[go: up one dir, main page]

WO2012088402A1 - Synthèse de la conolidine et découverte d'un analgésique non opioïde puissant pour la douleur - Google Patents

Synthèse de la conolidine et découverte d'un analgésique non opioïde puissant pour la douleur Download PDF

Info

Publication number
WO2012088402A1
WO2012088402A1 PCT/US2011/066810 US2011066810W WO2012088402A1 WO 2012088402 A1 WO2012088402 A1 WO 2012088402A1 US 2011066810 W US2011066810 W US 2011066810W WO 2012088402 A1 WO2012088402 A1 WO 2012088402A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
heteroatom
aryl
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2011/066810
Other languages
English (en)
Inventor
Laura M. Bohn
Glenn C. MICALIZIO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Scripps Research Institute
Original Assignee
Scripps Research Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scripps Research Institute filed Critical Scripps Research Institute
Publication of WO2012088402A1 publication Critical patent/WO2012088402A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems

Definitions

  • Embodiments of the invention comprise methods for synthesizing rare alkaloids, in particular C5-nor stemmadenine alkaloids. Further embodiments comprise novel synthetic alkaloids and uses in treatment of pain.
  • Figure 1 shows the chemical structure of C5-nor-stemmadenine (1) and stemmadenine (2-3) alkaloids.
  • Figures 2A and 2B are a schematic representation showing the development of a synthesis strategy for conolidine.
  • Figure 2A shows the biomimetic synthesis of vallesamine (5).
  • Figure 2B shows the retrosynthesis of conolidine.
  • H2SO4 salt (the compound employed in subsequent in vivo experiments).
  • PMB p- methoxybenzyl;
  • DCE 1 , 2-dichloroethane,
  • DCM dichloromethane.
  • ACE-C1 a-chloroethyl chloroformate.
  • FIGS 5A to 5F are graphs showing that conolidine is antinociceptive in visceral, tonic, and persistent pain models and is present at ⁇ levels in the brain after systemic injection.
  • Male adult C57BL/6 mice were treated with conolidine sulfate or vehicle (1 0% DMSO, i.p. 10 ⁇ -Vg) at the times indicated.
  • Figure 5A conolidine sulfate (10 or 20 mg/kg, i.p. of the indicated enantiomer) was injected 15 minutes prior to acetic acid (0.75% in H 2 0). Abdominal constrictions were recorded during the 30 minutes immediately following acetic acid injection.
  • Figure 5B formalin (25 ⁇ L ⁇ , 5%, in saline) was injected into the hind paw pad (intraplantar) 1 minutes after conolidine sulfate ( 10 mg/kg, i.p.); paw licking was recorded 40 minutes following formalin injection.
  • Phase 1 refers to the sum of time spent licking in the first 10 minutes of response and Phase 2 represents the 20-40 minute response period.
  • Figure 6 is a graph showing that conolidine's analgesic properties are not accompanied by central nervous system effects that impact locomotor activity.
  • FIG. 7 shows that conolidine leads to phosphorylation of Akt in primary dorsal root ganglion (DRG) cultures from adult mouse.
  • DRG primary dorsal root ganglion
  • Embodiments described herein are directed to methods for the synthesis of rare alkaloids and their use in the prevention or treatment of pain.
  • novel C5-nor stemmadenine compounds are described.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1 % of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term "about” meaning within an acceptable error range for the particular value should be assumed.
  • alkyl refers to an optionally substituted, saturated, straight or branched hydrocarbon having one or more carbon atoms (and all combinations and
  • _6 alkyl means a straight or branched alkyl containing at least 1 and at most 6 carbon atoms.
  • the alkyl is optionally substituted.
  • 1 or more of the hydrogen atoms on the alkyl group are substituted with a F, CI, Br, NH 2 , N0 2 , N 3 , CN, COOH, OH, etc.
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • cycloalkyi refers to an optionally substituted, mono-, di-, tri-, or other multicyclic alicyclic ring system having at least 3 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein).
  • C 3- 6 cycloalkyi means a mono- or bicyclic saturated ring structure containing at least 3 and at most 6 carbon atoms.
  • Multi-ring structures may be bridged or fused ring structures, wherein the additional groups fused or bridged to the cycloalkyi ring may include optionally substituted cycloalkyi, aryl, heterocycloalkyl, or heteroaryl rings.
  • Exemplary cycloalkyi groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, adamantyl, 2-[ 4-isopropyl-l -methyl-7-oxa-bicyclo[2.2.1 ]heptanyl], and 2-[l ,2,3,4-tetrahydro- naphthalenyl].
  • alkylcycloalkyl refers to an optionally substituted ring system comprising a cycloalkyi group substituted with one or more allyl substituents, wherein cycloalkyi and alkyl are each as previously defined.
  • exemplary alkylcycloalkyl groups include 2-methylcyclohexyl, 3,3-dimethylcyclopentyl, trans-2,3-dimethylcyclooctyl, and 4-methyl- decahydronaphthalenyl.
  • alkenyl as a group or a part of a group refers to an optionally substituted straight or branched hydrocarbon chain containing the specified number of carbon atoms and containing at least one double bond.
  • C 2 -6 alkenyl means a straight or branched alkenyl containing at least 2 and at most 10 carbon atoms and containing at least one double bond.
  • alkenyl groups of the invention may be optionally substituted and have at least 2 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein).
  • alkenyl as used herein include, but are not limited to, ethenyl, 2-propenyl, 3- butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-methylbut-2-enyl, 3-hexenyl and l , l -dimethylbut-2-enyl.
  • alkynyl as used herein as a group or a part of a group refers to an optionally substituted straight or branched hydrocarbon chain containing the specified number of carbon atoms and containing at least one triple bond.
  • C2-6 alkynyl means a straight or branched alkynyl containing at least 2, and at most 6, carbon atoms and containing at least one triple bond.
  • Multiple triple bonds may be conjugated or non-conjugated. In particular, multiple triple bonds are non-conjugated.
  • groups of the form -O-C2-6 alkynyl, the triple bond is preferably not adjacent to the oxygen.
  • the alkynyl groups of the invention may be optionally substituted and have from about 2 to about 10 (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein) carbon atoms, preferably 2 to 6 carbon atoms.
  • alkynyl as used herein include, but are not limited to, ethynyl, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyI, 3-pentynyl, 3-methyl- 2-butynyl, 3-methylbut-2-ynyl, 3-hexynyl and 1 , l -dimethylbut-2-ynyl.
  • aryl refers to an optionally substituted, mono-, di-, tri-, or other multicyclic aromatic ring system having from about 6 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), preferably with from about 6 to about 14 carbons, with about 6 to 10 carbon atoms being preferred.
  • Non-limiting examples include, for example, phenyl, naphthyl, anthracenyl, and phenanthrenyl.
  • Aryl may optionally be further fused to an aliphatic or aryl group or can be substituted with one or more substituents such as halogen (fluorine, chlorine and/or bromine), hydroxy, alkyl, alkoxy or aryloxy, amido, nitro, alkylenedioxy, alkylthio or arylthio,
  • alkylsulfonyl cyano, or primary, secondary or tertiary amino.
  • alkoxy refers to an optionally substituted straight or branched chain alkyl-O- group wherein alkyl is as previously defined.
  • C1.6 alkoxy means a straight or branched alkoxy containing at least 1 , and at most 6, carbon atoms.
  • alkoxy as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-l -oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy.
  • a C 1-4 alkoxy group comprises, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or 2-methylprop-2-oxy.
  • the alkyl moieties of the alkoxy groups have from about 1 to about 4 carbon atoms.
  • aryloxy refers to an optionally substituted aryl-O- group wherein aryl is as previously defined.
  • Exemplary aryloxy groups include, but are not limited to, phenoxy (phenyl-O-) and naphthoxy (naphthyl-O).
  • heteroaryl refers to an optionally substituted aryl ring system wherein, in at least one of the rings, one or more of the carbon atom ring members is
  • heteroaryl groups have a total of from about 5 to about 14 carbon atom ring members and heteroatom ring members (and all combinations and subcombinations of ranges and specific numbers of carbon and heteroatom ring members). Heteroaryl groups having a total of from about 5 to about 10 carbon atom ring members and heteroatom ring members (and all combinations and subcombinations of ranges and specific numbers of carbon and heteroatom ring members) are also preferred.
  • heteroaryl groups include, but are not limited to, pyrryl, furyl, pyridyl, pyridine-N-oxide, 1 ,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.
  • Heteroaryl may be attached to the rest of the. molecule via a carbon or a heteroatom.
  • heteroarylalkyl refers to an optionally substituted ring system comprising an alkyl radical bearing a heteroaryl substituent, each as defined above, having from about 6 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 6 to about 25 carbon atoms being preferred.
  • Non-limiting examples include 2-(l H-pyrrol-3-yl)ethyl, 3-pyridylmethyl, 5-(2H- tetrazolyl)methyl, and 3-(pyfimidin-2-yl)-2-methylcyclopentanyl.
  • heterocycloalkyl refers to an optionally substituted ring system composed of a cycloalkyl radical wherein, in at least one of the rings, one or more of the carbon atom ring members is independently replaced by a heteroatom group selected. From the group consisting of O, S, N, and NH, or NR wherein cycloalkyl is as previously defined and R is an optional substituent as defined herein.
  • Heterocycloalkyl ring systems having a total of from about 3 to about 14 carbon atom ring members and heteroatom ring members (and all combinations and subcombinations of ranges and specific numbers of carbon and heteroatom ring members).
  • the heterocyclic groups may be fused to one or more aromatic rings.
  • heterocycloalkyl moieties are attached via a ring carbon atom to the rest of the molecule.
  • heterocycloalkyl groups include, but are not limited to, azepanyl, tetrahydrofuranyl, hexahydropyrimidinyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, lhiazolidinyl, piperazinyl, 2-oxo-morpholinyl, morpholinyl, 2-oxo-piperidinyl, piperadinyl, decahydroquinolyl, octahydrochromenyl, octahydro-cyclopentapyranyl, 1 ,2,3,4,-tetrahydroquinolyl, 1 ,2,3,4-tetrahydroquinazolinyl, octahydro-[2]pyridinyl, decahydro-cycloocta
  • two moieties attached to a heteroatom may be taken together to form a heterocycloalkyl ring.
  • the resultant ring when a moiety containing one ring replacement atom replaces a ring carbon atom, the resultant ring, after replacement of a ring atom by the moiety, will contain the same number of ring atoms as the ring before ring atom replacement.
  • the resultant ring after replacement will contain one more ring atom than the ring prior to replacement by the moiety.
  • the resultant ring is a 7-membered ring containing 2 ring nitrogen atoms and the carbon of a carbonyl group in addition to 4 other carbon ring atoms (CH 2 groups) from the original piperidine ring.
  • the ring system may be saturated or may be partially unsaturated, i.e., the ring system may contain one or more non-aromatic C-C or C-N double bonds.
  • optionally substituted means that the group in question may be unsubstituted or it may be substituted one or several times, such as 1 to 3 times or 1 to 5 times.
  • an alkyl group that is “optionally substituted” with 1 to 5 chloro atoms may be unsubstituted, or it may contain 1 , 2, 3, 4, or 5 chlorine atoms.
  • substituted chemical moieties include one or more substituents that replace hydrogen.
  • each moiety "R” can be, independently, any of H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl, or when (R"(R")) is attached to a nitrogen atom, R" and R" can be taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered nitrogen heterocycle, wherein the heterocycloalkyl ring is optionally interrupted by one or more additional -0-, -S-, -SO, -S0 2 - , -NH-, -N(alkyl)-, or -N(aryl)groups, for example.
  • chemical moieties are substituted by at least one optional substituent, such as those provided hereinabove.
  • optional substituents when chemical moieties are substituted with optional substituents, the optional substituents are not further substituted unless otherwise stated.
  • R 1 when R 1 is an alkyl moiety, it is optionally substituted, based on the definition of "alkyl" as set forth herein. In some embodiments, when R 1 is alkyl substituted with optional aryl, the optional aryl substituent is not further substituted.
  • any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence.
  • the R 5 group is shown to be substituted with 0-2 substituents, then said group may optionally be substituted with up to two substituents and each substituents is selected independently from the definition of optionally substituted defined above.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • enantiomers refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • An equimolar mixture of two enantiomers is called a “racemic mixture” or a “racemate.”
  • isomers or stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • the compounds as described herein may contain any stereoisomer, racemate, or a mixture thereof.
  • radiochemical is intended to encompass any organic, inorganic or
  • organometallic compound comprising a covalently-attached radioactive isotope, any inorganic radioactive ionic solution (e.g., Na[' 8 F]F ionic solution), or any radioactive gas (e.g., ["C]C0 2 ), particularly including radioactive molecular imaging probes intended for administration to a patient (e.g., by inhalation, ingestion, or intravenous injection) for tissue imaging purposes, which are also referred to in the art as radiopharmaceuticals, radiotracers, or radioligands.
  • the compounds could also be readily adapted for synthesis of any radioactive compound comprising a radionuclide, including radio chemicals useful in other imaging systems, such as single photon emission computed tomography (SPECT).
  • SPECT single photon emission computed tomography
  • optical imaging agent refers to molecules that have wavelength emission greater than 400 nm and below 1200 nm.
  • optical imaging agents are Alex Fluor, BODIPY, Nile Blue, COB, rhodamine, Oregon green, fluorescein and acridine.
  • Radiolabeled compound of any of the formulae delineated herein.
  • Such compounds have one or more radioactive atoms (e.g., 3 H, 2 H, 14 C, l 3 C, 35 S, 32 P, ,25 I, 131 1) introduced into the compound.
  • radioactive atoms e.g., 3 H, 2 H, 14 C, l 3 C, 35 S, 32 P, ,25 I, 131 1.
  • Another aspect includes non-radioactive labeled compounds of any of the formulae delineated therein. These include fluorescent molecules, dyes, optical imaging agents, and the like.
  • Substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • a protecting group refers to a group that is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere. Protection and deprotection of functional groups may be performed by methods known in the art (see, for example, Green and Wuts Protective Groups in Organic Synthesis.
  • hydroxyl or amino groups may be protected with any hydroxyl or amino protecting group.
  • the amino protecting groups may be removed by conventional techniques.
  • acyl groups such as alkanoyl
  • alkoxycarbonyl and aroyl groups may be removed by solvolysis, e.g., by hydrolysis under acidic or basic conditions.
  • Arylmethoxycarbonyl groups e.g., benzyloxycarbonyl
  • a catalyst such as palladium-on-charcoal.
  • Tabernaemonta divaricata is a flowering tropical plant that has been used historically in traditional Chinese, Ayurvedic and Thai medicines, with applications spanning treatment of fever, pain, scabies and dysentery.
  • the search for the medicinally relevant components of this plant has resulted in the isolation of a vast array of indole alkaloids that possess diverse biological profiles.
  • Conolidine (1) is an exceedingly rare component of a Malayan T.
  • the molecular structure 1 defines conolidine as a member of the C5-nor stemmadenine family of natural products, other members of which have represented significant challenges to modern asymmetric synthesis. In fact, no asymmetric synthesis of any member of this natural product class has been described, and no robust source of conolidine has been identified to fuel medicinal evaluation. Before the studies herein, there was a lack of a source of conolidine (1) and a scarcity of chemical approaches suitable for the synthesis of the C5-nor stemmadenine skeleton. Since conolidine has a drug-like molecular structure it would be important to secure ample quantities of this rare alkaloid by synthetic means.
  • the retrosynthetic planning commenced with an examination of the biosynthetic pathway for conversion of stemmadenine (3) to vallesamine (5) ( Figure 2A).
  • excision of the C5 carbon occurs by a sequence of: 1 ) N-oxidation, 2) fragmentation, 3) hydrolysis, and 4) cyclization (via 4).
  • organolithium reagent 12 then furnished a mixture of stereoisomeric alcohols 13 that was subsequently advanced to the cyclization substrate 7 by a three-step sequence.
  • the success of this process validated this proposed strategy to access the strained azabicyclo-[4.2.2] core of the C5-nor stemmadenine family of natural products, and delivered the first synthetic sample of conolidine by a synthesis pathway that proceeds in just nine steps and 1 8%) overall yield from a readily available pyridine.
  • a method of synthesizing C5-nor stemmadenine alkaloids comprises the steps of: a) generating a substituted tetrahydropyridine for conversion to a 3-alkenyl-4- substituted piperidine comprising substitutions and stereochemistry for ring closure; b) converting a product of step (a) to an intermediate comprising a nucleophilic system, reactive for iminium-ion induced ring closure; and, c) converting the resulting bicyclo[4.2.2] system to C5- nor stemmadenine derivatives.
  • the following C5-nor stemmadenine enantiomers are prepared by resolution of an optionally N-protected piperidine:
  • R 1 comprises hydroxymethyl, hydroxyethyl, Pr, i-Pr, Ph, H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl, polyunsaturated alkyl, aryl, heteroaryl, cycloalkyl and heteroatom-substituted analogs;
  • R 2 comprises hydroxymethyl, hydroxyethyl, H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl, polyunsaturated alkyl, aryl, heteroaryl, cycloalkyl and heteroatom-substituted analogs;
  • R 3 comprises hydroxymethyl, hydroxyethyl, Pr, /-Pr, Ph H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl, polyunsaturated alkyl, aryl, heteroaryl, halogen, cycloalkyl and heteroatom-substituted analogs;
  • X comprises a substituted nitrogen or carbon atom, substituents comprising H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl, polyunsaturated alkyl, aryl, heteroaryl, cycloalkyl and heteroatom-substituted analogs, S, SO, S0 2 , , substituted PR 1 , substituted P(0)R' , substituted OR 1 , substituted NR' R 2 ,and substituted NR' X;
  • Y comprises H, D, NH 2 , NHR 1 , NR'R 2 , OR 1 , R 1 , hydrazones, and oximes;
  • Z comprises H, D, NH 2 , NHR 1 , NR'R 2 , OR 1 , R 1 , hydrazones, oximes; and, salts thereof.
  • the method of synthesizing conolidine and/or other C5-nor- stemmadenine alkaloids comprises subjecting a pyridine to N-alkylation followed by hydride reduction and producing an allylic alcohol 8 (Scheme 2); converting the allylic alcohol 8 to a functionalized (£)-exo-ethylidine-containing cycloalkane comprising the steps (i) a [2,3 ]-Wittig rearrangement reaction or a related SN2'-type addition reaction or metal catalyzed allylic substitution, to produce an intermediate compound, for example, a tributylstannylmethyl ether and (ii) exposing the intermediate compound to «-BuLi and forming isomer 10 (Scheme 2); oxidizing isomer 10 to a corresponding ⁇ , ⁇ -unsaturated aldehyde and producing a stereoisomeric alcohol 13 (Scheme 2); converting 13 to a cyclizing substrate, amino
  • the conolidine enantiomers (1) are prepared by resolution of a racemic piperidine (e.g. compound 8, Scheme 2) and reactions previously described in Scheme 2.
  • Scheme 3 illustrates one embodiment for the asymmetric synthesis of (+)-,(-)-, and(+/-)- conolidine.
  • one or more C5-nor stemmadenine alkaloids can also be asymmetrically synthesized by the steps set forth in Scheme 4:
  • the compounds made by the methods as described herein encompass various isomeric forms.
  • Such isomers include, e.g., stereoisomers, e.g., chiral compounds, e.g., diastereomers and enantiomers, e.g. racemates.
  • “Racemate” is an equimolar mixture of a pair of enantiomers. A racemate docs not exhibit optical activity.
  • the chemical name or formula of a racemate is distinguished from those of the enantiomers by the prefix ( ⁇ )- or rac- (or racem-) or by the symbols RS and SR.
  • C5-nor stemmadenine compounds comprise a molecule of general formulae set forth in Series 1 :
  • R 1 comprising: H, deuterium (D), alkyl, heteroatom substituted alkyl, unsaturated alkyl, polyunsaturated alkyl, aryl, heteroaryl, and cycloalkyl (and heteroatom-substituted analogs).
  • R 2 comprising: H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl,
  • R 3 comprising: H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl,
  • R 4 comprising: H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl,
  • R 5 comprising: D, halogen, alkyl, heteroatom substituted alkyl, unsaturated alkyl, polyunsaturated alkyl, aryl, heteroaryl, halogen, and cycloalkyl (and heteroatom-substituted analogs); this generalized depiction is not limited to a single site of substitution and includes derivatives with a combination of substitutions in the ring systems.
  • X comprising: a substituted nitrogen or carbon atom [substituents including H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl, polyunsaturated alkyl, aryl, heteroaryl, and cycloalkyl (and heteroatom-substituted analogs)], as well as S, SO, S0 2 , substituted PR 1 , P(0)R' , 0R' , NR' R 2 , and NR' X.
  • substituted nitrogen or carbon atom substituted nitrogen or carbon atom
  • Substituents Y and Z comprising a ring linking these two substituents.
  • ring structures comprise: cycloalkyl, heteroatom substituted cycloalkyl, saturated heterocycles, unsaturated heterocycles, substituted heterocycles, unsubstituted heterocycles, or combinations thereof.
  • C5-nor stemmadenine compounds comprise a molecule of general formulae set forth in Series 11:
  • R 1 comprising: H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl, polyunsaturated alkyl, aryl, heteroaryl, and cycloalkyl (and heteroatom-substituted analogs).
  • R 2 comprising: H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl,
  • R 3 comprising: H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl,
  • R 4 comprising: H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl,
  • Examples of ring structures comprise: cycloalkyl, heteroatom substituted cycloalkyl, saturated heterocycles, unsaturated heterocycles, substituted heterocycles, unsubstituted heterocycles, or combinations thereof.
  • R 3 comprising: D, halogen, alkyl, heteroatom substituted alkyl, unsaturated alkyl, polyunsaturated alkyl, aryl, heteroaryl, halogen, and cycloalkyl (and heteroatom-substituted analogs); this generalized depiction is not limited to a single site of substitution and includes derivatives with a combination of substitution about the ring systems.
  • R 6 comprising: D, halogen, alkyl, heteroatom substituted alkyl, unsaturated alkyl, polyunsaturated alkyl, aryl, heteroaryl, halogen, and cycloalkyl (and heteroatom-substituted analogs); this generalized depiction is not limited to a single site of substitution and includes derivatives with a combination of substitution about the ring systems.
  • X comprising: a substituted nitrogen or carbon atom [substituents including H, D, alkyl, heteroatom substituted alkyl, unsaturated alkyl, polyunsaturated alkyl, aryl, heteroaryl, and cycloalkyl (and heteroatom-substituted analogs)], as well as S, SO, S0 2 , substituted PR 1 and P(0)R', OR 1 , NR'R 2 , and NR'X.
  • substituted nitrogen or carbon atom substituted nitrogen or carbon atom
  • substituents Y and Z comprise a ring linking these two substituents.
  • substituents Y or Z comprise a ring structure that results in a linkage between these positions and R 4 , and R 6 or to the neighboring ring system(s). Examples of ring structures comprise: cycloalkyl, heteroatom substituted cycloalkyl, saturated
  • heterocycles unsaturated heterocycles, substituted heterocycles, unsubstituted heterocycles, or combinations thereof.
  • intermediates employed for the synthesis of one or more C5-nor stemmadenine compounds comprise:
  • the present invention further encompasses salts, solvates, prodrugs and active metabolites of the compounds.
  • salts can include acid addition salts or addition salts of free bases.
  • the salts are pharmaceutically acceptable.
  • acids which may be employed to form pharmaceutically acceptable acid addition salts include, but are not limited to, salts derived from nontoxic inorganic acids such as nitric, phosphoric, sulfuric, or hydrobromic, hydroiodic, hydrofluoric, phosphoric, as well as salts derived from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy!
  • alkanoic acids alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and acetic, maleic, succinic, or citric acids.
  • Non-limiting examples of such salts include napadisylate, besylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate,
  • pharmaceutically acceptable means approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in mammals, and more particularly in humans.
  • a pharmaceutically acceptable salt of a compound such as one made by the method of the present invention may be prepared by using a desired acid or base as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • an aqueous solution of an acid such as hydrochloric acid may be added to an aqueous suspension of a compound of formula I and the resulting mixture evaporated to dryness (lyophilized) to obtain the acid addition salt as a solid.
  • a compound may be dissolved in a suitable solvent, for example an alcohol such as isopropanol, and the acid may be added in the same solvent or another suitable solvent.
  • the resulting acid addition salt may then be precipitated directly, or by addition of a less polar solvent such as diisopropyl ether or hexane, and isolated by filtration.
  • the acid addition salts of the compounds may be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are ⁇ , ⁇ ' - dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.
  • the base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid.
  • solvates complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates".
  • a complex with water is known as a "hydrate”.
  • Solvates of the compound of the invention are within the scope of the invention.
  • the salts of the compound of formula 1 may form solvates (e.g., hydrates) and the invention also includes all such solvates.
  • the meaning of the word "solvates” is well known to those skilled in the art as a compound formed by interaction of a solvent and a solute (i.e., solvation).
  • Solvates may be represented, for example, by the formula R'(solvent), where R is a compound of the invention.
  • a given compound may form more than one solvate including, for example, monosolvates (R(solvent) or polysolvates (R(solvent) n ) wherein n is an integer), including, for example, disolvates (R(sol vent) 2 ), trisolvates (R(solvent)3), and the like, or hemisolvates, such as, for example, R(solvent) n /2, R(solvent)n/3, R(solvent) n /4 and the like wherein n is an integer.
  • Solvents herein include mixed solvents, for example, methanol/water, and as such, the solvates may incorporate one or more solvents within the solvate.
  • prodrug includes compounds with moieties, which can be metabolized in vivo. Generally, the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J P harm. Sci. 66: 1 -1 9; Silverman (2004) The Organic Chemistry of Drug Design and Drug Action, Second Ed., Elsevier Press, Chapter 8, pp. 497- 549).
  • the prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branch or unbranched lower ally!
  • ester moieties e.g., propionoic acid esters
  • lower alkenyl esters di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester)
  • acylamino lower alkyl esters e.g., acetyloxymethyl ester
  • acyloxy lower alkyl esters e.g., pivaloyloxymethyl ester
  • aryl esters phenyl ester
  • aryl-lower alkyl esters e.g., benzyl ester
  • substituted e.g., with methyl, halogen, or methoxy substituents
  • aryl and aryl-lower alkyl esters amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides.
  • Other prodrug moieties include propionoic and succinic acid esters, acyl
  • hydrate refers to a compound of the present invention which is associated with water in the molecular form, i.e., in which the H-OH bond is not split, and may be represented, for example, by the formula R*H 2 0, where R is a compound of the invention.
  • a given compound may form more than one hydrate including, for example, monohydrates (R- H 2 0) or polyhydrates (R(H 2 0) n ) wherein n is an integer > 1 ; including, for example, dihydrates (R(H 2 0) 2 ), trihydrates (R(H 2 0) 3 ), and the like, or hemihydrates, such as, for example, R(H 2 0) n/2 , R(H 2 0) n /3, R(H 2 0) n /4 and the like wherein n is an integer.
  • the term "acid hydrate” refers to a complex that may be formulated through association of a compound having one or more base moieties with at least one compound having one or more acid moieties or through association of a compound having one or more acid moieties with at least one compound having one or more base moieties, said complex being further associated with water molecules so as to form a hydrate, wherein said hydrate is as previously defined and R represents the complex herein described above.
  • tautomer or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is an imidazole moiety where the hydrogen may migrate between the ring nitrogens.
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compounds, including free acid, free base and zwitterions, are contemplated to be within the scope of the present invention. It is well known in the art that compounds containing both basic nitrogen atom and acidic groups often exist in equilibrium with their zwitterionic forms. Thus, any of the compounds described herein throughout that contain, for example, both basic nitrogen and acidic groups, also include reference to their corresponding zwitterions.
  • one or more C5-nor stemmadenine compounds are useful in pain management and therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which dysfunction of its targets are present or implicated.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the term “therapeutic” and “therapeutically” should be construed accordingly.
  • the term “therapy” within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition.
  • This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.
  • the compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
  • the compounds are useful in therapy for neuropathic pain.
  • the compounds are useful in therapy for chronic neuropathic pain.
  • the compounds are labeled with radiolabels or nonradioactive molecules. This is especially useful in imaging, tracing or tracking compounds in vivo, diagnostics and the like.
  • radioactive molecules include 57 Co, 67 Cu, 67 Ga, 68 Ga, 97 Ru, 99m Tc, 1 1 ' In, , 13m In, l 97 Hg, 198 Au, and 203 Pb.
  • Some radioactive atoms have superior properties for use in radiochemical imaging techniques.
  • technetium-99m 99m Tc
  • Rhenium-186 and -188 also have gamma emission which allows it to be imaged.
  • the compounds are labeled with non-radioactive labels, aromatic dyes that produce fluorescent or luminescent signal.
  • aromatic dyes that produce fluorescent or luminescent signal.
  • Non-radioactive labels include fluorescein, rhodamine, coumarin, porphyrins, and cyanine dyes such as Cy3 and Cy5.
  • Composite dyes have also been synthesized by fusing two different dyes together (Lee el al, ( 1992) Nucl. Acid Res. 20; 2471 -2488; Lee et al., U.S. Pat. No. 5,945,526 and Waggoner et al, in U.S. Pat. No. 6,008,3 73).
  • Non-radioactive labeling methods were initially developed to attach signal-generating groups onto proteins.
  • the compounds may be labeled with one or more agents, either from the same class of compounds or from another class of compounds.
  • agents either from the same class of compounds or from another class of compounds.
  • a non-radioactive label and a radiolabel for example, a radiolabel.
  • the compounds are labeled with luminescent producing agents.
  • luminescent producing agents There are several different classes of compounds that can produce luminescent signals including- 1 ,2-dioxetanes and luminols. Some forms of these compounds are very unstable and emit light as they decompose.
  • the presence of an adamantyl group can lead to a highly stable form with a half-life of several years. In some embodiments, a shorter half-life may be desirable, for example, in diagnostics. In other embodiments, a longer half-life luminescent signal may be desired, for example, following the in vivo path and localization or excretion, determining the stability of a newly synthesized compound, and the like.
  • a labeling reagent comprises a reactive group capable of creating a covalent bond between a marker or label and the desired target C5-nor
  • the labeling reagents comprise a ligand or dye portion and a reactive group capable of creating a covalent bond.
  • a linker arm that separates the ligand or dye portion from the reactive group. This may provide more efficient coupling between the labeling reagent and an intended target compound.
  • the presence and nature of the linker arm may also increase the biological or chemical activity of the labeled target compound.
  • Any type of agent can be used to label a compound as long as that compound can participate in bond formation with the reactive group of the labeling reagent.
  • the target molecule may be in its native state or it may have been modified to participate in formation of a covalent bond with the labeling agent.
  • Ligands that may find use with the present invention can include but not be limited to sugars, lectins, antigens, intercalators, chelators, biotin, digoxygenin and combinations thereof.
  • a dye used to synthesize a labeling reagent may depend upon physical characteristics such as absorption maxima, emission maxima, quantum yields, chemical stability and solvent solubility.
  • Examples of compounds that may be used as the dye portion can include but not be limited to xanthene, anthracene, cyanine, porphyrin and coumarin dyes.
  • xanthene dyes include but not be limited to fluorescein, 6-carboxyfluorescein (6-FAM), 5-carboxyfluorescein (5-FAM), 5- or 6-carboxy-4, 7,2', 7'-tetrachlorofluorescein (TET), 5- or e-carboxy- ⁇ ⁇ 'V hexachloro fluorescein (HEX), 5' or 6'-carboxy-4',5'-dichloro-
  • Cy 3.5 Cy 5, Cy 5.5, Cy 7 and Cy 7.5.
  • Other dyes include but not be limited to energy transfer dyes, composite dyes and other aromatic compounds that give fluorescent signals. It should also be understood that ligands and dyes are not mutually exclusive groups.
  • Examples of reactive groups which are capable of covalent bond formation can comprise but not be limited to alkenes, alkynes, metallo-organic compounds, halogenated compounds and the like.
  • the metallo-organic and halogenated compounds can comprise aromatic, heterocyclic, alkene, and alkyne groups as well as various combinations thereof.
  • a linking arm that comprises a portion of the labeling agents can be of any desired length and can be comprised of any suitable atoms that can include but not be limited to carbon, nitrogen, oxygen, sulfur and any combination thereof.
  • Chemical groups that can comprise the linker arm can include but not be limited to aliphatic bonds, double bonds, triple bonds, peptide bonds, aromatic rings, aliphatic rings, heterocyclic rings, ethers, esters, amides, and thioamides.
  • the linking arm can form a rigid structure or be flexible in nature.
  • compositions In use for therapy in a warm-blooded animal such as a human, the compounds of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, transdermally; intracerebroventricularly and by injection.
  • the dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage at the most appropriate level or concentration for a particular patient.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized moulds and allowed to cool and solidify.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low- melting wax, cocoa butter, and the like.
  • composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
  • Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid form compositions include solutions, suspensions, and emulsions.
  • sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical composition will preferably include from 0.05% to 99% w (percent by weight), more preferably from 0.10 to 50% w, of the compounds of the invention, all percentages by weight being based on total composition.
  • a therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.
  • any compound comprising a formula as for example, compounds shown in Series I or II, for the manufacture of a medicament for the therapy of pain.
  • any compound of Series I or II for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
  • a further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound of Series I or II above, is administered to a patient in need of such therapy.
  • composition comprising a compound of Series I or II or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
  • composition comprising a compound of Series I or II or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.
  • composition comprising a compound of Series I or I I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.
  • a pharmaceutical composition comprising a compound of Series I or I I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.
  • mice were also pretreated for 30 and 60 min.
  • mice were gently restrained, and 25 of a 5% formalin solution was injected just beneath the plantar surface of the right hind-paw using a 30-gauge needle and a microsyringe. Mice were immediately returned to their boxes and the time spent licking or biting the injected hind-paw was measured in 5 min intervals over a 40 min period using a stopwatch with recorded to time the nearest tenth of a second.
  • Vehicle-treated C57BI/6J mice display two distinct phases of the formalin response: the first phase occurs 0 to 10 min post-injection and the second phase occurs 20-40 min post-injection.
  • Locomotor activity Locomotor activity measurements were made using the Versamax Animal Activity Monitoring System [20 x 20 cm 2 ] (Accuscan Instruments, Columbus, OH) as previously described (Bohn et al., J. Neurosci. 23, 10265-10273, (2003)). Mice were injected i.p. with vehicle,(-) conolidine sulfate (10, 20 mg/kg), then immediately placed into a monitoring box where their activity was measured for 120 minutes in 5 min intervals.
  • Data were collected using Versadat software (Accuscan ' Instruments, Columbus, OH) and analyzed for the total number of beam breaks, total distance traveled (ec), vertical activity, stereotypic movements, and the time spent, in the center of the open field for each mouse. Data are presented as the counts or distance or time spent measured as a sum over 60 minutes.
  • (+/-)-conolidine (1) did not produce antinociception in the hot plate (51°C) or in the warm water tail immersion assay (49°C) following systemic injection of 10 mg/kg, i.p.
  • conolidine 10 mg/kg
  • conolidine differs from morphine in that it does not promote antinociception to acute thermal stimulation; however, like morphine, and a host of known analgesics, it does suppress the acetic acid-induced writhing response.
  • a pain model designed to assess both acute tonic and persistent inflammatory pain responses was also employed to ascertain conolidine's analgesic efficacy.
  • the formalin assay is a model that is effective at assessing the response to direct chemical action at nociceptors of primary nerves (Phase 1 - occurring within 10 minutes of injection of formalin), and pain associated with the inflammatory response (Phase 2 - occurring 20-40 minutes after injection).
  • the sulfate salts of(+/-)-,(+)- and (-)-conolidine were administered ( 10 mg/kg, i.p.) 1 5 minutes prior to formalin (5%, 25 xL, i. plantar) challenge.
  • (-)-conolidine sulfate was administered at increasing time points prior to formalin challenge. While one-way ANOVA revealed no time effect for either phase (p>0.05), Student's t test analysis revealed that while conolidine significantly attenuates the pain response compared to vehicle at 1 5 and 30 minutes prior to injection in phase 1 , and at 1 5 minutes prior to phase 2, it was less efficacious when administered 1 hour prior to formalin challenge for phase 1 or 30-60 minutes prior to the second phase assessment (Figure 5E). These data provide evidence that, like opioid analgesics, conolidine is effective in suppressing responses to both chemical-induced as well as inflammation-derived pain.
  • conolidine differs from opioid analgesics
  • pharmacological studies were performed. Based on ⁇ -arrestin-translocation assays, radioligand binding displacement and G protein coupling assays, conolidine has low affinity or efficacy for the mu opioid receptor, the primary target of morphine (Table 1 ). Moreover, radioligand displacement and ⁇ -arrestin translocation studies also reveal a low of affinity or efficacy for kappa and delta opioid receptors (Table 1 ).
  • Table 1 shows the relative drug potencies in both phases of the formalin test from data presented in Figures 5C and 5D.
  • (+/-)-conolidine sulfate was subjected to screening by the Psychoactive Drug Screening Program (PDSP) sponsored by the NIMH.
  • PDSP Psychoactive Drug Screening Program
  • the individual enantiomers of conolidine were also screened in a panel by the CEREP company (www.cerep.fr).
  • Conolidine was able to displace more than 50% of radio ligand binding to the serotonin 3 receptor ion channel, the norepinephrine transporter as well as the 2B adrenergic, a2C adrenergic and histamine 2 receptors, with low affinity (Ki > 1 ⁇ ).
  • Functional assays reveal very low potency for conolidine as an agonist or antagonist at these potential protein targets and they may not represent a primary mechanism of action for this compound.
  • the CEREP screen also provided initial properties regarding cytotoxicity, affinity for p-glycoproteins, solubility and competition with liver enzyme function.
  • It does not block ( ⁇ 14% inhibition at 3 ⁇ ) hepatic P450 enzymes (CYP-1A2, -2C8, -2C9, -2D6, & -3A4);
  • Cell viability assays indicate that it is not cytotoxic (IC 50 >200 ⁇ ); it is not a substrate of the multidrug resistance transporter 1 (p- glycoprotein); and the sulfate salt has good solubility ( ⁇ 183 ⁇ aqueous).
  • conolidine's analgesic properties are not accompanied by central nervous system effects that impact locomotor activity.
  • Conolidine (10 mg/kg, i.p.) in contrast to the opioid analgesic, morphine, which stimulates locomotion in mice, does not alter horizontal activity, total distance traveled, vertical rearing, or stereotypic movements in mice ( Figure 6). While it is clear that conolidine is not an opioid analgesic, its mechanism of action remains to be determined. Regardless, its lack of adverse effects on locomotor activity are encouraging as this may be indicative of fewer side effects, such as sedation or elevations of dopamine, a characteristic of all addictive substances.
  • this assay may serve as a means of determining activity and potency of conolidine sulfate and related compounds in dorsal root ganglion cultures ( Figure 7).
  • Example 2 Synthesis of Conolidine and Discovery of a Novel Analgesic for Neuropathic Pain
  • UV data for conolidine was obtained on a ThermoElectron Evolution 300, scanning 300-600 nm.
  • Flash column chromatography was performed on Silicycle SiliaFlash F60 silica gel, 40- 63 ⁇ particle size, with Fisher ACS-grade solvents. Compounds purified in this manner were sufficiently pure (>95%, ⁇ NMR) to be used in subsequent transformations.
  • (+)-Conolidine (1) Amine 7 (140 mg, 0.56 mmol) was dissolved in 5 mL of anh. MeCN, along with paraformaldehyde (30 mg, 1.0 mmol, 1.8 equiv.), and TFA (0.4 mL, 1.5 equiv.) and the reaction mixture heated to reflux over 2 hours. Acetonitrile was removed in vacuo and the crude product was freebased with sat'd NaHCC>3 to pH 9.0 and extracted with three 10-mL portions of CH2CI2.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne la première voie de synthèse de novo vers le produit naturel C5-nor stemmadénine exceptionnellement rare, la conolidine, et la première synthèse asymétrique de n'importe quel élément de cette classe de produits naturels. L'invention concerne également des compositions de C5-nor-stémmadénine. Ces composés, par exemple, la (+/-)-, la (+)- et la (-)-conolidine sont des analgésiques non opioïdes puissants et efficaces dans des douleurs toniques et persistantes.
PCT/US2011/066810 2010-12-22 2011-12-22 Synthèse de la conolidine et découverte d'un analgésique non opioïde puissant pour la douleur Ceased WO2012088402A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201061426023P 2010-12-22 2010-12-22
US61/426,023 2010-12-22

Publications (1)

Publication Number Publication Date
WO2012088402A1 true WO2012088402A1 (fr) 2012-06-28

Family

ID=46314474

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/066810 Ceased WO2012088402A1 (fr) 2010-12-22 2011-12-22 Synthèse de la conolidine et découverte d'un analgésique non opioïde puissant pour la douleur

Country Status (1)

Country Link
WO (1) WO2012088402A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114560861A (zh) * 2022-03-09 2022-05-31 昆明医科大学 一种单萜吲哚生物碱及其提纯方法及抗耐药菌的应用
WO2022136486A1 (fr) 2020-12-22 2022-06-30 Luxembourg Institute Of Health (Lih) Analogues de la conolidine servant de modulateurs sélectifs d'ackr3 pour traiter le cancer
US20230271976A1 (en) * 2014-11-26 2023-08-31 The Trustees Of Columbia University In The City Of New York Opioid receptor modulators

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2817623A (en) * 1956-03-22 1957-12-24 Ciba Pharm Prod Inc Tabernanthine, ibogaine containing analgesic compositions
US20070032385A1 (en) * 2005-06-20 2007-02-08 Dunetz Joshua R Sustainable chemical processes
US20090191183A1 (en) * 2007-07-30 2009-07-30 Auspex Pharmaceuticals, Inc. Substituted indoles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2817623A (en) * 1956-03-22 1957-12-24 Ciba Pharm Prod Inc Tabernanthine, ibogaine containing analgesic compositions
US20070032385A1 (en) * 2005-06-20 2007-02-08 Dunetz Joshua R Sustainable chemical processes
US20090191183A1 (en) * 2007-07-30 2009-07-30 Auspex Pharmaceuticals, Inc. Substituted indoles

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AMAT ET AL.: "Total syntheses of the Strychnos indole alkaloids (-)-tubifoline, (-)-tubifolidine, and ( -)-19,20-dihydroakuammicine.", TETRAHEDRON: ASYMMETRY, vol. 8, no. 6, 1997, pages 935 - 948, XP004094365, DOI: doi:10.1016/S0957-4166(97)00071-2 *
PRATCHAYASAKUL ET AL.: "Ethnobotany & ethnopharmacology of Tabernaemontana divaricata.", INDIAN J MED RES, vol. 127, April 2008 (2008-04-01), pages 317 - 335 *
TARSELLI ET AL.: "Synthesis of conolidine, a potent non-opioid analgesic for tonic and persistent pain.", NATURE CHEMISTRY, vol. 3, May 2011 (2011-05-01), pages 449 - 453 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230271976A1 (en) * 2014-11-26 2023-08-31 The Trustees Of Columbia University In The City Of New York Opioid receptor modulators
US12195478B2 (en) * 2014-11-26 2025-01-14 The Trustees Of Columbia University In The City Of New York Opioid receptor modulators
WO2022136486A1 (fr) 2020-12-22 2022-06-30 Luxembourg Institute Of Health (Lih) Analogues de la conolidine servant de modulateurs sélectifs d'ackr3 pour traiter le cancer
CN114560861A (zh) * 2022-03-09 2022-05-31 昆明医科大学 一种单萜吲哚生物碱及其提纯方法及抗耐药菌的应用

Similar Documents

Publication Publication Date Title
US12195478B2 (en) Opioid receptor modulators
ES2329739T3 (es) Analogos de cocaina.
JP2832754B2 (ja) サブスタンスｐアンタゴニストとしてのスピロアザ環式誘導体
JP5465241B2 (ja) ５−ｈｔ３受容体調節物質ならびにその作製方法および使用
JP2021501191A (ja) Ｗｅｅ１阻害剤としての大環状化合物及びその使用
GB2169292A (en) Carbocyclic and heterocyclic carbonylmethylene- and carbonylmethylpiperidines and - pyrrolidines as serotonin antagonists
JPH06135963A (ja) 置換ベンジルアミノキヌクリジン
EP2693876A1 (fr) Réactifs de méthylformyle substitué et procédé d'utilisation de ceux-ci pour modifier des propriétés physicochimiques et/ou pharmacocinétiques de composés
TW202304928A (zh) 抗癌核荷爾蒙受體標靶化合物
US8940754B2 (en) 10′-fluorinated Vinca alkaloids provide enhanced biological activity against MDR cancer cells
JP2004175809A (ja) 哺乳動物における嗜癖性障害および神経障害または精神障害の治療用医薬組成物
WO2012088402A1 (fr) Synthèse de la conolidine et découverte d'un analgésique non opioïde puissant pour la douleur
US20040259901A1 (en) Mixed kappa/mu opioids and uses thereof
ES2374581T3 (es) Derivados de azaindol con una combinación de agonismo parcial del receptor nicotínico de la acetilcolina e inhibición de la reabsorción de dopamina.
CA3267021A1 (fr) Inhibiteurs d'oncoprotéines yap/taz-tead
JP2906339B2 (ja) 活性成分としてデヒドロエボジアミン−ＨＣｌを含有する記憶増強および抗痴呆剤
AU2007224896A1 (en) Camptothecin derivatives and their use
ITTO980871A1 (it) Derivati basici di benz(e)isoindol-1-oni e pirrolo(3, 4-c) chinolin-1-oni ad attivita' 5ht3 antagonista, loro preparazione ed applicazione terapeutica.
US11352365B2 (en) Biased potent opioid-like agonists as improved medications to treat chronic and acute pain and methods of using the same
TW202112770A (zh) 具有β受體激動及Ｍ受體拮抗活性的雜環衍生物及其醫藥用途
US20250346581A1 (en) Process for synthesis of galbulimima alkaloid 18 and compounds useful as opioid receptor antagonists and agonists
Witiak et al. 3, 4-Methylenedioxyphenyl-, isopropylidenedioxyphenyl-, and benzyl-substituted chiral 2-aminosuccinimides and 3-aminopyrrolidines. Stereoselective investigations of potential anti-parkinsonian, antipsychotic, and anticonvulsant activities
Nava Synthesis of Precursors for Tetracyclic Bis-Piperidine Alkaloids as Anticancer Agents
WO2025174540A1 (fr) Nouveaux dérivés à structure morphine
WO2025171259A1 (fr) Composés, compositions et méthodes pour le traitement de maladies

Legal Events

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

Ref document number: 11850079

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11850079

Country of ref document: EP

Kind code of ref document: A1