (t, IH, J=7.8 Hz), 7.1 1 (s, IH, ), 7.43 (m, IH, J, 8.18 (dd, IH, J=7.8, 1.7 Hz) 8.33 (dd, IH, J=7.8, 4.1, 2.4 Hz). MS m/z: 189 (M+H)+, 206 (M+NH4)+; Anal. Calcd for Cl iHi2N2θ-1.4 HCl: C, 55.22; H, 5.64 N,
1 1.79. Found: C, 55.11; H, 5.41 N, 11.59
Example 37 Preparation of 2-(l-methyl-2-(S -pyrrolidinyl)furor3.2-clpyridine dihydrochloride
37a. 4-hvdroxy-3-iodopyridine
To a solution of 4-hydroxypyridine (4.76 g, 50.1 mmol) and Na2CO3 (10.8 g, 100 mmol) in 200 mL of water was added 12 (12.7 g, 50.1 mmol). The reaction mixture was stirred for 14 h then adjusted to pH 5 with concentrated HCl. The resulting solids were suspended in boUing ethanol and hot filtered. The solvent was removed and the resulting solids recrystallized from MeOH to afford 5.1 g (46%) of the title compound: *H NMR
(DMSO-d6) d 8.26 (br s, IH), 7.70 (s, IH), 7.69 (d, J = 7 Hz, IH), 6.14 (d, J = 7 Hz,
IH); MS (DCI/NH3) m/z: 222 (M+H)+, 239 (M+NH4)+.
37b. 2-(l-BOC-2-(S)-Pvnolidinvnfuror3.2-clpyridine
A sample of the compound from step lc above (1.95 g 12 mmol) was dissolved in
15 mL of DMF, and (Ph3P)2PdCl2 (0.6 mmol), Cul (0.74 mmol) and triethylamine (14.3 mmol) were added. The mixture was stirred at room temperature for 1 hour, then 2.65 g (12 mmol) of 4-hydroxy-3-iodopyridine from step 37a was added. The reaction mixture was stirred at 60 °C for 16 hours. The solution was cooled, dUuted with toluene, and the volatiles removed in vacuo. The residue was dissolved in 1 N aqueous HCl, and this solution was washed with ether. The acidic solution was adjusted to a pH 10 with K2CO3, and this solution was extracted with CH2CI2. The CH2CI2 extract was washed with 20% NaOH, dried over Mgθ4, and evaporated. The residue was chromatographed on silica gel, eluting with 100:0 to 95:5 hexane:EtOAc to give 1.64 g (59 %) of title compound: 1H NMR (CDCI3, 300 MHz) δ 1.30-1.50 (m, 9H), 1.90-2.20 (m, 4H), 2.95-3.15 (m, 2H), 5.05
(m, IH), 6.55 (br s, IH) 7.38 (d, IH, J=8 Hz), 8.45 (br s, IH), 8.85 (br s, IH); MS m/z: 289 (M+H)+. 37c 2-( 1 -methyl-2- (S Vpynolidinyllf uro l"3.2-clpyridine dihydrochloride
A 580 mg sample of the compound from step 37b above was dissolved in an aqueous solution of 37% formaldehyde (8 mL) and 88% formic acid (4 mL) and heated at reflux for 1 hour. The solution was cooled, dUuted with water, and adjusted to pH 10 with K2CO3. The mixture was extracted with CH2CI2, and the extract dried and concentrated.
The residue was purified by chromatography on sihca gel, eluting with 100:0 to 97:3 CHCl3:MeOH. The product was dissolved in ethanol at ambient temperature and a solution of hydrochloric acid in Et2θ was added dropwise. The resultant white precipitate was then collected by evaporation of solvent and triturated with three portions of Et2θ to give the title compound (552 mg, 70 %): *H NMR (D2O, 300 MHz) δ 2.20 (br s 2H), 2.38-2.57 (m, 3H), 2.85 (br s, 3H), 3.26 (br s, IH), 3. 85 (br s, IH), 7.44 (s, IH), 7.98 (d, IH, J=6.8 Hz), 8.56 (d, IH, J=2.3 Hz), 9.10 (s, IH, ); MS m/z; 203 (M+H)+; Anal. Calcd for C12H14N2O-2.0 HC1-0.2 H2O-0.2 ethanol: C, 51.72; H, 6.16 N, 9.73. Found: C, 51.86;
H, 6.13; N, 9.54.
Example 38
Figure imgf000073_0001
Preparation of 2-(Hexahvdro- lH-7a-pynolizinyl)-5.6-dichlorofuror3.2-b1pyridine hydrochloride
38a. 5.6-Dichloro-2-(hexahvdro-lH-7a-pynolizinyl furor3.2-blpyridine
2,3-Dichloro-6-iodo-5-pyridinol (163 mg, 0.56 mmol) from example 25a, copper(I) iodide (20 mg, 0.10 mmol), bis(triphenylphosphine)paUadium(II) chloride (20 mg, 0.030 mmol) and triethylamine (176 mL, 0.67 mmol) were combined and aUowed to stir for 1 hour at ambient temperature. 7a-ethynyl-hexahydro-lH-pynolizine (91 mg, 0.67 mmol) in DMF (1.0 mL) was added to the reaction mixture which was then heated to 60°C for 18 hours. After cooling to ambient temperature, 2 N aqueous HCl was added and the mixture was washed with Et2θ (2X), basified with 15% ΝaOH solution and extracted with CH2CI2 (2X). The CH2CI2 phases were combined, dried (MgSO4), concentrated and the residue was chromatographed (sihca gel; EtOAc/hexane, 1 :3) to afford a white sohd (116 mg, 70%): lH ΝMR (CDCI3, 300 MHz) δ 1.83-1.97 (m, 6H), 2.20-2.31 (m, 2H), 2.67-2.77 (m, 2H), 3.18-3.25 (m, 2H), 6.71 (s, IH), 7.78 (s, IH); MS (CI/ΝH3) m/z: 297 (M+H)+.
38b. 5.6-Dichloro-2-(hexahvdro-lH-7a-pynolizinyl)furor3.2-blpyridine hydrochloride
5,6-Dichloro-2-(hexahydro-lH-7a-pyrrolizinyl)furo[3,2-b]pyridine (108 mg, 0.36 mmol) was dissolved in Et2θ (7 mL) and a saturated solution of HCl in Et2θ was added dropwise. The solvent was removed and the product was recrystallized from MeOH/ΕtøO to afford a white sohd (88.5 mg, 74%): mp 229-231 °C; 1H NMR (D2O, 300 MHz) δ 2.28-
2.95 (m, 6H), 2.75-2.83 (m, 2H), 3.35-3.45 (m, 2H), 3.75-3.83 (m, 2H), 7.27 (s, IH), 8.24 (s, IH); MS (CI/NH3) m/z: 297 (M+H)+; Anal. Calcd for Ci Hi4Cl2N2θ»1.5 HC1-0.5 H2O: C, 46.60; H, 4.61; N, 7.76. Found: C, 46.74; H, 5.00; N, 7.67.
Example 39
Preparation of 5.6-Dichloro-2-(2-(R)-pyrrolidinyl)furol3.2-b1pyridine hydrochloride
39a. 5.6-Dichloro-2-(l-t-butyloxycarbonyl-2-(R)-pynolidinyl)furor3,2-b1pyridine
5,6-Dichloro-2-iodo-3-pyridinol (632 mg, 2.2 mmol), copper(I) iodide (75 mg, 0.40 mmol), bis(triphenylphosphine)palladium(II) chloride (77 mg, 0.11 mmol) and triethylamine (370 mL, 2.6 mmol) were combined in DMF (2.7 mL) and aUowed to stir for 1 hour. l-t-Butyloxycarbonyl-2-(R)-ethynylpyrroUdine (510 mg, 2.6 mmol) in DMF (1 mL) was added and the mixture was heated to 60 °C for 16 hours. After cooling to ambient temperature, the mixture was poured over Et2θ/saturated K2CO3 solution and the phases were separated. The organic phase was washed with brine:water (1:1) (4X), dried (MgSO4) and concentrated. The residue was chromatographed (sUica gel; EtOAc/hexane, 1:6) to afford an amber oil (365 mg, 46%): lH NMR (CDCI3, 300 MHz) δ 1.32 and 1.45 (two br s, 9H), 1.95-2.40 (m, 4H), 3.45-3.74 (m, 2H), 4.92-5.13 (m, IH), 6.62 (s, IH), 7.81 (s, IH); MS (CI/NH3) m/z: 357 (M+H)+.
39b. 5.6-Dichloro-2-(2-(R -pynolidinvnfuror3.2-b1pyridine
5,6-Dichloro-2-(l-t-butyloxycarbonyl-2-(R)-pynoUdinyl)furo[3,2-b]pyridine (355 mg, 1.0 mmol) was dissolved in CH2CI2 (3 mL) and TFA (3 mL) was added at ambient temperature. After stirring for 1 hour, the solvent was removed and the residue was redissolved in CH2CI2 and washed with saturated K2CO3 solution, dried (MgSO4) and concentrated. The crude product was chromatographed (sihca gel; CHCl3/MeOH, 98:2) to afford a solid (220 mg, 87%): 1H NMR (CDCI3, 300 MHz) δ 1.81-2.05 (m, 3H), 2.15-
2.29 (m, IH), 3.04-3.20 (m, 2H), 4.39-4.42 (m, IH), 6.70 (s, IH), 7.80 (s, IH); MS (CI/NH3) m/z: 257 (M+H)+.
39c. 5.6-Dichloro-2- (2- (R)-pynolidin yl)f uro \3 ,2-b1pyridine hydrochloride
5,6-Dichloro-2-(2-(R)-pynolidinyl)furo[3,2-b]pyridine (120 mg, 0.47 mmol) was slunied in Et2θ (5 mL) and a saturated solution of HCl in Et2θ was added dropwise. The solvent was removed and the product was recrystallized from MeOH Et2θ to afford short white needles (86 mg, 63%): mp >260 °C; [α]D 20 -4.5 (c 0.51, MeOH); -1H NMR (D2O, 300 MHz) δ 2.18-2.65 (m, 4H), 3.51-3.56 (m, 2H), 5.05 (dd, J=8, 8 Hz, IH), 7.16 (d, J=l Hz, IH), 8.24 (d, J=l Hz, IH); MS (CI/NH3) m/z: 257 (M+H)+; Anal. Calcd for CπHιoCl2N2θ«HCl: C, 45.00; H, 3.78; N, 9.54. Found: C, 45.01; H, 3.71; N, 9.48.
Example 40 Preparation of 5.6-Dichloro-2-( l-methyl-2-(R)-pynolidinyl)furor3.2-b1pyτidine hydrochloride
5,6-Dichloro-2-(2-(R)-pyrrolidinyl)furo[3,2-b]pyridine from Example 39b (56 mg, 0.22 mmol) was dissolved in an aqueous solution of 37% formaldehyde (excess) and 88% formic acid (excess). The aqueous mixture was heated to 60 °C for 1 hour and then allowed to cool to ambient temperature. The reaction mixture was washed with Et2θ, basified with 15% NaOH solution and extracted with CH2CI2 (2X). The organic phases were combined, dried (MgSO4), concentrated and chromatographed (sUica gel; CHCl3/MeOH, 98:2) to afford a solid. The sohd was dissolved in Et2θ (10 mL) and a saturated solution of HCl in Et2θ was added dropwise. The solvent was removed and the product recrystalhzed from MeOH/Et2θ to afford a white solid (31 mg, 46%): mp 244-246 °C; 1H NMR (D2O, 300 MHz) δ 2.27-2.37 (m, 2H), 2.47-2.71 (m, 2H), 2.93 (s, 3H), 3.38 (m, IH), 3.78 (m, IH), 4.81 (m, partially buried under H2O peak, IH), 7.27 (s, IH), 8.26 (s, IH); MS (CI/NH3) m/z: 271 (M + H)+; Anal. Calcd for Ci2Hi2Cl2N2θ-HCl: C, 46.85; H, 4.26; N, 9.1 1. Found: C, 46.53; H, 4.21 ; N, 8.82.
Figure imgf000075_0001
Preparation of 2-((lR,4S)-2-aza-3-(5)-bicyclor2.2.11heptyl)-furor3.2-blpyridine dihydrochloride
41a. Ethyl (lR.4S -3-(S -2-azabicyclol2.2.11heptanecarboxylate hydrochloride
A suspension of ethyl (lS,4R)-3-(S)-N-((R)-α-methylbenzyl)-2- azabicyclo[2.2.1]hept-5-enecarboxylate (2.40 g, 8.80 mmol, prepared according to the method described by L. Stella et al., Tetrahedron Lett., 31:2603 (1990)) in ethanol (100 mL) and 20% Pd/C (1.2 g) was placed under 4 atmosphere of H2 at room temperature for
12 hours. The reaction mixture was then filtered and concentrated in vacuo to give the free base as an oil (1.33 g). lH NMR (CDCI3, 300 MHz) δ 4.18 (q, 2H), 3.57 (br s, IH), 3.34 (s, IH), 2.63 (br s, IH), 2.12 (m, 2H), 1.68-1.28 (m, 5H), 1.28 (t, 3H); MS (CI/NH3) m/z: 170 (M+H)+. The resultant oil was dissolved in CH2CI2 (~ 20 mL) and upon addition of HCl/Et2θ (-6.25 M) a white sohd precipitated. The sohd was then recrystaUized from EtOH/Et2θ and dried under vacuum at 50 °C to give the title compound (0.94 g, 52%): mp
>200 °C. 41b. Ethyl (lR.4S)-N-BOC-2-aza-3-fSVbicvclor2.2.11heptanecarboxylate
To a solution of the compound of example 41a (5.0 g, 24.4 mmol) in CH2CI2 (100 mL) at room temperature under nitrogen was added NEt3 (3.4 g, 24.4 mmol) foUowed by di-t-butyldicarbonate (5.8 g, 26.8 mmol). After 18 hours aqueous pH 4 buffer was added and the mixture was extracted with Et2θ (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on sUica gel (EtOAc/hexane 1 :4) to yield the title compound (5.4 g, 82%) as an oil: *H NMR (CDCI3, 300 MHz) δ 1.28 (br d, IH), 4.18
(m, 2H), 3.78 (d, IH), 2.67 (br. s, IH), 1.94 (br d, IH), 1.80-1.40 (m, 5H), 1.44 (d, 9H), 1.28 (t, 3H); MS (CI/NH3) m/z: 270 (M+H)+, 287 (M+NH4)+. 41c (lR.4S -3-(^ -N-BOC-2-azabicvclor2.2.11heptanemethanol
To a solution of the product of example 41b (20.0 g, 74.3 mmol) in THF (100 mL) at 0 °C under nitrogen was added lithium aluminum hydride (5.64 g, 148.5 mmol) slowly. The mixture was stirred for 1.5 hours and then quenched with Na2SO4 • IOH2O. Et2θ was added and the mixture was stined for 1 h, filtered through diatomaceous earth and concentrated in vacuo to give the title compound (16.9 g, 100%) as a white sohd: ^H NMR (CDCI3, 300 MHz) δ 1.25 (d, J=10.5 Hz, IH), 1.49 (s, 9H), 1.58-1.78 (m, 4H), 2.30 (br d, J=1.8 Hz, IH), 3.43-3.63 (m, 4H), 4.10 (s, IH), 4.43 (dd, J=2.4, 2.4 Hz, IH); MS (CI/NH3) m/z: 171 (M-t-butyl+H)+, 228 (M+H)+.
41d. (lR.45 -N-BOC-2-aza-3-(S -bicvclor2.2.11heptanecarboxaldehvde To a mixture of the product of example 41c in DMSO (70 mL) was added a solution of sulfur trioxide pyridine complex (17.63 g, 110.7 mmol) in DMSO (30 mL). The mixture was then stirred for 15 minutes, poured into ice water, and extracted with Et2θ. The organic layer was then washed with saturated NaHCO3, 10% citric acid, H2O, and brine, dried (MgSO4), and concentrated in vacuo to give the title compound as an oil (5.08 g, 60%): lH NMR (CDC13, 300 MHz) δ 1.26 (m, IH), 1.45 (s, 9H), 1.61-1.81 (m, 5H), 2.75 (s, IH), 3.66 (s, IH), 4.31 (s, IH), 9.55 (d, J---2.1 Hz, IH); MS (CI/NH3) m/z: 226 (M+H)+, 243 (M+NH4)+.
41e. (lR.4S)-3-(S -(2.2-Dibromoethenyl)-N-BOC-2-azabicvclor2.2.11heptane
To a solution of triphenylphosphine (29.6 g, 113 mmol) in CH2CI2 (60 mL) under nitrogen at 0 °C was added carbon tetrabromide (14.9 g, 45.2 mmol). The mixture was warmed to room temperature and added slowly a solution of the product of example 41 d (5.08 g, 22.5 mmol) in CH2CI2 (10 mL). After 5 minutes, the mixture was diluted with Et2θ (50 mL) then filtered through sihca gel (EtOAc wash). The filtrate was concentrated and the residue was diluted with EtOAc/hexane ( 1 :4). The resulting precipitate was removed by filtration and the filtrate was concentrated. The resulting residue (9.77 g) was chromatographed (sUica gel; Hexane Et2θ, 95:5; Hexane/EtOAc, 90:10) to afford a sohd (4.33 g, 51%): lH NMR (CDCI3, 300 MHz) δ 1.32 (br s, IH), 1.45 (s, 9H), 1.60-1.80
(m, 5H), 2.45 (br s, IH), 3.83 (d, J=8.1 Hz, IH), 4.12 (br s, IH), 6.31 (d, J=8.1 Hz, IH); MS (CI/NH3): 382 (M+H)+
41f. (lR.4S -3-(S)-ethvnyl-N-BOC-2-azabicvclor2.2.11heptane A 2.5 M solution of n-BuLi in hexane (11.4 mL, 28.4 mmol) was added slowly to a solution of the product of Example 41e (4.33 g, 11.4 mmol) in THF (40 mL) under nitrogen at 0 °C. The mixture was then stirred for 10 minutes, quenched with saturated NaHCO3 and extracted with EtOAc (2X). The combined organic extracts were washed with H2O and brine, dried (MgSO4), and concentrated. The crude oil (2.87 g) was chromatographed (sihca gel; Hexane/EtOAc, 90:10) to afford a colorless oU (1.17 g, 46%): JH NMR
(CDC13, 300 MHz) δ 1.36-1.42 (m, 3H), 1.50 (s, 9H), 1.66-1.75 (m, 2H), 2.10 (m, IH), 2.25 (d, J=1.5 Hz, IH), 2.59 (s, IH), 3.89 (s, IH), 4.18 (s, IH); MS (CI/NH3): 222 (M+H)+, 239 (M+NH4)+. 41 g. 2-((lR.4SV2-aza-3-(S -bicvclor2.2.11heptyl)-furor3.2-b1pyridine dihydrochloride A solution of 2-iodo-3-hydroxypyridine (0.4 g, 1.8 mmol), bis(triphenylphosphine)-palladium(II)chloride (0.06 g, 0.09 mmol), copper (I) iodide (0.05 g, 0.27 mmol), and NEt3 (0.25 mL, 1.8 mmol) in DMF (2 mL) was stined for 1 hour.
Then a solution of the product of example 41f (0.4 g, 1.8 mmol) in DMF (0.5 mL) was added. The mixture was heated at 60 °C for 16, quenched with saturated NaHCO3, and extracted with EtOAc (2X). The combined EtOAc extracts were washed with H2O and brine, dried (MgSO4), and concentrated. The crude solid (0.64 g) was chromatographed
(sUica gel; hexane/EtOAc, 60:40) to give a yeUow colored solid (0.27 g). This was dissolved in CH2CI2 and upon addition of HCl/Et2θ a sohd precipitated which was coUected and further purified by heating in MeOH with activated carbon for 15 minutes. After filtering, the MeOH filtrate was concentrated to give the title compound (0.11 g, 22%) as a white solid: mp 182-185 °C; [α]D 23 +33.2 (c 0.29, MeOH); lH NMR (MeOH-d4, 300 MHz) δ 1.81-2.01 (m, 6H), 2.24-2.28 (br d, J=1 1.8 Hz, IH), 3.31 (s, IH), 4.28 (s, IH), 7.51 (s, IH), 7.87 (m, IH), 8.58 (br d, J=8.5 Hz, IH), 8.62 (br s, IH); MS (CI/NH3) m/z: 215 (M+H)+, 232 (M+NH4)+; Anal. Calcd for Ci3Hi6Cl2N2O-0.2 HC1-0.5 H2O: C, 51.45; H, 5.71; N, 9.23. Found: C, 51.48; H, 5.72; N, 8.98.
Figure imgf000078_0001
Preparation of 2-((lR.4SV2-aza-3-(S)-bicvclor2.2.11heptyl)-2-methyrfuror3.2-b1ρyridine dihydrochloride
5
To a solution of 2-((lR,4S)-2-aza-3-(S)-bicyclo[2.2.1]heptyl)furo[3,2-b]pyridine dihydrochloride (from Example 41, 0.08 g, 0.3 mmol) in EtOH (3.0 mL), formaldehyde (37% w/w aqueous) (5.0 mL) and HOAc (0.2 mL) was added sodium cyanoborohydride (0.08 g, 1.4 mmol). The mixture was stirred for 16 hours, quenched with saturated o NaHCO37 and extracted with Et2θ. The organic layer was washed with H2O, dried
(MgSO4) and concentrated. The crude product (0.22 g) was chromatographed (sUica gel; EtOH/EtOAc, 10:90) to afford an oU (0.06 g). The oil was dissolved in CH2CI2 and a solution of HCl in Et2θ was added. The solvent was removed and the product was recrystaUized from CH2θ2/Et2θ to afford the title compound as a white sohd (0.09 g, 5 100%): mp 225 °C (dec); [ ]D 23 +5.4 (c 0.35, MeOH); lH NMR (MeOH-d4, 300 MHz) δ 1.84-2.24 (m, 5H), 2.41 (m, IH), 3.12 (s, 3H), 3.20 (br s, IH), 4.22 (s, IH), 4.61 (s, IH), 7.62 (s, IH), 7.94 (dd, J=6.0, 6.0 Hz, IH), 8.73 (dd, J=0.9, 1.2 Hz, IH), 8.84 (br d, J=6.0 Hz, IH); MS (CI/NH3) m/z: 229 (M+H)+, 246 (M+NH4)+; Anal. Calcd for C14H18C12N2O-0.2 H2O: C, 55.17; H, 6.08; N, 9.19. Found: C, 55.24; H, 5.76; N, 0 9.05.
Example 43
Figure imgf000078_0002
Preparation of 2-((lR.4S)-2-aza-3-(SVbicvclor2.2.11heptyl)-5-chloro-furoF3.2-hlpyridine 5 dihydrochloride
A solution of 6-chloro-2-iodo-3-hydroxy pyridine (0.46 g, 1.8 mmol) from step 1 lc, bis(triphenylphosphine)-palladium(II)chloride (0.06 g, 0.09 mmol), copper (I) iodine (0.05 g, 0.27 mmol), NEt3 (0.25 mL, 1.8 mmol) in DMF (2 mL) was stirred for 1 hour. 0 Then a solution of (lR,4S)-3-(S)-ethynyl-N-t-butylcarboxyl-2-azabicyclo[2.2.1]heptane from Example 41f above (0.40 g, 1.8 mmol) in DMF (0.5 mL) was added. The mixture was heated at 60 °C for 16 h, quenched with saturated NaHCO3 and extracted with EtOAc. The combined EtOAc extracts were washed with H2O and brine, dried (MgSO4), and concentrated. The crude product (0.68 g) was chromatographed (sUica gel; hexane/EtOAc, 80:20) to give a solid (0.57 g). The solid was dissolved in CH2CI2 and a solution of HCl in Et2θ was added. The solvent was removed and the product was recrystaUized from EtOH Et2θ to afford the title compound as a white sohd (0.47 g, 93%): mp >200 °C; [α]D 23 +31.2 (c 0.29, MeOH); -Η NMR (MeOH-d4, 300 MHz) δ 1.77-1.99 (m, 5H), 2.24
(m, IH), 3.15 (s, IH), 4.23 (s, IH), 4.74 (s, IH), 7.15 (s, IH), 7.43 (d, J=9.0 Hz, IH), 8.00 (dd, J=0.9, 0.9 Hz, IH); MS (CI/NH3) m/z: 249 (M+H)+; Anal. Calcd for
C13H14C12N2O-0.1 HCl: C, 54.06; H, 4.92; N, 9.70. Found: C, 54.21; H, 4.90; N, 9.50.
Figure imgf000079_0001
Preparation of 2-((lR.4SV2-aza-3-(S)-bicvclor2.2. llheptyl>5-chloro-2-methylfuror3.2- blpyridine dihydrochloride
To a solution of 37% aqueous formaldehyde (12 mL) and 88% formic acid (6 mL) was added 2-((lR,45)-2-aza-3-(S)-bicyclo[2.2.1]heptyl)-5-chlorofuro[3,2-b]pyridine dihydrochloride from Example 43 above (0.4 g, 1.4 mmol). The reaction solution was refluxed for 16 hours. After cooling to ambient temperature, the solution was basified to pH 12 by the addition of solid K2CO3, and extracted with EtOAc. The organic extract was washed with H2O, dried (MgSO4), and concentrated. The crude sohd was dissolved in CH2CI2 and a solution of HCl in Et2θ was added. The solvent was removed and the title • compound (0.03 g, 22%) was collected as a white solid: mp 197-200 °C; [α]D 23 +5.6 (c 0.23, MeOH); 1H NMR (MeOH-d4, 300 MHz) δ 1.82-2.21 (m, 5H), 2.33-2.38 (m, 2H),
3.08 (s, 3H), 3.13 (br s, IH), 4.16 (s, IH), 4.45 (s, IH), 7.23 (s, IH), 7.43 (d, J=8.7 Hz, IH), 8.04 (dd, J=0.9, 1.2 Hz, IH); MS (CI/NH3) m/z: 263 (M+H)+; Anal. Calcd for Ci4HπCl3N2θ-0.2 HC1-0.9 H2O: C, 46.82; H, 5.33; N, 7.80. Found: C, 46.76; H,
5.34; N, 7.47.
Figure imgf000080_0001
Preparation of 2-((lR.4SV2-aza-3-(S)-bicvclor2.2.11heptyl -5.6-dichlorofuror3.2- blpyridine dihydrochloride
A solution of 2-iodo-3-hydroxy-5,6-dichloropyridine (0.45 g, 1.6 mmol) from Example 25a, bis(triphenylphosphine)palladium(π)chloride (0.06 g, 0.08 mmol), copper (I) iodide (0.05 g, 0.24 mmol), NEt3 (0.22 mL, 1.6 mmol) in DMF (1.5 mL) was stirred for 1 hour. Then a solution (lR,4S)-3-(S)-ethynyl-N-t-butyloxycarboxyl-2- azabicyclo[2.2.1]heptane from Example 4 If above (0.4 g, 1.8 mmol) in DMF (1.0 mL) was added. The mixture was heated at 60 °C for 16 hours, quenched with saturated ΝaHCθ3 and extracted with EtOAc (2X). The combined EtOAc extracts were washed with H2O, brine, dried (MgSO4), and concentrated. The crude solid (0.60 g) was chromatographed
(sUica gel; Hexane/EtOAc, 80:20) to give a sohd (0.2 g). The solid was then dissolved in CH2CI2 and a solution of HCl in Et2θ was added. The solvent was removed and the product was recrystalhzed from EtOH/Et2θ to afford a white solid (23 mg, 5.1%): mp >200 °C; *H NMR (MeOH-d4, 300 MHz) δ 1.74-1.99 (m, 5H), 2.20-2.25 (m, IH), 3.15 (s, IH), 4.23 (s, IH), 4.74 (s, IH), 7.19 (d, J=0.6 Hz), 8.30 (s, IH); MS (CI/NH3) m/z: 283 (M+H)+, 300 (M+NH4)+; Anal. Calcd for Ci3Hi2Cl2N2θ-0.6 EtOH-0.8 HCl: C, 50.17; H, 4.86; N, 8.24. Found: C, 50.12; H, 4.78; N, 8.15.
Example 46
Figure imgf000080_0002
Preparation of 6-bromo-2-(2-(S)-pynolidinyl)furor3.2-blpyridine dihydrochloride
46a. 2-H- BOC-2-(S -Pvnolidinyl)-6-bromofuror3.2-b1pyridine
A sample of 5-bromo-3-pyridinol (2.06 g, 11.8 mmol) (which may be prepared according to Clausson-Kass, et al.,U.S. patent 4,192,946) and Na2CO3 (3.65 g, 2.1 mmol) were dissolved in H2O (25 mL). To this solution was added I2 (3.0 g, 12 mmol), and the reaction mixture was stirred overnight. The mixture was then poured slowly into 2M aqueous HCl, and the acidity was adjusted to pH 3. The product was coUected by filtration and crystaUized from EtOH/ether, affording title compound (2.92 g, 83%): MS (C1/NH3) m/e: 300 (M+H)+, 317 (M+NH4)+; lH NMR (CDCI3, 300 MHz) δ 7.25 (d, J=2 Hz, IH), 7.93 (d, J=2 Hz, IH). A sample of 5-bromo-2-iodo-3-pyridinol (0.60 g, 2.0 mmol), from above, was dissolved in DMF (3 mL), and Pd(PPh3)2Cl2 (0.07 g, 0.1 mmol), Cul (0.077 g, 0.4 mmol) and triethylamine (0.33 mL, 2.4 mmol) were added. The mixture was stined under N2 at room temperature for 1 hour, then l-BOC-2-(S)-ethynylpyrrolidine (0.429 g, 2.2 mmol), from Example lc above, dissolved in DMF (1 mL), was added carefuUy. The reaction mixture was stined at 60 °C for 16 hours, then cooled to room temperature. The reaction mixture was diluted with ether, then washed with 10% NaOH and brine. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed
(sUica gel; hexane/EtOAc, 5:1 to 2:1) to give the title compound (0.32 g, 43%): H NMR
(CDCI3, 300 MHz) δ 1.32, 1.46 (2 s, 9H), 1.91-2.40 (m, 4H), 3.37-3.70 (m, 2H), 4.93- 5.15 (m, IH), 6.66 (s, IH), 7.85 (s, IH), 8.55 (s, IH); MS (CI/NH3) m/z: 367, 369
(M+H)+.
46b. 6-bromo-2-(2-(S)-pynolidinyl)furo[3.2-b1pyridine dihydrochloride
A sample (0.14 g, 0.38 mmol) of the compound from step 46a above was dissolved in a solution of hydrogen chloride in dioxane (4 N, 3 mL) and cooled to 0 °C. After stirring at room temperature for 16 hours, the solvent was evaporated under reduced pressure. The residue was then triturated with ether several times to give the hydrochloride salt as a white solid (0.119g, 92%): [ ]D 23 +4.09 (c 0.45, MeOH); 1H NMR (D2O, 300 MHz) δ 2.14-
2.50 (m, 3H), 2.59 (m, IH), 3.50-3.55 (m, 2H), 5.07 (t, IH, J=7.7 Hz), 7.22 (t, J=0.7 Hz, IH), 8.32 (dd, J=0.7, 1.8 Hz, IH), 8.66 (d, IH, J=1.8 Hz); MS (CI/NH3) m/z: 267, 269 (M+H)+; Anal. Calcd for Cl 1H1 iN2OBr-2.2HCl: C, 38.04; H, 3.83; N, 8.07. Found: C, 38.01; H, 3.75; N, 7.92.
Example 47
Figure imgf000081_0001
Preparation of 6-bromo-2-(l-methyl-2-(S -p,yrrolidinyl)furof3.2-blpyridine dihydrochloride A sample of 2-(l- BOC-2-(S)-pyrrolidinyl)-6-chlorofuro[3,2-b]pyridine (180 mg, 0.49 mmol), from Example 46a above, was dissolved in 1.5 mL of 88% formic acid and 3 mL of 37% aqueous formaldehyde and heated at 100 °C for 16 hours. The reaction mixture was cooled to ambient temperature, poured into saturated aqueous K2CO3, and extracted with CH2CI2. The organic extract was dried over MgSO4, and the solvent was removed.
The residue was chromatographed (sihca gel; EtOAc/MeOH, 10:1) to give the amine as colorless oU (92 mg, 67%). The amine was converted to the hydrochloride salt by treatment with HCl ether, and the salt was recrystalhzed from EtOH/EtOAc to give the title compound (68 mg, 61%) as a white solid: lH NMR (D2O, 300 MHz) δ 2.20-2.40 (m, 2H), 2.46-
2.80 (m, 3H), 3.00 (br s, 3H), 3.38 (m, IH), 3.88 (m, IH), 7.32 (s, IH), 8.31 (dd, J=0.7, 1.8 Hz, IH), 8.67 (d, J=1.8 Hz, IH); MS (CI/NH3) m/e: 281 (M+H)+, 283 (M+2H)+; Anal. Calcd for C12H13N2OB .8HCI: C, 41.56; H, 4.30; N, 8.08. Found: C, 41.60; H, 4.12; N, 7.89. [α]D -2.8 (c 0.20, MeOH)
Example 48
Figure imgf000082_0001
Preparation of 6-bromo-5-chloro-2-( l-methyl-2-(S)-pynolidinyl)furor3.2-blpyridine dihydrochloride
48a. 2-(l-BOC-2-(S)-pynolidinyl)-5-chloro-6-bromofuror3.2-blpyridine
3-Bromo-2-chloro-5-hydroxy-6-iodopyridine (2.0 g, 6.0 mmol)(prepared by treatment of 3-bromo-2-chloro-5-hydroxypyridine (Koch & Schnatterer, Synthesis 1990, 499) with 12 (ibid, p. 497), paUadium (II) bis(triphenylphosphine) chloride (0.21 g, 0.30 mmol), Cul (0.228 g, 1.2 mmol) and triethylamine (1.0 mL) were dissolved in DMF (8 mL). After stirring at room temperature for 1 hour, the acetylene from Example 3a (1.40 g, 7.2 mmol) was added and the resultant mixture was stirred at room temperature for 16 hours. The mixture was dUuted with EtOAc, and washed with H2O: brine (1:1, 3X). The organic layer was dried, concentrated and chromatographed (sUica gel; hexane EtOAc, 10: 1 to 5:1) to afford the title compound as colorless oil (170 mg, 11%): 1H NMR (CDCI3,
300MHz) δ 1.31 (s, 5H), 1.46 (s, 4H), 1.8-1.95 (m, 2H), 1.96-2.23 (m, 2H), 3.32-3.58 (m, 2H), 4.15-4.41 (m, IH), 6.60 (s, IH), 7.95 (s, IH); MS (CI/NH3) m/z: 403
(M+H)+. 48b. 6-bromo-5-chloro-2-(l-methyl-2-(S)-pynolidinyl)furor3.2-b1pyridine dihydrochloride A sample of 2-(2-(S)-pyrrolidinyl)-5-chloro-6-bromofuro[3,2-b]pyridine (170 mg, 0.42 mmol), from Example 48a above, was dissolved in 1.0 mL of 88% formic acid and 3 mL of 37% aqueous formaldehyde and heated at 100 °C for 16 hour. The reaction mixture was cooled, poured into saturated aqueous K2CO3, and the mixture was extracted with CH2CI2. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to give the amine as colorless oil (60 mg, 45%). The amine was converted to the hydrochloride salt by treatment with HCl/ether, and the salt was recrystalhzed from EtOH/EtOAc to give the title compound (50 mg, 71%): mp 250-253 °C; [α]D 23 -28.3 (c, 0.35, MeOH); -1H NMR (D2O, 300MHz) δ
2.26-2.38 (m, 2H), 2.47-2.72 (m, 2H), 2.93 (s, 3H), 3.41 (m, IH), 3.78 (m, IH), 7.27 (s, IH), 8.40 (s, IH); MS (CI/NH3) m/z: 315(M+H)+; Anal. Calcd for Cl2Hl2N2OBrCl-HCl: C, 40.94; H,3.72; N,7.96. Found: 40.76; H, 3.76; N, 7.79.
Example 49
Figure imgf000083_0001
Preparation of 6-bromo-5-chloro-2-(2-(R)-pynolidinyl)furo[3.2-b1pyridine hydrochloride
49a. 2-( 1 -BOC-2-(RVpyff olidinyl - 5-chloro-6-bromofuror3.2-b1pyridine
5-Bromo-6-chloro-3-hydroxy-2-iodopyridine (4.0 g, 12.0 mmol) from Example 48a, palladium (II) bis(triphenylphosphine) chloride (0.42 g, 0.60 mmol), Cul (0.456 g, 2.4 mmol) and triethylamine (2.0 mL) were mixed in DMF at room temperature. The mixture was stirred at room temperature for one hour, the acetylene of Example 3a (2.56 g, 13.2 mmol) was added. The mixture was heated at 55 °C over two nights. After cooling to room temperature, Et2θ (20 mL) was added and the mixture was washed with H2O: Brine (1:1,
3X). The organic layer was dried, concentrated and chromatographed (sUica gel; Hexane/EtOAc, 10:1 to 5:1) to afford the title compound as an oil (2.71 g, 56%): JH NMR (CDCI3, 300 MHz) δ 1.31, 1.46 (s, 9H), 1.95-2.06 (m, 2H), 2.06-2.20 (m, IH), 2.20- 2.35 (m, IH), 3.42-3.70 (m, 2H), 4.95, 5.07 (br s, IH), 6.60 (s, IH), 7.95 (s, IH); MS (CI/NH3) m/z: 403 (M+H)+.
49b. 6-bromo-5-chloro-2-(2-(R)-pyrtolidinyl)furoF3,2-b1pyridine hydrochloride
To a sample of the compound from step 49a above was added a 4.0 M solution of HCl in dioxane. After stirring for 12 hours, the solvent was evaporated. The white sohd was triturated with Et2θ and dried under vacuum to afford the hydrochloride salt: mp >250° C; [α]D 23 -4.83 (c 0.14, MeOH); *H NMR (D2O, 300 MHz) δ 2.20-2.50 (m, 3H), 2.5- 2.65 (m, IH), 3.51 (t, J=6.9 Hz, 2H), 5.04 (t, J=18.0 Hz, IH), 7.15 (s, IH), 8.39 (s, IH); MS (CI NH3) m/z: 301 (M+H)+; Anal. Calcd for CioHnN2OClBr-HCl: C, 39.09; H, 3.28; N, 8.29. Found: C, 39.12; H, 3.54; N, 7.91.
Example 50
Figure imgf000084_0001
Preparation of 6-bromo-5-chloro-2-( 1 -methyl-2-(R -pyrrolidinyl)furoF3,2-b1pyridine hydrochloride
50a. 6-bromo-5-chloro-2-(l-methyl-2-(R)-pynolidinyl)furoF3.2-b1pyridine
A sample of the compound from step 49a above (0.355 g, 0.88 mmol) in 88% formic acid (5.0 mL) and 37% aqueous formaldehyde (10 mL) was heated at 70 °C for two hours. After coohng to room temperature, the solution was basified to pH 9 with saturated aqueous NaHCO3 and extracted with CH2CI2 (3X). The combined organic extracts were dried, concentrated and chromatographed (sihca gel; CH2Cl2/ eOH, 10:0.2 to 10:0.5) to afford an oil (0.226 g, 81%): *H NMR (CDCI3, 300 MHz) δ 1.80-1.97 (m IH), 2.00-2.15
(m, 2H), 2.24 (m, IH), 2.33 (s, 3H), 3.25 (m, IH), 3.45 (m, IH), 4.73 (m, IH), 6.72 (s, IH), 7.98 (s, IH); MS (CI/NH3) m/z: 315 (M+H)+.
50b. 6-bromo-5-chloro-2-(l -methyl-2-(R)-pyrrolidinyl)furoF3-2-b1pyridine hydrochloride To an ethereal solution of the compound from step 50a at room temperature was added a 1.0 M solution of HCl in Et2θ dropwise until precipitation ceased. The solvent was removed, and the white solid was triturated with Et2θ then dried under vacuum to afford the title compound: mp 246-248 °C; [α]D 23 +32.65 (c 0.68, MeOH); *H NMR (D2O, 300 MHz) δ 2.25-2.40 (m, 2H), 2.46-2.70 (m, 2H), 2.94 (s, 3H), 3.40 (m, IH), 3.81 (m, IH), 4.83 (m, IH), 7.27 (s, IH), 8.40 (s, IH); MS (CI/NH3) m/z: 315(M+H)+; Anal. Calcd for Ci2H12N2OBrCl-l. lHCl-O.3H2O: C, 39.91; H, 3.82; N,7.76. Found: 40.26; H, 4.00; N, 7.39. Example 51
Figure imgf000085_0001
Preparation of 7-chloro-2-(l-methyl-2-(S)-pynolidinyl)furoF3.2-b1pyridine hydrochloride
51a. 2-(l-BOC-2-(SVpynohdinyl)-7-chloro-furoF3.2-blpyridine
To a solution of 4-chloro-3-hydroxy-2-iodopyridine (1.04 g, 4.10 mmol) in DMF (10 mL) was added (Ph3P)2PdCl2 (0.140 g, 0.20 mmol), Cul (0.152 g, 0.80 mmol) and Et3N (0.496 g, 4.90 mmol). The mixture was stirred at room temperature for one hour. A solution of l-Boc-2-(S)-ethynylpyrrolidine (0.80 g, 4.10 mmol), from step lc above, in DMF (10 mL) was added and the mixture was heated at 60 °C for 16 hours. The reaction mixture was cooled to room temperature and poured into saturated NaHCO3 and washed with Et2θ (4X lOOmL). The combined organic extracts were washed with brine/H2θ (1/1 400mL), dried (MgSO4), and concentrated . The crude product was chromatographed (sihca gel; CH2Cl2/MeOH, 90:10) to afford the title compound as a brown oU (0.180 g, 14%): lH NMR (CDCI3, 300MHz) δ 1.40 (s, 9H), 1.95-2.10 (m, 4H), 3.10-3.25 (m, 2H), 4.90-5.10 (m, IH), 6.65 (s, IH), 7.10 (br s, IH), 8.38 (br s, IH); MS (DCI/NH3) m/z: 323 (M+H)+. 51b. 7-chloro-2- ( 1 -methyl-2-(S)-pynolidinyl)furo F3.2-blpyridine hydrochloride
A solution of 2-(l-BOC-2-(S)-pynolidinyl)-7-chlorofuro[3,2-b]pyridine, from step 51a above, in HCO2H (15.0 mL, 88%) and H2CO (15mL, 37%) was refluxed for one hour. After cooling to room temperature and the solution was acidified to pH=2.0 with 1 N aqueous HCl and washed with Et2θ (150 mL). The aqueous layer was basified with 15% NaOH and extracted with CH2CI2 (4X 400mL). The combined CH2CI2 extracts were dried (MgSO4) and concentrated. The crude material was chromatographed (sihca gel; CH2Cl2:MeOH, 95:5) to afford the title compound as a light yeUow oil (0.036 g, 15%).
The amine was dissolved in Et2θ and cooled to 0 °C and a saturated solution of HCl in Et2θ was added until precipitation ceased. The solvent was removed and the yellow sohd was placed under vacuum to afford the title compound: [α]o23 +26.24 (c 0.05, H2O); ^H NMR (D2O, 300 MHz) δ 2.28-2.42 (m, 2H), 2.50-2.68 (m, 2H), 2.98 (s, 3H), 3.42 (br s, IH), 3.62 (br s, IH), 5.00 (m, IH), 7.38 (s, IH), 7.59 (d, J=6.0 Hz, IH), 8.44 (d, J=6.0 Hz, IH); MS (DCI/NH3) m/z: 237 (M+H)+; Anal. Calcd for Ci2Hi3N2θ-1.2 HCl-0.10H2θ-0.20Et2θ: C, 51.75; H, 5.56; N, 9.43. Found C, 51.40; H, 5.49; N,9.03.
Figure imgf000086_0001
(±)-2-(7-aza-2-exo-bicvcloF2.2. nheptyl)furoF3.2-blpyridine dihydrochloride
52a. (±)7-aza-7-(tert-butoxycarbonyl -2-exo-bicycloF2.2.11heptanemethanol
Figure imgf000086_0002
A solution of the exo-substituted ester (12.3 g, 48.1 mmol, prepared according to the procedure of Hernandez et al., J. Org. Chem., 60:2683-2691 (1995)) in THF (40 mL) was added to a suspension of lithium aluminum hydride (4.38 g, 115 mmol) in THF (120 mL) at - 10 °C. After 30 minutes, the reaction was quenched by the careful addition of sohd Na2Sθ4»10H2θ untU gas evolution ceased. The mixture was dUuted with Et2θ and some Celite was added. The mixture was stirred at ambient temperature for 1 hour then the solids were removed by filtration through a pad of Celite and anhydrous Na2SO4. Concentration of the filtrate afforded the title compound as a colorless oU (10.3 g, 94%): l NMR (CDC13, 300 MHz) δ 1.23-1.55 (m, 3H), 1.45 (s, 9H), 1.75-1.82 (m, 2H), 1.88-1.94 (m, 2H), 3.38-3.44 (m, 2H), 4.14-4.22 (m, 2H); MS (CI/NH3) m/z: 228 (M+H)+, 245 (M+NH )+.
Figure imgf000086_0003
To solution of oxalyl chloride (4.73 mL, 54.2 mmol) in CH2C12 (200 mL) at -78 °C was added dimethyl sulfoxide (7.70 mL, 108 mmol). After 10 minutes, a solution of (±)7- aza-7-(tert-butoxycarbonyl)-2-exo-(hydroxymethyl)-bicyclo[2.2.1]heptane, from step 52a above, in CH2CI2 (25 mL) was added. After 15 minutes, triethylamine (31.5 mL, 226 mmol) was added. The reaction mixture was stirred at -78 °C for 30 minutes, then warmed to -40 °C over a 30 minute period. The reaction was quenched by the addition of saturated aqueous NH4CI, warmed to ambient temperature, and extracted with CH2CI2 (2X). The combined organic extracts were dried (Na2SO4) and concentrated to afford the title compound as a pale yellow oil (9.82 g, 96%): *H NMR (CDCI3, 300 MHz) δ 1.42 (s, 9H), 1.39-1.60 (m, 3H), 1.84 (m, IH), 2.20 (m, IH), 2.50 (m, IH), 3.09 (m, IH), 4.29 (br s, IH), 4.53 (br s, IH), 9.64 (d, J=2.0 Hz, IH); MS (CVNH3) m/z: 226 (M+H)+,
243 (M+NH4)+.
Figure imgf000087_0001
Carbon tetrabromide (28.9 g, 87.2 mmol) was added to a 0 °C solution of triphenyphosphine (57.2 g, 218 mmol) in CH2CI2 (200 mL) under a nitrogen atmosphere. The solution was warmed to ambient temperature, stirred for 10 minutes, then a solution of the aldehyde from step 52b in CH2CI2 (20 mL) was added via cannula. After 15 minutes, the reaction mixture was dUuted with 1 : 1 EtOAc/hexane (300 mL) and filtered through a pad of Cehte and sUica gel (1 : 1 EtOAc/hexane wash). The filtrate was concentrated and the residue was purified by chromatography (sUica gel; hexane/EtOAc 90:10) to afford the title compound as a colorless oil (12.8 g, 77%): :H NMR (CDCI3, 300 MHz) δ 1.46 (s, 9H), 1.38-1.60 (m, 3H), 1.70-1.86 (m, 3H), 2.56 (dt, J=4.4, 8.8 Hz, IH), 4.05 (br s, IH), 4.24 (br s, IH), 6.39 (d, J=8.8 Hz, IH); MS (CI/NH3) m/z: 382 (M+H)+, 399 (M+NH4)+.
52d. (±)-7-(tert-butoxycarbonyl)-2-e -ethynyl-7-azabicvcloF2.2.11heptane
Figure imgf000087_0002
To a solution of the vinyl dibromide (12.8 g, 33.7 mmol), from step 52c above, in THF (170 mL) at -78 °C was added a 2.5 M solution of n-butyUithium in hexane (27.6 mL, 69.0 mmol). The reaction was quenched after 15 minutes at -78 °C by the addition of saturated aqueous NH4CI and warmed to ambient temperature. The mixture was extracted with EtOAc (2X). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. Purification of the residue by chromatography (sUica gel; hexane/EtOAc 80:20) afforded the title compound as a colorless oil (6.95 g, 93%): lH NMR (CDCI3, 300 MHz) δ 1.24-1.48 (m, 2H), 1.46 (s, 9H), 1.64-1.92 (m, 4H), 2.09 (d, J=2.4 Hz, IH), 2.50 (m, IH), 4.32 (br s, 2H); MS (CI/NH3) m/z: 222 (M+H)+, 239 (M+NH )+.
Figure imgf000087_0003
3-Hydroxypyridine (366 mg, 1.65 mmol), copper(I) iodide (47 mg, 0.25 mmol), bis(triphenylphosphine)palladium(II) chloride (58 mg, 0.083 mmol) and triethylamine (242 mL, 1.74 mmol) were combined in DMF (3.0 mL) and allowed to stir for 1 hour. A solution of (±)-7-(tert-Butoxycarbonyl)-2-exo-ethynyl-7-azabicyclo[2.2.1]heptane (366 mg, 1.65 mmol), from step 52d, in DMF (1 mL) was added and the reaction mixture was heated to 60°C for 12 hours then 80 °C for 4 hours. After cooling to ambient temperature, the mixture was diluted with 15% NaOH and extracted with Et2θ (3X). The combined organic extracts were dried (MgSO4), concentrated and purified by chromatography (sUica gel;
EtOAc/hexane, 50:50) to afford the title compound as a white sohd (362 mg, 70%): XH NMR (CDCI3, 300 MHz) δ 1.24 (br s, 9H), 1.38-1.64 (m, 2H), 1.79-2.01 (m, 3H), 2.13
(m, IH), 3.15 (dd, J=5.3, 8.6 Hz, IH), 4.42 (br s, IH), 4.50 (br s, 1 H), 6.64 (s, IH), 7.14 (dd, J=5.4, 8.2 Hz, IH), 7.64 (d, J=8.2 Hz, IH), 8.48 (d, J=5.4 Hz, IH); MS (CI/NH3) m/z: 315 (M + H)+.
Figure imgf000088_0001
The compound from step 52e above (330 mg, 1.05 mmol) was dissolved in CH2CI2 (3 mL) and TFA (3 mL) was added at ambient temperature. After stirring for 30 minutes, the solvent was removed and the residue was diluted with CH2CI2 and washed with saturated K2CO3 solution, dried (MgSO4) and concentrated. The crude product was chromatographed (sihca gel; CHCl3/MeOH/NH4OH, 90:10:0.1) to afford the amine as a light yellow oil (223 mg, 99%): 1H NMR (CDCI3, 300 MHz) δ 1.40-1.58 (m, 2H), 1.66- 2.14 (m, 6H), 3.15 (dd, J=5.4, 9.3 Hz, IH), 3.83 (br s, 2H), 6.60 (s, IH), 7.16 (dd, J=5.4, 8.4 Hz, IH), 7.64 (dd, J=1.0, 6.5 Hz, IH), 8.48 (dd, J=1.0, 5.4 Hz, IH); MS (CI/NH3) m/z: 215 (M + H)+.
Figure imgf000088_0002
The compound from step 52f above (219 mg, 1.02 mmol) was dissolved in Et2θ and a saturated solution of HCl in Et2θ was added dropwise. The solvent was removed and the precipitate was triturated with Et2θ (3X) then placed under vacuum to afford the title compound as white sohd (245 mg, 80%): 1H NMR (D2O, 300 MHz) δ 1.85-2.32 (m,
7H), 3.77 (dd, J=5.8, 9.5 Hz, IH), 4.47 (m, IH), 4.65 (d, J=3.8 Hz, IH), 7.07 (s, IH), 7.64 (dd, J=5.4, 8.5 Hz, IH), 8.30 (dd, J=1.0, 6.5 Hz, IH), 8.55 (dd, J=1.0, 5.8 Hz, IH); MS (CI/NH3) m/z: 215 (M+H)+, 232 (M+NH4)+; Anal. Calcd for C13H14N2O-2.OHCI-O.8H2O: C, 51.77; H, 5.88; N, 9.29. Found: C, 51.81; H, 5.66; N, 9.07.
Example 53
Preparation of 2-((S)-pyrrolidinyl)-6-phenylfuror3,2-b1pyridine dihydrochloride
53a 2-(l-Boc-2-(SVpynohdinyl)-6-phenylfuro(3.2-b)pyridine
The 2-(l-BOC-2-(S)-pynolidinyl)-6-bromofuro[3,2-b]pyridine (0.2g, 0.54 mmol) obtained from Example 46a above was dissolved in toluene (2 mL). Phenylbororic acid (0.19 g, 1.62 mmol), palladium (0) tetrakis(triphenyl phosphine) (40 mg) and 2 M Na2CO3 solution (1 mL) were then added to the toluene solution. The resultant mixture was heated under reflux for 16 h. The desired product was extracted with CH2CI2, dried over MgSO4 and filtered. Solvent was then removed under reduced pressure and the residue was chromatographed (silica gel: Hexane/EtOAc, 5:1 to 2:1) to afford an oil (0.22 g, 100%). MS (CI/NH3) m/z: 365 (M+H)+; IH NMR (CDC13, 300 MHz) 1.32, 1.50 (2s, 9H),
1.90-2.22 (m, 3H), 2.30 (m, IH), 3.42-3.73 (m, 2H), 4.97-5.20 (m, IH), 6.92-7.02 (m, IH), 7.33-7.66 (m, 5H), 7.93 (s, IH), 8.90 (s, IH).
53b 2-(2-(S)-pynohdinyl)-6-phenylfurof3,2-b1pyridine dihydrochloride A sample of compound 53a (50 mg, 0.14 mmol) from above was dissolved in hydrogen chloride in dioxane (4 N, 3 mL) at 0 °C. After stirring at room temperature for 16 h, the solvent was evaporated under reduced pressure. The residue was then triturated with ether several times to give the hydrochloride salt as a white sohd (19 mg, 51%): mp 220- 225 °C; [α]D 23 +11.5 (c 0.20, MeOH); MS (CI/NH3) m/z: 265 (M+H)+; 1 H NMR (D2O, 300 MHz) : 2.19-2.54 (m, 4H), 2.70 ( , IH), 3.53-3.58 (m, 2H), 5.10 (m, IH), 7.32 (d, J=0.7 Hz, IH), 7.50-7.63 (m, 3H), 7.75-7.78 (m, 2H), 8.46 (dd, J=0.8, 1.5 Hz, IH), 8.87 (d, J=1.8 Hz, IH). Anal. Calcd. for CπHi6N2*2 HC1-0.2 H2O: C, 60.55; H, 5.38;
N, 8.31. Found: C, 59.91; H, 5.44; N, 8.22.
Example 54
Preparation of 2-(l-methyl-2-(S)-pynolidinyl)-6-phenylfuror3-2-blpyridine dihydrochloride
A sample of compound (170 mg, 0.47 mmol) from Example 53 above, was dissolved in 1 mL of HCOOH and 2 mL of HCHO and heated at 100 °C for 16 hour. The reaction mixture was cooled, poured into saturated aqueous K2CO3, and the mixture was extracted with CH2CI2. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed (sihca gel; EtOAc/MeOH, 10:1) to give the amine as colorless oti (48 mg, 40%). The amine was converted to the hydrochloride salt by treatment with HCl/ether, and the salt was recrystalhzed from EtOH/EtOAc to give the title compound (39 mg, 64%): mp 188-191° C; [α]D -1 (c 0.48, MeOH); MS (CI/NH3) m/e: 279 (M+H)+; lH NMR (D2O, 300 MHz) 2.32-2.36 (m, 2H), 2.52-2.74 (m, 3H), 3.02 (br s, 3H), 3.40 (m, IH), 3.90 (m, IH), 7.40 (s, IH), 7.52-7.63 (m, 3H), 7.74-7.78 (m, 2H), 8.39 (dd, J=0.73, 1.84 Hz, IH), 8.86 (d, J=1.84 Hz, IH). Anal. Calcd. for C18H18N2O-2.0HC1-0.5 H2O: C, 60.01; H, 5.87; N, 7.78. Found: C, 59.95; H, 5.79;
N, 7.61.
Example 55
Preparation of 2-(2-(R)-pyrrolidinyl)-5-chloro-6-phenyl furor3.2-b1pyridine hydrochloride 55a 2-(l-Boc-2(R)-pynoUdinyl-5-chloro-6-phenyl furo(3.2-b)pyridine
The 2-(l-Boc-2(R)-pynolidinyl)-5-chloro-6-bromofuro[3,2-b]pyridine (0.495 g, 1.23 mmol) obtained in Example 50a above, was dissolved in toluene (15 mL).
Phenylbororic acid (0.18 g, 1.48 mmol), paUadium (0) tetrakis(triphenylphosphine) (40 mg) and 2 M aqueous Na2CO3 (1.3 mL) were added to the reaction mixture and refluxed overnight. The solvent was evaporated and the residue was chromatographed (sUica gel; Hexane/EtOAc, 100:5 to 5:1) to afford an oil (0.41 g, 83%). MS (CI/NH3) m/z: 399 (M+H)+; 1H NMR (CDCI3, 300 MHz) δ 1.35, 1.46 (s, 9H), 1.95-2.07 ( , 2H), 2.16
(m, IH), 2.30 (m, IH), 3.41-3.70 (m, 2H), 4.96, 5.10 (br s, IH), 6.67 (s, IH), 7.46 (s, 5H), 7.68 (s, IH).
55b 2-(2-(R)-pyrrolidinyl)-5-chloro-6-phenyl furor3.2-blpyridine hydrochloride The compound of Example 55a was added to a solution of 4.0 M HCl in dioxane.
The mixture was stirred at room temperature overnight. The solvent was evaporated and the salt was then triturated in Et2θ and dried under vacuum, mp >250 °C. [OC]D23-6.50 (C 0.40, MeOH); MS (CI/NH3) m/z: 300 (M+H)+; 1H NMR (D2O, 300 MHz) δ 2.20-2.56 (m,
4H), 2.60 (m, IH), 3.55 (t, J=7.5 Hz, 2H), 5.07 (t, J=8.0 Hz, IH), 7.19 (d, J=0.7 Hz, IH), 7.57 (s, 5H), 8.03 (d, J=l.l Hz, IH); Anal. Calcd. for C17H15N2OCI-I.2 HCl: C,
59.61; H, 4.77; N; 8.18. Found: C, 59.32; H, 4.67; N, 8.30. Example 56
Preparation of 5-chloro-2-(l-methyl-2-(R -pynolidinyl)-6-phenyl furor3.2-blpyridine hydrochloride
5
56a 5-chloro-2-(l-methyl-2-(R -pyrrolidinyl)-6-phenyl furo(3-2-b)pyridine
To the compound obtained in Example 55a (0.22 g, 0.55 mmol) was added formic acid (3.0 mL) and formaldehyde (37%, 6 mL). The mixture was heated at 80 °C for two hours. After cooling to room temperature, the solution was basified to pH 9 with saturated o aqueous NaHCO3 followed by extraction with CH2CI2 (3X). The combined organic layers were dried, concentrated and chromatographed (sUica gel; CH2θ2/MeOH, 10:0.3 to 10:0.5) to afford an oil (0.11 g, 62%). MS (CI/NH3) m/z: 313 (M+H)+; 1H NMR (CDCI3, 300 MHz) δ 1.91 (m, IH), 2.01-2.30 (m, 3H), 2.36 (s, 3H), 3.27 (t, J=7.6 Hz, IH), 3.46 (t, J=8.3 Hz, IH), 4.91 (m, IH), 6.78 (s, IH), 7.46 (s, 5H), 7.68 (s, IH). 5
56b 5-chloro-62-(l -methyl- 2-(R)-pynolidinvD— phenyl furor3,2-blpyridine hydrochloride The compound obtained in Example 56a was dissolved in Et2θ and 1.0 HCl in Et2θ was added dropwise. The solvent was evaporated and the salt was triturated in Et2θ and dried under vacuum, mp 252-254 °C; [α]D 23 +38.79 (c 0.50, MeOH); MS (CI/NH3) 0 m/z: 313 (M+H)+; 1 H NMR (D2O, 300 MHz) δ 2.28-2.40 (m, 2H), 2.50-2.70 (br, 2H),
2.97 (br s, 3H), 3.40 (br s, IH), 3.80 (br s, IH), 4.86 (br s, IH), 7.30 (s, IH), 7.58 (s, 5H), 8.05 (s, IH); Anal. Calcd. for C18H17N2OC .3HCI: C, 60.02; H, 5.12; N, 7.78.
Found: 60.07; 5.09; N, 7.81.
5 Example 57
Preparation of 6-(3-aminophenyl)-5-chloro-2-(2-(R)-pynolidinyl)furor3.2-b1pyridine hydrochloride
57a 2-(l-Boc-2-(R)-pynohdinyl)-5-chloro-6-(3-aminophenvf) furo[3.2-bl pyridine 0 The 2-(l-Boc-2-(R)-pyrrolidinyl)-5-chloro-6-bromo furo[3,2-b]pyridine (0.469 g,
1.2 mmol), obtained in Example 50a above, was dissolved in toluene (10 mL). 3- Aminophenyl boric acid (0.445 g, 2.87 mmol), Pd(0) tetrakis(tri-phenylphosphine) (0.04 g) and 2 M aqueous NaHCO3 (1.5 mL) were added to the solution. The mixture was refluxed for two days. The solvent was evaporated and the residue was chromatographed (stiica gel; 5 hexane EtOAc, 5: 1 to 2: 1) to afford an oil (0.20 g, 41 %). MS (CI/NH3) m/z: 414 (M+H)+; *H NMR (CDCI3, 300 MHz) δ 1.34, 1.46 (s, 9H), 1.95-2.08 (m, 2H), 2.15 (m, IH), 2.28 (m, IH), 3.58-3.68 (m, 2H), 4.98, 5.10 (br s, IH), 6.24 (m, IH), 6.63 (s, IH), 6.76 (d, J=9.3 Hz, 2H), 6.82 (d, J=9.3 Hz, IH) 7.62 (s, IH).
57b 6-(3-aminophenyl -5-chloro-2-(2-(R)-pynohdinyl)-furor3-2-b1pyridine The compound obtained above (0.193 g, 0.47 mmol) was dissolved in CH2CI2 (2 mL) at 0 °C and TFA (1 mL) was added. The mixture was stirred and warmed to room temperature. After stirring for 30 min, it was basified with saturated aqueous NaHCO3 to pH 9 and extracted with CH2CI2 (3X). The combined organic layers were dried, concentrated and chromatographed (sihca gel; CH2Cl2/MeOH, 10:0.5 to 10:1) to afford an oil (0.125 g, 85%). MS (CI/NH3) m/z: 313 (M+H)+; 1H NMR (CDCI3, 300 MHz) δ 1.99-2.05 ( , 3H), 2.23 (m, IH), 3.70-3.82 (m, 2H), 4.43 ( , IH), 6.73 (d, J=9.3 Hz, 2H), 6.82 (d, J=9.3 Hz, IH), 7.28 (d, J=1.3 Hz, 2H), 7.66 (s, IH).
57c 6-(3-aminopheny -5-chloro-2-(2-(R -pyτrolidinyl -furor3,2-blpyridine hydrochloride The compound obtained above was dissolved in Et2θ and 1.0 M HCl in Et2θ was added dropwise. The solvent was evaporated and the salt was then triturated in Et2θ and dried under vacuum. mp >250° C; MS (CI/NH3) m/z: 313 (M+H)+; 1H NMR (D2O, 300 MHz) δ 2.20-2.45 (m, 3H), 2.46-2.64 (m, IH), 3.56 (t, J=7.1 Hz, 2H), 5.06 (t, J=7.8
Hz, IH), 6.99-7.05 (m, 3H), 7.19 (s, IH), 7.35-7.42 (m, IH), 8.02 (s, IH); Anal. Calcd. for CπHi6N30Cl-1.2HCl: C, 57.11; H, 4.85; N, 11.75. Found: C, 57.07; H, 4.87; N,
1 1.54.
Example 58
Preparation of 5-chloro-2-(2-(RVpyτrolidinyl)-6-(2-(4-pyridylethenyl) furo[3-2-b1pyridine hydrochloride
58a 2-(l-Boc-2-(RVpyrtolidinyl)-5-chloro-6-(4-vinylpyridyl) furo(3.2-b)pyridine
6-bromo-5-chloro-2-(l-methyl-2-(R)-pyτrohdinyl)furo[3,2-b]pyridine (0.522 g, 1.30 mmol) from Example 50a above was dissolved in acetonitrile (10 mL). To this solution was added Pd(II) acetate (0.052 g, 0.23 mmol), tri-o-tolyphosphine (0.26 g, 0.85 mmol), triethylamine (2.8 mL) and 4-vinylpyridine (0.17 mL, 1.56 mmol). The mixture was heated at 85 °C for two days. EtOAc (15 mL) was added, and the mixture was washed with saturated NaHCθ3. The organic layer was dried, concentrated and chromatographed (sihca gel; Hexane/EtOAc, 4:1 to 1:2) to afford an oil (0.22 g, 40%). MS (CI/NH3) m/z: 426 (M+H)+; 1H NMR (CDCI3, 300 MHz) δ 1.32, 1.46 (s, 9H), 1.96-2.05 (m, 2H),
2.15 (m, IH), 2.28 (m, IH), 3.60 (br s, 2H), 4.98, 5.1 1 (br s, IH), 6.62 (s, IH), 6.98 (d, J=18.3 Hz, IH), 7.42 (d, J=7.0 Hz, 2H), 7.74 (d, J=18.3 Hz, IH), 7.99 (s, IH), 8.64 (d, J=7.0 Hz, 2H).
58b 5-chloro-6-(2-(4-pyridylethenyl)-2-(2-(R)-pyrrolidinvDfuro(3.2-b)pyridine The compound obtained above (0.21 g, 0.49 mmol) was dissolved in CH2CI2 (2 mL) at 0 °C and then TFA (1.3 mL) was added. The mixture was stirred and warmed to room temperature. After stirring for 30 min, it was basified with saturated aqueous NaHCO3 to pH 9 and extracted with CH2CI2 (3X). The combined organic layer was dried, concentrated and chromatographed (sihca gel; CH2θ2/MeOH, 10:0.2 to 10:0.5) to afford an oil (0.123 g, 77%). MS (CI NH3) m/z: 326 (M+H)+; 1H NMR (CDCI3, 300 MHz) δ 1.80-2.10 (m, 3H), 2.26 (m, IH), 3.06-3.22 (m, 2H), 4.42(m, IH), 6.70 (s, IH), 6.95 (d, J=16.6 Hz, IH), 7.42 (d, J=5.0 Hz, 2H), 7.70 (d, J=16.6 Hz, IH), 8.00 (s, IH), 8.61 (d, J=5.0 Hz, 2H).
58c 5-chloro-6-(2-(4-pyridylethenyl)-2-(2-(R -pynolidinyl -furor3.2-blpyridine hydrochloride
The compound from step 58b above was dissolved in Et2θ and 1.0 M HCl in Et2θ was added dropwise. The solvent was evaporated and the salt was triturated in Et2θ and dried under vacuum, mp 230 °C (dec); [α]D 23 - 16.25 (c 0.40, MeOH); MS (CI/NH3) m/z: 326 (M+H)+; 1H NMR (D2O, 300 MHz) δ 2.00-2.20 (m, 2H), 2.29 (m, IH), 2.45 (m, IH), 3.30-3.40 (m, 2H), 5.00 (m, IH), 7.43 (s, IH), 7.65 (d, J=16.3 Hz, IH), 7.95 (d, J=16.3 Hz, IH), 8.03 (d, J=15.8 Hz, 2H), 8.76 (s, IH), 8.79 (d, J=6.1 Hz, 2H); Anal. Calcd. for C18H16N3OC1- 2.2HCl-0.3Et2θ: C, 53.85; H, 4.99; N, 9.81. Found: C, 53.89; H, 4.85; N,9.50.
Example 59
Preparation of 5-chloro-2-(l-methyl-2-(S')-pyrrolidinyl)-6-(3-pyridyl)furor3-2-b1pyridine hydrochloride 59a. 2-(l-Boc-2-(S -pyrrolidinvn-6-(3-pyridyl) furo (3.2-b) pyridine
The 2-(l-BOC-2-(S)-pynolidinyl)-6-bromofuro[3,2-b]pyridine (0.24g, 0.64 mmol) obtained from Example 46a above was dissolved in toluene (6 mL). Tributyl-3-pyridyltin (0.36 g, 1.3 mmol), palladium (0) tetrakis(triphenyl phosphine) (40 mg) was then added to the toluene solution and the resultant mixture was heated under reflux for 16 h. The desired product was extracted with CH2CI2, dried over MgSO4 and filtered. Solvent was then removed under reduced pressure and the residue was chromatographed (sihca gel: Hexane/EtOAc, 5:1 to EtOAc) to afford an oil (0.13 g, 56%). MS (CI/NH3) m/z: 366 (M+H)+; IH NMR (CDC13, 300 MHz) δ 1.33, 1.55 (2s, 9H), 1.92-2.38 ( , 3H), 3.43- 3.70 (m, 2H), 5.08 (m, IH), 5.15 (m, IH), 6.75 (brs, IH), 7.43 (m, IH), 7.86 (s, IH), 7.93 (m, IH), 8.66 (m, IH), 8.72 (brs, IH), 8.89 (s, IH).
59b. 5-chloro-2-(l-methyl-2-(S -pyrrolidinyl)-6-(3-pyridyl -furor3.2-blpyridine hydrochloride
A sample of compound (130 mg, 0.36 mmol), from Example 59a above, was dissolved in 1 mL of HCOOH and 2 mL of HCHO and heated at 100 °C for 16 hour. The reaction mixture was cooled, poured into saturated aqueous K2CO3, and the mixture was extracted with CH2CI2. The extract was dried over MgSO4, and the solvent was removed.
The residue was chromatographed (sihca gel; EtOAc/MeOH, 10:1) to give the amine as colorless oU (67 mg, 68%). The amine was converted to the hydrochloride salt by treatment with HCl/ether, and the salt was recrystalhzed from EtOH/EtOAc to give the title compound (65 mg): mp 155-163° C; [α]D +1-5 (c 0.40, MeOH); MS (CI/NH3) m/e: 280 (M+H)+; lH NMR (D2O, 300 MHz) δ 2.30-2.45 (m, 2H), 2.52-2.74 (m, 3H), 3.05 (br s, 3H), 3.40
(m, IH), 3.92 (m, IH), 7.47 (s, IH), 8.23 (dd, J=6, 9 Hz, IH), 8.50 (m, IH), 8.86 (m, IH), 8.95 (m, IH), 8.87 (m, IH), 9.20 (m, IH). Anal. Calcd. for Ci8Hi8N2θ-3.4 HC1-H2O: C, 48.43; H, 5.81; N, 10.06. Found: C, 48.46; H, 5.36; N, 9.97.
The foUowing examples until example 133 may readUy be made according to the procedures described below or as generaUy described, where applicable, herein. Examples 134-136 were made as described in those examples.
Examples 60 ■ 82
Following the procedure of Example 53, replacing the 2-(l-BOC-2(-pynolidinyl)-6- bromofuro[3,2-b]pyridine with the starting material compounds shown in Table 3 and replacing the phenylboronic acid reagent thereof with a R-B(OH)2 reagent shown in Table 3 below, the desired compounds 60-82 having R as described in Table 3 are prepared. The S compounds or the racemic compounds may also readtiy be prepared from the appropriate precursor(s) as shown in the schemes or tables herein. L can be varied as well and is selected from those variables hsted as R in formula I. L at the position shown in Table 3 is prefenably chosen from H, F, Cl or Me. able 3
Figure imgf000095_0001
Ex. No. n L R of reagent R
60 2 (R) H 3-quinolinyl 3-quinolinyl
61 2 (R) H 2-naphthyl 2-naphthyl
62 2 (R) H biphenyl biphenyl
63 2 (R) H 2-thienyl 2-thienyl
64 2 (R) H 4-fluorophenyl 4-fluorophenyl
65 2 (R) H 5-pyrimidinyl 5-pyrimidinyl
66 2 (R) H 3,5- 3,5- bis(trifluoromethyl)phenyl bis(trifluoromethyl)phenyl
67 2 (R) Cl 4-chlorophenyl 4-chlorophenyl
68 2 (R) H 2,4-dichlorophenyl 2,4-dichlorophenyl
69 2 (R) H 4-methylphenyl 4-methylphenyl
70 2 (R) H 3-chloro-4-fluorophenyl 3-chloro-4-chlorophenyl
71 2 (R) H 2-formylphenyl 2-formylphenyl
72 2 (R) H 4-trifluoromethylphenyl 4-trifluoromethylphenyl
73 2 (R) H 2-hydroxy-l -naphthyl 2-hydroxy- 1 -naphthyl
74 2 (R) H 4'-nitro-4-biphenyl 4'-nitro-4-biphenyl
75 2 (R) H 4'-fluoro-4-biphenyl 4'-fluoro-4-biphenyl
76 2 (R) H 4'-methyl-4-biphenyl 4'-methyl-4-biphenyl
77 2 (R) H 4-methyl-3-thienyl 4-methyl-3-thienyl
78 2 (R) H 2-cyano-3-thienyl 2-cyano-3-thienyl
79 2 (R) H 2-chloro-3-thienyl 2-chloro-3-thienyl
80 2 (R) H 2,4-dimethoxy-5- 2,4-dimethoxy-5-pyrimidinyl pyrimidinyl
81 2 (R) H 5-bromo-phenyl 5-bromo-phenyl
82 2 (R) H 4-methyl-l-naphthyl 4-methyl- 1 -naphthyl Examples 83-91
Following the procedure of Example 58 and replacing the 4-vinylpyridine reagent with alkene or alkyne reagent shown in Table 4 below, the desired compounds 83-91 having R as described in Table 4 are prepared The S compound or racemic compounds may also be prepared from the appropriate precursor(s). L is chosen from R as described for formula I for the designated position and is prefenably selected from H, F, Cl or Me.
Tahle 4
Figure imgf000096_0001
Ex. No. n L R of reagent R
83 2 (R) H 1-hexyne hexynyl
84 2 (R) H ethylene vinyl
85 2 (R) H 5,5-dimethyl-l,3- 5,5-dimethyl-l,3- hexadiene hexadienyl
86 2 (R) H 5-cyano-l-pentyne 5-cyano- 1-pentynyl
87 2 (R) H 5-phenyl-l-pentyne 5-phenyl- 1 -pentynyl
88 2 (R) H 6-hydroxyl-l-hexyne 6-hydroxyl- 1 -hexynyl
89 2 (R) H 2-phenyl-ethyne 2-phenyl ethynyl
90 2 (R) H 3,3-dimethylbutyne 3,3-dimethylbutynyl
91 2 (R) H 1-octyne 1 -octynyl
Example 92
2-(l-Boc-2-(R -pynolidinyl -6-cyanofuror3.2-b1pyridine hydrochloride
To a flamed dried flask purged with nitrogen is added 2-(l-Boc-2-(R)-pynohdinyl)-
6-bromo-furo[3,2-b]pyridine, zinc cyanide and tetrakis(triphenylphosphine)-palladium(0). To the mixture is added degassed DMF (20 mL), and the mixture is heated to 80°C for 16 hours. The mixture is poured into saturated NaHCO3 (200 mL), and extracted with EtOAc (450 mL), which is dried (MgSO4) and concentrated. The mixture is then purified by chromatography. Example 93
6-benzoyl-2-(2-(R)-pyrrolidinyl)furor3.2-blpyridine hydrochloride
93a. 6-benzoyl-2-(l-Boc-2-(R)-pynolidinyl)furor3.2-blpyridine hydrochloride 5 The 2-(l-Boc-2-(R)-pyrrohdinyl)-6-cyanofuro[3,2-b]pyridine of Example 92 in anhydrous ether at 0°C is treated with 1.5 equivalents of phenylmagnesium bromide in ether and stirring is maintained at 0 to 35 °C until the nitrile is largely consumed. The solvent is evaporated and the residue is treated with 2M aqueous potassium hydrogen sulfate to hydrolyze the intermediate imine. The solution is made basic with potassium carbonate and o extracted with EtOAc. The combined extracts are dried (Na2SO4) and concentrated to a residue which is chromatographed (sihca gel) to afford the title compound. 93.b 6-benzoyl-2-(2-(R)-pyrrolidinyl)furor3.2-blpyridine hydrochloride
6-(benzoyl)-2-(l-Boc-2-(R)-pyrrolidinyl)furo[3,2-b]pyridine is dissolved in CH2CI2 (10 mL). The mixture is cooled to 0°C, TFA (10 mL) is added and the reaction is 5 stirred for 45 minutes as it warms to room temperature. The mixture is concentrated in vacuo and taken up in a minimum amount of H2O. The aqueous mixture is basified with 15% NaOH and extracted with CH2CI2 (200 mL), which is dried (MgSO4) and concentrated. The residue is chromatographed (sihca gel) to afford the free amine. The isolated free amine is taken up in a minimum amount of Et2θ, cooled to 0°C, and treated 0 with HCl in EtOH to afford the hydrochloride salt.
Examples 94- 97
Following the procedure of Example 93, replacing the 2-(l-Boc-2-(R)-pynolidinyl)- 5 6-cyanofuro[3,2-b]pyridine with the starting material compounds shown in Table 5 and replacing the phenylmagnesium bromide reagent thereof with a R5-Mg-Br Grignard reagent shown in Table 5 below, the desired compounds 94-97 having L and R5 as described in Table 5 are prepared. S or R or racemic compounds may be prepared from the appropriate precursor(s). L is equal to R as described for formula I at that position. R-5 is also selected 0 from the variables as hsted in formula I. Table 5
Figure imgf000098_0001
Ex. No. L R5 of reagent R5
94 2 (R) H n-hexyl n-hexyl
95 2 (R) H 3-quinolinyl 3-quinolinyl
96 2 (R) H 2-naphthyl 2-naphthyl
97 2 (R) H 4- methyl- 1 -naphthyl 4- methyl- 1- naphthyl
xi am ies 98 - 103
Following the procedure of Example 93, replacing the 2-(l-Boc-2-(R)-pyrrolidinyl)- 6-cyano-furo[3,2-b]pyridine with the starting material compounds shown in Table 6 and replacing the phenylmagnesium bromide reagent thereof with a R5-Mg-Br Grignard reagent shown in Table 6 below, the desired compounds 112 - 117 having L and R5 as described in Table 6 are prepared.
Table 6
Figure imgf000099_0001
Ex. No. L R5 of Grignard agent R5
98 2 (R) H 3-pyridinyl 3-pyridinyl
99 2 (R) H 5-pyrimidinyl 5-pyrimidinyl
100 2 (R) H 3-pyridazinyl 3-pyridazinyl
101 2 (R) H 2-thienyl 2-thienyl
102 2 (R) H phenylmethyl phenylmethyl
103 2 (S) H 2-(4-methoxy- 2-(4-methoxy- phenyl)ethyl phenyl)ethyl
Examples 104 ■ 107
Following the procedure of Example 58, replacing 6-bromo-5-chloro-2-(l-methyl-2- (R)-pyrrohdinyl)furo[3,2-b]pyridine with starting material compounds shown in Table 7, replacing the 4-vinylpyridine starting reagent thereof with the starting reagent compounds shown in Table 7, then hydro genating the product thereof with paUadium or platinum on charcoal the desired compounds 104 - 107 having L and R9 as described in Table 7 are prepared. S, R or racemic compounds may be prepared from the appropriate precursor(s). L is chosen from R in formula I and is prefenably chosen from H, Cl, F or Me. This reaction is partially described in Scheme 19.
TaMe 7
Figure imgf000100_0001
Ex. No. Starting reagent W
104 2 (R) H 5-carbomethoxy-3- 2-(5-carbomethoxy- vinylpyridine pyridinyl)ethyl
105 2 (R) H 5-bromo-3- 2-(5-bromo- vinylpyridine pyridinyl)ethyl
106 2 (R) H 6-amino-5-bromo-3- 2-(6-amino-5- vinylpyridine bromo- pyridinyl)ethyl
107 2 (R) H 5-bromo-6- 2-(5-bromo-6- methylamino-3- methylamino- vinylpyridine pyridinyl)ethyl
Example 108
2-( 1 -methvl-2-(R)-pvrrolidir ιvl -6-(5-methvl-3-pvridvl)-furor3.2-blovridine dihvdrochloride
108a. 2-π-methvl-2-(R)-ovr Tolidinyl -6-(5-methvl-3-pvridvr )-furor3.2-blovridine
To a solution of 2-(l-methyl-2-(R)-pyrrohdinyl)-6-(bromo)-furo[3,2-b]pyridine from Example 47 in toluene are added (5-methyl3-pyridyl)ltributyltin and tetrakis(triphenylphosphine)paUadium(0). After being refluxed overnight, the resulting mixture is cooled to room temperature. Solvent is removed, and the residue is chromatographed on a sihca gel column.
108b. 2-(l-methyl-2-(R)-pynohdinyl -6-(5-methyl-3-pyτidyl)-furor3.2-blpyridine dihydrochloride
To a solution of 6-pyridyl-2-(l-methyl-2-(R)-pynolidinyl)furo[3,2-b]pyridine from step 108a in THF is added hydrogen chloride (1.0 M in Et2θ). A precipitate forms which is fUtered, washed (Et2θ) and vacuum-dried to afford the hydrochloride salt.
Examples 109-117
Following the procedure of Example 108, replacing the 2-(l-methyl-2-(R)- pynohdinyl)-6-(bromo)-furo[3,2-b]pyridine thereof with the starting material compound shown in Table 8 and replacing the 3-pyridinyltributyltin reagent thereof with the reagent shown in Table 8, the desired compounds 109-117 having L and R as described in Table 8 are prepared. L may also be selected from the groups listed for R of formula I at the designated position. The heteroaryl groups (het) shown at position Y-2 of formula I are added as described above using the appropriate tributyltin reagent. R or S or racemic compounds may be prepared from the appropriate precursor and are included within the scope of the invention. The reagents are either readily avaUable or may be prepared from commercially avaUable starting materials by standard synthetic methods.
able 8
Figure imgf000102_0001
Ex. No. n * L reagent het
109 2 (R) H (5-carbomethoxy-3- 5-carboxy-3- pyridinyl)tributyltin * pyridinyl
110 2 (R) H (5-carbomethoxy-3- 5-formyl-3-pyridinyl pyridinyl)tributyltin **
111 2 (R) H (5 -hydroxymethyl-3 - 5-hydroxymethyl-3- pyridinyl)tributyltin pyridinyl
112 2 (R) H (2,4-dimethoxy-5- 2,4-dimethoxy-5- pyrimidinyl)tributyltin pyrimidinyl
113 2 (R) H (2-chloro-3- 2-chloro-3-thienyl thienyl)tributyltin
114 2 (R) H (2-cyano-3- 2-cyano-3-thienyl thienyl)tributyltin
115 2 (S) H (4-methyl-3- 4-methyl-3-thienyl thienyl)tributyltin
116 2 (S) H (4-hydroxymethyl-5- 4-hydroxymethyl-5- carbomethoxy-3- carbomethoxy-3- thienyl)tributyltin thienyl
117 2 (S) H (4-methoxymethoxy- 4-methoxymethoxy-
5-carbomethoxy-3- 5 -carbomethoxy-3 - thienyl)tributyltin thienyl
*After following the procedures of Example 108, with substitutions as indicated, the carbomethoxy group is hydrolyzed with base as additional step in this preparation. **After following the procedures of Example 108, with substitutions as indicated, the following additional steps are necessary: the carbomethoxy group is hydrolyzed with base; the resulting free acid is reduced to the alcohol with LiAlH4, and the resulting alcohol is oxidized to the aldehyde with Swern or Colhns reagents.
Examples 118 - 120
FoUowing the procedure of Example 58, replacing 6-bromo-5-chloro-2-(2-(R)- pynolidinyl)furo[3,2-b]pyridine with starting material compounds shown in Table 9, replacing the vinylpyridine starting reagent thereof with the starting reagent compounds shown Table 9, then optionally hydrogenating the product thereof with palladium on charcoal the desired compounds 118-120 having L and R9 as described in Table 9 are prepared. L may be selected from the group R of formula I as described herein for the designated position and R^, in Table 9, is chosen from arylCi-C6alkyl moieties as exemplified below. As with the previous compounds, the R or S or racemic compounds may be prepared from the appropriate precursor(s). In addition, as is required for all nucleophilic additions to the bicychc ring system, L is not selected from a moiety which prevents the regioselective addition to position Y-2 on the compound of formula I.
Table 9
Figure imgf000103_0001
Ex. No. Starting reagent W
118 (R) H 4-methyl-3- 2-(4-methyl-3- vinylbenzene phenyl)ethyl 119 (R) H 4-methoxy-3- 2-(4-methoxy-3- vinylbenzene phenyl)ethyl 120 (R) H 4-trifluoromethyl-3- 2-(4-trifluoromethyl- vinylbenzene 3-phenyl)ethyl Example 21
6-benzoylaminomethyl(2-(2-(R)-pyτrolidinyl furor3,2-b1pyridine hydrochloride
121a. 2-(l-Boc-2-(Tl)-pyrrolidinv -6-(N-aminomethyl)) furor3.2-blpyridine 2-(l-Boc-2-(R)-pyrrolidinyl)-6-(cyano) furo[3,2-b]pyridine from step 92 is stirred in the presence of Raney nickel and ammonium hydroxide under 1 atm of hydrogen at room temperature. The mixture is filtered, and the solvent is removed to give the title compound
121b. 6-benzoylaminomethyl-2-( 1 -Boc-2-(R)-pyrrolidinyl furo [3 -2-blpyridine To 2-(l-Boc-2-(R)-pynolidinyl)-6-(N-aminomethyl)) furo[3,2-b]pyridine from step
121a are added CH2CI2, triethylamine and benzoyl chloride . The mixture is stirred at room temperature overnight, then concentrated under vacuum. The residue is chromatographed to afford the title compound.
121c 6-benzoylaminomethyl- 2-(l-Boc-2-(RVpyrrolidinyi)-furof3.2-blpyridine hydrochloride
2-( 1 -Boc-2-(R)-pyrrohdinyl)-6-(N-benzoylamino)methyl)) furo[3,2-b]pyridine from step 121b was dissolved in CH2CI2. The mixture was cooled to 0°C, TFA was added and the reaction was stirred for 45 minutes as it warmed to room temperature. The mixture was concentrated in vacuo and taken up in a minimum amount of H2O. The aqueous mixture was basified with 15% NaOH and extracted with CH2CI2, which was dried (MgSO4) and concentrated. The residue was chromatographed to afford a free base. The isolated free base was taken up in a minimum amount of Et2θ, cooled to 0°C, and treated with HCl in
EtOH to afford the hydrochloride salt. The material was dried overnight under vacuum to afford a white sohd
Examples 122 - 127
Following the procedure of Example 121, replacing the 2-(l-Boc-2-(R)- pyrrolidinyl)-6-cyanofuro[3,2-b]pyridine starting material thereof with the starting materials shown in Table 10 below, and replacing the benzoyl chloride of step 121b with the acylating reagent shown in Table 10, the desired compounds 122-127 having L and R5 as described in Table 10 are prepared. L may be selected from R as described previously for groups at that position and R, S or racemic compounds may be prepared from the appropriate precursor. In addition, the cyano group may be further extended via carbon-carbon homologations to form extended alkyl (branched or unbranched) amines which can be further treated with X(CO)R-5 or other acylating reagents or alkylating reagents to form, for example, -(Ci-C6alkyl)amide compounds within the scope of the invention. The nitrogen atom on the left hand side of the molecule should be protected during the acylation process. In Table 10, m is selected from 1-6-e.g., C1-C6.
Table 10
Figure imgf000105_0001
Ex.No. Acylating agent R5
122 2 (R) H acetic anhydride acetyl 123 2 (S) H 6-chlorohexanoyl 6-chlorohexanoyl chloride
124 2 (R) Cl ethyl formate H 125 2 (S) Cl dimethyl dicarbonate methoxy 126 2 (R) H furoyl chloride furanyl 127 2 (S) H 3-nicotinoyl chloride 3-pyridyl
Examples 128-133
Figure imgf000105_0002
Following the procedure of Example 121, replacing the 2-(l-Boc-2-(R)- pynohdinyl)-6-(cyano)-furo[3,2-b]pyridine starting material thereof with the starting materials shown in Table 11 below, and replacing the benzoyl chloride of step 121b with the acylating reagent shown in Table 11, the desired compounds 128-132 having L and R5 as described in Table 11 are prepared. As in the previous examples, L can be selected from the R group of formula I at the designated position and R^ is selected from, for example, those alkanoyl- or benzoylating reagents as hsted below or from those reagents of like kind which are known, available or readUy prepared. S, R and racemic compounds may be prepared from the appropriate precursor(s). An N-alkyl or suitable protecting group is necessary on the left hand side to permit acylation. Table H
Ex. No. n * L Acylating agent R5
128 2 (R) H 3-phenylpropanoyl 2-phenylethyl chloride
129 2 (S) H 4-chlorobenzoyl 4-chlorophenyl chloride
130 2 (R) Cl 3-nitrobenzoyl 3-nitrophenyl chloride
131 2 (S) Cl 2-pynolecarboxylic 2-pyrrolyl acid + EDC
132 2 (R) H 5-nitro-2-furan- 5-nitrofuranyl carboxylic acid + EDC
133 2 (S) H 2-pyrazine-carboxylic 2-pyrazinyl acid + EDC
Substituted azacyclic compound- » could be also prepared according the Schemes shown above.
The foUowing examples were made according to the procedures described below.
Example 134
2-( 1-n lethv 'l-2-(SVov nohdinvDl furo[ 2.3-blpvridine hydrochloride The title compound was prepared from 2-( 1 -BOC-2-(S)-pynolidinyl)furo[2,3- b]pyridine, from step Id above, according to the procedures of Example 12 above: H NMR (D2O, 300 MHz) δ 2.35 (m, 2H), 2.60 (m, 2H), 2.95 (s, 3H), 3.35 (m, 2H), 3.81 (m,
IH), 4.83 (m, IH), 7.24 (s, IH), 7.46 (m, IH) 8.22 (m, IH), 8.36 (dd, J = 1.5, 5 Hz, IH); MS m/z: 203 (M+H)+, 220 (M+NH4)+; Anal. Calcd for Cl2Hl4N2θ-1.6 HCl: C, 55.31; H, 6.03 N, 10.75. Found: C, 55.43; H, 6.09 N, 10.54.
Example 135.
(±)-2-(7-aza-2-e o-bicyclor2.2.11heptyl)-5-chlorofuro[3.2-b1pyridine hydrochloride
Figure imgf000106_0001
135a. (± -2-(7-aza-7-(tert-butoxycarbonv -2-ejco-bicvclor2.2.11heptyl -5-chlorofuro[3.2- blpyridine
Figure imgf000107_0001
6-Chloro-2-iodo-3-pyridinol (693 mg, 2.71 mmol) from step 1 lc above, copper(I) iodide (77 mg, 0.41 mmol), bis(triphenylphosphine)paUadium(II) chloride (95 mg, 0.14 mmol) and triethylamine (416 mL, 2.98 mmol) were combined in DMF (5.0 mL) and allowed to stir for 1 hour. A solution of (±)-7-(tert-butoxycarbonyl)-2-e o-ethynyl-7- azabicyclo[2.2.1]heptane (600 mg, 2.71 mmol), from step 52d above, in DMF (1 mL) was added and the reaction mixture was heated at 80 °C for 14 hours. After cooling to ambient temperature, the mixture was dUuted with Et2θ and washed with saturated aqueous
NaHCO3 and brine. The organic extract was dried (MgSO4), concentrated and purified by chromatography (sihca gel; EtOAc/hexane, 20:80) to afford 596 mg of a mixture of the title compound contaminated with a minor by-product. Further purification by chromatography (sUica gel; CH2θ2/MeOH, 95:5) afforded the pure title compound as a white sohd (296 mg, 31%): !H NMR (CDC1 , 300 MHz) δ 1.31 (br s, 9H), 1.45-1.65 (m, 2H), 1.85-2.00 (m, 3H), 2.10 (m, IH), 3.13 (dd, J = 5.1, 8.8 Hz, IH), 4.41 (br s, IH), 4.88 (br s, 1 H), 6.58 (d, J = 0.8 Hz, IH), 7.15 (d, J = 8.5 Hz, IH), 7.60 (dd, J = 0.8, 8.6 Hz, IH); MS (CI NH3) m/z: 349, 351 (M + H)+ 135b. (± -2-(7-aza-2-e o-bicvclor2.2.11heptyl)-5-chlorofuror3.2-blpyridine
Figure imgf000107_0002
The compound from step 135a above (178 mg, 0.510 mmol) was dissolved in 1:1 CH2CI2/TFA (4 mL) and stirred at ambient temperature for 45 min. The solvent was removed in vacuo and the residue was dUuted with saturated aqueous K2CO3 and extracted with CH2CI2 (3X). The combined organic extracts were dried (Na2SO4) and concentrated. The crude product was chromatographed (sihca gel; CHCl3/MeOH, 90:10) to afford the titie compound as a white solid (125 mg, 99%): 1H NMR (CDCI3, 300 MHz) δ 1.40-1.60 (m, 2H), 1.66-2.14 (m, 5H), 3.11 (dd, J = 5.2, 8.8 Hz, IH), 3.82-3.86 (m, 2H), 6.55 (s, IH), 7.15 (d, J = 8.5 Hz, IH), 7.62 (dd, J = 0.9, 8.6 Hz, IH); MS (CI/NH3) m/z: 249, 251 (M + H)+. 35c (±)-2-(7-aza-2-eΛ:o-bicvclor2.2. llheptyl)-5-chlorofuror3.2-blpyridine hydrochloride
Figure imgf000108_0001
The compound from step 135b above (115 mg, 0.462 mmol) was slunied in 2:1 Et2θ/CH2θ2 (6 mL) and a saturated solution of HCl in Et2θ was added dropwise. The solvent was removed and the precipitate was triturated with Et2θ and then placed under vacuum to afford the title compound as white solid (117 mg, 89%): mp >260 °C; H NMR (D2O, 300 MHz) δ 1.89-2.10 (m, 4H), 2.31 (m, IH), 2.44 (m, IH), 3.68 (dd, J = 5.6, 9.6 Hz, IH), 4.45 (m, IH), 4.60 (d, J = 3.7 Hz, IH), 6.82 (s, IH), 7.38 (d, J = 8.8 Hz, IH), 7.90 (d, J = 8.8 Hz, IH); MS (CI/NH3) m/z: 249, 251 (M+H)+; Anal. Calcd for Cι3Hι4ClN2O-HCl: C, 54.75 H, 4.95; N, 9.82. Found: C, 54.63; H, 4.85; N, 9.67.
Example 136 (± -2-(7-aza-2-eΛ:o-bicvclor2.2.nheptyl)-5-fluorofuror3.2-blpyridine hydrochloride
Figure imgf000108_0002
136a. 2-fluoro-5-nitropyridine
2-Chloro-5-nitropyridine (100 g, 0.656 mol, Aldrich), spray-dried potassium fluoride (84.1 g, 1.45 mol, Aldrich), tetraphenylphosphonium bromide (95.3 g, 0.227 mol), and anhydrous acetonitrUe (1.5 L) were combined and heated at reflux overnight. The volume of the mixture was reduced to 750 mL and the mixture was dUuted with 2 L of ether, filtered and then concentrated. The residue was triturated with hot hexane (5 x 1 L), and the combined hexane extracts were concentrated to give the title compound as a pale yellow oU (48 g, 54%): *H NMR (CDCI3, 300 MHz) δ 7.14 (dd, J = 3.5, 9.0 Hz, IH), 8.63 (m, IH), 9.15 (d, J =
1.6 Hz, IH).
136b. 5-amino-2-fluoropyridine
2-Fluoro-5-nitropyridine from step 136a above (54.1 g, 379), 62.6 g) was combined with 10% Pd/C (1 g) in EtOH (1.4 L) and the mixture was stirred under H2 (4 atm, 3 h). After filtration, the crude product was combined with that from a similar run (441 mmol) and chromatographed (sUica gel; 100% hexane to 50:50 hexane/EtOAc gradient) to afford 74.1 g (81%) of a sohd. This material was recrystaUized from EtOAc to afford the title compound (67 g, 72%): !H NMR (DMSO-dβ, 300 MHz) δ 6.74 (dd, J = 3, 6 Hz, IH), 7.11 (m, IH), 7.26 (t, J = 1 Hz, IH); MS (DCI NH3) m/z: 113 (M+H)+, 130 (M+NH4 )+.
136c 5 -diazonium-2-fluoropyridine tetrafluoroborate
5-Amino-2-fluoropyridine from step 136b above (45.5 g, 406 mmol) was dissolved in DME (200 mL) and cooled to -10 °C under an atmosphere of nitrogen. Boron trifluoride etherate (100 mL, 812 mmol) was added dropwise. Then a solution of tert-butyl nitrite (51.0 mL, 490 mmol) in CH2CI2 (50 mL) was added at a rate which maintained the internal reaction temperature below 0 °C. After 20 minutes at -10 °C, pentane (250 ml) was added to aid stirring, foUowed by an additional portion of pentane (250 ml) after 20 minutes. The solid was coUected by suction filtration, washed with pentane (2 x 250 mL) and ether (4 x 100 mL), and air dried to afford 83.6 g (98%) of the title compound which was immediately used without further purification.
136d. 5-acetoxy-2-fluoropyridine
The diazonium salt from step 136c above (83.6 g) was suspended in acetic anhydride (500 mL) and quickly warmed to 110 °C ± 5 °C until nitrogen evolution became minimal (approximately 1 hour). The solvent was removed in vacuo with a rotary evaporator (bath temperature 70 °C) and the residue was dUuted with Et2θ (1 L) and saturated aqueous Na2CO3 (300 mL). The layers were separated and the aqueous phase was extracted with Et2θ (4 x 500 mL). The combined ethereal extracts were dried (MgSO4) and concentrated. Purification by chromatography (sitica gel; hexane/EtOAc, 95:5 to 70:30) afforded the title compound (24 g, 38%): lH NMR (CDCI3 300 MHz) δ 2.32 (s, 3H), 6.96 (dd, J = 3, 9 Hz, IH), 7.59 (m, IH), 8.03 (dd, J = 0.5, 1 Hz, IH); MS (DCI/NH3) m/z: 156 (M+H)+, 171 (M+NH4)+.
136e. 2-fluoro-5-hydroxypyridine
5-Acetoxy-2-fluoropyridine (70.5 g, 454 mmol) from step 136d above was suspended in 20% aqueous NaOH (200 mL) at 0 °C and stirred at ambient temperature overnight. The solution was neuttahzed (pH ~6) by the addition of concentrated HCl. The aqueous mixture was extracted with EtOAc (5 x 200 mL), then the combined organic extracts were dried (MgSO4), and concentrated to afford 47.9 g (93%) of a solid. The crude product was recrystaUized from EtOAc to afford the title compound as a white solid (30.5 g, 59% ). The 2nd and 3rd crops were combined and recrystaUized to afford an additional 9.3 g (18%) of the title compound: JH NMR (CDCI3, 300 MHz) δ 6.84 (dd, J = 1.9, 5.1 Hz, IH), 7.43 (m, 1 ' H), 7.81 (t, J = 2.8 Hz, IH); MS m/z: 114 (M+H)+, 131 (M+NH4)+. 136f. 6-fluoro-2-iodo-3-pyridinol
The title compound was prepared from 2-fluoro-5-hydroxypyridine (from step 136e above) according to the procedures of step 28d above: 1H NMR (DMSO-dβ, 300 MHz) δ
7.03 (dd, J = 3.9, 8.7 Hz, IH), 7.30 (dd, J = 7.0, 8.6 Hz, IH), 10.81 (br s, IH); MS 5 m/z: 240 (M+H)+, 257 (M+NH4)+.
136g. (±)-2-(7-aza-7-(tert-butoxycarbonyl)-2-e o-bicyclol2.2.nheptyl -5-fluorofuro[3.2- blpyridine
Figure imgf000110_0001
o 6-Fluoro-2-iodo-3-pyridinol (860 mg, 3.60 mmol) from step 136f, copper(I) iodide
(103 mg, 0.540 mmol), bis(triphenylphosphine)palladium(II) chloride (126 mg, 0.180 mmol) and triethylamine (552 mL, 3.96 mmol) were combined in DMF (6 mL) and allowed to stir for 1 hour. A solution of (±)-7-(tert-butoxycarbonyl)-2-erø-ethynyl-7- azabicyclo[2.2.1]heptane (796 mg, 3.60 mmol), from step 52d above, in DMF (1 mL) was 5 added and the reaction mixture was heated at 80 °C for 14 hours. After coohng to ambient temperature, the mixture was dUuted with Et2θ and washed with saturated aqueous NaHCO3 and brine. The organic extract was dried (MgSO4), concentrated and purified by chromatography (sUica gel; MeOH/CH2θ2, 2:98 to 5:95) to afford the title compound as a white solid (277 mg, 23%): mp 96-98 °C; 1H NMR (CDC13, 300 MHz) δ 1.29 (br s, 9H), 0 1.40-1.65 (m, 2H), 1.80-2.00 (m, 3H), 2.10 (m, IH), 3.13 (dd, J = 5.1, 8.8 Hz, IH), 4.42 (br s, IH), 4.49 (br s, 1 H), 6.55 (s, IH), 6.76 (dd, J = 1.5, 8.7 Hz, IH), 7.71 (m, IH); MS (CI/NH3) m/z: 333 (M + H)+.
136h. (±)-2-(7-aza-2-e.to-bicvclor2.2.11heptvn-5-fluorofuror3.2-blpyridine 5
Figure imgf000110_0002
The compound from step 136g above (245 mg, 0.737 mmol) was dissolved in 1:1 CH2CI2/TFA (6 mL) and stirred at ambient temperature for 30 minutes. The solvent was removed in vacuo and the residue was partitioned between CH2CI2 and saturated aqueous 0 K2CO3. The organic extract was dried (Na2SO4) and concentrated. The crude product was chromatographed (sihca gel; CHCl3/MeOH, 90:10) to afford the title compound as a white solid (153 mg, 89%): mp 104-106 °C; 1H NMR (CDCI3, 300 MHz) δ 1.40-1.56 (m, 2H), 1.67-1.78 (m, 2H), 1.85 (m, IH), 1.98 (m, IH), 2.11 (br s, IH), 3.10 (dd, J = 5.1, 8.8 Hz, IH), 3.83-3.86 (m, 2H), 6.52 (m, IH), 6.75 (dd, J = 1.7, 8.8 Hz, IH), 7.72 (ddd, J = 0.8, 6.4, 7.3 Hz, IH); MS (CI/NH3) m/z: 233 (M + H)+.
Figure imgf000111_0001
The compound from step 136h above (144 mg, 0.620 mmol) was slu ied in Et2θ and a saturated solution of HCl in Et2θ was added dropwise. The solvent was removed and the precipitate was triturated with Et2θ and then placed under vacuum to afford the title compound as white sohd (160 mg, 96%): mp >260 °C; 1H NMR (D2O, 300 MHz) δ 1.93- 2.15 (m, 4H), 2.27-2.50 (m, 2H), 3.68 (m, IH), 4.45 (br s, IH), 4.60 (m, IH), 6.80 (br s, IH), 7.00 (br d, J = 8.8 Hz, IH), 8.03 (m, IH); MS (CI/NH3) m/z: 233 (M+H)+; Anal. Calcd for Cι3Hi4FN2O-HCl: C, 58.11 H, 5.25; N, 10.42. Found: C, 57.95; H, 4.95; N, 10.23. The prefened compounds are those designated as Examples 15, 23, 26, 55 and 58 which are the most potent binders to the nicotinic acetylcholine receptor. The prefened use of compounds of the invention is as a nicotinic acethycholine receptor modulator as described herein. The prefened compounds, for the most part, have a chlorine at the 5- position of the moiety and, thus, the preferred class of compounds is directed thereto.

Claims

WE CLAIM:
1. A compound of formula (I):
Figure imgf000112_0001
(i) or a pharmaceuticaUy acceptable salt or pro-drug thereof wherein:
A is selected from the group consisting of:
Figure imgf000112_0002
wherein
* denotes a chiral center, n is 1, 2 or 3,
R1 is selected from the group consisting of H, aUyl and Cι-C3-alkyl;
R2 is selected from the group consisting of H,
Cι-C3-alkyl, Cι-C3-alkoxyl, hydroxymethyl, fluoromethyl, methoxymethyl, and, R2 when substituted at a position other than alpha to the ring nitrogen atom is selected from Br, Cl, F, OH, CN, -O-CO-CH3 and -O-methanesulfonyl;
(b)
Figure imgf000112_0003
(C)
Figure imgf000113_0001
wherein p and q are independently 1 or 2;
( )
Figure imgf000113_0002
wherein p and q are independently 1 or 2;
(e)
Figure imgf000113_0003
(f)
R1
I
Figure imgf000113_0004
R is independently selected at each occunence from the group consisting of
Cι-C4-alkyl, vinyl, bromo, chloro, fluoro, trifluoro-C ι -C4-aU yl, trichloro-Cι-C4-alkyl,
COOH,
CO2-Ci-C4-alkyl, CN, nitro, 50 amino, hydroxy,
NH-CO-Cι-C3-alkyl, and
NR R3, wherein R3 is H or Cι-C3-alkyl; or, when substituted at the Y-2 position R can additionally be selected 55 from:
NR R4, wherein R3 is H or C1-C3 alkyl and R4 is hydrogen, Ci-Cδ-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, substituted-phenyl-Cι-C6-alkyl-, 60 heteroaryl-Cι-C6-alkyl-, and substituted-heteroaryl-Cι-C6-alkyl-;
C(O)-R5< where R5 is hydrogen, Ci-Cg-alkyl, substituted-Ci-Cg-alkyl, phenyl, substituted-phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Ci-Cό-alkyl-, substituted-phenyl-Cι-C6-alkyl-, 65 heteroaryl-Cι-C6-alkyl-, substituted-heteroaryl-Cι-C6-alkyl-, and
O-Cι-C6-alkyl-, N-R6R7, wherein R6 is selected from the group consisting of H and Cι-C3-alkyl-, and R7 is selected from the group consisting of H, Cι-C3-alkyl-, phenyl and substituted-phenyl;
OR8, wherein R8 is Ci-Cs-alkyl, phenyl, substituted-phenyl, 70 heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6-alkyl-, CONR3R4; phenyl; naphthyl; 75 substituted-phenyl; substituted-naphthyl; biphenyl; substituted-biphenyl; heteroaryl; 80 substituted-heteroaryl; phenyl-Ci-Cό-alkyl-; substituted-phenyl-Ci-Cβ-alkyl-; heteroaryl-Cι-C6-alkyl-; and substituted-heteroaryl-Cι-C6-alkyl-; 5 =----= — R9 , wherein R9 is selected from the group consisting of hydrogen, Ci-Cs-alkyl, substituted-Ci-Cs-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6-alkyl-, and o substituted-heteroaryl-C i -C6-alkyl-;
Λ- J m , wherein m is 1 or 2, and R9 is as defined above;
-CH2-NH-CO-R-5, wherein R5 is as defined above; and -CH2-CH2-CO-O-Cι-C6-alkyl; 5
X is -O-, -S- or -NR3, wherein R3 is H or Cι-C3-alkyl; m on formula (I) is 0, 1, 2 or 3;
Y1, Y2 and Y3 are N or CH, with the provisos that at least one of Y1, Y2 and Y3 must be N and, 0 when group A is selected from option (b), except for those compounds additionaUy substituted at Y^ above, then Y2 and Y3 must be CH.
2. A compound according to claim 1 of the formula:
Figure imgf000115_0001
or a pharmaceuticaUy acceptable salt or pro-drug thereof wherein:
A is selected from the group consisting of:
Figure imgf000115_0002
o wherein * denotes a chiral center, m is 0, 1 or 2; n is 1, 2 or 3,
R1 is selected from the group consisting of H and 15 Cι-C3-alkyl, and
R2 is H, or when n is 2 or 3 is selected from the group consisting of Cι-C3-aIkyl, Cι-C3-alkoxyl, 20 hydroxymethyl, fluoromethyl, methoxymethyl, or at a position other than alpha to the nitrogen may additionaUy be selected from, Br, 25 Cl,
F, OH, CN,
-O-CO-CH3 and 30 -O-methanesulfonyl;
(b)
(c)
Figure imgf000116_0001
35 wherein p and q are independently 1 or 2;
(d)
Figure imgf000116_0002
wherein p and q are independently 1 or 2;
(e)
Figure imgf000117_0001
(f)
R1
I
Figure imgf000117_0002
R is independently selected at each occurrence from the group consisting of
Ci- -alkyl, bromo, chloro, fluoro, trifluoro-C i -C4-alkyl, trichloro-Cι-C4-alkyl,
COOH,
CO2-Cι-C4-alkyl,
CN, nitro, amino,
NH-CO-Cι-C -alkyl, and
NR R3, wherein R3 is H or Cι-C3-alkyl;
X is -O-, -S- or -NR3, wherein R3 is H or Cι-C3-alkyl;
Y1, Y2 and Y3 are N or CH, with the provisos that at least one of Y1, Y2 and Y3 must be N and when group A is selected from option (b), then Y2 and Y3 must be CH.
3. A compound according to claim 1 of formula (EH):
Figure imgf000118_0001
or a pharmaceuticaUy acceptable salt or pro-drug thereof wherein:
A is selected from the group consisting of:
Figure imgf000118_0002
o wherein
* denotes a chiral center, n is 1, 2 or 3,
R1 is selected from the group consisting of H, aUyl and
Cι-C3-alkyl; 5 R2 is selected from the group consisting of
H,
Cι-C3-alkyl,
Cι-C3-alkoxyl, hydroxy methyl, 0 fluoromethyl, methoxymethyl, and, R2 when substituted at a position other than alpha to the ring nitrogen atom is selected from
Br, Cl, F, OH, CN, -O-CO-CH3 and
-O-methanesulfonyl; 5 (b)
Figure imgf000118_0003
(C)
Figure imgf000119_0001
wherein p and q are independently 1 or 2;
(d)
Figure imgf000119_0002
wherein p and q are independently 1 or 2;
(e)
Figure imgf000119_0003
(f)
R1
I
Figure imgf000119_0004
R is independently selected at each occunence from the group consisting of
Cι-C4-alkyl, vinyl, bromo, chloro, fluoro, trifluoro-C i -C4-alkyl, trichloro-Cι-C4-alkyl,
COOH,
CO2-Ci-C4-alkyl, CN, nitro, 50 amino, hydroxy,
NH-CO-Cι-C3-alkyl, and
NR R3, wherein R3 is H or Cι-C3-alkyl; and, at the Y2 position, R can additionally be selected from: 55 NR R4, wherein R3 is H or C1-C3 alkyl and R4 is hydrogen,
Ci-Cg-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6- alkyl-, and substituted-heteroaryl-Cι-C6-aUcyl-; 60 C(O)-R5 ' where R-5 is hydrogen, Ci-Cg-alkyl, substituted-Cι-C8- alkyl, phenyl, substituted-phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6- alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6-alkyl-, substituted-heteroaryl-Cι-C6-alkyl-, and 65 O-Cι-C6-alkyl-, N-R6R7, wherein R6 is selected from the group consisting of H and Cι-C3-alkyl-, and R7 is selected from the group consisting of H, Cι-C3-alkyl-, phenyl and substituted-phenyl;
OR8, wherein R8 is Ci-Cs-alkyl, phenyl, substituted-phenyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, 70 substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6-alkyl-,
CONR3R4; phenyl; naphthyl; substituted-phenyl; 75 substituted-naphthyl; biphenyl; substituted-biphenyl; heteroaryl; substituted-heteroaryl; 80 phenyl-Cι-C6-alkyl-; substituted-phenyl-Cι-C6-alkyl-; heteroaryl-Cι-C6-alkyl-; and substituted-heteroaryl-Cι-C6-alkyl-; = — R9 , wherein R9 is selected from the group consisting of hydrogen, Ci-Cs-alkyl, substituted-Ci-Cs-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6-a!kyl-, and substituted-heteroaryl-C i -Ce-alkyl-;
- mRO , wherein m is 1 or 2, and Ry is as defined above;
-CH2-NH-CO-R-5, wherein R5 is as defined above; and -CH2-CH2-CO-O-Cι-C6-alkyl;
X is -O-, -S- or -NR3, wherein R3 is H or Cι-C3-alkyl; m is 0, 1 or 2;
Y1, Y2 and Y3 are N or CH, with the provisos that at least one of Y1, Y2 and Y3 must be N and, when group A is selected from option (b), except for those compounds additionaUy substituted at Y2 above, then Y2 and Y3 must be CH.
4. A compound according to claim 3 of formula (HI):
Figure imgf000121_0001
or a pharmaceuticaUy acceptable salt or pro-drug thereof wherein:
A is selected from the group consisting of:
Figure imgf000121_0002
o wherein * denotes a chiral center, n is 1, 2 or 3,
R1 is selected from the group consisting of H, aUyl and Cι-C3-alkyl; 15 R2 is selected from the group consisting of
H,
Cι-C3-alkyl,
Cι-C3-alkoxyl, hydroxymethyl, 20 fluoromethyl, methoxymethyl, and, R2 when substituted at a position other than alpha to the ring nitrogen atom is selected from Br, Cl,
F, OH, CN, -O-CO-CH3 and
-O-methanesulfonyl;
25 (b)
(c)
Figure imgf000122_0001
wherein p and q are independently 1 or 2;
30 (d)
Figure imgf000122_0002
wherein p and q are independently 1 or 2; (e)
Figure imgf000123_0001
(f)
R1
I
Figure imgf000123_0002
R is independently selected at each occunence from the group consisting of
Cι-C4-alkyl, vinyl, bromo, chloro, fluoro, trifluoro-C i -C4-alkyl, trichloro-Cι-C4-alkyl,
COOH,
CO2-Ci-C4-alkyl,
CN, nitro, amino, hydroxy,
NH-CO-C1-C3-alkyl, and
NR R3, wherein R3 is H or Cι-C3-alkyl; and, at the Y2 position, R can additionally be selected from:
NR3R4, wherein R3 is H or C1-C3 alkyl and R4 is hydrogen, Ci-Cs-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-C i -Cg-alkyl-, substituted-phenyl-C i -C - alkyl-, heteroaryl-Cι-C6-alkyl-, and substituted-heteroaryl-Ci-Cβ-alkyl-; 60 C(O)-R5> where R5 is hydrogen, Ci-Cs-alkyl, substituted-Cι-C8-alkyl, phenyl, substituted-phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6-alkyl-, substituted-heteroaryl-Cι-C6-alkyl-, and
65 O-Cι-C6-alkyl-, N-R6R7, wherein R6 is selected from the group consisting of H and Cι-C3-alkyl-, and R7 is selected from the group consisting of H, Cι-C3-alkyl-, phenyl and substituted-phenyl;
OR8, wherein R8 is Ci-Cs-alkyl, phenyl, substituted-phenyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-,
70 substituted-phenyl-Cι-C6-alkyl-, heteroaryl-Cι-C6-alkyl-,
CONR3R4; phenyl; naphthyl; substituted-phenyl; 75 substituted-naphthyl; biphenyl; substituted-biphenyl; heteroaryl; substituted-heteroaryl; 80 phenyl-Cι-C6-alkyl-; substituted-phenyl-Cι-C6-alkyl-; heteroaryl-Cι-C6-alkyl-; and substituted-heteroaryl-Cι-C6-alkyl-; -= R9 , wherein R9 is selected from the group
85 consisting of hydrogen, Ci-Cs-alkyl, substituted-Ci-Cs-alkyl, phenyl, substituted-phenyl, naphthyl, substituted-naphthyl, heteroaryl, substituted-heteroaryl, phenyl-Cι-C6-alkyl-, substituted-phenyl-Ci-Cβ-alkyl-, heteroaryl-Cι-C6-alkyl-, and substituted-heteroaryl-Cι-C6-alkyl-;
90 m , wherein m is 1 or 2, and R9 is as defined above;
-CH2-NH-CO-R5, wherein R5 is as defined above; and -CH2-CH2-CO-O-Cι-C6-alkyl;
95 X is -O-, -S- or -NR3, wherein R3 is H or Cι-C3-alkyl; m on formula (IH) is 0 or 1; Y1, Y2 and Y3 are N or CH, with the provisos that at least one of Y1, Y2 and Y3 must be N.
5. A compound as defined by Claim 1 having the formula
Figure imgf000125_0001
or a pharmaceutically acceptable salt or pro-drug thereof wherein X, A, R and m are as defined therein.
6. A compound as defined by Claim 5 wherein A is selected from the group consisting of
Figure imgf000125_0002
R1
I
Figure imgf000125_0003
or a pharmaceutically acceptable salt or pro-drug thereof.
7. A compound as defined by Claim 6 wherein Rm is at the position designated as Y2 in formula I and is selected from phenyl, 4-pyridyl-2-ethenyl, pyridyl and benzoylaminomethyl.
8. A compound defined by Claim 1 or 2 wherein R is selected from the group consisting of Cl and Cι-C4-alkyl or m is equal to 0 or a pharmaceuticaUy acceptable salt or pro-drug thereof.
9. A compound as defined by Claim 1 selected from the group consisting of 2- ( 1 -methy 1-2- (S )-pynohdinyl)f ur o [3 ,2-b]pyridine; -(2-(S)-pynohdinyl)furo[3,2-b]pyridine;
2-(2-(R)-pyrroUdinyl)furo[3,2-b]pyridine; 2-( 1 -methyl-2-(R)-pynohdinyl)furo[3,2-b]pyridine;
5-methyl-2-(2-(S)-pyrroUdinyl)furo[3,2-b]pyridine;
2-( 1 -methyl- 2-(S)-pyrrolidinyl)-5-methylfuro[3,2-b]pyridine;
6-chloro-2-(2-(S)-pynolidinyl)furo[3,2-b]pyridine;
6-chloro-2-(l-methyl-2-(S)-pynolidinyl)furo[3,2-b]pyridine; 2-(2-(S)-pyrrolidinyl)furo[2,3-c]pyridine;
2-(l-methyl-2-(S)-pyrrolidinyl)furo[2,3-c]pyridine;
5-chloro-2-(2-(S)-pyτrolidinyl)furo[3,2-b]pyridine;
5-chloro-2-(l-methyl-2-(S)-pynolidinyl)furo[3,2-b]pyridine;
5-chloro-2-(2-(S)-pynolidinyl)furo[2,3-b]pyridine; 5-chloro-2-(l-methyl-2-(S)-pyrroUdinyl)-furo[2,3-b]pyridine;
2-(hexahydro-lH-7a-pynolizinyl)furo[3,2-b]pyridine;
2-(hexahydro-lH-7a-pyrrohzinyl)-5-methylfuro[3,2-b]pyridine;
2-(hexahydro-lH-7a-pynohzinyl)furo[2,3-c]pyridine; endø-2-(hexahydro-lH-3-(R)-pyrcohzinyl)furo[2,3-c]pyridine; exo-2-(hexahydro-lH-3-(S)-pynolizinyl)furo[2,3-c]pyridine; exo-2-(hexahydro-lH-3-(R)-pynohzinyl)furo[2,3-c]pyridine; e/ιdo-2-(hexahydro-lH-3-(S)-pyrrolizinyl)furo[2,3-c]pyridine;
2-( 1 -pyrrohdinylmethyl)furo(3,2-b) pyridine;
5-chloro-2-(hexahydro-lH-7a-pynolizinyl)furo[3,2-b]pyridine; 2-(hexahydro- lH-7a-pynohzinyl)thieno[3,2-b]pyridine;
5,6-dichloro-2-(2-(S)-pyrrolidinyl)furo[3,2-b]pyridine;
5,6-dichloro-2-(l-methyl-2-(S)-pyrrolidinyl)furo[3,2-b]pyridine;
2-(hexahydro-lH-7a-pynolizinyl)-4-methylthieno[3,2-b]pyridine;
5-bromo-2-(2-(S)-pyrrolidinyl) furo[3,2-b]pyridine; 5-methyl-2-(2-(R)-pynoUdinyl)furo[3,2-b]pyridine;
2-(l-methyl-2-(R)-pynolidinyl)-5-methylfuro[3,2-b]pyridine;
6-chloro-2-(2-(R)-pyrrohdinyl)furo[3,2-b]pyridine;
5-chloro-2-( 1 -methyl- 2-(R)-pynolidinyl) furo[3,2-b]pyridine;
5-bromo-2-(2-(R)-pyrrolidinyl) furo[3,2-b]pyridine; 2-(2-(R)-pynolidinyl)furo[2,3-c]pyridine;
5-chloro-2-(2-(R)-pyrrohdinyl)furo[3,2-b]pyridine;
2- (2- (S )-pynohdinyl)furo [2,3-b]pyridine;
2-(l-methyl-2-(S)-pynolidinyl)furo[3,2-c]pyridine;
5,6-dichloro-2-(hexahydro-lH-7a-pynolizinyl)-furo[3,2-b]pyridine; 5,6-dichloro-2-(2-(R)-pynolidinyl)furo[3,2-b]pyridine;
5,6-dichloro-2-(l-methyl-2-(R)-pyrrohdinyl)furo[3,2-b]pyridine;
2-((lR,4S)-2-aza-3-(S)-bicyclo[2.2.1]heptyl) furo[3,2-b]pyridine;
2-((lR,4S)-2-aza-3-(S)-bicyclo[2.2.1]heptyl)-2-methylfuro[3,2-b]pyridine;
2-((lR,4S)-2-aza-3-(S)-bicyclo[2.2.1]heptyl)-5-chlorofuro[3,2-b]pyridine; 2-((lR,4S)-2-aza-2-methyl-3-(S)-bicyclo[2.2. l]heptyl)-5-chloro furo[3,2- b]pyridine;
2-((lR,4S)-2-aza-3-(S)-bicyclo[2.2.1]heptyl)-5,6-dichloro furo[3,2-b]pyridine;
6-bromo-2-(2-(S)-pyrrolidinyl)furo[3,2-b]pyridine;
6-bromo-2-(l-methyl-2-(S)-pyrrolidinyl)furo[3,2-b]pyridine; 6-bromo-5-chloro-2-(l-methyl-2-(S)-pyrrohdinyl)furo[3,2-b]pyridine;
6-bromo-5-chloro-2-(2-(R)-pyrrolidinyl)furo[3,2-b]pyridine;
6-bromo-5-chloro-2-(l-methyl-2-(R)-pynolidinyl)furo[3,2-b]pyridine;
7-chloro-2-(l-methyl-2-(S)-pyrrolidinyl)furo[3,2-b]pyridine;
(±)-2-(7-aza-2-exo-bicyclo[2.2.1]heptyl)furo[3,2-b]pyridine; 2-( 1 -methyl-2-(S )-pynohdinyl)furo(2,3-b)pyridine hydrochloride;
(±)-2-(7-aza-2-exo-bicyclo(2.2.1)heptyl)-5-chlorofuro(3,2-b)pyridine hydrochloride;
(±)-2-aza-2-exo-bicyclo(2.2.1)heptyl)-5-fluorofuro(3,2-b)pyridine hydrochloride;
6-phenyl-2-((S)-pyrrolidinyl)furo[3,2-b]pyridine dihydrochloride; 6-phenyl-2-(l-methyl-2-(S)-pynolidinyl)furo[3,2-b]pyridine dihydrochloride;
5-chloro-6-phenyl-2-(2-(R)-pyrrohdinyl)furo(3,2-b)pyridine hydrochloride;
5-chloro-2-( 1 -methyl-2-(R)-pynohdinyl)-6-phenylfuro(3,2-b)pyridine hydrochloride;
(3-aminophenyl)-5-chloro-2-(2-(R)-pyrrolidinyl)-6-furo(3,2-b)pyridine hydrochloride;
5-chloro-2-(2-(R)-pyrrohdinyl)-6-(4-vinylpyridyl)-furo(3,2-b)pyridine hydrochloride; and
5-chloro-2-(l-methyl-2-(S)-pyrrolidinyl)-6-(3-pyridyl)-furo(3,2-b)pyridine hydrochloride or a pharmaceuticaUy acceptable salt or prodrug thereof.
10. A compound as defined by Claim 6 selected from the group consisting of
2-(l-methyl-2-(S)-pynohdinyl)furo[3,2-b]pyridine; 2-(2-(S)-pynohdinyl)furo[3,2-b]pyridine; 2-(2-(R)-pynohdinyl)furo[3,2-b]pyridine; 2-( 1 -methyl-2-(R)-pynohdinyl)furo[3,2-b]pyridine;
5 -methyl- 2- (2- (S )-pynohdinyl)f uro [3 ,2-b]pyridine;
2-( 1 -methyl- 2-(S)-pynolidinyl)-5-methylfuro[3,2-b]pyridine;
6-chloro-2-(2-(S)-pynolidinyl) furo[3,2-b]pyridine; 6-chloro-2-(l-methyl-2-(S)-pynohdinyl) furo[3,2-b]pyridine;
5-chloro-2-(2-(S)-pynolidinyl) furo[3,2-b]pyridine;
5-chloro-2-(l-methyl-2-(S)-pyrrohdinyl) furo[3,2-b]pyridine;
5-chloro-2-(hexahydro- lH-7a-pyrrolizinyl) furo[3,2-b]pyridine;
2-(hexahydro-lH-7a-pyrrohzinyl)thieno[3,2-b]pyridine; 5,6-dichloro-2-(2-(S)-pyrrolidinyl) furo[3,2-b]pyridine;
5,6-dichloro-2-(l-methyl-2-(S)-pynolidinyl) furo[3,2-b]pyridine;
2-(hexahydro-lH-7a-pynolizinyl)-4-methylthieno[3,2-b]pyridine;
5-bromo-2-(2-(S)-pyrrolidinyl) furo[3,2-b]pyridine;
5-methyl -2-(2-(R)-pynolidinyl)-furo[3,2-b]pyridine; 2-(l-methyl-2-(R)-pynolidinyl)-5-methyl furo[3,2-b]pyridine;
6-chloro-2-(2-(R)-pyrrolidinyl) furo[3,2-b]pyridine;
5-chloro-2-( 1 -methyl- 2-(R)-pynolidinyl) furo[3,2-b]pyridine;
5-bromo-2-(2-(R)-pynolidinyl) furo[3,2-b]pyridine;
2-(2-(R)-pynolidinyl)-5-chlorofuro[3,2-b]pyridine; 2- (hexahydro- 1 H-7a-pynolizinyl)- 5 ,6-dichlorofuro[3 ,2-b] pyridine;
5,6-dichloro-2-(2-(R)-pyrrolidinyl)furo[3,2-b]pyridine;
5,6-dichloro-2-(l-methyl-2-(R)-pyrrohdinyl)furo[3,2-b]pyridine;
6-bromo-2-(2-(S)-pyrrolidinyl)furo[3,2-b]pyridine;
6-bromo-2-(l-methyl-2-(S)-pynolidinyl)furo[3,2-b]pyridine; 6-bromo-5-chloro-2-(l-methyl-2-(S)-pyrrohdinyl)furo[3,2-b]pyridine;
6-bromo-5-chloro-2-(2-(R)-pynolidinyl)furo[3,2-b]pyridine;
6-bromo-5-chloro-2-(l-methyl-2-(R)-pyrrolidinyl)furo[3,2-b]pyridine;
7-chloro-2-(l-methyl-2-(S)-pynolidinyl)furo[3,2-b]pyridine;
(±)-2-(7-aza-2-exo-bicyclo[2.2. l]heptyl)furo[3,2-b]pyridine; and 2-((lR,4S)-2-aza-2-methyl-3-(S)-bicyclo[2.2.1]heptyl)furo[3,2-b]pyridine; or
a pharmaceuticaUy acceptable salt or prodrug thereof.
1. A compound as defined by Claim 8 selected from the group consisting of
2-(l-methyl-2-(S)-pynohdinyl)furo[3,2-b]pyridine; 2-(2-(S)-pynohdinyl)furo[3,2-b]pyridine; 5 2-(2-(R)-pynohdinyl)furo[3,2-b]pyridine;
2-( 1 -methyl-2-(R)-pynohdinyl)furo[3,2-b]pyridine;
5-methyl-2-(2-(S)-pynohdinyl)furo[3,2-b]pyridine;
2-( 1 -methyl- 2-(S)-pyrrolidinyl)-5-methylfuro[3,2-b]pyridine;
6-chloro-2-(2-(S)-pyrrolidinyl)furo[3,2-b]pyridine; o 6-chloro-2-(l-methyl-2-(S)-pyrrolidinyl)furo[3,2-b]pyridine;
5-chloro-2-(2-(S)-pyrrolidinyl)furo[3,2-b]pyridine;
5-chloro-2-( 1 -methyl-2-(S)-pyrrolidinyl)furo[3,2-b]pyridine;
5-chloro-2-(hexahydro-lH-7a-pyrrolizinyl)furo[3,2-b]pyridine;
5,6-dichloro-2-(2-(S)-pyrrolidinyl)furo[3,2-b]pyridine; 5 5,6-dichloro-2-(l -methyl-2-(S)-pyrrolidinyl)furo[3,2-b]pyridine;
5-methyl2-(2-(R)-pynolidinyl)furo[3,2-b]pyridine;
2-(l-methyl-2-(R)-pynolidinyl)-5-methylfuro[3,2-b]pyridine;
6-chloro-2-(2-(R)-pynohdinyl)furo[3,2-b]pyridine;
5-chloro2- ( 1 -methy l-2-(R)-pyrrohdiny l)furo [3 ,2- b] pyridine; 0 5-chloro-2-(2-(R)-pyrrolidinyl)-furo[3,2-b]pyridine;
5 ,6-dichloro-2-(hexahydro- 1 H-7a-pynohzinyl)furo[3 ,2-b]pyridine;
5,6-dichloro-2-(2-(R)-pyrrolidinyl)furo[3,2-b]pyridine;
5,6-dichloro-2-(l-methyl-2-(R)-pynohdinyl)furo[3,2-b]pyridine;
7-chloro-2-(l-methyl-2-(S)-pyrrolidinyl)furo[3,2-b]pyridine; 5 6-bromo-2-(2-(S)-pyrrolidinyl)furo[3,2-b]pyridine;
6-bromo-2-(l-methyl-2-(S)-pyrrolidinyl)furo[3,2-b]pyridine;
6-bromo-5 -chloro-2- ( 1 -methyl-2- (S )-pynohdiny l)f uro [3 ,2-b] pyridine;
6-bromo-5-chloro-2-(2-(R)-pyrrolidinyl)furo[3,2-b]pyridine;
6-bromo-5-chloro-2-( 1 -methyl-2-(R)-pynolidinyl)furo[3,2-b]pyridine; 0 (±)-2-(7-aza-2-exo-bicyclo[2.2.1]heptyl)furo[3,2-b]pyridine; and
2-(( lR,4S)-2-aza-2-methyl-3-(S)-bicyclo[2.2. ljheptyl) f uro [3, 2-b] pyridine; or
a pharmaceuticaUy acceptable salt or prodrug thereof.
12. A compound according to claim 4 selected from the group consisting of 6-phenyl-2-((S)-pynolidinyl)furo[3,2-b]pyridine dihydrochloride; 2-(l-methyl-2-(S)-pyrrolidinyl)-6-phenylfuro[3,2-b]pyridine dihydrochloride; 5-chloro-6-phenyl-2-(2-(R)-pyπOhdinyl)furo[3,2-b]pyridine hydrochloride; 5 5-chloro-6-phenyl-2-(l-methyl-2-(R)-pyrrohdinyl)furo[3,2-b]pyridine hydrochloride; 6-(3-aminophenyl)-5-chloro-2-(2-(R)-pynoUdinyl)-furo[3,2-b]pyridine hydrochloride;
5-chloro-2-(2-(R)-pynolidinyl)-6-(4-pyridyl-2-ethenyl)furo[3,2-b]pyridine o hydrochloride; and
5-chloro-2-(l-methyl-2-(S)-pyrrolidinyl)-6-(3-pyridyl)-furo[3,2-b]pyridine hydrochloride or a pharmaceuticaUy acceptable salt or prodrug thereof.
13. A pharmaceutical composition comprising a pharmaceuticaUy effective amount of a compound according to claim 1 or 2 in combination with a pharmaceutically acceptable carrier.
14. A method of modulating chemical synaptic transmission in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound as defined by Claim 1 or 2.
PCT/US1998/007128 1997-04-11 1998-04-10 Furopyridine, thienopyridine, pyrrolopyridine and related pyrimidine, pyridazine and triazine compounds useful in controlling chemical synaptic transmission WO1998046609A1 (en)

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