WO2006019673A2 - Analogues de jiadifenine et utilisations - Google Patents

Analogues de jiadifenine et utilisations Download PDF

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WO2006019673A2
WO2006019673A2 PCT/US2005/024483 US2005024483W WO2006019673A2 WO 2006019673 A2 WO2006019673 A2 WO 2006019673A2 US 2005024483 W US2005024483 W US 2005024483W WO 2006019673 A2 WO2006019673 A2 WO 2006019673A2
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hydrogen
aryl
protecting group
heterocyclic
compound
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PCT/US2005/024483
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WO2006019673A3 (fr
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Samuel J. Danishefsky
Young Shin Cho
David A. Carcache
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Memorial Sloan-Kettering Cancer Center
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Publication of WO2006019673A3 publication Critical patent/WO2006019673A3/fr

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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
    • C07D491/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • peripheral neuropathies are characterized by the loss of feeling, experiencing pain, and even paralysis of or in the extremities.
  • peripheral neuropathies result from disease states such as ALS, Multiple Sclerosis, AIDS, diabetes, and various neuropathies induced by chemotherapeutic treatments such as cisplatin, vinblastine and taxane (Taxol.TM. and Taxotere.TM.) treatment for cancer therapy, and D4T for the treatment of HIV (Human Insufficiency Virus).
  • the present invention provides a compound of general formula (I):
  • Xi and X 2 are independently O or NR X1 , wherein R X1 is hydrogen, an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl moiety, or a nitrogen protecting group;
  • Ri is hydrogen, halogen, -OR 1A , -SR 1A , -NR 1A R 1B , or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; wherein R 1A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R 1B is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety;
  • R 3 , R 4 and R 5 are independently hydrogen, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety
  • R 6 is hydrogen, halogen, -OR 6 ⁇ , -SR 6A , -NR 6 ⁇ R 6B , or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety
  • R 6A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety
  • R 6B is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety.
  • the present invention provides pharmaceutical compositions comprising an inventive compound and a pharmaceutically acceptable carrier, optionally further comprising an additional therapeutic agent.
  • the present invention provides methods for treating a neurodegenerative disorder/ or condition comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the invention in an amount effective to promote neurite outgrowth.
  • the present invention provides methods for treating Alzheimer's disease and/or Parkinson's disease.
  • protecting group By the term “protecting group”, has used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound.
  • a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction.
  • oxygen, sulfur, nitrogen and carbon protecting groups may be utilized.
  • certain exemplary oxygen protecting groups are utilized.
  • oxygen protecting groups include, but are not limited to methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), MTM (methylthiomethyl ether), BOM (benzyloxymethyl ether), PMBM (p- methoxybenzyloxymethyl ether), to name a few), substituted ethyl ethers, substituted benzyl ethers, silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS (t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS (t-butyldiphenyl silyl ether)), esters (e.g., formate, acetate, benzoate (Bz), trifluoroacetate, dichloroacetate, to name a few), carbonates, cyclic acetals and
  • nitrogen protecting groups are utilized. These nitrogen protecting groups include, but are not limited to, carbamates (including methyl, ethyl and substituted ethyl carbamates (e.g., Troc), to name a few) amides, cyclic imide derivatives, N-Alkyl and N-Aryl amines, imine derivatives, and enamine derivatives, to name a few. Certain other exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the present invention. Additionally, a variety of protecting groups are described in "Protective Groups in Organic Synthesis" Third Ed. Greene, T. W. and Wuts, P.G., Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
  • the compounds, as described herein, may be substituted with any number of substituents or functional moieties.
  • substituted whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic, carbon and heteroatom substituents of organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment and prevention, for example of disorders, as described generally above.
  • the term “stable”, as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • aliphatic as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
  • alkyl includes straight and branched alkyl groups.
  • alkenyl alkynyl
  • alkynyl alkynyl
  • lower alkyl is used to indicate those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-6 carbon atoms.
  • the alkyl, alkenyl and alkynyl groups employed in the invention contain 1 -20 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 carbon atoms.
  • Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n- propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, and the like.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1- propynyl and the like.
  • alicyclic refers to compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to cyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups.
  • alicyclic is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups.
  • Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, -CH 2 - cyclopropyl, cyclobutyl, -CH 2 -cyclobutyl, cyclopentyl, -CH 2 -cyclopentyl-n, cyclohexyl, -CH 2 -cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norborbyl moieties and the like, which again, may bear one or more substituents.
  • alkoxy refers to an alkyl or cycloalkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom or through a sulfur atom.
  • the alkyl or cycloalkyl group contains 1-20 aliphatic or alicyclic carbon atoms.
  • the alkyl or cycloalkyl group contains 1-10 aliphatic or alicyclic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic or alicyclic carbon atoms.
  • the alkyl group contains 1 -6 aliphatic or alicyclic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic or alicyclic carbon atoms.
  • alkoxy include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
  • thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
  • alkylamino refers to a group having the structure - NHR'wherein R' is alkyl or cycloalkyl, as defined herein.
  • dialkylamino refers to a group having the structure -N(R') 2 , wherein each occurrence of R' is independently alkyl or cycloalkyl, as defined herein.
  • aminoalkyl refers to a group having the structure NH 2 R'-, wherein R' is alkyl or cycloalkyl, as defined herein.
  • the alkyl group contains 1-20 aliphatic or alicyclic carbon atoms.
  • the alkyl or cycloalkyl group contains 1- 10 aliphatic or alicyclic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic or alicyclic carbon atoms.
  • the alkyl or cycloalkyl group contains 1 -6 aliphatic or alicyclic carbon atoms.
  • the alkyl or cycloalkyl group contains 1 -4 aliphatic or alicyclic carbon atoms.
  • alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.
  • aryl and heteroaryl refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. It will also be appreciated that aryl and heteroaryl moieties, as defined herein may be attached via an alkyl or heteroalkyl moiety and thus also include - (alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)aryl, and -(heteroalkyl)heteroaryl moieties.
  • aryl or heteroaryl and “aryl, heteroaryl, -(alkyl)aryl, -(heteroalkyl)aryl, -(heteroalkyl)aryl, and -(heteroalkyl)heteroaryl” are interchangeable.
  • Substituents include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • 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, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
  • aryl and heteroaryl groups can be unsubstituted or substituted, wherein substitution includes replacement of one or more of the hydrogen atoms thereon independently with any one or more of the substituents generally described above. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
  • cycloalkyl refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of other alicyclic, heteroalicyclic or heterocyclic moieties, may optionally be substituted with one or more of the substituents generally described above.
  • An analogous convention applies to other generic terms such as “cycloalkenyl", “cycloalkynyl” and the like.
  • any of the alicyclic or heteroalicyclic moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
  • heteroaliphatic refers to aliphatic moieties in which one or more carbon atoms in the main chain have been substituted with a heteroatom.
  • a heteroaliphatic group refers to an aliphatic chain which contains one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms, e.g., in place of carbon atoms.
  • Heteroaliphatic moieties may be branched or linear unbranched.
  • heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more of the substituents generally described above. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
  • heteroalicyclic refers to compounds which combine the properties of heteroaliphatic and cyclic compounds and include but are not limited to saturated and unsaturated mono- or polycyclic heterocycles such as morpholino, pyrrolidinyl, furanyl, thiofuranyl, pyrrolyl etc., which are optionally substituted with one or more functional groups, as defined herein.
  • any of the alicyclic or heteroalicyclic moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
  • haloalkyl denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
  • heterocycloalkyl refers to a non-aromatic 5-, 6- or 7- membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6- membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to a substituted or unsubstituted aryl or heteroaryl ring.
  • heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • a "substituted heterocycloalkyl or heterocycle” group refers to a heterocycloalkyl or heterocycle group, as defined above, substituted by the independent replacement of one or more of the hydrogen atoms thereon with one or more of the substituents generally described above. Additional examples or generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
  • aliphatic As used herein, the terms “aliphatic”, “heteroaliphatic”, “alkyl”, “alkenyl”, “alkynyl”, “heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”, and the like encompass substituted and unsubstituted, saturated and unsaturated, and linear and branched groups. Similarly, the terms “alicyclic”, “heteroalicyclic”, “heterocycloalkyl”, “heterocycle” and the like encompass substituted and unsubstituted, and saturated and unsaturated groups.
  • cycloalkyl cycloalkenyl
  • cycloalkynyl cycloalkenyl
  • heterocycloalkyl cycloalkenyl
  • heterocycloalkynyl cycloalkenyl
  • aryl heteroaryl
  • pharmaceutically acceptable derivative denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof.
  • pro-drugs thus include among others pro-drugs.
  • a pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety, which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species.
  • An example of a pro-drug is an ester, which is cleaved in vivo to yield a compound of interest.
  • Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from an animal (e.g., mammal) or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • biological sample refers to any solid or fluid sample obtained from, excreted by or secreted by any living organism, including single-celled micro-organisms (such as bacteria and yeasts) and multicellular organisms (such as plants and animals, for instance a vertebrate or a mammal, and in particular a healthy or apparently healthy human subject or a human patient affected by a condition or disease to be diagnosed or investigated).
  • the biological sample can be in any form, including a solid material such as a tissue, cells, a cell pellet, a cell extract, cell homogenates, or cell fractions; or a biopsy, or a biological fluid.
  • the biological fluid may be obtained from any site (e.g. blood, saliva (or a mouth wash containing buccal cells), tears, plasma, serum, urine, bile, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or cells therefrom, aqueous or vitreous humor, or any bodily secretion), a transudate, an exudate (e.g. fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint (e.g.
  • the biological sample can be obtained from any organ or tissue (including a biopsy or autopsy specimen) or may comprise cells (whether primary cells or cultured cells) or medium conditioned by any cell, tissue or organ.
  • Biological samples may also include sections of tissues such as frozen sections taken for histological purposes.
  • Biological samples also include mixtures of biological molecules including proteins, lipids, carbohydrates and nucleic acids generated by partial or complete fractionation of cell or tissue homogenates.
  • biological samples may be from any animal, plant, bacteria, virus, yeast, etc.
  • the term animal refers to humans as well as non-human animals, at any stage of development, including, for example, mammals, birds, reptiles, amphibians, fish, worms and single cells. Cell cultures and live tissue samples are considered to be pluralities of animals.
  • the non- human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig).
  • An animal may be a transgenic animal or a human clone.
  • the biological sample may be subjected to preliminary processing, including preliminary separation techniques.
  • Figure 1 depicts results of neurite outgrowth experiments in PC 12 cells treated with inventive compounds. Pictures of neurons after treatment with DMSO and compounds of the invention are shown.
  • the present invention provides novel polycyclic compounds, as described in more detail herein, which exhibit neurotrophic activity (e.g., promotion of neurite outgrowth). Therefore, the compounds may be useful as neurotrophic agents. In certain embodiments, compounds of the invention may find use in the treatment of Alzheimer's Disease (AD).
  • AD Alzheimer's Disease
  • Xi and X 2 are independently O or NR XI , wherein R xl is hydrogen, an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl moiety, or a nitrogen protecting group;
  • Ri is hydrogen, halogen, -OR 1A , -SR 1 A , -NR 1 ⁇ R 1B , or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; wherein R 1A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R 1 B is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety;
  • R 3 , R 4 and R 5 are independently hydrogen, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety;
  • R 6 is hydrogen, halogen, -OR 6A , -SR 6A , -NR 6A R 6B , or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; wherein R 6A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety; and R is hydrogen, a nitrogen protecting group, or an aliphatic, alicyclic heteroaliphatic, heterocyclic, aryl, or heteroaryl moiety.
  • compounds of the invention have the following stereochemistry:
  • compounds of formula (I) exclude compounds having the following structure:
  • the present invention defines particular classes of compounds which are of special interest.
  • one class of compounds of special interest includes those compounds of Formula I wherein: n is 0 or 1; m is 1 or 2;
  • Xi and X 2 are independently O or NR , wherein R is hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, acyl moiety, or a nitrogen protecting group;
  • Ri is hydrogen, halogen, -OR 1A , -SR 1 ⁇ , -NR 1A R 1B , or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R IA is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R 1B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;
  • R 3 , R 4 and R 5 are independently hydrogen, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;
  • R 6 is hydrogen, halogen, -0R 6A , -SR 6A , -NR 6A R 6B , or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R 6A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R 6B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety.
  • Another class of compounds of special interest includes those compounds having the structure:
  • R 1 -R 6 , X 1 , X 2 and m are as described generally and in classes and subclasses herein.
  • Another class of compounds of special interest includes those compounds having the structure:
  • Ri-R 6 , Xi, X 2 and m are as described generally and in classes and subclasses herein.
  • n is 0; [0043] ii) n is 1; [0044] iii) m is l; [0045] iv) m is 2; [0046] v) X 1 is O;
  • X] is NR X1 wherein R X1 is hydrogen, lower alkyl or acyl;
  • X 2 is NR X2 wherein R X2 is hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, acyl moiety, or a nitrogen protecting group;
  • X 2 is NR ⁇ wherein R x2 is hydrogen, lower alkyl or acyl;
  • R 1 is hydrogen, halogen, -OR 1A , -SR 1 A , -NR 1A R 1 B , or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R 1A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R 1B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;
  • Ri is hydrogen, halogen, -OR 1A , or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R 1A is hydrogen, an oxygen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;
  • Ri is hydrogen or -OR 1A ; wherein R IA is hydrogen, an oxygen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;
  • ZR A wherein Z is -O-, -S-, -NR B , wherein each occurrence of R A and R B is independently hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
  • R 1 is hydrogen or -OH
  • Ri is hydrogen
  • R 1 is OH
  • R 2 is hydrogen, halogen, -OR 2A , -SR 2A , -NR 2A R 2B , -CO 2 R 2A , -
  • R 2A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety
  • R 2B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety
  • R 2C and R 2D are indenpently hydrogen, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;
  • R 2 is hydrogen, halogen, -OR 2A or -CO 2 R 2A ; wherein R 2A is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R 2B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R 2C and R 2D are indenpently hydrogen, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;
  • ZR A wherein Z is -O-, -S-, -NR D , wherein each occurrence of R A and R B is independently hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
  • R 2 is hydrogen or -CO 2 R 2A ; wherein R 2A is hydrogen or lower alkyl;
  • R 2 is hydrogen or -CO 2 Me
  • R 2 is hydrogen
  • R 2 is -CO 2 R 2A ; wherein R 2A is hydrogen or lower alkyl;
  • R 2 is -CO 2 Me
  • R 3 , R 4 and R 5 are independently hydrogen, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;
  • R 3 , R 4 and R 5 are independently hydrogen or lower alkyl
  • R 3 , R 4 and R 5 are independently hydrogen or methyl;
  • R 6 is hydrogen, halogen, -OR 6A , -SR 6 ⁇ , -NR 6A R 6B , or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R 6 ⁇ is hydrogen, an oxygen protecting group, a sulfur protecting group, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; and R 6B is hydrogen, a nitrogen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;
  • R 6 is hydrogen, halogen, -OR 6A , or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety; wherein R 6A is hydrogen, an oxygen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;
  • R 6 is hydrogen or -OR 6A ; wherein R 6A is hydrogen, an oxygen protecting group, or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, or heteroaryl moiety;
  • ZR A wherein Z is -O-, -S-, -NR B , wherein each occurrence of R A and R B is independently hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
  • R 6 is hydrogen or -OR 6A ; wherein R 6A is hydrogen or lower alkyl;
  • R 6 is hydrogen or -OR 6A ; wherein R 6A is hydrogen or methyl;
  • R 6 is hydrogen
  • any one or more occurrences of aliphatic, alicyclic heteroaliphatic, heterocyclic, alkyl, heteroalkyl may independently be substituted or unsubstituted, cyclic or acyclic, linear or branched and any one or more occurrences of aryl, heteroaryl, alicyclic, heteroalicyclic may be substituted or unsubstituted.
  • compounds of particular interest include, among others, those which share the attributes of one or more of the foregoing subclasses. Some of those subclasses are illustrated by the following sorts of compounds:
  • Ri-R 6 , m and X 2 are as efined generally above and in classes and subclasses herein.
  • the compounds have the following stereochemistry:
  • Ri-R 6 , m and X 2 are as defined generally above and in classes and subclasses herein.
  • the compounds have the following stereochemistry:
  • Ri-R 6 and m are as defined generally above and in classes and subclasses herein.
  • the compounds have the following stereochemistry:
  • the compound has one of the following structures:
  • the compound has the structure:
  • Ri-R 6 and m are as defined generally above and in classes and subclasses herein.
  • the compounds have the following stereochemistry:
  • the compound has one of the following structures:
  • the compound has the structure:
  • the compound has the structure:
  • Ri-R 6 and m are as defined generally above and in classes and subclasses herein.
  • the compounds have the following stereochemistry:
  • the compound has the structure:
  • Ri-R 6 , m and X 2 are as defined generally above and in classes and subclasses herein.
  • the compounds have the following stereochemistry:
  • w erein Ri-R 6 , m and X 2 are as defined gen above and in classes and subclasses herein. In certain embodiments, the compounds have the following stereochemistry:
  • RpR 6 and m are as defined generally above and in classes and subclasses herein.
  • the compounds have the following stereochemistry:
  • the compound has the structure:
  • Ri-R 6 and m are as defined generally above and in classes and subclasses herein.
  • the compounds have the following stereochemistry:
  • the compound has the structure:
  • Ri-R 6 and m are as defined generally above and in classes and subclasses herein.
  • the compounds have the following stereochemistry:
  • Ri-R 6 and m are as defined generally above and in classes and subclasses herein.
  • the compounds have the following stereochemistry:
  • Ri is hydrogen or OH.
  • R 2 is hydrogen or -CO 2 Me.
  • R 3 and R 4 are independently hydrogen or lower alkyl.
  • R 3 and R 4 are independently hydrogen or methyl.
  • R 3 is methyl and R 4 is hydrogen.
  • R 5 is hydrogen or lower alkyl.
  • R 5 is hydrogen or methyl.
  • R 6 is hydrogen or OH.
  • m is 1.
  • each of the compounds described herein and each of the subclasses of compounds described above may be substituted as described generally herein, or may be substituted according to any one or more of the subclasses described above and herein (e.g., i- xxxvii).
  • inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers.
  • the compounds of the invention are enantiopure compounds.
  • mixtures of stereoisomers or diastereomers are provided.
  • mixture may or may not be racemic.
  • the mixture is racemic.
  • certain compounds, as described herein may have one or more double bonds that can exist as either the Z or E isomer, unless otherwise indicated.
  • the invention additionally encompasses the compounds as individual isomers substantially free of other isomers and alternatively, as mixtures of various isomers, e.g., racemic mixtures of stereoisomers.
  • this invention also encompasses pharmaceutically acceptable derivatives of these compounds and compositions comprising one or more compounds of the invention and one or more pharmaceutically acceptable excipients or additives.
  • Compounds of the invention may be prepared by crystallization of compound of formula (I) under different conditions and may exist as one or a combination of polymorphs of compound of general formula (I) forming part of this invention.
  • different polymorphs may be identified and/or prepared using different solvents, or different mixtures of solvents for recrystallization; by performing crystallizations at different temperatures; or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
  • Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffractogram and/or other techniques.
  • the present invention encompasses inventive compounds, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and pharmaceutically acceptable compositions containing them.
  • this invention provides novel compounds with a range of biological properties. Preferred compounds of this invention have biological activities relevant for the treatment of neurodegenerative diseases and disorders.
  • Compounds of this invention include those specifically set forth above and described herein, and are illustrated in part by the various classes, subgenera and species disclosed elsewhere herein. [0125] 1) Synthetic Methodology
  • the present invention provides methods for preparing novel polycycles having formula (I) a described above and in certain classes and subclasses herein.
  • An overview of exemplary synthesic approaches to the inventive compounds is provided below, as detailed in Schemes 1-13, and in the Exemplification herein. It will be appreciated that the methods as described herein can be applied to each of the compounds as disclosed herein and equivalents thereof. Additionally, the reagents and starting materials are well known to those skilled in the art. Although the following schemes describe certain exemplary compounds, it will be appreciated that the use of alternate starting materials will yield other analogs of the invention. [0129] As disccused previously, Fukuyama et. al.
  • the moderate selectivity (3:1) is presumably a result of stereoelectronic effect in the enolate intermediate with the bulky TBS protected hydroxymethyl group configured in an pseudo-equatorial position.
  • the C-I methyl group may be introduced at an earlier stage in the synthesis.
  • conversion of the ester moiety to the ⁇ - ketophosphonate followed by intramolecular Horner-Emmons-Wadsworth reaction 6 led to cyclopentenone 16 in 91% yield (Scheme 6).
  • ⁇ -methylation at C 1 occurred primarily from the ⁇ -face, anti to the pendant allyl functionality to afford, upon deprotection, 17, as a 7:1 mixture of isomers.
  • the bulkier TBDPS ether 23 was prepared under standard conditions. Alkylation to provide tri substituted cyclohexanone 25 and subsequent treatment with t-BuOK and allylchloroformate furnished allyl cyclohexenol carbonate 27 (Scheme 8). Upon exposure of carbonate 27 to [Pd(PPh 3 ) 4 ] in THF at -40 0 C, ⁇ , ⁇ '-tetrasubstituted cyclohexanone 28 and 29 were obtained in a 1 :8.7 ratio. Attempts to run the reaction at lower temperature led to poor conversion.
  • Deuterated Jio-diallylcarbonate 36 was prepared by reacting J 5 -allyl alcohol and ⁇ N-carbonyldiimidazole in DMF. A solution of carbonate 27 and 10 equivalents of 36 in THF was then treated with [Pd(PPh 3 ) 4 ] for 15 minutes. To our surprise, the mixture of ⁇ , ⁇ '-tetrasubstituted cyclohexanones, after purification, showed 67% of d 5 -allyl incorporation. This result clearly invalidated the hypothesis that the enhanced selectivity observed during the formation of the 14/15, and 28/29 respectively, by Pd-catalyzed allylation originates from an intrmolecular process.
  • Thioester 33 was formed under standard procedure from carboxylic 31, and subsequently reduced by a mild Fukuyama reduction to give rise to aldehyde 34.
  • the neurotrophic activity of 10, 22, 27 and 1 was examined (See Example 16).
  • the ability of jiadifenin (1) to promote neurite outgrowth was measured in both the presence and absence of nerve growth factor (NGF).
  • NGF nerve growth factor
  • jiadifenin enhanced neurite lengths by 162% (P ⁇ 0.05).
  • no neurite outgrowth was observed, indicating that jiadifenin operates by upregulating the action of NGF rather than functioning independently.
  • NGF nerve growth factor
  • we evaluated the in vitro neurotrophic activity of several synthetic analogs of the natural product in order to establish an SAR profile See Table 1 and Figure 1 - data shown for 22 and 1 only).
  • Neurite lengths enhanced by 27, 22 and 1 were 181% (/ > ⁇ 0.01), 184% (PO.01) and 162% (P ⁇ 0.05), respectively, relative to the DMSO control.
  • each of the components used in the synthesis of jiadifenin analogues can be diversified either before synthesis or alternatively after the construction of the polycycle.
  • the term "diversifying” or “diversify” means reacting an inventive compound (I) or any of the precursor fragments as defined herein (or any classes or subclasses thereof) at one or more reactive sites to modify a functional moiety or to add a functional moiety (e.g., nucleophilic addition of a substrate).
  • Described generally herein are a variety of schemes to assist the reader in the synthesis of a variety of analogues, either by diversification of the intermediate components or by diversification of the macrocyclic structures as described herein, and classes and subclasses thereof. It will be appreciated that a variety of diversification reactions can be employed to generate novel analogues. For additional guidance available in the art, the practitioner is directed to "Advanced Organic Chemistry", March, J. John Wiley & Sons, 2001, 5 th ed., the entire contents of which are hereby incorporated by reference. For example, analogs of the structure depicted below may be prepared:
  • Rl H, OH, OR, alkyl, heteroalkyl, aryl, heteroaryl, amino, halogen, SH, SR 1 .
  • R3, R4, R5 H, alkyl, aryl, heteroalkyl
  • R6 H, OH, OR, alkyl, heteroalkyl, aryl, heteroaryl, amino, halogen, SH, SR 1
  • this invention provides novel compounds that have biological properties useful for the treatment of any disorder or condition that would benefit from promotion of neurite outgrowth.
  • compositions which comprise any one of the compounds described herein (or a prodrug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative thereof), and optionally comprise a pharmaceutically acceptable carrier.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • a compound of this invention may be administered to a patient in need thereof in combination with the administration of one or more other therapeutic agents.
  • additional therapeutic agents for conjoint administration or inclusion in a pharmaceutical composition with a compound of this invention may be an approved agent for the treatment of a neurodegenerative disease or disorder, or it may be any one of a number of agents undergoing approval in the Food and Drug Administration that ultimately obtain approval for the treatment of any disorder or condition that benefits from promotion of neurite outgrowth. It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof.
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a pro-drug or other adduct or derivative of a compound of this invention which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • the composition may include one or more additional inventive compounds.
  • the composition when used to treat Alzheimer's disease, the composition optionally may contain therapeutically effective amount of one or more compounds that are used to treat cognitive symptoms of Alzheimer's disease including but not limited to: cholinesterase inhibitors (e.g., donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Reminyl®) and Tacrine (Cognex®)) and N- methyl-D-aspartate (NMDA) receptor antagonists (e.g., Memantine (Namenda®)).
  • cholinesterase inhibitors e.g., donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Reminyl®) and Tacrine (Cognex®)
  • NMDA N- methyl-D-aspartate
  • the composition when used to treat Alzheimer's disease, the composition optionally may contain therapeutically effective amount of vitamin E.
  • Vitamin E supplements are often prescribed as a treatment for Alzheimer's disease, because they may help brain cells defend themselves from “attacks.” Normal cell functions create a byproduct a called free radical, a kind of oxygen molecule that can damage cell structures and genetic material. This damage, called oxidative stress, may play a role in Alzheimer's disease.
  • the composition when used to treat Parkinson's disease, the composition optionally may contain therapeutically effective amount of one or more compounds that are used to treat Parkinson's disease including but not limited to: Anticholinergics (e.g., Benztropine, Ethropropazine, Procyclidine and Trihexyphenidyl), COMT Inhibitors (such as Entacapone or Tolcapone), Dopamine Precursor (such as levodopa), Dopamine Receptor Agonists (e.g., Bromocriptine, Cabergoline, Pergolide, Pramipexole and Ropinirole) and MAO-B Inhibitors (e.g., Amantadine).
  • Anticholinergics e.g., Benztropine, Ethropropazine, Procyclidine and Trihexyphenidyl
  • COMT Inhibitors such as Entacapone or Tolcapone
  • Dopamine Precursor such as levodopa
  • a wide variety of carriers may be selected of either polymeric or non- polymeric origin which may be biodegradable or non-biodegradable. Examples of suitable carriers are described in published U.S. Patent Application 2002/0128471, paragraphs [0111] through [0123] which are incorporated herein by reference.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. For example, S. M.
  • suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • ester refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the issues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • the pharmaceutical compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, 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; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsif ⁇ ers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents
  • the oral compositions can 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.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drug release can be controlled.
  • biodegradable polymers include (poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • compositions for rectal or vaginal administration 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 solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar— agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
  • the dosage form 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.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. 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 polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose and starch.
  • inert diluent such as sucrose, lactose and starch.
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the present invention encompasses pharmaceutically acceptable topical formulations of inventive compounds.
  • pharmaceutically acceptable topical formulation means any formulation which is pharmaceutically acceptable for intradermal administration of a compound of the invention by application of the formulation to the epidermis.
  • the topical formulation comprises a carrier system.
  • Pharmaceutically effective carriers include, but are not limited to, solvents (e.g., alcohols, poly alcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline) or any other carrier known in the art for topically administering pharmaceuticals.
  • solvents e.g., alcohols, poly alcohols, water
  • creams e.g., lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline) or any other carrier known in the art for topically administering pharmaceuticals.
  • buffered solutions e.g., hypotonic or buffered saline
  • the topical formulations of the invention may comprise excipients.
  • Any pharmaceutically acceptable excipient known in the art may be used to prepare the inventive pharmaceutically acceptable topical formulations.
  • excipients that can be included in the topical formulations of the invention include, but are not limited to, preservatives, antioxidants, moisturizers, emollients, buffering agents, solubilizing agents, other penetration agents, skin protectants, surfactants, and propellants, and/or additional therapeutic agents used in combination to the inventive compound.
  • Suitable preservatives include, but are not limited to, alcohols, quaternary amines, organic acids, parabens, and phenols.
  • Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid.
  • Suitable moisturizers include, but are not limited to, glycerine, sorbitol, polyethylene glycols, urea, and propylene glycol.
  • Suitable buffering agents for use with the invention include, but are not limited to, citric, hydrochloric, and lactic acid buffers.
  • Suitable solubilizing agents include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.
  • Suitable skin protectants that can be used in the topical formulations of the invention include, but are not limited to, vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.
  • the pharmaceutically acceptable topical formulations of the invention comprise at least a compound of the invention and a penetration enhancing agent.
  • a penetration enhancing agent means an agent capable of transporting a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably, with little or no systemic absorption.
  • penetration enhancing agent means an agent capable of transporting a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably, with little or no systemic absorption.
  • a wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H. I.
  • penetration agents for use with the invention include, but are not limited to, triglycerides (e.g., soybean oil), aloe compositions ⁇ e.g., aloe- vera gel), ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate) and N-methyl pyrrolidone.
  • triglycerides e.g., soybean oil
  • aloe compositions ⁇ e.g., aloe- vera gel
  • ethyl alcohol isopropyl alcohol
  • octolyphenylpolyethylene glycol oleic acid
  • polyethylene glycol 400 propylene glycol
  • the compositions may be in the form of ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • formulations of the compositions according to the invention are creams, which may further contain saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleyl alcohols, stearic acid being particularly preferred.
  • Creams of the invention may also contain a non-ionic surfactant, for example, polyoxy-40-stearate.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are made by dissolving or dispensing the compound in the proper medium.
  • penetration enhancing agents can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another therapeutic agent useful for the treatment of a suitable neuridegenerative diseases or disorder), or they may achieve different effects (e.g., control of any adverse effects).
  • the pharmaceutical compositions of the present invention further comprise one or more additional therapeutically active ingredients (e.g., neurotrophic agent and/or palliative).
  • additional therapeutically active ingredients e.g., neurotrophic agent and/or palliative.
  • palliative refers to treatment that is focused on the relief of symptoms of a disease and/or side effects of a therapeutic regimen, but is not curative.
  • palliative treatment encompasses painkillers, antinausea medications and anti-sickness drugs.
  • the inventive compounds may be assayed in any of the available assays known in the art for identifying compounds having neurotrophic activity.
  • the assay may be cellular or non-cellular, in vivo or in vitro, high- or low-throughput format, etc.
  • compounds of this invention which are of particular interest include those which:
  • inventive compounds as described herein exhibit activity generally as neurotrophic agents. More specifically, compounds of the invention act as modulators of neurite outgrowth.
  • inventive compounds exhibit neurite length enhancement > about 50% at a concentration between about 0.1 ⁇ M and 10 ⁇ M.
  • inventive compounds exhibit exhibit neurite length enhancement > about 70% at a concentration between about 0.1 ⁇ M and 10 ⁇ M.
  • inventive compounds exhibit exhibit neurite length enhancement > about 80% at a concentration between about 0.1 ⁇ M and 10 ⁇ M.
  • inventive compounds exhibit exhibit exhibit neurite length enhancement > about 90% at a concentration between about 0.1 ⁇ M and 10 ⁇ M. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 100% at a concentration between about 0.1 ⁇ M and 10 ⁇ M. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 120% at a concentration between about 0.1 ⁇ M and 10 ⁇ M. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 150% at a concentration between about 0.1 ⁇ M and 10 ⁇ M. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 160% at a concentration between about 0.1 ⁇ M and 10 ⁇ M.
  • inventive compounds exhibit exhibit neurite length enhancement > about 170% at a concentration between about 0.1 ⁇ M and 10 ⁇ M. In certain other embodiments, inventive compounds exhibit exhibit neurite length enhancement > about 180% at a concentration between about 0.1 ⁇ M and 10 ⁇ M. In certain embodiments, the following compounds exhibited the following neurite length enhancements at a concentration of 0.3 ⁇ M. neurite lengths enhanced relative to the DMSO-NGF control
  • the present invention provides methods for treating or lessening the severity of any disorder or condition that would benefit from promotion of neurite outgrowth.
  • methods of using the compounds of the present invention comprise administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention.
  • Diseases that may be treated with the compounds of the present invention are those that are associated with neurotrophic activity, such as neurodegenerative disorders.
  • neurodegenerative disorders include, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease and Lou Gehrig's disease.
  • methods for the treatment of a neurodegenerative disorder comprising administering a therapeutically effective amount of a compound of formula (I), as described herein, to a subject in need thereof, wherein the amount is effective to promote neurite outgrowth.
  • a method for the treatment of a neurodegenerative disorder comprising administering a therapeutically effective amount of an inventive compound, or a pharmaceutical composition comprising an inventive compound to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result.
  • the method involves the administration of a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to a human or animal) in need of it.
  • a neurodegenerative disorder including, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease and Lou Gehrig's disease.
  • the compounds in accordance with the present invention may be used in combination with a supplementary active compound or as a substitution for treating a subject suffering from a neurodegenerative disease or disorder.
  • a supplementary active compound such as cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine and Tacrine), N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., Memantine) and/or vitamin E supplements.
  • cholinesterase inhibitors e.g., donepezil, rivastigmine, galantamine and Tacrine
  • NMDA N-methyl-D-aspartate
  • Memantine vitamin E supplements.
  • the compound when used to treat or lessen to the severity of Parkinson's disease, the compound may be used alone or combination with one or more supplementary active compounds such as Anticholinergics (e.g., Benztropine, Ethropropazine, Procyclidine and Trihexyphenidyl), COMT Inhibitors (such as Entacapone or Tolcapone), Dopamine Precursor (such as levodopa), Dopamine Receptor Agonists (e.g., Bromocriptine, Cabergoline, Pergolide, Pramipexole and Ropinirole) and MAO-B Inhibitors (e.g., Amantadine).
  • Anticholinergics e.g., Benztropine, Ethropropazine, Procyclidine and Trihexyphenidyl
  • COMT Inhibitors such as Entacapone or Tolcapone
  • Dopamine Precursor such as levodopa
  • Dopamine Receptor Agonists
  • a compound of the invention may be used alone or in combination with another neurotrophic agent, or a second compound of the invention to treat, prevent or inhibit Alzheimer's disease.
  • treatment of a subject with a therapeutically effective amount of the compounds fo the invention can include a single treatment or, preferably, can include a series of treatments.
  • inventive compounds can be administered in any manner sufficient to achieve the above endpoints.
  • Exemplary methods of administration include intravenous, oral, or subcutaneous, intramuscular or intrathecal injection.
  • the inventive compounds can be administered as a chronic low dose therapy to prevent disease progression, prolong disease remission or decrease symptoms in active disease.
  • the therapeutic agent can be administered in higher doses as a "pulse" therapy to induce remission in acutely active disease.
  • the minimum dose capable of achieving these endpoints can be used and can vary according to patient, severity of disease, formulation of the administered agent, and route of administration.
  • an effective therapy for Alzheimer's disease will accomplish one or more of the following: (i) decrease the severity of symptoms (e.g., forgetfulness, memory loss, decision making impairment, problems speaking, understanding, reading, or writing, anxiety, aggressivity); (ii) decrease the severity of clinical signs of the disease (e.g., beta-amyloid deposits in the brain, massive loss of cortical neurons and accumulation of paired helical filaments (PHFs) in the neurofibrillary tangles (NFTs)); (iii) increase the frequency and duration of disease remission/symptom-free periods; and (iv) prevent/attenuate chronic progression of the disease.
  • symptoms e.g., forgetfulness, memory loss, decision making impairment, problems speaking, understanding, reading, or writing, anxiety, aggressivity
  • clinical signs of the disease e.g., beta-amyloid deposits in the brain, massive loss of cortical neurons and accumulation of paired helical filaments (PHFs) in the neurofibrill
  • Another aspect of the invention relates to a method for promoting neurite outgrowth in a biological sample or a subject, which method comprises administering to the subject, or contacting said biological sample with a compound of formula I or a composition comprising said compound.
  • Another aspect of the invention relates to a method of treating or lessening the severity of a neurodegenerative disease or condition associated in a subject, said method comprising a step of administering to said subject, a compound of formula I or a composition comprising said compound.
  • the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for the treatment of neurodegenerative disorders.
  • the expression "effective amount” as used herein refers to a sufficient amount of agent to promote neurite outgrowth, or refers to a sufficient amount to reduce the effects/symptoms of Alzheimer's disease.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the diseases, the particular compound, its mode of administration, and the like.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. 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 or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the 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 coincidental with the specific compound employed; and like factors well known in the medical arts (see, for example, Goodman and Gilman's, "The Pharmacological Basis of Therapeutics", Tenth Edition, A. Gilman, J.Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein by reference in its entirety).
  • the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, creams or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered at dosage levels of about 0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. It will also be appreciated that dosages smaller than 0.001 mg/kg or greater than 50 mg/kg (for example 50-100 mg/kg) can be administered to a subject. In certain embodiments, compounds are administered orally or parenterally.
  • the present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention.
  • the pharmaceutical pack or kit comprises one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • kits are especially suited for the delivery of solid oral forms such as tablets or capsules.
  • Such a kit preferably includes a number of unit dosages, and may also include a card having the dosages oriented in the order of their intended use.
  • a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.
  • placebo dosages, or calcium dietary supplements can be included to provide a kit in which a dosage is taken every day.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • any available techniques can be used to make or prepare the inventive compounds or compositions including them.
  • a variety of solution phase synthetic methods such as those discussed in detail below may be used.
  • the inventive compounds may be prepared using any of a variety combinatorial techniques, parallel synthesis and/or solid phase synthetic methods known in the art.
  • inventive compounds can be synthesized according to the methods described herein.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, WI), Bachem (Torrance, CA), Sigma (St. Louis, MO), or are prepared by methods well known to a person of ordinary skill in the art following procedures described in such references as Fieser and Fieser 1991, “Reagents for Organic Synthesis", vols 1-17, John Wiley and Sons, New York, NY, 1991; Rodd 1989 “Chemistry of Carbon Compounds", vols.
  • the starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data.
  • Lactone 9 To a cooled (0 0 C) solution of alcohol 14a (1.05 g, 4.50 mmol) in CH 2 Cl 2 (90 mL) were added DMAP (1 1 mg, 0.02 equiv), pyridine (8.5 mL, 23 equiv) and ethyl chloroformate (5.2 mL, 12 equiv) and the resulting mixture was stirred at room temperature for 21 h. Another 2.6 mL of ethyl chloroformate was added and the reaction mixture was stirred for an additional 15 min. The reaction mixture was quenched with 2N aqueous HCl (200 mL) and extracted with EtOAc (3 X 200 mL).
  • Lactone 10 To a cooled (-45 0 C) solution of LDA (3.5 equiv) in THF (20 mL) was added a solution of diol 19 (153 mg, 0.548 mmol) in THF (2.5 mL) and the resulting mixture was warmed to -15 0 C over 55 min. The reaction mixture was cooled to -40 0 C, treated with a mixture of iodomethane (40 ⁇ L, 1.2 equiv) and HMPA (90 ⁇ L, 1.0 equiv), and stirred at -35 0 C for 18 h. The reaction mixture was quenched with saturated NH 4 Cl (125 mL) and extracted with EtOAc (3 X 150 mL).
  • Alcohol 20 (69.5 mg, 0.236 mmol) was azeotroped with anhydrous benzene (3 X 80 mL) and placed under high vacuum for 1 h. Then the alcohol was dissolved in THF (80 mL), cooled to -78 0 C, and treated with a solution of NaHMDS (0.93 mL, 3.9 equiv) in THF (1.0 M). The resultant mixture was stirred at -78 0 C for 6 min.
  • Compound 25 Alcohol 24 (113.8 mg, 0.406 mmol) was azeotroped with anhydrous benzene (60 mL x 3) and placed under high vacuum for 1 h. Then the alcohol was dissolved in THF (110 mL) and cooled to -78 0 C. To this solution was added a solution of NaHMDS in THF (1.0 M, 0.93 mL). The resultant mixture was stirred at -78 0 C for 6 minutes.
  • Neurotrophic factors which play an important role in neuronal survival, differentiation, growth, and apoptosis, have emerged as a potential therapy for Alzheimer's disease (AD) and other neurodegenerative disorders. Interventions that mimic NGF action in patients may facilitate the maintenance of neuronal function and could potentially be used to treat neurodegenerative diseases. However, due to poor pharmacokinetics and bioavailability of NGF and other neurotrophins, the use of these proteins as therapeutic agents is limited. Developing small molecules that enhance or mimic NGF function would be a practical and promising approach to treat AD and other human disorders.
  • the PC- 12 cell line was derived from a transplantable rat pheochromocytoma (Greene, L. A.; Tischler, A. S. P. Natl. Acad. Sci. U.S.A. 1976, 73, 2424). Since PC 12 cells can be induced to differentiate toward sympathetic neurons after treatment with nerve growth factor (NGF), it has been a useful model for the study of neuronal development. Therefore, the PC 12 cells were chosen to assay the activities of jiadifenin and its analogs.
  • NGF nerve growth factor
  • PC 12 cells were cultured in a 96- well collagen coated plate in

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Abstract

L'invention concerne des composés de formule (I) et des procédés relatifs à leur synthèse, des compositions correspondantes, et des procédés d'utilisation correspondants pour le traitement de troubles neurodégénérescents, sachant que R1-R6, m et n sont tels que définis dans la description.
PCT/US2005/024483 2004-07-08 2005-07-08 Analogues de jiadifenine et utilisations WO2006019673A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105732654A (zh) * 2016-01-29 2016-07-06 暨南大学 二氢青蒿素-美金刚二联体化合物及其合成方法和用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
I. KOUNO ET AL: "Sesquiterpene Lactones from the Pericarps of Illicium majus; 2-Oxy Derivatives of Neomajucin and 3,4-Dehydroxyneomajucin" CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 38, no. 2, 1990, pages 422-5, XP008066830 cited in the application *
R. YOKOYAMA ET AL: "New seco-Prezizaane-Type Sesquiterpenes, Jiadifenin with Neurotropic Activity and 1,2-Dehydroneomajucin from Illicium jiadifengpi" JOURNAL OF NATURAL PRODUCTS, vol. 65, no. 4, 2002, pages 527-531, XP002391240 *
YOUNG SHIN CHO ET AL: "Total Synthesis of (+-)-Jiadifenin, a Non-peptidyl Neurotrophic Modulator" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 126, no. 44, 16 October 2004 (2004-10-16), pages 14358-14359, XP002391242 cited in the application *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105732654A (zh) * 2016-01-29 2016-07-06 暨南大学 二氢青蒿素-美金刚二联体化合物及其合成方法和用途

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