WO2009048559A1 - Maxi-k channel blockers and methods of use - Google Patents

Maxi-k channel blockers and methods of use Download PDF

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Publication number
WO2009048559A1
WO2009048559A1 PCT/US2008/011557 US2008011557W WO2009048559A1 WO 2009048559 A1 WO2009048559 A1 WO 2009048559A1 US 2008011557 W US2008011557 W US 2008011557W WO 2009048559 A1 WO2009048559 A1 WO 2009048559A1
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WIPO (PCT)
Prior art keywords
paspalinine
carbamoyloxypaspalinine
ethyloxy
oxo
hydroxy
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PCT/US2008/011557
Other languages
French (fr)
Inventor
Ed Brnardic
James B. Doherty
Jimmy Dorsey
Charles Ellwood
Martin Fillmore
Mike Malaska
King Nelson
Mustapha Soukri
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Merck & Co., Inc.
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Publication of WO2009048559A1 publication Critical patent/WO2009048559A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—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 three hetero rings
    • C07D491/18—Bridged systems

Definitions

  • Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.
  • the present invention relates to novel indole diterpene alkaloids which are useful as potassium channel antagonists, particularly as Maxi-K channel antagonists. These alkaloids are useful in treating glaucoma and other associated conditions, and macular degeneration. More particularly, the present invention includes compounds of formula I and pharmaceutically acceptable salts thereof:
  • R is H, OPO3, COR2, OCOR2, -NHR2, OR2, CH(R2)2, OCNHR2, (CHR2)nNR2C(O)O(CH 2 ) n R2, (C(Rl)2)pNRiR 2 ; -NCOR 2 , (CH 2 ) n ORl ; Ci- 6 alkyl, (CH2) n C6-10 aryl, (CH 2 ) n heterocyclyl, C2-6 alkenyl, (CH2) n C3-6 cycloalkyl, THF, - (CH2) n NR2(CH2)n-, -(CH2) n O) s R2-, or OCOC(R2)2N(R2)2, said alkyl, alkenyl, cycloalkyl, aryl and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
  • Rl and Ri a independently represent H, (CH2) n OCONH(CH2) n R, (CH2) n C00R, (CH2) n 0R, COR, COO-C6-10aryl, COOalkylR, OCOC(R)2N(R)2, C0NR(CH2) n R, (CH2) n OCOalkylR, halogen, COalkyl, Ci_6alkyl, C2-6alkenyl, (CH2) n C3-6cycloalkyl, (CH2) n C(S)N(R)2, (CH 2 )nC5-10 heterocyclyl, (CH 2 ) n C6-10 aryl, (-(CH 2 ) n O) s , (CH 2 )nC(O)(CH2) n C(O)OR, (CH2) n OP(O)(OR)2, or -(CHR) n N(R2)2, said alkyl, alkenyl, aryl, and
  • R2 is H, (CH2) n C00R, (CH2) n 0R, COR, NRCOR, C0NR(CH2) n R, halogen, (CH2) n COalkyl, C 1 -6alkyl, C2-6alkenyl, (CH2) n C3-6cycloalkyl, (CH2) n C5- 10 heterocyclyl, (CH2) n C6- 10 aryl, (-(CH2)nO)s, or -CHRN(R)2, said alkyl, alkenyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of R a ;
  • R3 is H, Ci-6 alkyl, -Si((R)2)R, (CH2) n C5-10 heterocyclyl, -P(O)(OR)2,or -PO3, said alkyl and heterocyclyl optionally substituted with 1 to 3 groups of R a ;
  • R5 is CO2R1, CH2OR, or halo
  • Rl 3 is H, or CON(Ri )2;
  • R21 and R23 independently represent hydrogen, CN, COOR, CONR 1 R 2 , CONHR 1 , halogen, SO 2 R, C5-10 heterocyclyl, NO 2 , H, OR, COR, Ci -6 alkyl, C2-6 alkenyl, (CH2) n C5-10 aryl, said a ⁇ kyl, alkenyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of R a ;
  • Ra is OH, C 1-6 alkyl, C3-6 cycloalkyl, (CH2) n C6-10 aryl, -O(CH2) n C6-10 aryl, CF3, halo, -SR, -0-, NO2, (CH2) n 0Rl, C2-6 alkenyl, CN, N(Ri)2, COOR3, SO2R, -OP(O)(OR)2, -OPO3, or -
  • the claimed compounds lack the tremorgenic liability of other indole diterpenes, yet retain excellent potency against the Maxi-K channel.
  • the present invention is directed to novel indole diterpenes of formula I described above.
  • the compounds of this invention block the Maxi-K channel and do not have a tremorgenic effect.
  • This invention is also directed to a method for treating ocular hypertension or glaucoma which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having structural formula I.
  • An embodiment of this invention is realized when Ri a is hydrogen, C] -6 alkyl, COO-C6- 1 OarylR, COOalkylR, (CH2) n OCONH(CH2) n R, COOR, or OCOC(R)2N(R)2, and all other variables are as originally described.
  • Another embodiment of this invention is realized when Ri is hydrogen and all other variables are as originally described.
  • Yet another embodiment is realized when Ri a is (CH2)nOCONH(CH2)nR and all other variables are as originally described.
  • Still another embodiment of this invention is realized when Rl 3 is CONR and all other variables are as originally described.
  • Ri 4 is Ci -6 alkyl, (CH2) n C3-6 cycloalkyl, C2-6 alkenyl, (CH2) n heterocyclyl, (CH2) n aryl, (CH2) n CON(Ri)2, (CH2) n OR3, (CH2) n C(Rl)2C(R2)2 ⁇ R3, or (CH2) n C(R2)2 ⁇ R3 and all other variables are as originally described.
  • Ri 4 is (CH2)nCON(Ri)2 5
  • Still another embodiment of this invention is realized when R21 is hydrogen.
  • Another embodiment of this invention is realized when R21 is CN, halogen, COOR, C2-6 alkenyl, OR, or NO2,
  • Rl 0 a and R] a is hydrogen.
  • Rl a is halogen, C2-6 alkenyl, C 1-6 alkyl, C0NH(CH2) n R, (CH2) n OR, COR, (CH2) n C00R.
  • the compounds of the present invention may have asymmetric centers, chiral axes and chiral planes, and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. (See E.L. Eliel and S. H. Wilen Stereochemistry of Carbon Compounds
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl, cyclopentyl and cyclohexyl. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group”.
  • Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, unless otherwise defined, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings, which are fused. Examples of such cycloalkyl elements include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkenyl is C2-C6 alkenyl.
  • Alkoxy refers to an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, with the alkyl group optionally substituted as described herein.
  • Said groups are those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond.
  • Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, propargyloxy, and the like.
  • Halogen refers to chlorine, fluorine, iodine or bromine.
  • Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like.
  • An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms.
  • aryl groups are phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl and phenanthrenyl, preferably phenyl, naphthyl or phenanthrenyl.
  • Aryl groups may likewise be substituted as defined.
  • Preferred substituted aryls include phenyl and naphthyl.
  • heterocyclyl or heterocyclic represents a stable 3- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
  • heterocycle or heterocyclic includes heteroaryl moieties.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydropyrrolyl, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholin
  • heterocycle is selected from 2-azepinonyl, benzimidazolyl, 2-diazapinonyl, dihydroimidazolyl, dihydropyrrolyl, imidazolyl, 2-imidazolidinonyl, indolyl, isoquinolinyl, morpholinyl, piperidyl, piperazinyl, pyridyl, pyrrolidinyl, 2-piperidinonyl, 2-pyrimidinonyl, 2-pyrollidinonyl, quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl.
  • heteroatom means O, S or N, selected on an independent basis.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein.
  • heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolin
  • This invention is also concerned with compositions and methods of treating ocular hypertension or glaucoma by administering to a patient in need thereof one of the compounds of formula I alone or in combination with one or more of the following active ingredients, in combination with a ⁇ -adrenergic blocking agent such as timolol, betaxolol, levobetaxolol, carteolol, and levobunolol; a parasympathomimetic agent such as epinephrine, iopidine, brimonidine, clonidine, para-aminoclonidine, carbonic anhydrase inhibitor such as dorzolamide, acetazolamide, metazolamide or brinzolamide, an EP4 agonist (such as those disclosed in WO 02/24647, WO 02/42268, EP 1114816, WO 01/46140, PCT Appln.
  • a ⁇ -adrenergic blocking agent such as timolol, betaxo
  • hypotensive lipid (the carboxylic acid group on the ⁇ -chain link of the basic prostaglandin structure is replaced with electrochemically neutral substituents) is that in which the carboxylic acid group is replaced with a Ci_6 alkoxy group such as OCH3 (PGF2a 1- OCH3), or a hydroxy group (PGF2 a 1 -OH).
  • Preferred potassium channel blockers are calcium activated potassium channel blockers. More preferred potassium channel blockers are high conductance, calcium activated potassium (Maxi-K) channel blockers. Maxi-K channels are a family of ion channels that are prevalent in neuronal, smooth muscle and epithelial tissues and which are gated by membrane potential and intracellular Ca2+.
  • the present invention is based upon the finding that Maxi-K channels, if blocked, inhibit aqueous humor production by inhibiting net solute and H2O efflux and therefore lower
  • Maxi-K channel blockers which lower IOP are useful for providing a neuroprotective effect. They are also believed to be effective for increasing retinal and optic nerve head blood velocity and increasing retinal and optic nerve oxygen by lowering IOP, which when coupled together benefits optic nerve health. As a result, this invention further relates to a method for increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension as well as providing a neuroprotective effect or a combination thereof.
  • This invention is also concerned with the use of a compound of Formula I in the manufacture ot a medicament tor me treatment ot ocular diseases such as ocular hypertension and/or glaucoma.
  • a number of marketed drugs function as potassium channel antagonists. The most important of these include the compounds Glyburide, Glipizide and Tolbutamide. These potassium channel antagonists are useful as antidiabetic agents.
  • the compounds of this invention may be combined with one or more of these compounds to treat diabetes.
  • Potassium channel antagonists are also utilized as Class 3 antiarrhythmic agents and to treat acute infarctions in humans.
  • a number of naturally occuring toxins are known to block potassium channels including Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide, and ⁇ -Bungarotoxin ( ⁇ - BTX).
  • the compounds of this invention may be combined with one or more of these compounds to treat arrhythmias.
  • Depression is related to a decrease in neurotransmitter release.
  • Current treatments of depression include blockers of neurotransmitter uptake, and inhibitors of enzymes involved in neurotransmitter degradation which act to prolong the lifetime of neurotransmitters.
  • Alzheimer's disease is also characterized by a diminished neurotransmitter release.
  • Alzheimer's disease cholinergic potentiators such as the anticholinesterase drugs (e.g., physostigmine (eserine), and Tacrine (tetrahydroaminocridine)); nootropics that affect neuron metabolism with little effect elsewhere (e.g., Piracetam, Oxiracetam; and those drugs that affect brain vasculature such as a mixture of ergoloid mesylates and calcium channel blocking drugs including Nimodipine.
  • Selegiline a monoamine oxidase B inhibitor which increases brain dopamine and norepinephrine has reportedly caused mild improvement in some Alzheimer's patients.
  • Aluminum chelating agents have been of interest to those who believe Alzheimer's disease is due to aluminum toxicity. Drugs that affect behavior, including neuroleptics and anxiolytics, have been employed. Anxiolytics, which are mild tranquilizers, are less effective than neuroleptics.
  • the present invention is related to novel compounds which are useful as potassium channel antagonists.
  • the compounds of this invention may be combined with anticholinesterase drugs such as physostigmine (eserine) and Tacrine (tetrahydroaminocridine), nootropics such as Piracetam, Oxiracetam, ergoloid mesylates, selective calcium channel blockers such as Nimodipine, or monoamine oxidase B inhibitors such as Selegiline, in the treatment of Alzheimer's disease.
  • anticholinesterase drugs such as physostigmine (eserine) and Tacrine (tetrahydroaminocridine)
  • nootropics such as Piracetam, Oxiracetam, ergoloid mesylates
  • selective calcium channel blockers such as Nimodipine
  • monoamine oxidase B inhibitors such as Selegiline
  • the compounds of this invention may also be combined with Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide, ⁇ -Bungarotoxin ( ⁇ -BTX) or a combination thereof in treating arrythmias.
  • the compounds of this invention may further be combined with Glyburide, Glipizide, Tolbutamide or a combination thereof to treat diabetes.
  • each of the claimed compounds are potassium channel antagonists and are thus useful in the described neurological disorders in which it is desirable to maintain the cell in a depolarized state to achieve maximal neurotransmitter release.
  • the compounds produced in the present invention are readily combined with suitable and known pharmaceutically acceptable excipients to produce compositions which may be administered to mammals, including humans, to achieve effective potassium channel blockage.
  • salts of the compounds of formula I will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • suitable “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, iV-ethylmorpholine, jV-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as argin
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
  • composition is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms.
  • the Maxi-K channel blockers used can be administered in a therapeutically effective amount intravenously, subcutaneously, topically, transdermally, parenterally or any other method known to those skilled in the art.
  • Ophthalmic pharmaceutical compositions are preferably adapted for topical administration to the eye in the form of solutions, suspensions, ointments, creams or as a solid insert.
  • Ophthalmic formulations of this compound may contain from 0.01 ppm to 5% and especially 0.1 ppm to 1% of medicament. Higher dosages as, for example, about 10% or lower dosages can be employed provided the dose is effective in reducing intraocular pressure, treating glaucoma, increasing blood flow velocity or oxygen tension.
  • For a single dose from between 1 ng to 5000 ⁇ g, preferably 10 ng to 500 ⁇ g, and especially 100 ng to 200 ⁇ g of the compound can be applied to the human eye.
  • the pharmaceutical preparation which contains the compound may be conveniently admixed with a non-toxic pharmaceutical organic carrier, or with a non-toxic pharmaceutical inorganic carrier.
  • a non-toxic pharmaceutical organic carrier or with a non-toxic pharmaceutical inorganic carrier.
  • pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols?, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethyl-cellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers.
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non- injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium borate, sodium acetate, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetracetic acid, and the like.
  • auxiliary substances such as emul
  • suitable ophthalmic vehicles can be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like.
  • the pharmaceutical preparation may also be in the form of a microparticle formulation.
  • the pharmaceutical preparation may also be in the form of a solid insert. For example, one may use a solid water soluble polymer as the carrier for the medicament.
  • the polymer used to form the insert may be any water soluble non-toxic polymer, for example, cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, (hydroxyloweralkyl cellulose), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose; acrylates such as polyacrylic acid salts, ethylacrylates, polyactylamides; natural products such as gelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia; the starch derivatives such as starch acetate, hydroxymethyl starch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and xanthan gum, gellan gum, and mixtures of said polymer.
  • cellulose derivatives such as methylcellulose, sodium carboxymethyl
  • Suitable subjects for the administration of the formulation of the present invention include primates, man and other animals, particularly man and domesticated animals such as cats and dogs.
  • the pharmaceutical preparation may contain non-toxic auxiliary substances such as antibacterial components which are non-injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenylethanol; buffering ingredients such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffers; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethylenediamine tetraacetic acid, and the like.
  • the ophthalmic solution or suspension may be administered as often as necessary to maintain an acceptable IOP level in the eye. It is contemplated that administration to the mammalian eye will be about once or twice daily.
  • novel formulations of this invention may take the form of solutions, gels, ointments, suspensions or solid inserts, formulated so that a unit dosage comprises a therapeutically effective amount of the active component or some multiple thereof in the case of a combination therapy.
  • compounds of this invention are:
  • CCCXXI 14(5)-(2 ' -Hydroxy-ethoxy)-21 -bromopaspalinine
  • CCCXXII 14(5)-[2'-(Methoxycarbonyl)-ethyloxy]-21-bromo-paspalinine
  • CCCXXIII 14(5)-(Methyl-allyloxy)-21 -bromopaspalinine
  • CCCXXIV 14(5 ⁇ -(N-Propyl-acetamide)-paspalinine
  • CCCXLV 14(S)-(Methyl-allyloxy)-21 -cyanopaspalinine
  • CCCXL 14(5)-(3 ' -Hydroxy-propoxy-phosphono-oxy(bis-triethylammonium))-propyloyloxy)-21 -(cyano)- paspalinine
  • CCCXLI 14(5)-(2'-Hydroxyethyloxy)-21-(cyano)-paspalinine
  • HPLC purification was performed by redissolving the residue in a small volume of DMSO and filtering through a 0.45 micron (nylon disc) syringe filter. The solution was then purified via reverse-phase preparatory HPLC purification system using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C 8 column. The initial gradient of 40- 80% MeOH:H 2 O was selected as appropriate for the target compound. This initial gradient was maintained for 0.5 minutes then ramped up to 100% MeOH:0% H 2 O over 5 minutes. 100% MeOH was maintained for 2 more minutes before it was re-equilibrated back to the initial starting gradient. Total run time was 8 minutes. The resulting fractions were analyzed, combined as appropriate, and then evaporated to provide purified material.
  • Proton magnetic resonance ( 1 H NMR) spectra were recorded on either a Varian INOVA 400 MHz ( 1 H) NMR spectrometer, Varian INOVA 500 MHz ( 1 H) NMR spectrometer, Bruker ARX 300 MHz ( 1 H) NMR spectrometer, Bruker DPX 400 MHz ( 1 H) NMR spectrometer, or a Bruker DRX 500 MHz ( 1 H) NMR spectrometer. All spectra were determined in the solvents indicated. Although chemical shifts are reported in parts per million (ppm) downfield of tetramethylsilane, they are referenced to the residual proton peak of the respective solvent peak for 1 H NMR.
  • ppm parts per million
  • LCMS spectra were obtained using a ThermoFinnigan AQA MS ESI instrument.
  • the samples were sent through a Phenomenex Aqua 5 micron C )8 125A 50 x 4.60 mm column.
  • the initial gradient was 55% MeOH: 1% CH 3 CN in H 2 O which was ramped up to 100% MeOH over 3 minutes. 100% MeOH was maintained for 2 minutes before it was re- equilibrated to the initial starting gradient.
  • the spray setting for the MS probe was at 350 ⁇ L/min with a cone voltage at 25 mV and a probe temperature at 450°C.
  • the 3-bromo-l-propanol (0.77 g, 0.49 mL, 5.5 mmol, 5 eq.) was subsequently added followed immediately by the tetrabutyl ammonium bromide (1.07 g, 3.3 mmol, 3 eq.).
  • the reaction was stirred at 75 deg. C for 16 hours.
  • An additional 5 eq. of 3-bromo-l-propanol was added and stirring was continued for 16 more hours.
  • the reaction mixture was allowed to cool and was transferred to a 125-mL separatory funnel, taken up in 30-40 mL of ethyl acetate, and washed twice with a 1 : 1 brine/water mixture and once with a saturated aqueous KF solution.
  • 14(S)-hydroxypaspalinine (I) 25 mg, 0.056 mmol, 1 eq.
  • the phase transfer catalyst tetrabutylammonium hydrogen sulfate
  • base solution 0.1 mL of 5Naq. KOH, 0.56 mmol, 10 eq.
  • XXXIV A sealed tube was charged with the starting material (XXXIV) (20.5 mg, 0.046 mmol, 1 eq.) and 1 mL of Aw-xylene.
  • the trimethylsilylazide (0.050 mL, 0.38 mmol, 8.3 eq.) reagent was then added, and the resulting mixture heated at 130 deg. C. After 16 hours, the reaction was checked by LCMS and appeared to be complete. The mixture was concentrated under a stream of nitrogen. The resulting residue was stirred vigorously with approximately 3 mL of methanol and then concentrated again under a stream of nitrogen. The residue was then purified by HPLC. LCMS m/e 553 (M+Na).
  • a solution was prepared by the addition of potassium hydroxide (88 mg, 1.5 mmol, 30 eq.) into 1.5 mL of ethanol. To this solution was added the starting material (XXXV) (29 mg, 0.048 mmol, 1 eq.). The resulting suspension was heated with stirring at 75 deg. C for 3.5 hours. The reaction was allowed to cool and the solvent evaporated from the reaction. Addition of H 2 O (0.5 mL) followed by extraction with ethyl ether (3 x 1 mL) and evaporation of the combined organic phases provided a residue. Purification by chromatography with a 1 g SPE cartridge using hexanes: ethyl acetate provided the desired material. LCMS m/e 600 (M+Na).
  • reaction mixture was filtered through a thin pad of silica gel, rinsed with approximately 200 mL of 1 : 1 EtO Ac/heptane, and the collected filtrate was then evaporated in vacuo. The resulting residue was subsequently purified by HPLC. LCMS m/e 740 (M+H).
  • the reaction was filtered through a 0.45 micron (nylon disc) syringe filter and injected directly onto the Chromeleon purification system using a Varian Dynamax HPLC 250 x 41.4 mm Compression Module Microsorb 60-8 C18 column.
  • the purification method starts with 40:60 MeOH:H2O (0.1% TEA modifier) which is ramped up to 85:15 MeOH:H2O over 45 minutes. Flow rate is 35 mL/min. The column is then flushed with 100% MeOH for 15 minutes prior to re-equilibration back to 40:60 MeOH:H2O. Total run time is 70.1 minutes.
  • Method A To a 2-dram vial fitted with a magnetic stir bar was added 14-hydroxypaspalinine (10 mg, 0.022 mmol, 1 eq.) in dry pyridine (0.5 mL). In a second vial, 4-bromobenzoyl chloride (53.4 mg, 0.24 mmol, 11 eq.) and acetone (0.5 mL) were combined. The pyridine solution was heated in an oil bath to 50 0 C. The acetone solution was added to the heated pyridine solution in a drop-wise manner. The vial was capped and stirred at 50 0 C for several hours.
  • the resulting residue was re- dissolved in a small volume of DMSO, filtered through a 0.45 micron (nylon disc) syringe filter, and purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C 8 column.
  • the purification method starts with 50:50 MeOHiH 2 O maintained for 0.5 minute and is ramped up to 100:0 Me0H:H 2 O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 50:50 MeOH:H 2 O. Total run time is 8 minutes.
  • Method B To a one dram vial fitted with a magnetic stir bar was added N- cyclohexylcarbodiimide, N 5 -methyl polystyrene HL (PoIy-DCC, 200-400 mesh, 2.3 mmol/g loading) (130 mg, 0.22 mmol, 10 eq), 2-morpholino acetic acid (33.1 mg, 0.23 mmol, 10.45 eq), N,N-dimethylaminopyridine ( 5.7 mg, 0. 047 mmol, 2.1 eq), toluene (0.5 mL) and 1,2- dichloroethane (0.5 mL).
  • N- cyclohexylcarbodiimide N 5 -methyl polystyrene HL (PoIy-DCC, 200-400 mesh, 2.3 mmol/g loading) (130 mg, 0.22 mmol, 10 eq)
  • 2-morpholino acetic acid 33.1 mg, 0.23 mmol, 10.
  • the purification method starts with 50:50 MeOH:H 2 O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H 2 O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 50:50 MeOH:H 2 O. Total run time is 8 minutes.
  • LCMS m/e 577 (M+H).
  • the reaction was filtered through a 0.45 micron (nylon disc) syringe filter.
  • the sample was then washed one time with a 10% HCl solution, one time with a saturated sodium bicarbonate solution and concentrated under nitrogen.
  • the sample was then taken up in DMSO and purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C 8 column.
  • the purification method starts with 40:60 MeOH:H 2 O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H 2 O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH :H2 ⁇ .
  • the purification method starts with 40:60 MeOH:H 2 ⁇ maintained for 0.5 minute and is ramped up to 100:0 MeOH:H 2 O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH:H 2 O. Total run time is 8 minutes.
  • LCMS m/e 532 (M+H).
  • CCCII 14-Hydroxypaspalinine I (30 mg, 0.066 mmol, 1 eq.), tetrapropyl ammonium perruthenate (TPAP, 7.2 mg, 0.020 mmol, 0.3 eq.), 4-Methylmorpholine N-oxide (15.6 mg, 0.13 mmol, 2 eq.) and 4 angstroms powdered sieves (0.075 g) were combined in a 1 dram vial. A stir bar was added along with dry methylene chloride (2 mL). The vial was capped and stirred at room temperature. The reaction was monitored by TLC (1 :1 Hept./EtOAc) which indicated the reaction was complete after 16 hours.
  • the DDQ solution was then added dropwise over a period of approximately 20 minutes to the flask containing the starting material. After the addition of the DDQ solution was complete, the reaction was allowed to stir overnight at room temperature. After this time the reaction mixture was filtered through a pad of silica gel and rinsed with ethyl acetate (150 mL). The organic filtrate was washed two times with a saturated sodium bicarbonate solution and one time with a saturated brine solution. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. The material was purified by HPLC. LCMS m/e 464 (M+H).
  • CCCVIII CCCXI To a solution of 14(5)-Hydroxypaspalin-10-exo-ene (14 mg, 0.031 mmol, 1 eq) (CCCVIII) in ethanol (5 mL) was added 10% Palladium on Carbon (3 mg, 0.2 eq) and ammonium formate (10 mg, 0.16 mmol, 5 eq). The reaction was heated to reflux and stirred overnight. After this time the reaction was cooled to room temperature and filtered. The reaction was purified by HPLC. LCMS m/e 448(M-H).
  • Example 152 (14(5 r )-7V-(3-Hydroxy-2,2-dimethyl-propyl))-(21-bromo)-acetamide-paspalinine (CCCXV)
  • 21-Bromo-14-hydroxypaspalinine (CCCXIII) (100 mg, 0.189 mmol, 1 eq), triethylamine (0.034 mL, 0.246 mmol, 1.3 eq), [(i?)-(+)-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl]palladium(II) chloride (4.5 mg, 0.006 mmol, 0.03 eq) and methanol (7 mL) were combined in a 22 mL steel pressure vessel with a magnetic stir bar. The system was closed, evacuated under vacuum and then charged with carbon monoxide (50 psi). This step was repeated two more times.
  • Compound CCCXVIII was prepared in the same manner as CXIX. Purification was performed by reverse-phase HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The aqueous phase contained 0.1% Et ⁇ N in H2 ⁇ . The initial gradient of 5% MeOH:aqueous phase was maintained for 1 minute then ramped up to 100% MeOH:0% aqueous phase over 4.1 minutes. 100% MeOH was maintained for 3.3 more minutes. A flow rate of 28 mL/min. Under these conditions, compound (CCCXVIII) eluted at a retention time of 3.3 minutes.
  • the reaction was cooled to room temperature and filtered through a 0.45 micron (nylon disc) syringe filter.
  • the reaction was then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C 8 column.
  • the purification method starts with 40:60 MeOHiH 2 O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H 2 O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re- equilibrated back to 40:60 MeOH:H 2 O. Total run time is 8 minutes.
  • the reaction was then cooled to room temperature and filtered through a 0.45 micron (nylon disc) syringe filter.
  • the reaction was then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C 8 column.
  • the purification method starts with 40:60 MeOH:H 2 ⁇ maintained for 0.5 minute and is ramped up to 100:0 MeOH:H 2 O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH:H 2 O. Total run time is 8 minutes.
  • the reaction was then cooled to room temperature and filtered through a 0.45 micron (nylon disc) syringe filter.
  • the reaction was then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C 8 column.
  • the purification method starts with 40:60 MeOHiH 2 O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H 2 O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH:H 2 O. Total run time is 8 minutes.

Abstract

This invention relates to the use of potent potassium channel blockers or a formulation thereof in the treatment of glaucoma and other conditions which leads to elevated intraocular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans.

Description

TITLE OF THE INVENTION
MAXI-K CHANNEL BLOCKERS AND METHODS OF USE
BACKGROUND OF THE INVENTION Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.
There are several therapies for treating glaucoma and elevated intraocular pressure, but the efficacy and the side effect profiles of these agents are not ideal. Recently, potassium channel blockers were found to reduce intraocular pressure in the eye and therefore provide yet one more approach to the treatment of ocular hypertension and the degenerative ocular conditions related thereto. Blockage of potassium channels can diminish fluid secretion, and under some circumstances, increase smooth muscle contraction and would be expected to lower IOP and have neuroprotective effects in the eye. (see US Patent Nos. 5,573,758 and 5,925,342; Moore, et al., Invest. Ophthalmol. Vis. Sci 38, 1997; WO 89/10757, WO94/28900, and WO 96/33719). Some Maxi-K channel blockers containing ketone functional groups have quite low aqueous solubility. This presents a serious problem when used to treat ocular diseases such as glaucoma because treatment is typically in the form of aqueous ophthalmic solution formulations.
The following publications are of interest as background: WO03/105868, US2001/0047025, WO06/115423, WO05/016337, WO94/09004, WO2007/009462,
WO95/19771, US Pat. Nos. 5,130,326; 5,227,396; 4,973,601; and 5,492,902. See also Garcia et al., Biochemistry 1994, 33, 5819-5828. See also simultaneously filed patent application referred to as Attorney Docket No. 22499PV.
SUMMARY OF THE INVENTION
The present invention relates to novel indole diterpene alkaloids which are useful as potassium channel antagonists, particularly as Maxi-K channel antagonists. These alkaloids are useful in treating glaucoma and other associated conditions, and macular degeneration. More particularly, the present invention includes compounds of formula I and pharmaceutically acceptable salts thereof:
Figure imgf000003_0001
I or a pharmaceutically acceptable salt, ester, including phosphate, enantiomer, diastereomer or mixture thereof.
Wherein: R is H, OPO3, COR2, OCOR2, -NHR2, OR2, CH(R2)2, OCNHR2, (CHR2)nNR2C(O)O(CH2)nR2, (C(Rl)2)pNRiR2; -NCOR2, (CH2)nORl; Ci-6alkyl, (CH2)nC6-10 aryl, (CH2)nheterocyclyl, C2-6 alkenyl, (CH2)nC3-6 cycloalkyl, THF, - (CH2)nNR2(CH2)n-, -(CH2)nO)sR2-, or OCOC(R2)2N(R2)2, said alkyl, alkenyl, cycloalkyl, aryl and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
Rl and Ri a independently represent H, (CH2)nOCONH(CH2)nR, (CH2)nC00R, (CH2)n0R, COR, COO-C6-10aryl, COOalkylR, OCOC(R)2N(R)2, C0NR(CH2)nR, (CH2)nOCOalkylR, halogen, COalkyl, Ci_6alkyl, C2-6alkenyl, (CH2)nC3-6cycloalkyl, (CH2)nC(S)N(R)2, (CH2)nC5-10 heterocyclyl, (CH2)nC6-10 aryl, (-(CH2)nO)s, (CH2)nC(O)(CH2)nC(O)OR, (CH2)nOP(O)(OR)2, or -(CHR)nN(R2)2, said alkyl, alkenyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
R2 is H, (CH2)nC00R, (CH2)n0R, COR, NRCOR, C0NR(CH2)nR, halogen, (CH2)nCOalkyl, C 1 -6alkyl, C2-6alkenyl, (CH2)nC3-6cycloalkyl, (CH2)nC5- 10 heterocyclyl, (CH2)nC6- 10 aryl, (-(CH2)nO)s, or -CHRN(R)2, said alkyl, alkenyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
R3: is H, Ci-6 alkyl, -Si((R)2)R, (CH2)nC5-10 heterocyclyl, -P(O)(OR)2,or -PO3, said alkyl and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
R5: is CO2R1, CH2OR, or halo;
RlOa, RlOb: together represent =0, =CH2, =NR, provided that when RlOa and Riob represent =0 then Ri, Ri a, Ri 3, Ri 4, R21 and R23 cannot all be hydrogen, also provided that when RlQa, and Riob represent =0 then Ri cannot be (CHR)nN(R2)2 when Ria, Rl3, R21 and R23 are hydrogen, and R] 4 is (CH2)nCORi;
or Rioa, Riob independently represent H, Ci-6 alkyl, C2-6 alkenyl, OH, OCOR, =CHC(O)OR, - N(Ri)COR2, said alkyl, and alkenyl, optionally substituted with 1 to 3 groups of Ra;
or Rj oa5 Rl Ob together with an oxygen atom form a 3 membered heterocyclic ring;
Rl 3: is H, or CON(Ri )2;
R14: is H, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, S(O)2, C3_6cycloalkyl, (CH2)nCORi, (CH2)nCO2R, (CH2)nCN, (CH2)nheterocyclyl, (CH2)naryl, (CH2)nCON(Ri)2, (CH2)nOR3, (CH2)nC(Rl)2C(R2)2OR3, (CH2)nC(R2)2θR3, (CH2)nC(Rl)=CHC(θ2)R, ((-CH2)nO(CH2)n- )s, (CH2)nCR=C(R)2, (CH2)nC(S)N(R)2, -(CH2)nC(CH2)R5, (CH2)nOC(O)R, (CH2)nOCH2R, said alkyl, alkenyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
R21 and R23: independently represent hydrogen, CN, COOR, CONR1R2, CONHR1, halogen, SO2R, C5-10 heterocyclyl, NO2, H, OR, COR, Ci -6 alkyl, C2-6 alkenyl, (CH2)nC5-10 aryl, said aϊkyl, alkenyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
Ra is OH, C 1-6 alkyl, C3-6 cycloalkyl, (CH2)nC6-10 aryl, -O(CH2)nC6-10 aryl, CF3, halo, -SR, -0-, NO2, (CH2)n0Rl, C2-6 alkenyl, CN, N(Ri)2, COOR3, SO2R, -OP(O)(OR)2, -OPO3, or -
Figure imgf000004_0001
s is 1-5; n is 0-6; and p is 0-1.
The claimed compounds lack the tremorgenic liability of other indole diterpenes, yet retain excellent potency against the Maxi-K channel.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to novel indole diterpenes of formula I described above. The compounds of this invention block the Maxi-K channel and do not have a tremorgenic effect. This invention is also directed to a method for treating ocular hypertension or glaucoma which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having structural formula I.
An embodiment of this invention is realized when Ri a is hydrogen, C] -6 alkyl, COO-C6- 1 OarylR, COOalkylR, (CH2)nOCONH(CH2)nR, COOR, or OCOC(R)2N(R)2, and all other variables are as originally described. Another embodiment of this invention is realized when Ri is hydrogen and all other variables are as originally described. Yet another embodiment is realized when Ri a is (CH2)nOCONH(CH2)nR and all other variables are as originally described. Still another embodiment is realized when Ri 0a and Rio'3 together represent =0 and all other variables are as originally described.
Another embodiment of this invention is realized when Rl 3 is hydrogen and all other variables are as originally described.
Still another embodiment of this invention is realized when Rl 3 is CONR and all other variables are as originally described.
Another embodiment of this invention is realized when Ri 4 is Ci -6 alkyl, (CH2)nC3-6 cycloalkyl, C2-6 alkenyl, (CH2)nheterocyclyl, (CH2)naryl, (CH2)nCON(Ri)2, (CH2)nOR3, (CH2)nC(Rl)2C(R2)2θR3, or (CH2)nC(R2)2θR3 and all other variables are as originally described. Another embodiment of this invention is realized when Ri 4 is (CH2)nCON(Ri)25
(CH2)nOR3, (CH2)nC(Rl)2C(R2)2θR3, or (CH2)nC(R2)2θR3 and all other variables are as originally described.
Still another embodiment of this invention is realized when R21 is hydrogen. Another embodiment of this invention is realized when R21 is CN, halogen, COOR, C2-6 alkenyl, OR, or NO2,
Another embodiment of this invention is realized by the compound of Formula
IA:
Figure imgf000005_0001
IA or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof, wherein Rl 0a and R] O^ together is =0, =NR, =CH2, or =CHC(O)OR, and all other variables are as previously described. A sub-embodiment of this invention is realized when Rl 0a and
Figure imgf000006_0001
together is =0 and R] a is hydrogen. Another embodiment of Formula IA is realized when Rl a is halogen, C2-6 alkenyl, C 1-6 alkyl, C0NH(CH2)nR, (CH2)nOR, COR, (CH2)nC00R.
Yet another embodiment of of Formula IA is realized when Rl 0a and Ri (fi together is -O and Ria is halogen, C2-6 alkenyl, Ci_6 alkyl, C0NH(CH2)nR, (CH2)n0R, COR,
(CH2)nCOOR. The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes, and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. (See E.L. Eliel and S. H. Wilen Stereochemistry of Carbon Compounds
(John Wiley and Sons, New York 1994 - in particular pages 1119-1190). When any variable (e.g. aryl, heterocycle, R^, R^ etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
When reference is made to "-O-" and it is attached to a carbon it is referred to as a carbonyl group and when it is attached to a nitrogen (e.g., nitrogen atom on a pyridyl group) or sulfur atom it is referred to as N-oxide and sulfoxide group, respectively, unless otherwise indicated.
The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopropyl, cyclopentyl and cyclohexyl. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group".
Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, unless otherwise defined, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings, which are fused. Examples of such cycloalkyl elements include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Alkenyl is C2-C6 alkenyl.
Alkoxy refers to an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, with the alkyl group optionally substituted as described herein. Said groups are those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, propargyloxy, and the like.
Halogen (halo) refers to chlorine, fluorine, iodine or bromine. Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. Examples of aryl groups are phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl and phenanthrenyl, preferably phenyl, naphthyl or phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl.
The term heterocyclyl or heterocyclic, as used herein, represents a stable 3- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring. The term heterocycle or heterocyclic includes heteroaryl moieties.
Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydropyrrolyl, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl. Preferably, heterocycle is selected from 2-azepinonyl, benzimidazolyl, 2-diazapinonyl, dihydroimidazolyl, dihydropyrrolyl, imidazolyl, 2-imidazolidinonyl, indolyl, isoquinolinyl, morpholinyl, piperidyl, piperazinyl, pyridyl, pyrrolidinyl, 2-piperidinonyl, 2-pyrimidinonyl, 2-pyrollidinonyl, quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl. The term "heteroatom" means O, S or N, selected on an independent basis. The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, thienyl and triazolyl. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole.
This invention is also concerned with compositions and methods of treating ocular hypertension or glaucoma by administering to a patient in need thereof one of the compounds of formula I alone or in combination with one or more of the following active ingredients, in combination with a β-adrenergic blocking agent such as timolol, betaxolol, levobetaxolol, carteolol, and levobunolol; a parasympathomimetic agent such as epinephrine, iopidine, brimonidine, clonidine, para-aminoclonidine, carbonic anhydrase inhibitor such as dorzolamide, acetazolamide, metazolamide or brinzolamide, an EP4 agonist (such as those disclosed in WO 02/24647, WO 02/42268, EP 1114816, WO 01/46140, PCT Appln. No. CA2004000471 , and WO 01 /72268), a prostaglandin such as latanoprost, travaprost, unoprostone, rescula, S 1033 (compounds set forth in US Patent Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444); a hypotensive lipid such as lumigan and the compounds set forth in US Patent No. 5,352,708; a neuroprotectant disclosed in US Patent No. 4,690,931, particularly eliprodil and i?-eliprodil as set forth in WO 94/13275, including memantine; an agonist of 5-HT2 receptors as set forth in PCT/USOO/31247, particularly l-(2-aminopropyl)-3 -methyl- lH-imdazol- 6-ol fumarate and 2-(3-chloro-6-methoxy-indazol-l-yl)-l-methyl-ethylamine or a mixture thereof. An example of a hypotensive lipid (the carboxylic acid group on the α-chain link of the basic prostaglandin structure is replaced with electrochemically neutral substituents) is that in which the carboxylic acid group is replaced with a Ci_6 alkoxy group such as OCH3 (PGF2a 1- OCH3), or a hydroxy group (PGF2a 1 -OH). Preferred potassium channel blockers are calcium activated potassium channel blockers. More preferred potassium channel blockers are high conductance, calcium activated potassium (Maxi-K) channel blockers. Maxi-K channels are a family of ion channels that are prevalent in neuronal, smooth muscle and epithelial tissues and which are gated by membrane potential and intracellular Ca2+.
The present invention is based upon the finding that Maxi-K channels, if blocked, inhibit aqueous humor production by inhibiting net solute and H2O efflux and therefore lower
IOP. This finding suggests that Maxi-K channel blockers are useful for treating other ophthamological dysfunctions such as macular edema and macular degeneration. It is known that lowering IOP promotes blood flow to the retina and optic nerve. Accordingly, the compounds of this invention are useful for treating macular edema and/or macular degeneration.
It is believed that Maxi-K channel blockers which lower IOP are useful for providing a neuroprotective effect. They are also believed to be effective for increasing retinal and optic nerve head blood velocity and increasing retinal and optic nerve oxygen by lowering IOP, which when coupled together benefits optic nerve health. As a result, this invention further relates to a method for increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension as well as providing a neuroprotective effect or a combination thereof.
This invention is also concerned with the use of a compound of Formula I in the manufacture ot a medicament tor me treatment ot ocular diseases such as ocular hypertension and/or glaucoma.
A number of marketed drugs function as potassium channel antagonists. The most important of these include the compounds Glyburide, Glipizide and Tolbutamide. These potassium channel antagonists are useful as antidiabetic agents. The compounds of this invention may be combined with one or more of these compounds to treat diabetes.
Potassium channel antagonists are also utilized as Class 3 antiarrhythmic agents and to treat acute infarctions in humans. A number of naturally occuring toxins are known to block potassium channels including Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide, and β-Bungarotoxin (β- BTX). The compounds of this invention may be combined with one or more of these compounds to treat arrhythmias.
Depression is related to a decrease in neurotransmitter release. Current treatments of depression include blockers of neurotransmitter uptake, and inhibitors of enzymes involved in neurotransmitter degradation which act to prolong the lifetime of neurotransmitters. Alzheimer's disease is also characterized by a diminished neurotransmitter release. Three classes of drugs are being investigated for the treatment of Alzheimer's disease cholinergic potentiators such as the anticholinesterase drugs (e.g., physostigmine (eserine), and Tacrine (tetrahydroaminocridine)); nootropics that affect neuron metabolism with little effect elsewhere (e.g., Piracetam, Oxiracetam; and those drugs that affect brain vasculature such as a mixture of ergoloid mesylates and calcium channel blocking drugs including Nimodipine. Selegiline, a monoamine oxidase B inhibitor which increases brain dopamine and norepinephrine has reportedly caused mild improvement in some Alzheimer's patients. Aluminum chelating agents have been of interest to those who believe Alzheimer's disease is due to aluminum toxicity. Drugs that affect behavior, including neuroleptics and anxiolytics, have been employed. Anxiolytics, which are mild tranquilizers, are less effective than neuroleptics. The present invention is related to novel compounds which are useful as potassium channel antagonists.
The compounds of this invention may be combined with anticholinesterase drugs such as physostigmine (eserine) and Tacrine (tetrahydroaminocridine), nootropics such as Piracetam, Oxiracetam, ergoloid mesylates, selective calcium channel blockers such as Nimodipine, or monoamine oxidase B inhibitors such as Selegiline, in the treatment of Alzheimer's disease. The compounds of this invention may also be combined with Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide, β-Bungarotoxin (β-BTX) or a combination thereof in treating arrythmias. The compounds of this invention may further be combined with Glyburide, Glipizide, Tolbutamide or a combination thereof to treat diabetes.
The herein examples illustrate but do not limit the claimed invention. Each of the claimed compounds are potassium channel antagonists and are thus useful in the described neurological disorders in which it is desirable to maintain the cell in a depolarized state to achieve maximal neurotransmitter release. The compounds produced in the present invention are readily combined with suitable and known pharmaceutically acceptable excipients to produce compositions which may be administered to mammals, including humans, to achieve effective potassium channel blockage.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. When the compound of the present invention is acidic, suitable "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ΛζΛ^-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, iV-ethylmorpholine, jV-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al. , "Pharmaceutical Salts," J. Pharm. ScL, 1977:66:1-19. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms.
The Maxi-K channel blockers used can be administered in a therapeutically effective amount intravenously, subcutaneously, topically, transdermally, parenterally or any other method known to those skilled in the art. Ophthalmic pharmaceutical compositions are preferably adapted for topical administration to the eye in the form of solutions, suspensions, ointments, creams or as a solid insert. Ophthalmic formulations of this compound may contain from 0.01 ppm to 5% and especially 0.1 ppm to 1% of medicament. Higher dosages as, for example, about 10% or lower dosages can be employed provided the dose is effective in reducing intraocular pressure, treating glaucoma, increasing blood flow velocity or oxygen tension. For a single dose, from between 1 ng to 5000 μg, preferably 10 ng to 500 μg, and especially 100 ng to 200 μg of the compound can be applied to the human eye.
The pharmaceutical preparation which contains the compound may be conveniently admixed with a non-toxic pharmaceutical organic carrier, or with a non-toxic pharmaceutical inorganic carrier. Typical of pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols?, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethyl-cellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non- injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium borate, sodium acetate, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetracetic acid, and the like. Additionally, suitable ophthalmic vehicles can be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like. The pharmaceutical preparation may also be in the form of a microparticle formulation. The pharmaceutical preparation may also be in the form of a solid insert. For example, one may use a solid water soluble polymer as the carrier for the medicament. The polymer used to form the insert may be any water soluble non-toxic polymer, for example, cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, (hydroxyloweralkyl cellulose), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose; acrylates such as polyacrylic acid salts, ethylacrylates, polyactylamides; natural products such as gelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia; the starch derivatives such as starch acetate, hydroxymethyl starch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and xanthan gum, gellan gum, and mixtures of said polymer.
Suitable subjects for the administration of the formulation of the present invention include primates, man and other animals, particularly man and domesticated animals such as cats and dogs. The pharmaceutical preparation may contain non-toxic auxiliary substances such as antibacterial components which are non-injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenylethanol; buffering ingredients such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffers; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethylenediamine tetraacetic acid, and the like.
The ophthalmic solution or suspension may be administered as often as necessary to maintain an acceptable IOP level in the eye. It is contemplated that administration to the mammalian eye will be about once or twice daily.
For topical ocular administration the novel formulations of this invention may take the form of solutions, gels, ointments, suspensions or solid inserts, formulated so that a unit dosage comprises a therapeutically effective amount of the active component or some multiple thereof in the case of a combination therapy. Examples of compounds of this invention are:
14(iS)-(3 ' -Hydroxypropyloxy)paspalinine (II),
14-(S)-(Allyloxy)paspalinine (III),
14-(5)-(Propyloxy)paspalinine (FV),
14-(S)-(Ethoxycarbonylmethyloxy)paspalinine (V), 14-(5)-([(3'-(Methoxycarbonyl)-allyl]oxy)ρaspalinine (VI),
14-(5)-((2'-[l",3"]-Dioxolan-2"-yl)-ethyloxy)paspalinine (VII),
14-(5)-((2'-(i?/5)-2',3'-dihydroxy)-propyloxy)paspalinine (mixture of 2 diastereomers) (VIII),
14-(5)-(Ethyloxy)paspalinine (IX),
14-(5)-([2'-(2"-Methoxy-ethoxy)]-ethyloxy)paspalinine (X), 14-(S)-((2'-(/?/S)-2'-hydroxy)-propyloxy)paspalinine (mixture of 2 diastereomers) (XI),
14-(S)-((2 ' -Methoxy)-ethyloxy)paspalinine (XII),
14-(S)-(([2',5']-Dioxo-pyrrolidin-[r]-yl-oxycarbonyl)-methyloxy)paspalinine (XIII),
14-(5)-(Cyclopropylmethyloxy)paspalinine (XIV),
14-(5)-((2'-Diethylamino)-ethyloxy)paspalinine (XV), 14-(5)-((Pyridin-4'-yl)-methyloxy)paspalinine (XVI),
14-(S)-(Cyanomethyloxy)paspalinine (XVII),
14-(5)-((6 ' -Hydroxymethyl-pyridin-2 ' -yl)-methyloxy)paspalinine (XVIII),
14-(S)-(Pyridin-2'-yl methyloxy)paspalinine (XIX), 14-(5)-(Pyridin-3'-yl methyloxy)paspalinine (XX), 14-(5)-((6'-Hydroxy)-hexyloxy)paspalinine (XXI), 14-(5)-((7 ' -Hydroxy)-heptyloxy)paspalinine (XXII),
14-(5)-((8'-Hydroxy)-octyloxy)paspalinine (XXIII),
14-(5)-((9 ' -Hydroxy)-nonyloxy)paspalinine (XXIV),
14-(5)-((l 1 '-Hydroxy)-undecyloxy)paspalinine (XXV), 14-(5)-((12'-Hydroxy)-dodecyloxy)paspalinine (XXVI),
14-(S)-((4'-Cyano)-butyloxy)paspalinine (XXVII),
14-(£)-((5'-Cyano)-pentyloxy)paspalinine (XXVIII),
14-(5)-((6'-Cyano)-hexyloxy)paspalinine (XXIX),
14-(S)-(Methoxycarbonylmethyl ether)paspalinine (XXX), 14-(S)-(Methoxycarbonylpropyl ether)paspalinine ( XXXI ),
14-(5)-(Methoxycarbonylbutyloxy)paspalinine ( XXXII ),
14-(5)-((3'-Cyano)-propyloxy)paspalinine ( XXXIII ),
14-(S)-(Prop-2 ' -ynyloxy)paspalinine (XXXIV),
14-(S)-(([2' , 4']-Diethoxy-4'-oxo)-but-2'-enyloxy)paspalinine (XXXV), 14-(S)-(Benzyloxy)paspalinine (XXXVI),
14-(S)-(Pyrimidin-4'-yl methyloxy)paspalinine (XXXVII),
14-(5)-((2'-Oxo-2'-phenyl)-ethyloxy)paspalinine (XXXVIII),
14-(5)-((4',4',4'-Trifluoro)-butyloxy)paspalinine (XXXIX),
14-(5)-((2'-(i?/S)-2'-methyl-4',4',4'-trifluoro)-butyloxy)paspalinine (mixture of 2 diastereomers) (XL),
14-(S)-(( 1 H-tetrazol-5 ' -yl)-methyloxy)paspalinine (XLI),
14-(5)-((l '-Methyl-imidazol-2'-yl)-methyloxy)paspalinine (XLII),
14-(5)-((2'-Methyl)-allyloxy)paspalinine (XLIII),
14-(5)-((2 ' - Acetoxy)-ethyloxy)paspalinine (XLIV), 14-(5)-((3'-Methyl)-but-2'-enyloxy)paspalinine (XLV),
14-(5)-((2'-Ethόxycarbonyl)-prop-l '-enyloxy)paspalinine (XLVI),
14-(5)-((2'-Hydroxymethyl)-allyloxy)paspalinine (XLVII),
14-(S)-((2'-Chloro)-allyloxy)paspalinine (XLVIII),
14-(5)-((4' -Bromo)-benzyloxy)paspalinine (XLIX), 14-(S)-((4'-Cyano)-benzyloxy)paspalinine (L),
14-(5)-((4'-Trifluoromethyl)-benzyloxy)paspalinine (LI),
14-(S)-((3 ' -Bromo)-benzyloxy)paspalinine (LII),
14-(5)-((2'-Bromo)-benzyloxy)paspalinine (LIII),
14-(5)-((2'-(7?)-2'-Methyl-3'-hydroxy)-propyloxy)paspalinine (LIV), 14-(5)-((2'-(5)-2'-Methyl-3'-hydroxy)-propyloxy)paspalinine (LV), 14-(5)-([2'-(tert-butyldimethylsilyloxy)]-ethyloxy)paspalinine (LVI), 14-(5)-((2 ' -Phenylcarbonyloxy)-ethyloxy)paspalinine (LVII), 14-(S)-((2 ' -Benzyloxy)-ethyloxy)paspalinine (LVIII), 14-(5)-([3 ' -(tert-butyldimethylsilyloxy)]-propyloxy)paspalinine (LEX), 14-(5)-((2'-[N-(3"-hydroxy-2",2"-dimethylpropylamino)]-2'-oxo)-ethyloxy)paspalinine (LX), 14-(5)-((2 ' - [iV-benzylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXI), 14-(S)-((2 ' -Oxo-2 ' -piperidin- 1 "-yl)-ethyloxy)paspalinine (LXII), 14-(5)-((2 ' - LV-cyclopropylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXIII) , 14-(5)-((2 ' - [iV-pentylamino] -2' -oxo)-ethyloxy)paspalinine (LXTV), 14-(5)-((2 ' - [N, JV-dimethylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXV) , 14-(5)-((2'-Morpholin-4"-yl-2'-oxo)-ethyl oxy)paspalinine (LXVI), 14-(5)-((2'-[N-pyridin-2"-ylmethyl]-2'-oxo)-ethyloxy)paspalinine (LXVII), 14-(5)-((2'-Amino-2'-oxo)-ethyloxy)paspalinine (LXVIII), 14-(S)-((2 ' -Methylamino-2 ' -oxo)-ethyloxy)paspalinine (LXTX), 14-(5)-((2'-(4"-Methyl-piperazin-l"-yl)-2'-oxo)-ethyloxy)paspalinine (LXX), 14-(5)-((2 ' -Oxo-2 ' -piperazin- 1 "-yl)-ethyloxy)paspalinine (LXXI), 14-(5)-((2 ' - [N-isopropylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXXII), 14-(5)-((2 ' - [iV-cyclohexylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXXIII), 14-(S)-((2 ' -[iV-ethylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXXTV), 14-(5)-((2'-[N-(2"-dimethylamino)]-ethylamino-2'-oxo)-ethyloxy)paspalinine (LXXV), 14-(5)-((2'-(2"-Methoxy)-ethylamino-2'-oxo)-ethyloxy)paspalinine (LXXVI), 14-(5)-((2 ' -[iV-cyclopentylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXXVII), 14-(5)-((2'-[N-(2"-acetylamino)]-ethylamino-2'-oxo)-ethyloxy)paspalinine (LXXVIII), 14-(5)-((2'-[iV-cyclopropylmethylamino]-2'-oxo)-ethyloxy)paspalinine (LXXTX), 14-(5)-((2'-[7V-cyclobutylamino]-2'-oxo)-ethyloxy)paspalinine (LXXX), 14-(S)-((2 ' - [N-(propylamino)] -2 ' -oxo)-ethyloxy)paspalinine (LXXXI), 14-(5)-((2'-[N-(butylamino)]-2'-oxo)-ethyloxy)paspalinine (LXXXII), 14-(5)-((2 ' - [7V-(2"-diethylamino)] -ethylamino-2' -oxo)-ethyloxy)paspalinine (LXXXIII), 14-(S)-((2 ' -(2"-Hydroxy)-ethylamino-2 ' -oxo)-ethyloxy)paspalinine (LXXXTV), 14-(5)-((2'-[N-(2"-butyl-2"-(5)-amino)]-2'-oxo)-ethyloxy)paspalinine (LXXXV), 14-(5)-((2'-[N-(2"-butyl-2"-(R)-amino)]-2'-oxo)-ethyloxy)paspalinine (LXXXVI), 14-(5)-((2'-(l"-Methoxypropyl-2"-(5)-amino)-2'-oxo)-ethyloxy)paspalinine (LXXXVII), 14-(S)-((2'-(l"-Hydroxypropyl-2"-(i?)-amino)-2'-oxo)-ethyloxy)paspalinine (LXXXVIII), 14-(S)-((2'-(l"-Hydroxypropyl-2"-(5)-amino)-2'-oxo)-ethyloxy)paspalinine (LXXXTX), 14-(S)-((2'-(l"-Methoxypropyl-2"-(Λ/5)-amino)-2'-oxo)-ethyloxy)paspalinine (XC), 14-(5)-((2 ' - [JV-(3 "-hydroxy-propylamino)] -2 ' -oxo)-ethyloxy)paspalinine (XCI),
14-(5)-((2'-[N-(2"-(^)-hydroxy-2"-phenyl-ethylamino)]-2'-oxo)-ethyloxy)paspalinine (XCII),
14-(lS)-((2'-[N-(2"-(5)-hydroxy-2"-phenyl-ethylamino)]-2'-oxo)-ethyloxy)paspalinine (XCIII),
14-(5)-((2'-[N-(2"-hydroxy-l"-(/?)-phenyl-ethylamino)]-2'-oxo)-ethyloxy)paspalinine (XCIV), 14-(5)-((2'-[N-(2"-hydroxy-l"-(S)-phenyl-ethylamino)]-2'-oxo)-ethyloxy)paspalinine (XCV),
14-(5)-((2'-[jV-(l"-hydroxy-cyclohexylmethylamino)]-2'-oxo)-ethyloxy)paspalinine (XCVI),
14-(5)-((2'-Oxo-2'-[7V-phenylamino])-ethyloxy)paspalinine (XCVII),
14-(5)-((l 'H-[I ',2',3']-triazol-4'-yl)-methyloxy)paspalinine (XCVIII),
14-(5)-((2'H-pyrazol-3 '-yl)-methyloxy)paspalinine (XCIX), 14-(S)-((3'-Methylisoxazol-5'-yl)-methyloxy)paspalinine (C),
(5)-((2 ' - Amino-2 ' -thioxo)-ethyloxy)paspalinine (CI),
14-(5)-((4 ' -Cyclopropyl-thiazol-2 ' -yl)-methyloxy)paspalinine (CII) ,
14-(5)-((4 ' -Methyl-thiazol-2 ' -yl)-methyloxy)paspalinine (CIII),
14-(5)-((4 ' ,5 ' -Dimethyl-thiazol-2 ' -yl)-methyloxy)paspalinine (CIV), 14-(5)-([6'-(2'-Methyl-3'H-pyrimid-4'-onyl)]-methyloxy)paspalinine (CV),
14(S>([6'-(3'H-pyrimid-4'-onyl)]-methyloxy)paspalimne (CVI),
14(5)-((3 ' -Ethoxycarbonyl-2 ' -oxo)-propyloxy)paspalinine (CVII),
14-(S)-([6 ' -(2 ' -terf-butyl-3 'H-pyrimid-4 ' -onyl)] -methyloxy)paspalinine (C VIII),
14(5)-(3'-Oxypropyl phosphoric acid diphenyloxo)paspalinine (CDC), 14(5)-((2'-Ηydroxy)-ethyloxy)paspalinine (CX),
14(5)-((3'-Hydroxy-2'-(i?/S)-methyl)-propyloxy)paspalinine (mixture of 2 diastereomers) (CXI),
14(1S)-((2'-(Λ/5)-Hydroxy-3'-methyl)-butyloxy)paspalinine (mixture of 2 diastereomers) (CXII),
14(5)-((2' -Hydroxy-2 ' -methyl)-propyloxy)paspalinine (CXIϋ),
14(S)-((3 ' -Hydroxy-3 ' -methyl)-butyloxy)paspalinine (CXTV), 14-(5)-((3'-Oxy)-propyl ether-3 '-phosphoric acid mono-p-nitrophenyloxo)paspalinine (CXIII),
14(S)-((3 ' -Hydroxy)-benzyloxy)paspalinine (CXVI),
14(5)-((2'-Hydroxy)-benzyloxy)paspalinine (CXVII),
14(5)-(3'-Oxypropyl phosphoric acid dibenzyloxo)paspalinine (CXVIII),
14(5)-(3'-Oxypropyl phosphorate bis-triethylammonium)paspalinine (CXTX), 10-(E/Z)-([(4'-Methyl)-ben2ylimino]-14(5)-[N-(2'-cyclopropylamino)]-2'-oxo- ethyloxy)paspalinine (CXX),
10-(E/2)-([N-(propylimino)] - 14(S)- [N-(2 ' -propylamino)] -2' -oxo-ethyloxy)paspalinine (ratio of
EIZ isomers = 1/0.4) (CXXI),
10-(E/Z)-([N-(cyclopropylmethylimino)]- 14(5)-[N-(2'-cyclopropylamino)]-2'-oxo- ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXXII), 10-(2s/Z)-([7V-(cyclobutylimino)]- 14(5)-[7V-(2'-cyclobutylamino)]-2'-oxo-ethyloxy)paspalinine
(ratio of EIZ isomers = 1/0.4) (CXXIII),
10-(£/Z)-([iV-(cyclopentylimino)]- 14(S)- [N-(2 ' -cyclopentylamino)] -2 ' -oxo-ethyloxy)paspalinine
(ratio of EIZ isomers = 1/0.4) (CXXTV), 10-(E/Z)-([N-(butylimino)]-14(S)-[N-(2'-butylamino)]-2'-oxo-ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXXV),
10-(E/Z)-([iV-(ethylimino)] - 1 A(S)-[N-(I ' -ethylamino)] -2 ' -oxo-ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXXVI),
10-(£/Z)-([N-(2-methoxyethylimino)]- 14(S)- [_V-(2 ' -(2-methoxyethyl)amino)] -2 ' -oxo- ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXXVI),
10-(JE'/Z)-([imino)]-14(1S)-[iV-(2'-(cyclopropylamino)]-2'-oxo-ethyloxy)paspalinine (ratio of EIZ isomers = 1/1) (CXXVIII),
10-(E/Z)-([N-(methyrimino)] - 14(S)- [N-(2 ' -propylamino)]-2 ' -oxo-ethyloxy)paspalinine (ratio of
EIZ isomers = 1/0.7) (CXXTX), 1 Q-(EI Z)-([N-(3 -hydroxypropylimino)] - 14(S)-[_V-(2 ' -isopropylamino)] -2 ' -oxo- ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXXX),
10-(E/Z)-([iV-(4-methylbenzylimino)] - 14(S)- [_V-(2 ' -isopropylamino)] -2 ' -oxo- ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.7) (CXXXI),
14(S)-(4 ' -Bromobenzoyloxy)paspalinine (CXXXII), 14(S)-(Morpholin-4-yl-acetoyloxy)paspalinine (CXXXV),
14(5)-Isonicotinoyloxy-paspalinine (CXXXVI),
14(S)-Nicotinoyloxy-paspalinine (CXXXVII), 14(5)-(Methoxy-acetoxy)paspalinine (CXXXTX), 14(5)-(Dimethylamino-acetoxy)paspalinine (CXL), H^-Cyclopropanecarbonyloxypaspalinine (CXLI), 14(5)-Propionoyloxypaspalinine (CXLII),
14(S)-Ethoxy-acetoxypaspalinine (CXLIII), 14(5)-(3 ' -Methoxypropionoyloxy)paspalinine (CXLTV), 14(5)-Cyclobutanecarbonyloxypaspalinine (CXLV), 14(S)-Cyclopentanecarbonyloxypaspalinine (CXLVI),
14(5)-(3 ' ,3 ' ,3 ' -Trifluoropropionoyloxy)paspalinine (CXL VII), 14(5)-(2 ' -Methoxy-ethoxy)-acetoxypaspalinine (CXLVIII), 14(5)-(Furan-2 ' -carbonyloxy)paspalinine (CXLIX), 14(S)-(Tetrahydro-fiiran-2'-carbonyloxy)paspalinine (CL),
14(S)-Methylsulfanyl-acetoxypaspalinine (CLI),
14(5)-((5)-2 ' -Dimethylamino-3 ' -phenyl -propionoyloxy)paspalinine (CLII), 14(S)-Acetoxypaspalinine (CLIII), 14(iS)-Butyroyloxypaspalinine (CLV),
14(5)-(3 ' ,3 ' -Dimethyl-butyroyloxy)paspalinine (CLVI), 14(.S)-(I '-Methyl-cyclopropanecarbonyloxy)paspalinine (CLVII), 14(5)-(2'-Methyl-cyclopropanecarbonyloxy)paspalinine (CLVIII), 14(S)-(Benzyloxycarbonylamino-acetoxy)paspalinine (CLEX),
14(5)-(Benzyloxycarbonyl-methyl-amino)-acetoxypaspalinine (CLX), 14(5)-(3 ' -Benzyloxycarbonylamino-propionoyloxy)paspalinine (CLXI), 14(S)-Pentanoyloxypaspalinine (CLXII), 14(5)-((i?)-Tetrahydro-furan-2 ' -carbonyloxy)paspalinine (CLXIII), 14(5)-((5)-2 ' -Benzyloxycarbonylamino-3 ' -methyl -butyroyloxy)paspalinine (CLXTV), 14(5)-(Tetrahydro-pyran-4 ' -carbonyloxy)paspalinine (CLXV), 14(S)-((2'£,4'E)-Hexa-2',4'-dienoyloxy)paspalinine (CLXVI), . 14(5)-Acryloyloxypaspalinine (CLXVII), 14(5)-Hexanoyloxypaspalinine (CLXVIII, 14(5)-Benzoyloxypaspalinine (CLXTX),
14(5)-((iS)-2'-(9'H-Fluoren-9'-ylmethoxycarbonylamino)-3'-methyl-butyroyloxy)paspalinine (CLXX),
14(5)-((9'H-Fluoren-9'-ylmethoxycarbonylamino)-acetoxy)paspalinine (CLXXI), 14(5)-([2-(2-Methoxy-ethoxy)-ethoxy]-acetoxy)paspalinine (CLXXII), 14(5)-Cycloheptanecarbonyloxypaspalinine (CLXXHI), 14(5)-Diphenyl-acetoxypaspalinine (CLXXTV), 14(5)-((Λ)-2 ' -Methoxy-3 ' -methyl-butyroyloxy)paspalinine (CLXXV), 14(5)-[4'-(r-Methoxycarbonyl)-piperidinyl-carbonyloxy]-paspalinine (CLXXVI),
14(.S)-((S)-2 ' -Dimethylamino-propionoyloxy)paspalinine (CLXXVII),
14(S)-((S)-2 ' -Methoxy-3 ' -phenyl-propionoyloxy)paspalinine (CLXXVIII), 14(5)-(1 '-Methoxy-cyclopropanecarbonyloxy)paspalinine (CLXXIX), 14(5)-(2 ' -Methoxy-2 ' -methyl-propionoyloxy)paspalinine (CLXXX), 14(S)-( 1 ' -Dimethylamino-cyclopropanecarbonyloxy)paspalinine (CLXXXI),
14(S)-((i?)-2'-Dimethylamino-propionoyloxy)paspalinine (CLXXXII),
14(S)-(2 ' -Methyl-5 ' -trifluoromethyl-oxazole-4 ' -carbonyloxy)paspalinine (CLXXXIII),
14(5)-(Pyrimidine-5 ' -carbonyloxy)paspalinine (CLXXXIV), 14(S)-Nonanoyloxypaspalinine (CLXXXV),
14(S)-(2 ' -Bromo-3 ' -methyl-butyroyloxy)paspalinine (CLXXXVI),
14(S)-Undecanoyloxypaspalinine (CLXXXVII),
14(S)-Decanoyloxypaspalinine (CLXVIII),
14(S)-Octanoyloxypaspalinine (CLXXXIX), 14(S)-Heptanoyloxypaspalinine (CXC),
14(S)-(5 ' -Bromo-furan-2 ' -carbonyloxy)paspalinine (CXCI),
14(S)-(2 ' -Methyl-imidazo[ 1 ' ,2 ' -α]pyridine-3 ' -carbonyloxy)paspalinine (CXCII),
14(S)-(BeIiZO [ό]furan-2 ' -carbonyloxy)paspalinine (CXCIII),
14(S)-(Benzo [d] imidazo [2 ' , 1 ' -b] thiazole-2 ' -carbonyloxy)paspalinine (CXCIV), 14(S>(3 ' -Oxo-butyroyloxy)ρaspalinine (CXCV),
14(S)-(Thiophene-2 ' -carbonyloxy)paspalinine (CXCVI),
14(S)-(Adamantane-r-carbonyloxy)paspalinine (CXCVII),
14(5)-((S)-2 ' -Dimethylamino-butyroyloxy)paspalinine (CXCVIII),
14(S')-Cyclohexanecarbonyloxypaspalinine (CXCEX), 14(Sr)-(Pyridine-2'-carbonyloxy)paspalinine (CC),
14(SΗ(Z?)-2 ' -Methoxy-3 ' -phenyl-propionoyloxy)paspalinine (CCI),
14(S)-(Pyridin-2'-yl-acetoxy)paspalinine (CCπ),
14(5)-((4' -Oxo-3 ' ,4 ' -dihydro-phthalazin- 1 ' -yl)-acetoxy)paspalinine (CCIV),
14(S)-(3 ' -Iodo-benzoyloxy)paspalinine (CCV), 14(S)-(4'-Iodo-benzoyloxy)paspalinine (CCVI),
14(5)-(Phenylacetyl)paspalinine (CCVII),
14(S)-Dodecanoyloxypaspalinine (CCVIII),
14(ιS)-(4 ' -Bromo-phenyl)carbamoyloxypaspalinine (CCDC),
14(S)-(3 '-Chloropropyl)carbamoyloxypaspalinine (CCX), 14(S)-(Benzyl)carbamoyloxypaspalinine (CCXI),
14(S)-(Cyclohexyl)carbamoyloxypaspalinine (CCXII),
14(S)-(Allyl)carbamoyloxypaspalinine (CCXIII),
14(S)-(Isopropyl)carbamoyloxyρaspalinine (CCXIV),
14(S)-(«-Propyl)carbamoyloxypaspalinine (CCXV),
Figure imgf000019_0001
methyl)carbamoyloxypaspalinine (CCXVI), 14(5)-((5)-(-)-2'-Butyroyloxy methyl)carbamoyloxypaspalinine (CCXVII),
14(S)-((S)-(-)-2 ' -Valeroyloxy methyl)carbamoyloxypaspalinine (CCXVIII),
14(S)-(2 ' -Bromoethyl)carbamoyloxypaspalinine (CCXIX),
14(iS)-(4'-Dimethylaminophenyl)carbamoyloxypaspalinine (CCXX), 14(5)-Cyclopentylcarbamoyloxypaspalinine (CCXXI),
14(5)-(3',4'-methylenedioxyphenyl)carbamoyloxypaspalinine (CCXXII),
14(S)-Morpholinocarbamoyloxypaspalinine (CCXXIII),
14(S)-Pyrrolindinecarbamoyloxypaspalinine (CCXXIV),
14(5)-Piperidinecarbamoyloxypaspalinine (CCXXV), 140S)-te^Butylcarbamoyloxypaspalinine (CCXXVI),
14(S)-(N, N-Dimethyl)carbamoyloxypaspalinine (CCXXVII),
14(5)-(Ethylcarbamyl)carbamoyloxypaspalinine (CCXXVIII)
14(5)-(4' -Methyl- r-piperazine)carbamoyloxypaspalinine (CCXXEX),
14(S)-(«-Hexyl)carbamoyloxypaspalinine (CCXXX), 14(S)-(N, N-Diethyl)carbamoyloxypaspalinine, (CCXXXI)
14(5)-(«-Butyl)carbamoyloxypaspalinine (CCXXXII),
14(S)-Carbamoyloxypaspalinine (CCXXXIII),
14(5)-(Cyclopropyl)carbamoyloxypaspalinine (CCXXXIV),
14(S)-(4' -Benzyl- r-piperazine)carbamoyloxypaspalinine (CCXXXV), 14(S)-(4 ' -Phenyl- 1 ' -piperazine)carbamoyloxypaspalinine (CCXXXVI),
14(S)-(2'-pyrimidyl-l '-piperazine)carbamoyloxypaspalinine (CCXXXVII),
14(S)-(4'-acetyl-l '-piperazine)carbamoyloxypaspalinine (CCXXXVIII),
14(S)-[(4 ' -tert-Butoxycarbonylpiperazin- 1 ' -yl)-carbonyloxy] -paspalinine (CCXXXIX),
14(iS)-(4'-Ethyl-l '-piperazine)carbamoyloxypaspalinine (CCXL), 14(5)-(4'-Isopropyl-r-piperazine)carbamoyloxypaspalinine (CCXLI),
14(5)-(4' -Cyclopentyl- 1 ' -piperazine)carbamoyloxypaspalinine (CCXLII),
14(S)-(4 ' -(2 ' -Pyridyl)- 1 ' -piperazine)carbamoyloxypaspalinine (CCXLIII),
14(S)-(2 ' -Hydroxyethyl)carbamoyloxypaspalinine (CCXLIV),
14(S)-(2 ' -Morpholinoethy^carbamoyloxypaspalinine (CCXLV), 14(5)-(2 ' - Aminobenzyl)carbamoyloxypaspalinine (CCXLVI),
14(S)-(Cyclobutyl)carbamoyloxypaspalinine (CCXL VII),
14(5)-(Methylcyclohexyl)carbamoyloxypaspalinine (CCXLVIII),
14(5)-(4'-Methoxybenzyl)carbamoyloxypaspalinine (CCXLEX),
14(S)-(N, N-Diethylamino ethyl)carbamoyloxypaspalinine (CCL), 14(5)-(3'-Moφholinopropyl)carbamoyloxypaspalinine (CCLI), 14(5)-((i?)-2 ' -Hydroxy- 1 ' -methyl-ethyOcarbamoyloxypaspalinine (CCLII), 14(S)-(4 ' -Benzylpiperidine)carbamoyloxypaspalinine (CCLIII), 14(5)-[(4'-Methoxycarbonylpiperidin-r-yl)-carbonyloxy]-paspalinine (CCLIV), 14(S)-((S)-1 ' -Hydroxymethyl-3 '-methyl-butyl) carbamoyloxypaspalinine (CCLV), 14(5)-((5)- 1 ' -Hydroxymethyl-3 ' -methylsulfanyl-propyOcarbamoyloxypaspalinine (CCLVI), 14(S)-(I '-Ethylpropyl)carbamoyloxypaspalinine (CCLVII), 14(S)-(Ethyl)carbamoyloxypaspalinine (CCLVIII), 14(5)-(2'-(N,N-Dimethylamino)ethyl)carbamoyloxypaspalinine (CCLLX), 14(S)-(2'-Methoxyethyl)carbamoyloxypaspalinine (CCLX), 14(S)-( 1 ' -Hydroxymethyl-cyclopenty^carbamoyloxypaspalinine (CCLXI), 14(5)-(3 ' -MethoxypropyOcarbamoyloxypaspalinine (CCLXII), 14(S)-(Cycloproplymethyl)carbamoyloxypaspalinine (CCLXIII), 14(S)-( 1 ' -Hydroxymethyl-3 ' -methyl-butyl)carbamoyloxypaspalinine (CCLXTV), 14(S)-((i?)- 1 ' -Hydroxymethyl-2 ' -methyl-propy^carbamoyloxypaspalinine (CCLXV), 14(5)-((5)- 1 ' -Hydroxymethyl-3 ' -methyl-buty^carbamoyloxypaspalinine (CCLXVI), 14(5^-(1 '-Hydroxymethyl-benzy^carbamoyloxypaspalinine (CCLXVII), 14(5)-(4'-Aminobenzyl)carbamoyloxypaspalinine (CCLXVIII), 14(5)-(2 ' -Methylpropyl)carbamoyloxypaspalinine (CCLXIX), 14(5)-(3'-Ethoxypropyl)carbamoyloxypaspalinine (CCLXX), 14(5)-(4'-Hydroxypiperidine)carbamoyloxypaspalinine (CCLXXI),
14(5)-(4'-(2'-Hydroxyethyl)piperidine)carbamoyloxypaspalinine (CCLXXII), 14(5)-(2'-Pyridin-2'-yl-ethyl)carbamoyloxypaspalinine (CCLXXIII), 140S>(Pyridine-4 ' -yl-methyOcarbamoyloxypaspalinine (CCLXXIV), 14(S)-(I '-Benzyl-piperidin-4'-yl)carbamoyloxypaspalinine (CCLXXV), 14(S>(2',2'-Dimethoxy-ethyl)carbamoyloxypaspalinine (CCLXXVI),
14(5)-((4'-Methoxy-phenyl)-ethyl)carbamoyloxypaspalinine (CCLXXVII), 14(5)-(3 ' -Isopropoxy-propy^carbamoyloxypaspalinine (CCLXXVIII), 14(S)-((Λ)-1 '-Phenyl-ethyOcarbamoyloxypaspalinine (CCLXXIX), 14(JS)-(2',2'-Dimethyl-[l ',3']dioxolan-4'-ylmethyl)carbamoyloxypaspalinine (CCLXXX), 14(5)-(2', 2 '-Dimethyl-3'-hydroxy-propyl)carbamoyloxypaspalinine (CCLXXXI), 14(5)-(2'-Piperidin-r-yl-ethyl)carbamoyloxypaspalinine (CCLXXXII), 14(5)-(Furan-2'-yl-methyl)carbamoyloxypaspalinine (CCLXXXIII), 14(£)-(Cycloheptyl)carbamoyloxypaspalinine (CCLXXXIV), 14(5)-(4'-Methyl-benzyl)carbamoyloxypaspalinine (CCLXXXV), 14(1S)-((4'-Hydroxy)phenethyl)carbamoyloxypaspalinine (CCLXXXVI), 14(S)-((S)-1 '-Phenyl-ethyOcarbamoyloxypaspalinine (CCLXXXVII),
14(SH(S>sec-Butyl)carbamoyloxypaspalinine (CCLXXXVIII),
14(S)-CCS)- 1 ' -(Tetrahydro-furan-2 ' -yl)methyl)carbamoyloxypaspalinine (CCLXXXIX),
14(5)-((i?)-r-(Tetrahydro-furan-2'-yl)methyl)carbamoyloxypaspalinine (CCXC), 14(5)-((5)-2'-Methoxymethyl-pyrrolidine)carbamoyloxypaspalinine (CCXCI),
14(1S)-((i?)-2'-Hydroxymethyl-pyrrolidine)carbamoyloxypaspalinine (CCXCII),
14(5)-((i?)-3 '-Hydroxy-pyrrolidine)carbamoyloxypaspalinine (CCXCIII),
14(5)-((5)-2'-Hydroxymethyl-pyrrolidine)carbamoyloxypaspalinine (CCXCIV),
14(5)-(3', 6 '-Dihydro-2'H-pyridine)carbamoyloxypaspalinine (CCXCV), 14(5)-(2'-(l ',3'-Dihydro-isoindole))carbamoyloxypaspalinine (CCXCVI),
14(5)-(r-(4'-Methyl-piperidine))carbamoyloxypaspalinine (CCXCVII),
14(S)-(V- Azepane)carbamoyloxypaspalinine (CCXCVIII),
14(S)-(Toluene-4'-sulfonoyloxypaspalinine (CCXCIX),
14(S)-tert-Butoxycarbonyloxypaspalinine (CCC), 14(5)-(2'-(Pyridin-2'-yloxy)paspalinine (CCCI),
Paspalin-14-one (CCCII),
14(i?)-Hydroxypaspalinine (CCCIII),
13,14-(Dioxanoyloxypaspalinine (CCCIV),
Paspalin-13-ene (CCCVI), 14(5)-Hydroxy- 17-oxo-paspalinine (CCC Vn),
14(5)-Hydroxypaspalin- 10-exo-ene (CCC VIII),
10(SHOxaspiro)- 14(5)-hydroxypaspalinine (CCCLX),
10-(Carbomethoxymethylene)- 14-(<S)-hydroxypaspalinine (CCCX),
10(S)-Methyl- 14(5')-hydroxypaspalinine (CCCXI), 11,14-Thiophene-paspalinine (CCCXII),
14(5)-Hydroxyl-21 -bromopaspalinine (CCCXIII),
(14(5)-N-(3-Hydroxy-2,2-dimethyl-propyl))-(21-bromo)-acetamide-paspalinine (CCCXV),
14(S)-Hydroxy-21 -methoxycarbonylpaspalinine (CCCXVI),
14(5)-( Acetamide-7V-(3 ' -hydroxy-2 ' ,2 ' -dimethyl-propyl)-3 ' -phosphonooxy (bis- triethylammonium))paspalinine (CCCXVIII),
14(S)-(2 ' -Hydroxy-ethoxy-phosphonooxy (bis-triethylammonium))-ethyloyloxy)paspalinine
(CCCXX),
14(5)-(2 ' -Hydroxy-ethoxy)-21 -bromopaspalinine (CCCXXI), 14(5)-[2'-(Methoxycarbonyl)-ethyloxy]-21-bromo-paspalinine (CCCXXII), 14(5)-(Methyl-allyloxy)-21 -bromopaspalinine (CCCXXIII), 14(5}-(N-Propyl-acetamide)-paspalinine (CCCXXIV),
14(S)-(2'-Hydroxy-2'-methyl-propoxy)-21-bromopaspalinine (CCCXXV),
14(S),21 -Dihydroxypaspalinine (CCCXXVII),
14(5)-Hydroxy-21 -vinylpaspalinine (CCCXXVIII), 14(S)-Hydroxy-21 -phenylpaspalinine (CCCXXIX),
14(5)-Hydroxy-21 -methoxypaspalinine (CCCXXX),
14(5)-Hydroxy-21 -nitropaspalinine (CCCXXXI),
14(5)-Hydroxy-21 -cyanopaspalinine (CCCXXXII),
14(S)-[2'-(Methoxycarbonyl)-ethyloxy]-21 -cyano-paspalinine (CCCXXXϋl), 14(5>(iV-Isopropyl-acetamide)-21 -cyanopaspalinine (CCCXXXTV),
14(5)-(N-Butyl-acetamide)-21 -cyanopaspalinine (CCCXXXV),
14(S)-(jV-te/t-Butyl-acetamide)-21 -cyanopaspalinine (CCCXXXVI),
14(S)-(N-Propyl-acetamide)-21 -cyanopaspalinine (CCCXXXVII),
14(5)-(N-Ethyl-acetamide)-21 -cyanopaspalinine (CCCXXXVϋl), 14(5)-(3-Hydroxypropyloxy)-21 -cyanopaspalinine (CCCXXXIX),
14(5)-(3 ' -Hydroxy-propoxy-phosphono-oxy(bis-triethylammonium))-propyloyloxy)-21 - cyanopaspalinine (CCCXL),
14(S)-(2'-Hydroxyethyloxy)-21 -cyanopaspalinine (CCCXLI),
14(S)-(2 ' -Hydroxy-ethoxy-phosphono-oxy (bis-triethylammonium))-ethyloyloxy)-21 - cyanopaspalinine (CCCXLIII),
14(5)-((Isobutryoyloxy 2 '-ethoxy)-21 -cyanopaspalinine (CCCXLIV),
14(S)-(Methyl-allyloxy)-21 -cyanopaspalinine (CCCXLV), l-«-Butylcarbamoyl-14(5)-[«-butyl-carbamoyloxy]-paspalinine (CCCXLVI),
1 -Carboxoyloxy pentylamide- 14(5}- [n-pentyl-carbamoyloxy] -paspalinine (CCCXLVII), 1 -Bromo- 14(5)-hydroxypaspalinine (CCCXLVIII),
1 - Allyl- 14(S> allyloxypaspalinine (CCCXLIX),
1 -Allyl- 14(5)-propyloxypaspalinine (CCCL),
1 -Propyl- 14(5)-allyloxypaspalinine (CCCLI),
1 -Methoxymethyl- 14(5)-propyloxypaspalinine (CCCLII), 1 -Acetyl- 14(S>propyloxypaspalinine (CCCLIII),
1 -(2 ' ,2 ' -Dimethyl-methylpropionoyloxy)- 14(5)-propyloxypaspalinine (CCCLIV),
1 -(2-Hydroxyethyloxycarbonyl)- 14(5)-propyloxypaspalinine (CCCLV),
1 -Carbonyloxy propylamide-14(iS)-propyloxypaspalinine (CCCLVI),
1 -(3-Hydroxypropyloxycarbonyl)- 14(5)-propyloxypaspalinine (CCCLVII), 1 - [(3 ' -(N, N-Dimethylaminoacetoxy)-propyloxy)-carbonyl] - 14(5)-propyloxypaspalinine
(CCCLVIII),
14-(S)-((4'-Cyano)-butyloxy)-21 -bromopaspalinine (CCCXCI),
14(S)-Isopropylcarbamoyloxy-21 -bromopaspalinine (CCCXCIII), 1 -(Hydroxymethyl)- 14-(S)-propyloxypaspalinine (CCCXCVII),
1 -(rc-Propylcarbamoyloxymethyl)- 14-(5)-propyloxypaspalinine (CCCXCVIII), or a pharmaceutically acceptable salt, ester, including phosphate, enantiomer, diastereomer or mixture thereof.
Other examples of this invention are: 14(S)-(3'-hydroxypropyloxy)paspalinine (II),
14-(5)-((2'-(i?/S)-2'-hydroxy)-propyloxy)paspalinine (mixture of 2 diastereomers) (XI),
14-(5)-((2'-(i?)-2'-methyl-3'-hydroxy)-propyloxy)paspalinine (LiV),
14-(S)-((2 ' -(S)-2 ' -methyl-3 ' -hydroxy)-propyloxy)paspalinine (LV) ,
14-(5)-((2'-[N-(3"-hydroxy-2",2"-dimethylpropylamino)]-2'-oxo)-ethyloxy)paspalinine (LX), 14(S)-(3 ' -oxypropyl phosphorate bis-triethylammonium)paspalinine (CXTX), 14(5)-
(isopropyl)carbamoyloxypaspalinine (CCXIV),
(14(5)-iV-(3-Hydroxy-2,2-dimethyl-propyl))-(21 -bromo)-acetamide-paspalinine (CCCXV),
14(5)-(Acetamide-7V-(3'-hydroxy-2', 2' -dimethyl -propyl)-3'-phosphonooxy (bis- triethylammonium))paspalinine (CCCXVIII), 14(5)-(2'-Hydroxy-ethoxy-phosphonooxy (bis-triethylammonium))-ethyloyloxy)paspalinine (CCCXX),
14(S)-Hydroxy-21 -cyanopaspalinine (CCCXXXII),
1 -(3 -Hydroxypropyloxycarbonyl)- 14(5)-propyloxypaspalinine (CCCLVII),
14(5)-((2'-hydroxy)-ethyloxy)paspalinine (CX), 14(5)-(2'-Hydroxy-ethoxy)-(21-bromo)-paspalinine (CCCXXI),
14(5)-(Methyl acetate)-21-(bromo)-paspalinine (CCCXXϋ),
14(5)-(3-Hydroxypropyloxy)-21 -(cyano)-paspalinine (CCCXXXLX),
14(5)-(3 ' -Hydroxy-propoxy-phosphono-oxy(bis-triethylammonium))-propyloyloxy)-21 -(cyano)- paspalinine (CCCXL), 14(5)-(2'-Hydroxyethyloxy)-21-(cyano)-paspalinine (CCCXLI),
14(5)-(2'-Hydroxy-ethoxy-phosphono-oxy (bis-triethylammonium))-ethyloyloxy)-21 -(cyano)- paspalinine (CCCXLIII),
1 -(Hydroxymethyl)- 14-(5)-propyloxypaspalinine (CCCXCVII) or a pharmaceutically acceptable salt, ester, including phosphate, enantiomer, diastereomer or mixture thereof.
The following abbreviations are used throughout and are defined as follows, unless otherwise indicated.
UV ultraviolet calc. calculated
DCM dichloromethane
EtOAc ethyl acetate HPLC High pressure liquid chromatography
MHz Megahertz
NMR Nuclear Magnetic Resonance
THF Tetrahydrofuran
DMSO - dimethyl sulfoxide, TLC - thin layer chromatography, h = hr = hour,
DMF - dimethylformamide, min - minute,
LCMS - liquid chromatography/mass spectrometry, Equiv. = eq. = equivalent,
NBS -N-Bromosuccinimide,
DCM - Dichloromethane,
IOP - Intraocular pressure,
EDC - jV-(3-Dimethylaminopropyl)-Λ^-ethylcarbodiimide hydrochloride, Ph - phenyl, deg. C = degrees Celsius
DMAP - 4-dimethylaminopyridine,
TBAB - tetrabutylamrnonium bromide,
Hept. - heptane. The following examples given by way of illustration are demonstrative of the present invention. The compounds of this invention can be made, with modification where appropriate, in accordance with Schemes 1-11.
Scheme 1. Synthesis of 10-methylene derivative.
Figure imgf000026_0001
Scheme 2. Inversion of 14-hydroxyl
Figure imgf000026_0003
Figure imgf000026_0002
Scheme 3. Synthesis of 14-ethers of paspalinine.
Br ^^
OBu2SnO,
Figure imgf000026_0004
Scheme 5. Synthesis of 14-esters of paspalinine.
Figure imgf000027_0001
Scheme 6. Synthesis of 14-carbamates of paspalinine.
Figure imgf000027_0002
Scheme 7. Oxidation of 17-position of paspalinine.
Figure imgf000027_0003
Scheme 8. Modification of 21 -position of paspalinine.
Figure imgf000027_0004
Scheme 9. Example synthesis of 14-position alkoxyphosphates of paspalinine.
Figure imgf000028_0001
Figure imgf000028_0002
CXIX CXVIII
Scheme 10. Example synthesis of iV-carbonylalkyloxy derivatives of paspalinine. Br ^^
diol
Figure imgf000029_0001
H0^NMe2
Figure imgf000029_0002
CCCLVII
Figure imgf000029_0003
Scheme 11. Example synthesis of iV-methylcarbamoyloxy derivatives of paspalinine. drops),
Figure imgf000029_0004
Figure imgf000029_0005
CCCXCVII
Figure imgf000029_0006
All temperatures are given in degrees Centigrade or Celsius. Reagents were purchased from commercial sources or prepared following literature procedures.
Unless otherwise noted, HPLC purification was performed by redissolving the residue in a small volume of DMSO and filtering through a 0.45 micron (nylon disc) syringe filter. The solution was then purified via reverse-phase preparatory HPLC purification system using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The initial gradient of 40- 80% MeOH:H2O was selected as appropriate for the target compound. This initial gradient was maintained for 0.5 minutes then ramped up to 100% MeOH:0% H2O over 5 minutes. 100% MeOH was maintained for 2 more minutes before it was re-equilibrated back to the initial starting gradient. Total run time was 8 minutes. The resulting fractions were analyzed, combined as appropriate, and then evaporated to provide purified material.
Proton magnetic resonance (1H NMR) spectra were recorded on either a Varian INOVA 400 MHz (1H) NMR spectrometer, Varian INOVA 500 MHz (1H) NMR spectrometer, Bruker ARX 300 MHz (1H) NMR spectrometer, Bruker DPX 400 MHz (1H) NMR spectrometer, or a Bruker DRX 500 MHz (1H) NMR spectrometer. All spectra were determined in the solvents indicated. Although chemical shifts are reported in parts per million (ppm) downfield of tetramethylsilane, they are referenced to the residual proton peak of the respective solvent peak for 1H NMR. Interproton coupling constants are reported in Hertz (Hz). Analytical HPLC was performed using a Phenomenex Aqua 5 micron Ci8 125 A 50 x 4.60 mm column coupled with an Agilent 1100 series VWD UV detector. A neutral 0.1% BES (w/v) pH 7.1 buffer with LiOH and 1% CH3CN in H2O are used as the aqueous phase. The initial gradient was 55% MeOH : aqueous buffer which was ramped up to 100% MeOH over 3 minutes. 100% MeOH was maintained for 2 minutes before it was re-equilibrated to the initial starting gradient. Spectra were analyzed at 254 nm. LCMS spectra were obtained using a ThermoFinnigan AQA MS ESI instrument. The samples were sent through a Phenomenex Aqua 5 micron C)8 125A 50 x 4.60 mm column. The initial gradient was 55% MeOH: 1% CH3CN in H2O which was ramped up to 100% MeOH over 3 minutes. 100% MeOH was maintained for 2 minutes before it was re- equilibrated to the initial starting gradient. The spray setting for the MS probe was at 350 μL/min with a cone voltage at 25 mV and a probe temperature at 450°C.
The following preparations illustrate procedure from the preparation of intermediates and methods for the preparation of products according to this invention. It should be evident to those skilled in the art that appropriate substitution of both the materials and methods disclosed herein will produce the examples illustrated below and those encompassed by the scope of the invention. Example 1 - 14(5)-(3'-hydroxypropyloxy)paspalinine (II)
Figure imgf000030_0001
To a 40-mL scintillation vial fitted with a magnetic stir bar was added 0.5 g, 1.1 mmol, 1 eq of the starting 14-(5)-hydroxypaspalinine material I (See US Pat No. 5,227,396, incorporated herein in its entirety for process of making material I), dibutyl tin oxide (0.83 g, 3.3 mmol, 3 eq.), powdered 4 Angstrom molecular sieves (1.25 g, 2.5 x the amount of starting material by wt), and 10 mL each of anhydrous THF and anhydrous toluene. The vial was capped tightly, placed in a preheated 75 deg. C oil bath, and heated for 3 hours with stirring. The 3-bromo-l-propanol (0.77 g, 0.49 mL, 5.5 mmol, 5 eq.) was subsequently added followed immediately by the tetrabutyl ammonium bromide (1.07 g, 3.3 mmol, 3 eq.). The reaction was stirred at 75 deg. C for 16 hours. An additional 5 eq. of 3-bromo-l-propanol was added and stirring was continued for 16 more hours. The reaction mixture was allowed to cool and was transferred to a 125-mL separatory funnel, taken up in 30-40 mL of ethyl acetate, and washed twice with a 1 : 1 brine/water mixture and once with a saturated aqueous KF solution. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. Purification was performed by HPLC. LCMS m/e 530 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ: 8.92 (br s, 1, 7.33 (ddd, J= 14.55, 7.03, 1.46 Hz, 2H), 7.05 (dddd, J= 14.35, 7.13, 1.37, 1.37 Hz, 2H), 5.88 (d, J= 0.74 Hz, IH), 4.33 (d, J= 1.17 Hz, IH), 3.92 (dd, J= 10.45, 5.27 Hz, IH), 3.83-3.88 (m, IH), 3.52-3.62 (m, 3H), 3.51 (s, IH), 2.73-2.84 (m, 2H), 2.58-2.71 (m, 2H), 2.53 (dd, J= 5.17, 5.17 Hz, IH), 2.42 (dd, J= 13.08, 10.54 Hz, IH), 2.31 (ddd, J= 12.10, 5.47, 2.44 Hz, IH), 1.70-1.91 (m, 4H), 1.40 (s, 3H), 1.35 (s, 3H), 1.19 (s, 3H), 1.14 (s, 3H).
Example 2 - 14-(S)-(allyloxy)paspalinine (III)
Figure imgf000031_0001
III
Compound prepared using similar procedure to that of (II). LCMS m/e 490 (M+H). 1H NMR (400 MHz, ACETONITRJLE-d3) δ (ppm): 8.93 (s, 1 H), 7.33 (dd, J=I 5.22, 7.86 Hz, 2 H), 6.95 - 7.05 (m, 2 H), 5.93 - 6.05 (m, 1 H), 5.90 (s, 1 H), 5.32 (dd, J=I 7.31, 1.81 Hz, 1 H), 5.17 (dd, J=10.49, 1.70 Hz, 1 H), 4.28 - 4.38 (m, 2 H), 4.02 - 4.09 (m, 1 H), 3.98 (dd, J=10.49, 5.33 Hz, 1 H), 3.48 (s, 1 H), 2.58 - 2.85 (m, 4 H), 2.42 (dd, J=13.08, 10.55 Hz, 1 H), 2.25 - 2.34 (m, 1 H), 1.76 - 1.92 (m, 2 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.19 (s, 3 H), 1.13 (s, 3 H).
Example 3 - 14-(5)-(propyloxy)paspalinine (FV)
Figure imgf000032_0001
IV
Compound prepared using similar procedure to that of (II). LCMS m/e 492 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.93 (s, 1 H), 7.27 - 7.38 (m, 2 H), 6.95 - 7.06 (m, 2 H), 5.88 (d, J=0.88 Hz, 1 H), 4.33 (d, J=1.32 Hz, 1 H), 3.91 (dd, J=10.44, 5.38 Hz, 1 H), 3.71 - 3.80 (m, 1 H), 3.50 (s, 1 H), 3.38 - 3.46 (m, 1 H), 2.58 - 2.85 (m, 4 H), 2.42 (dd, J=13.13, 10.60 Hz, 1 H), 2.26 - 2.34 (m, 1 H), 1.67 - 1.91 (m, 2 H), 1.53 - 1.65 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.19 (s, 3 H), 1.14 (s, 3 H), 0.90 - 0.98 (m, 6 H).
Example 4 - 14-(5)-([(3'-(methoxycarbonyl)-allyl]oxy)paspalinine (VI)
Figure imgf000032_0002
VI
Compound prepared using similar procedure to that of (II). LCMS m/e 547 (M+H). 1R NMR (400 MHz, ACETONITRILE-di) δ (ppm): 8.94 (s, 1 H), 7.28 - 7.38 (m, 2 H), 6.95 - 7.06 (m, 2 H), 6.09 - 6.17 (m, 1 H), 5.83 (d, J=LlO Hz, 1 H), 4.46 - 4.56 (m, 1 H), 4.34 (d, J=1.32 Hz, 1 H), 4.18 - 4.27 (m, 1 H), 4.01 (dd, J=10.55, 5.16 Hz, 1 H), 3.70 (s, 3 H), 3.55 (s, 1 H), 2.59 - 2.86 (m, 4 H), 2.42 (dd, J=13.08, 10.55 Hz, 1 H), 2.23 - 2.31 (m, 1 H), 1.79 - 1.90 (m, 2 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.19 (s, 3 H), 1.13 (s, 3 H), 0.87 - 1.00 (m, 3 H).
Example 5 - 14-(5)-((2'-[l",3"]-dioxolan-2"-yl)-ethyloxy)paspalinine (VII)
Figure imgf000032_0003
VII Compound prepared using similar procedure to that of (II). LCMS m/e 549 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.92 (s, 1 H), 7.28 - 7.39 (m, 2 H), 6.94 - 7.07 (m, 2 H), 5.89 (d, J=0.88 Hz, 1 H), 4.90 (dd, J=5.60, 4.50 Hz, 1 H), 4.32 (d, J=I.32 Hz, 1 H), 3.76 - 3.97 (m, 5 H), 3.56 - 3.64 (m, 1 H), 3.54 (s, 1 H), 2.57 - 2.85 (m, 4 H), 2.42 (dd, J=13.13, 10.49 Hz, 1 H), 2.27 - 2.35 (m, 1 H), 1.68 - 1.91 (m, 3 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.18 (s, 3 H), 1.13 (s, 3 H), 0.87 - 1.01 (m, 4 H).
Example 6 - 14-(lS)-((2'-(i?/Sr)-2',3'-dihydroxy)-propyloxy)paspalinine (mixture of 2 diastereomers) (VIII)
Figure imgf000033_0001
VIII
To a solution of 14-(S)-(allyloxy)paspalinine (III) (8.8 mg, 0.018 mmol, 1 eq.) in pyridine (0.4 mL) was added a solution of OsO4 (172 μL of a 4% solution in H2O, 0.027 mmol, 1.5 eq.). After stirring for 48 h, 0.5 mL of a 4% solution of sodium bisulfite in 2:3 pyridine:H2O was added and the mixture allowed to stir for 2 h, after which the volatiles were removed by N2 blowdown. The residue was mixed with H2O and extracted with ethyl acetate (3 x 2 mL). The combined organic phases were concentrated by N2 blowdown and the residue purified by HPLC. LCMS m/e 524 (M+H). 1H NMR (500 MHz, ACETOMTRlLE-di) δ (ppm): 8.94 (s, 1 H), 7.28 - 7.39 (m, 2 H), 6.94 - 7.07 (m, 2 H), 5.98 (d, J=13.92 Hz, 1 H), 4.33 (s, 1 H), 3.89 - 3.99 (m, 1 H), 3.82 (dd, J=9.34, 4.03 Hz, 1 H), 3.67 - 3.76 (m, 2 H), 3.56 (s, 1 H), 3.54 (s, 1 H), 3.39 - 3.51 (m, 3 H), 2.73 - 2.84 (m, 2 H), 2.59 - 2.71 (m, 2 H), 2.42 (dd, J=13.00, 10.62 Hz, 1 H), 2.26 - 2.34 (m, 1 H), 1.78 - 1.89 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.18 (s, 3 H), 1.14 (s, 3 H).
Example 7 - 14-(5)-([2'-(2"-methoxy-ethoxy)]-ethyloxy)paspalinine (X)
Figure imgf000033_0002
X
Compound prepared using similar procedure to that of (II). LCMS m/e 574 (M+Na). 1H NMR (400 MHz, ACETONITRILE-di) δ (ppm): 8.92 (s, 1 H), 7.28 - 7.37 (m, 2 H), 6.95 - 7.05 (m, 2 H)5 6.16 (d, J=LlO Hz, 1 H), 4.30 (d, J=1.32 Hz, 1 H), 3.99 (dd, J=10.49, 5.33 Hz, 1 H), 3.83 - 3.90 (m, 1 H), 3.46 - 3.67 (m, 8 H), 2.58 - 2.84 (m, 4 H), 2.42 (dd, J=13.19, 10.55 Hz, 1 H), 2.25 - 2.33 (m, 1 H), 1.75 - 1.91 (m, 5 H), 1.39 (s, 3 H), 1.35 (s, 3 H), 1.19 (s, 3 H), 1.13 (s, 3 H).
Example 8 - 14-(S)-(([2',5']-dioxo-pyrrolidin-[r]-yl-oxycarbonyl)-methyloxy)paspalinine (XHT)
Figure imgf000034_0001
XIII
Compound prepared using similar procedure to that of (II). LCMS m/e 627 (M+Na). 1H NMR (500 MHz, ACETONITRILE-di) δ (ppm): 8.93 (s, 1 H), 7.28 - 7.38 (m, 2 H), 6.95 - 7.06 (m, 2 H), 6.16 (d, J=0.85 Hz, 1 H), 4.31 (d, J=1.34 Hz, 1 H), 4.19 - 4.26 (m, 1 H), 3.63 (s, 1 H), 3.53 (s, 1 H), 2.53 - 2.89 (m, 6 H), 2.40 (dd, J=13.18, 10.62 Hz, 1 H), 1.78 - 1.89 (m, 2 H), 1.37 - 1.42 (m, 5 H), 1.34 (s, 3 H), 1.23 (s, 1 H), 1.19 (s, 3 H), 1.11 - 1.15 (m, 4 H).
Example 9 - 14-(iS)-(cyclopropylmethyloxy)paspalinine (XIV)
Figure imgf000034_0002
XIV
Compound prepared using similar procedure to that of (II). LCMS m/e 526 (M+Na). 1H NMR (500 MHz, ACETONITRILE-di) δ (ppm): 8.93 (s, 1 H), 7.29 - 7.37 (m, 2 H), 6.95 - 7.05 (m, 2 H), 6.00 (d, J=0.85 Hz, 1 H), 4.33 (d, J=I.34 Hz, 1 H), 3.94 (dd, J=10.50, 5.37 Hz, 1 H), 3.62 (dd, J=10.07, 6.78 Hz, 1 H), 3.51 (s, 1 H), 3.33 (dd, J=10.01, 6.96 Hz, 1 H), 2.73 - 2.83 (m, 2 H), 2.59 - 2.70 (m, 2 H), 2.41 (dd, J=13.18, 10.62 Hz, 1 H), 2.24 - 2.30 (m, 1 H), 1.76 - 1.89 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.18 (s, 3 H), 1.14 (s, 3 H), 1.00 - 1.10 (m, 1 H), 0.50 - 0.56 (m, 2 H), 0.22 - 0.27 (m, 2 H). Example 10 - 14-(5)-((2'-diethylamino)-ethyloxy)paspalinine (XV)
Figure imgf000035_0001
XV
Compound prepared using similar procedure to that of (II). LCMS m/e 549 (M+H). 1H NMR (500 MHz, ACETONITRILE-di) δ (ppm): 8.95 (s, 1 H), 7.29 - 7.37 (m, 2 H), 6.96 - 7.05 (m, 2 H), 5.82 (s, 1 H), 4.46 (s, 1 H), 4.34 (d, J=I.22 Hz, 1 H), 4.05 - 4.12 (m, 1 H), 4.02 (dd, J=10.62, 5.25 Hz, 1 H), 3.70 - 3.77 (m, 1 H), 3.28 (d, J=5.13 Hz, 1 H), 3.07 - 3.20 (m, 3 H), 2.75 - 2.87 (m, 2 H), 2.61 - 2.72 (m, 2 H), 2.44 (dd, J=13.00, 10.56 Hz, 1 H), 2.28 - 2.34 (m, 1 H), 1.77 - 1.87 (m, 2 H), 1.40 (d, J=7.08 Hz, 7 H), 1.31 (t, J=7.26 Hz, 6 H), 1.19 (s, 3 H), 1.14 (s, 3 H), 0.89 - 0.99 (m, 3 H).
Example 11 - 14-(S)-((pyridin-4'-yl)-methyloxy)paspalinine (XVI)
Figure imgf000035_0002
XVI Compound prepared using similar procedure to that of (II). LCMS m/e 541 (M+H).
1H NMR (500 MHz, ACETONITRILE-d^) δ (ppm): 8.95 (s, 1 H), 8.52 - 8.55 (m, 2 H), 7.30 - 7.38 (m, 4 H)5 6.96 - 7.05 (m, 2 H), 5.90 (d, J=0.85 Hz, 1 H), 4.90 (d, J=13.18 Hz, 1 H), 4.64 (d, J=13.18 Hz, 1 H), 4.33 (d, J=1.34 Hz, 1 H), 4.14 (dd, J=10.62, 5.25 Hz, 1 H), 3.58 (s, 1 H), 2.76 - 2.88 (m, 2 H), 2.60 - 2.74 (m, 2 H), 2.44 (dd, J=13.12, 10.56 Hz, 1 H), 2.33 - 2.39 (m, 1 H), 1.78 - 1.92 (m, 1 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.22 (s, 3 H), 1.13 (s, 3 H).
Example 12 - 14-(5)-((6'-hydroxymethyl-pyridin-2'-yl)-methyloxy)paspalinine (XVIII)
Figure imgf000036_0001
XVIII
Compound prepared using similar procedure to that of (II). LCMS m/e 571 (M+H). 1H NMR (500 MHz, ACETONITRILE-d^) δ (ppm): 8.99 (s, 1 H), 7.81 (t, J=7.69 Hz, 1 H), 7.34 7.43 (m, 4 H), 7.01 - 7.10 (m, 2 H), 6.28 (d, J=1.28 Hz, 1 H), 4.96 (d, J=12.51 Hz, 1 H), 4.68 - 4.73 (m, 2 H), 4.36 (d, J=1.40 Hz, 1 H), 4.20 (dd, J=10.62, 5.31 Hz, 1 H), 3.75 (s, 1 H), 3.73 (t, J=5.95 Hz, 1 H), 2.64 - 2.91 (m, 4 H), 2.42 - 2.56 (m, 2 H), 1.83 - 1.94 (m, 2 H), 1.44 (s, 3 H), 1.42 (s, 3 H), 1.25 (s, 3 H), 1.17 (s, 3 H), 0.93 (t, J=6.99 Hz, 2 H).
Example 13 14-(5)-(methoxycarbonylmethyl ether)paspalinine (XXX)
XXX
Compound prepared using similar procedure to that of (II). LCMS m/e 544 (M+Na). 1H NMR (400 MHz, ACETONITRILE-di) δ (ppm): 8.94 (s, 1 H), 7.29 - 7.37 (m, 2 H), 6.96 - 7.05 (m, 2 H), 6.41 (d, J=0.83 Hz, 1 H), 4.25 - 4.37 (m, 3 H), 4.22 (dd, J=10.71, 5.30 Hz, 1 H), 3.73 (s, 3 H), 3.58 (s, 1 H), 2.59 - 2.83 (m, 4 H), 2.43 (dd, J=13.O8, 10.54 Hz, 1 H), 2.20 - 2.27 (m, 1 H), 1.80 - 1.89 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.19 (s, 3 H), 1.14 (s, 3 H).
Example 14 - 14-(5)-((3 ' -cyano)-propyloxy)paspalinine ( XXXiπ )
Figure imgf000037_0001
XXXIII
Compound prepared using similar procedure to that of (II). LCMS m/e 539 (M+Na). 1H NMR (400 MHz, ACETOMTRlLE-di) δ (ppm): 8.93 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.95 - 7.06 (m, 2 H), 5.80 (s, 1 H), 4.34 (d, J=0.98 Hz, 1 H), 3.93 (dd, J=10.40, 5.37 Hz, 1 H), 3.81 - 3.88 (m, 1 H), 3.55 - 3.62 (m, 1 H), 3.51 (s, 1 H), 2.58 - 2.84 (m, 4 H), 2.39 - 2.52 (m, 3 H), 2.26 - 2.33 (m, 1 H), 1.81 - 1.92 (m, 4 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.17 (s, 3 H), 1.14 (s, 3 H).
Example 15 - 14-(S)-(prop-2'-ynyloxy)paspalinine (XXXIV)
Figure imgf000037_0002
XXXIV
Compound prepared using similar procedure to that of (II). LCMS m/e 510 (M+Na). 1H NMR (300 MHz, ACETONITRILE-d3) δ (ppm): 8.94 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.95 - 7.07 (m, 2 H), 6.11 (d, J=0.88 Hz, 1 H), 4.30 - 4.47 (m, 3 H), 4.17 (dd, J=I 0.56, 5.31 Hz, 1 H), 3.43 (s, 1 H), 2.58 - 2.84 (m, 5 H), 2.38 - 2.48 (m, 1 H), 2.25 - 2.33 (m, 1 H), 1.77 - 1.91 (m, 3 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.20 (s, 3 H), 1.14 (s, 3 H).
Example 16 - Alternative procedure for the preparation of \4-(S)-([3'-(tert- butyldimethylsilanyloxy)] -propyl oxy)paspalinine (LFX)
Figure imgf000037_0003
Phase transfer conditions using
Figure imgf000037_0004
10eq. aq. KOH (5N) / Chlorobenzene at 50 deg. C ( 16 hours)
Figure imgf000037_0005
To a 2-dram vial with magnetic stirbar was added the 14(S)-hydroxypaspalinine (I) (25 mg, 0.056 mmol, 1 eq.) and 1 mL of chlorobenzene. The phase transfer catalyst (tetrabutylammonium hydrogen sulfate) (1.9 mg, 0.0056 mmol, 0.1 eq.) was then added followed by the base solution (0.1 mL of 5Naq. KOH, 0.56 mmol, 10 eq.). The 3-[(tert- butyldimethylsilyl)-oxy]-propanol (140 mg, 0.56 mmol, 10 eq.) was then added. The reaction was heated to 50 deg. C with stirring for 16 hours. The reaction was taken up in 3 mL of DCM and 1 mL of water was added to the mixture. The DCM layer was removed and set aside. The remaining aqueous layer was extracted x 3 with DCM, and the organic layers were combined and evaporated to dryness in vacuo. The resulting residue was purified via HPLC. LCMS m/e 622 (M+H). 1H NMR (400 MHz, DICHLOROMETHANE-d!) δ (ppm): 7.81 (s, 1 H), 7.37 - 7.42 (m, 1 H), 7.27 - 7.33 (m, 1 H), 6.99 - 7.09 (m, 2 H), 5.86 (d, J=0.93 Hz, 1 H), 4.29 (d, J=1.37 Hz, 1 H), 3.84 - 3.94 (m, 2 H), 3.65 - 3.75 (m, 2 H), 3.51 - 3.59 (m, 1 H), 3.26 (s, 1 H), 2.64 - 2.88 (m, 4 H), 2.43 - 2.51 (m, 1 H), 2.28 - 2.35 (m, 1 H), 1.74 - 2.01 (m, 5 H), 1.41 (s, 3 H), 1.39 (s, 3 H), 1.22 (s, 3 H), 1.16 (s, 3 H), 0.91 (s, 9 H), 0.07 (s, 6 H).
Example 17 - 14-(5)-(benzyloxy)paspalinine (XXXVI)
Figure imgf000038_0001
XXXVI
Compound prepared using similar procedure to that of (II). LCMS m/e 562 (M+Na). 1H NMR (300 MHz, ACETONITRILE-d3) δ (ppm): 8.94 (s, 1 H), 7.27 - 7.43 (m, 7 H), 6.96 - 7.07 (m, 2 H), 5.94 (d, J=I.05 Hz, 1 H), 4.85 (d, J=I 1.50 Hz, 1 H), 4.58 (d, J=I 1.44 Hz, 1 H), 4.31 (d, J=I.33 Hz, 1 H), 4.06 (dd, J=I 0.50, 5.31 Hz, 1 H), 3.51 (s, 1 H), 2.58 - 2.86 (m, 4 H), 2.35 - 2.49 (m, 2 H), 1.79 - 1.92 (m, 2 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.18 (s, 3 H), 1.14 (s, 3 H).
Example 18 -14-(5)-(pyrimidin-4'-yl methyloxy)paspalinine (XXXVII)
Figure imgf000039_0001
XXXVII
Compound prepared using similar procedure to that of (II). LCMS m/e 564 (M+Na).
1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 9.11 (s, 1 H), 8.95 (s, 1 H), 8.74 (s, 1 H),
7.56 (s, 1 H), 7.29 - 7.39 (m, 2 H), 6.95 - 7.06 (m, 2 H), 5.98 (d, J=0.66 Hz, 1 H), 4.91 (d,
J=14.62 Hz, 1 H), 4.68 (d, J=I 4.69 Hz, 1 H), 4.34 (d, J=I.17 Hz, 1 H), 4.18 (dd, J=10.63, 5.23
Hz, 1 H), 3.64 (s, 1 H), 2.77 - 2.87 (m, 2 H), 2.62 - 2.73 (m, 2 H), 2.43 (dd, J=13.15, 10.60 Hz, 1
H), 2.33 - 2.39 (m, 1 H), 1.82 - 1.91 (m, 1 H), 1.41 (s, 3 H), 1.38 (s, 3 H), 1.22 (s, 3 H), 1.13 (s, 3
H).
Example 19 - 14-(S)-((2'-oxo-2'-phenyl)-ethyloxy)paspalinine (XXXVIU)
Figure imgf000039_0002
XXXVIII
Compound prepared using similar procedure to that of (II). LCMS m/e 590 (M+Na). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.61 (s, 1 H), 7.97 - 8.05 (m, 2 H), 7.65 - 7.72 (m, 1 H), 7.52 - 7.60 (m, 2 H), 7.27 (d, J=7.97 Hz, 2 H), 6.86 - 6.99 (m, 2 H), 6.48 (d, J=LlO Hz, 1 H), 5.07 - 5.20 (m, 2 H), 4.42 (d, J=I .17 Hz, 1 H), 4.26 (dd, J=10.56, 4.93 Hz, 1 H), 2.56 - 2.85 (m, 3 H), 2.37 (dd, J=12.86, 10.60 Hz, 1 H), 2.19 - 2.28 (m, 1 H), 1.92 - 2.03 (m, 1 H), 1.79 - 1.90 (m, 2 H), 1.37 (s, 3 H), 1.32 (s, 3 H), 1.16 (s, 3 H), 1.10 (s, 3 H).
Example 20 - 14-(5)-((4',4',4'-trifluoro)-butyloxy)paspalinine (XXXIX)
Figure imgf000040_0001
XXXIX
Compound prepared using similar procedure to that of (II). LCMS m/e 582 (M+Na). 1H NMR (400 MHz, ACETONITRILE-di) δ (ppm): 8.92 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.96 - 7.05 (m, 2 H), 5.80 (d, J=I.12 Hz, 1 H), 4.34 (d, J=1.32 Hz, 1 H), 3.90 (dd, J=10.49, 5.32 Hz, 1 H), 3.79 - 3.86 (m, 1 H), 3.51 - 3.58 (m, 1 H), 3.49 (s, 1 H), 2.58 - 2.83 (m, 4 H), 2.42 (dd, J=13.03, 10.45 Hz, 1 H), 2.23 - 2.34 (m, 3 H), 1.76 - 1.88 (m, 4 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.17 (s, 3 H), 1.14 (s, 3 H).
Example 21 - 14-(S>(( 1 H-tetrazol-5 ' -yl)-methyloxy)paspalinine (XLI)
Figure imgf000040_0002
XLI
Compound prepared using similar procedure to that of (II). LCMS m/e 554 (M+Na). 1H NMR (400 MHz, DMSO-dβ) δ (ppm): 10.58 (s, 1 H), 7.24 - 7.31 (m, 2 H), 6.86 - 6.98 (m, 2 H), 6.20 (d, J=I.02 Hz, 1 H), 4.79 - 4.85 (m, 1 H), 4.69 - 4.75 (m, 1 H), 4.53 (s, 1 H), 4.36 (d, J=I.17 Hz, 1 H), 3.95 (dd, J=10.41, 4.93 Hz, 1 H), 2.59 - 2.79 (m, 3 H), 2.37 - 2.45 (m, 2 H), 1.89 - 2.02 (m, 1 H), 1.74 - 1.84 (m, 3 H), 1.34 (s, 3 H), 1.31 (s, 3 H), 1.09 (s, 3 H), 1.06 (s, 3 H).
Example 22 - 14-(S)-((r-methyl-imidazol-2'-yl)-methyloxy)paspalinine (XLII)
Figure imgf000041_0001
XLII
Compound prepared using similar procedure to that of (II). LCMS m/e 544 (M+H). 1K NMR (300 MHz, METHANOL-d*) δ (ppm): 7.30 - 7.38 (m, 2 H), 7.19 (d, J=Ll 1 Hz, 1 H), 6.93 - 7.07 (m, 3 H), 5.76 (d, J=1.27 Hz, 1 H), 4.32 (d, J=L38 Hz, 1 H), 4.14 (dd, J=10.42, 5.17 Hz, 1 H), 3.80 (s, 3 H), 2.81 - 2.97 (m, 2 H), 2.64 - 2.78 (m, 2 H), 2.35 - 2.52 (m, 2 H), 1.92 - 2.00 (m, 2 H), 1.44 (s, 3 H), 1.43 (s, 3 H), 1.26 (s, 3 H), 1.16 (s, 3 H).
Example 23 - 14-(1S)-((2'-methyl)-allyloxy)paspalinine (XLIII)
Figure imgf000041_0002
XLIII
Compound prepared using similar procedure to that of (II). LCMS m/e 504 (M+H). 1U NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.93 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.96 - 7.06 (m, 2 H), 5.90 (d, J=0.88 Hz, 1 H), 5.00 (d, J=0.68 Hz, 1 H), 4.88 (d, J=0.68 Hz, 1 H), 4.32 (d, J=1.37 Hz, 1 H), 4.24 (d, J=12.20 Hz, 1 H), 3.91 - 4.01 (m, 2 H), 3.45 (s, 1 H), 2.74 - 2.84 (m, 2 H), 2.60 - 2.72 (m, 2 H), 2.43 (dd, J=I 3.18, 10.54 Hz, 1 H), 2.29 - 2.35 (m, 1 H), 1.80 - 1.90 (m, 2 H), 1.76 (s, 3 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.20 (s, 3 H), 1.14 (s, 3 H).
Example 24 - 14-(5)-((2'-acetoxy)-ethyloxy)paspalinine (XLIV)
Figure imgf000042_0001
XLIV
Compound prepared using similar procedure to that of (II). LCMS m/e 558 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.93 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.95 - 7.05 (m, 2 H), 6.06 (s, 1 H), 4.32 (d, J=1.07 Hz, 1 H), 4.13 - 4.26 (m, 2 H), 3.93 - 4.02 (m, 2 H), 3.64 - 3.72 (m, 1 H), 3.49 (s, 1 H), 2.59 - 2.84 (m, 4 H), 2.39 - 2.51 (m, 1 H), 2.26 - 2.32 (m, 1 H), 2.07 (s, 3 H), 1.75 - 1.92 (m, 3 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.19 (s, 3 H), 1.14 (s, 3 H).
Example 25 - 14-(5)-((3'-methyl)-but-2'-enyloxy)paspalinine (XLV)
Figure imgf000042_0002
XLV
Compound prepared using similar procedure to that of (II). LCMS m/e 540 (M+Na). 1H NMR (400 MHz, ACETOΗITRILE-di) δ (ppm): 8.93 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.95 - 7.06 (m, 2 H), 5.93 (d, J=I.07 Hz, 1 H), 5.33 - 5.40 (m, 1 H), 4.27 - 4.35 (m, 2 H), 4.01 - 4.08 (m, 1 H), 3.97 (dd, J=10.45, 5.47 Hz, 1 H), 3.46 (s, 1 H), 2.58 - 2.83 (m, 3 H), 2.42 (dd, J=13.08, 10.54 Hz, 1 H), 2.30 - 2.36 (m, 1 H), 1.79 - 1.89 (m, 3 H), 1.76 (s, 3 H), 1.72 (s, 3 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.19 (s, 3 H), 1.13 (s, 3 H).
Example 26 - 14-(5)-((2'-ethoxycarbonyl)-prop-r-enyloxy)paspalinine (XLVI)
Figure imgf000042_0003
XLVI Compound prepared using similar procedure to that of (II). LCMS m/e 584 (M+Na). 1H NMR (400 MHz, ACETONITRILE-di) δ (ppm): 8.94 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.95 - 7.06 (m, 2 H), 6.24 (d, J=I.17 Hz, 1 H), 5.90 (d, J=1.37 Hz, 2 H), 4.50 (d, J=13.18 Hz, 1 H), 4.32 (d, J=I.31 Hz, 1 H), 4.19 - 4.28 (m, 3 H), 4.06 (dd, J=10.59, 5.22 Hz, 1 H), 3.49 (s, 1 H), 2.59 - 2.85 (m, 4 H), 2.39 - 2.51 (m, 1 H), 2.31 - 2.37 (m, 1 H), 1.75 - 1.89 (m, 2 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.28 (t, J=7.13 Hz, 3 H), 1.20 (s, 3 H), 1.13 (s, 3 H).
Example 27 - 14-(S)-((2'-hydroxymethyl)-allyloxy)paspalinine (XLVH)
Figure imgf000043_0001
XLVII
Compound prepared using similar procedure to that of (II). LCMS m/e 542 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.94 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.95 - 7.06 (m, 2 H), 5.91 (d, J=0.88 Hz, 1 H), 5.10 - 5.15 (m, 2 H), 4.30 - 4.36 (m, 2 H), 4.02 - 4.09 (m, 3 H), 3.98 (dd, J=10.54, 5.27 Hz, 1 H), 3.47 (s, 1 H), 2.59 - 2.90 (m, 5 H), 2.39 - 2.52 (m, 2 H), 2.29 - 2.36 (m, 1 H), 1.84 - 1.90 (m, 2 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.20 (s, 3 H), 1.14 (s, 3 H).
Example 28 - 14-(5)-([3'-(tert-Butyldimethylsilanyloxy)]-propyloxy)paspalinine (LIX)
Figure imgf000043_0002
LIX
Compound prepared using similar procedure to that of (II). LCMS m/e 622 (M+H). 1U NMR (400 MHz, DICHLOROMETHANE^) δ (ppm): 7.81 (s, 1 H), 7.37 - 7.42 (m, 1 H), 7.27 - 7.33 (m, 1 H), 6.99 - 7.09 (m, 2 H), 5.86 (d, J=0.93 Hz, 1 H), 4.29 (d, J=I .37 Hz, 1 H), 3.84 - 3.94 (m, 2 H), 3.65 - 3.75 (m, 2 H), 3.51 - 3.59 (m, 1 H), 3.26 (s, 1 H), 2.64 - 2.88 (m, 4 H), 2.43 - 2.51 (m, 1 H), 2.28 - 2.35 (m, 1 H), 1.74 - 2.01 (m, 5 H), 1.41 (s, 3 H), 1.39 (s, 3 H), 1.22 (s, 3 H), 1.16 (s, 3 H), 0.91 (s, 9 H), 0.07 (s, 6 H).
Example 29 - 14-(S)-((4'-bromo)-benzyloxy)paspalinine (XLIX)
Figure imgf000044_0001
XLIX
Compound prepared using similar procedure to that of (II). LCMS m/e 618 (M+Na). 1H NMR (400 MHz, DICHLOROMETHANE-di) δ (ppm): 7.85 (s, 1 H), 7.49 - 7.53 (m, 2 H), 7.39 - 7.42 (m, 1 H), 7.29 - 7.33 (m, 1 H), 7.25 (d, J=8.30 Hz, 2 H), 7.01 - 7.09 (m, 2 H), 5.91 (s, 1 H), 4.79 (d, J=I 1.32 Hz, 1 H), 4.55 (d, J=I 1.32 Hz, 1 H), 4.29 (d, J=I.07 Hz, 1 H), 4.04 (dd, J=10.54, 5.37 Hz, 1 H), 3.20 (s, 1 H), 2.65 - 2.88 (m, 4 H), 2.50 (dd, J=12.98, 10.45 Hz, 1 H), 2.36 - 2.42 (m, 1 H), 1.94 - 2.06 (m, 2 H), 1.76 - 1.85 (m, 1 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.24 (s, 3 H), 1.17 (s, 3 H).
Example 30 - 14-(S)-((4'-cyano)-benzyloxy)paspalinine (L)
Figure imgf000044_0002
Compound prepared using similar procedure to that of (II). LCMS m/e 565 (M+H). 1H NMR (400 MHz, DICHLOROMETHANE-dj) δ (ppm): 7.85 (s, 1 H), 7.67 (d, J=8.20 Hz, 2 H), 7.46 (d, J=8.20 Hz, 2 H), 7.38 - 7.43 (m, 1 H), 7.29 - 7.33 (m, 1 H), 7.01 - 7.10 (m, 2 H), 5.88 (d, J=0.59 Hz, 1 H), 4.90 (d, J=12.30 Hz, 1 H), 4.66 (d, J=12.20 Hz, 1 H), 4.30 (d, J=I .17 Hz, 1 H), 4.08 (dd, J=10.54, 5.37 Hz, 1 H), 3.17 (s, 1 H), 2.66 - 2.89 (m, 4 H), 2.50 (dd, J=13.03, 10.49 Hz, 1 H), 2.34 - 2.42 (m, 1 H), 1.94 - 2.09 (m, 2 H), 1.42 (s, 3 H), 1.41 (s, 3 H), 1.25 (s, 3 H), 1.16 (s, 3 H).
Example 31 - 14-(5)-((4'-trifluoromethyl)-benzyloxy)paspalinine (LI)
Figure imgf000045_0001
LI
Compound prepared using similar procedure to that of (II). LCMS m/e 608 (M+H). 1H NMR (400 MHz, DICHLOROMETHANE-di) δ (ppm): 7.86 (s, 1 H), 7.65 (d, J=8.20 Hz, 2 H), 7.49 (d, J=8.10 Hz, 2 H), 7.39 - 7.43 (m, 1 H), 7.29 - 7.34 (m, 1 H), 7.01 - 7.10 (m, 2 H), 5.92 (s, 1 H), 4.91 (d, J=I 1.81 Hz, 1 H), 4.66 (d, J=I 1.81 Hz, 1 H), 4.30 (s, 1 H), 4.08 (dd, J=10.45, 5.37 Hz, 1 H), 3.20 (s, 1 H), 2.66 - 2.90 (m, 4 H), 2.50 (dd, J=13.03, 10.49 Hz, 1 H), 2.37 - 2.44 (m, 1 H), 1.95 - 2.09 (m, 2 H), 1.42 (s, 3 H), 1.41 (s, 3 H), 1.26 (s, 3 H), 1.17 (s, 3 H).
Example 32 - 14-(5)-((2'-(i?)-2'-methyl-3'-hydroxy)-propyloxy)paspalinine (LIV)
Figure imgf000045_0002
LIV
Compound prepared using similar procedure to that of (II). LCMS m/e 544 (M+Na). 1H NMR (400 MHz, ACETONITRILE-Ci3) δ (ppm): 8.92 (s, 1 H), 7.29 - 7.37 (m, 2 H), 6.96 - 7.05 (m, 2 H), 5.89 (d, J=0.59 Hz, 1 H), 4.33 (d, J=I.37 Hz, 1 H), 3.90 (dd, J=I 0.49, 5.22 Hz, 1 H), 3.76 (dd, J=8.88, 5.95 Hz, 1 H), 3.48 (s, 1 H), 3.40 - 3.46 (m, 2 H), 3.36 (dd, J=8.69, 5.95 Hz, 1 H), 2.73 - 2.81 (m, 1 H), 2.65 - 2.71 (m, 1 H), 2.54 - 2.63 (m, 2 H), 2.38 - 2.46 (m, 1 H), 2.28 - 2.35 (m, 1 H), 1.75 - 1.89 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.19 (s, 3 H), 1.14 (s, 3 H), 0.92 (d, J=6.93 Hz, 3 H).
Example 33 - 14-(5)-((2'-(5)-2'-methyl-3'-hydroxy)-propyloxy)paspalinine (LV)
Figure imgf000045_0003
LV Compound prepared using similar procedure to that of (II). LCMS m/e 544 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.93 (s, 1 H), 7.29 - 7.37 (m, 2 H), 6.96 - 7.05 (m, 2 H), 5.87 (s, 1 H), 4.33 (d, J=0.88 Hz, 1 H), 3.90 (dd, J=10.49, 5.32 Hz, 1 H), 3.69 (dd, J=8.79, 5.76 Hz, 1 H), 3.38 - 3.48 (m, 4 H), 2.73 - 2.83 (m, 2 H), 2.65 - 2.71 (m, 1 H), 2.55 - 2.63 (m, 2 H), 2.42 (dd, J=13.18, 10.54 Hz, 1 H), 2.28 - 2.35 (m, 1 H), 1.76 - 1.89 (m, 3 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.19 (s, 3 H), 1.14 (s, 3 H), 0.92 (d, J=6.93 Hz, 3 H).
Example 34 - 14-(5)-([2'-(ter/-butyldimethylsilanyloxy)]-ethyloxy)paspalinine (LVI)
Figure imgf000046_0001
LVI
Compound prepared using similar procedure to that of (II). LCMS m/e 608 (M+H). 1H NMR (400 MHz, ACETOΗITMLE-di) δ (ppm): 8.93 (s, 1 H), 7.28 - 7.38 (m, 2 H), 6.95 - 7.06 (m, 2 H), 6.06 (d, J-0.49 Hz, 1 H), 4.31 (d, J=0.98 Hz, 1 H), 4.03 (dd, J=10.49, 5.42 Hz, 1 H), 3.76 - 3.84 (m, 3 H), 3.56 - 3.64 (m, 1 H), 3.46 (s, 1 H), 2.58 - 2.83 (m, 4 H), 2.42 (dd, J=13.18, 10.54 Hz, 1 H), 2.28 - 2.35 (m, 1 H), 1.75 - 1.89 (m, 3 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.19 (s, 3 H), 1.12 (s, 3 H), 0.90 (s, 9 H), 0.08 (s, 6 H).
Example 35 - 14-(5)-((2'-phenylcarbonyloxy)-ethyloxy)paspalinine (LVII)
Figure imgf000046_0002
LVII
Compound prepared using similar procedure to that of (II). LCMS m/e 598 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.93 (s, 1 H), 8.04 (dd, J=8.25, 1.12 Hz, 2 H), 7.59 - 7.65 (m, 1 H), 7.46 - 7.53 (m, 2 H), 7.29 - 7.38 (m, 2 H), 6.96 - 7.05 (m, 2 H), 6.02 (s, 1 H), 4.40 - 4.52 (m, 2 H), 4.28 (d, J=I.17 Hz, 1 H), 4.00 - 4.11 (m, 2 H), 3.82 - 3.90 (m, 1 H), 3.55 (s, 1 H), 2.58 - 2.83 (m, 4 H), 2.42 (dd, J=13.08, 10.54 Hz, 1 H), 2.30 - 2.37 (m, 1 H), 1.79 - 1.91 (m, 2 H), 1.39 (s, 3 H), 1.34 (s, 3 H), 1.18 (s, 3 H), 1.12 (s, 3 H). Example 36 - 14-(S)-((2'-benzyloxy)-ethyloxy)paspalinine (LVIII)
Figure imgf000047_0001
LVIII
Compound prepared using similar procedure to that of (II). LCMS m/e 606 (M+Na). 1H NMR (400 MHz, DICHLOROMETHANE-(I1) δ (ppm): 7.81 (s, 1 H), 7.24 - 7.43 (m, 7 H), 6.98 - 7.10 (m, 2 H), 6.14 (s, 1 H), 4.48 - 4.63 (m, 2 H), 4.29 (d, J=1.07 Hz, 1 H), 3.89 - 3.98 (m, 2 H), 3.59 - 3.73 (m, 3 H), 3.25 (s, 1 H), 2.64 - 2.89 (m, 4 H), 2.47 (dd, J=12.89, 10.35 Hz, 1 H), 2.25 - 2.33 (m, 1 H), 1.74 - 2.02 (m, 3 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.23 (s, 3 H), 1.16 (s, 3 H).
14-(5)-([3'-(ferf-ButyldimethylsilanyIoxy)]-propyloxy)paspalinine (LIX)
Figure imgf000047_0002
LIX
Compound prepared using similar procedure to that of (II).
LCMS m/e 622 (M+H). 1H NMR (400 MHz, DICHLOROMETHANE-dj) δ (ppm): 7.81 (s, 1 H), 7.37 -
7.42 (m, 1 H), 7.27 - 7.33 (m, 1 H), 6.99 - 7.09 (m, 2 H), 5.86 (d, J=0.93 Hz, 1 H), 4.29 (d, J=I.37 Hz, 1 H), 3.84 - 3.94 (m, 2 H), 3.65 - 3.75 (m, 2 H), 3.51 - 3.59 (m, 1 H), 3.26 (s, 1 H), 2.64 - 2.88 (m, 4 H),
2.43 - 2.51 (m, 1 H), 2.28 - 2.35 (m, 1 H), 1.74 - 2.01 (m, 5 H), 1.41 (s, 3 H), 1.39 (s, 3 H), 1.22 (s, 3 H), 1.16 (s, 3 H), 0.91 (s, 9 H), 0.07 (s, 6 H).
Alternative procedure for the preparation of 14-(5)-([3'-(tert-butyldimethyIsilanyloxy)]- propyloxy)paspalinine (LIX)
Figure imgf000047_0003
To a 2-dram vial with magnetic stirbar was added the 14(S)-hydroxypaspalinine (I) (25 mg, 0.056 mmol, 1 eq.) and 1 mL of chlorobenzene. The phase transfer catalyst (tetrabutylammonium hydrogen sulfate) (1.9 mg, 0.0056 mmol, 0.1 eq.) was then added followed by the base solution (0.1 mL of 5N aq. KOH, 0.56 mmol, 10 eq.). The 3-[(/ert-butyldimethylsilyl)-oxy]-propanol (140 mg, 0.56 mmol, 10 eq.) was then added. The reaction was heated to 50 deg. C with stirring for 16 hours. The reaction was taken up in 3 mL of DCM and 1 mL of water was added to the mixture. The DCM layer was removed and set aside. The remaining aqueous layer was extracted x 3 with DCM, and the organic layers were combined and evaporated to dryness in vacuo. The resulting residue was purified via HPLC. LCMS m/e 622 (M+H). 1H NMR (400 MHz, DICHLOROMETHANE-h) δ (ppm): 7.81 (s, 1 H), 7.37 -
7.42 (m, 1 H), 7.27 - 7.33 (m, 1 H), 6.99 - 7.09 (m, 2 H), 5.86 (d, 7=0.93 Hz, 1 H), 4.29 (d, J=I .37 Hz, 1 H), 3.84 - 3.94 (m, 2 H), 3.65 - 3.75 (m, 2 H), 3.51 - 3.59 (m, 1 H), 3.26 (s, 1 H), 2.64 - 2.88 (m, 4 H),
2.43 - 2.51 (m, 1 H), 2.28 - 2.35 (m, 1 H), 1.74 - 2.01 (m, 5 H), 1.41 (s, 3 H), 1.39 (s, 3 H), 1.22 (s, 3 H), 1.16 (s, 3 H), 0.91 (s, 9 H), 0.07 (s, 6 H).
Alternative procedure for the preparation of 14(iS)-(3 '-hydroxypropyloxy)paspalinine (II).
Figure imgf000048_0001
To a 100 mL round bottom flask with magnetic stirbar under nitrogen atmosphere was added the starting material (LIX) (65 mg, 0.1 mmol, 1 eq.) and 3 mL of anhydrous THF at room temperature Tetrabutylammonium fluoride (1 M in THF) (55 mg, 0.2 mL, 0.21 mmol, 2 eq.) was then added dropwise and stirring was continued for 90 minutes. The reaction was taken up into ethyl acetate and washed with water x 1 and brine x 1. The organic layer was evaporated to dryness in vacuo. The resulting residue was purified via HPLC. LCMS m/e 530 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.92 (br s, IH), 7.33 (ddd, J= 14.55, 7.03, 1.46 Hz, 2H), 7.05 (dddd, J= 14.35, 7.13, 1.37, 1.37 Hz, 2H), 5.88 (d, J= 0.74 Hz, IH), 4.33 (d, J= 1.17 Hz, IH), 3.92 (dd, J= 10.45, 5.27 Hz, IH), 3.83-3.88 (m, IH), 3.52-3.62 (m, 3H), 3.51 (s, IH), 2.73-2.84 (m, 2H), 2.58-2.71 (m, 2H), 2.53 (dd, J= 5.17, 5.17 Hz, IH), 2.42 (dd, J= 13.08, 10.54 Hz, IH), 2.31 (ddd, J= 12.10, 5.47, 2.44 Hz, IH), 1.70-1.91 (m, 4H), 1.40 (s, 3H), 1.35 (s, 3H), 1.19 (s, 3H), 1.14 (s, 3H).
Example 37 - 14-(lS)-((2'-[7V-(3"-hydroxy-2",2"-dimethylpropylamino)]-2'-oxo)- ethyloxy)paspalinine (LX)
Figure imgf000049_0001
To a 20-mL scintillation vial fitted with a magnetic stir bar was added the starting material (XXX) (150 mg, 0.29 mmol, 1 eq.), neopentanolamine (300 mg, 2.9 mmol, 10 eq.), and 3 mL of anhydrous THF. The vial was capped tightly and heated with stirring at 50 deg. C for 16 hours. The reaction was checked by LCMS and found to be complete. The reaction was then taken up into ethyl acetate and evaporated to dryness in vacuo. Purification was performed by HPLC. LCMS m/e 615 (M+Na). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.61 (s, 1 H), 8.02 (t, J=6.50 Hz, 1 H), 7.28 (d, J=7.60 Hz, 2 H), 6.87 - 6.99 (m, 2 H), 5.79 (s, 1 H), 5.33 (s, 1 H), 4.47 (t, ./=6.21 Hz, 1 H), 4.44 (d, J=0.95 Hz, 1 H), 4.20 (d, J=I 5.20 Hz, 1 H), 3.97 - 4.07 (m, 2 H), 2.99 - 3.12 (m, 3 H), 2.78 - 2.91 (m, 2 H), 2.55 - 2.71 (m, 2 H), 2.30 - 2.40 (m, 1 H), 2.13 - 2.21 (m, 1 H), 1.73 - 2.03 (m, 3 H), 1.37 (s, 3 H), 1.33 (s, 3 H), 1.14 (s, 3 H), 1.08 (s, 3 H), 0.76 (s, 3 H), 0.74 (s, 3 H).
Example 38 - 14-(5)-((2'-[jV-benzylamino]-2'-oxo)-ethyloxy)paspalinine (LXI)
Figure imgf000049_0002
LXI
Compound prepared using similar procedure to that of (LX). LCMS m/e 619 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.93 (s, 1 H), 7.21 - 7.44 (m, 7 H), 6.95 - 7.07 (m, 2 H), 5.90 (d, J=0.88 Hz, 1 H), 4.44 - 4.51 (m, 1 H), 4.25 - 4.40 (m, 3 H), 4.00 - 4.08 (m, 2 H), 3.62 (s, 1 H), 2.59 - 2.85 (m, 4 H), 2.41 (dd, J=13.04, 10.49 Hz, 1 H), 2.22 - 2.29 (m, 1 H), 1.80 - 1.91 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H), 1.19 (s, 3 H), 1.15 (s, 3 H).
Example 39 - 14-(5)-((2'-oxo-2'-piperidin-l"-yl)-ethyloxy)paspalinine (LXII)
Figure imgf000050_0001
LXII
Compound prepared using similar procedure to that of (LX). LCMS m/e 575 (M+H). 1H NMR (400 MHz, ACETONITRILE-d2) δ (ppm): 8.93 (s, 1 H), 7.29 - 7.37 (m, 2 H), 6.95 - 7.06 (m, 2 H), 6.42 (d, ./=0.73 Hz, 1 H), 4.40 - 4.46 (m, 1 H), 4.26 - 4.35 (m, 3 H), 4.17 (s, 1 H), 3.50 (q, J=4.94 Hz, 2 H), 3.35 (d, J=4.53 Hz, 2 H), 2.59 - 2.85 (m, 4 H), 2.43 (dd, ./=13.08, 10.52 Hz, 1 H), 2.21 - 2.28 (m, 1 H)5 1.79 - 1.91 (m, 2 H), 1.49 - 1.68 (m, 6 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.19 (s, 3 H), 1.13 (s, 3 H).
Example 40 - 14-(5)-((2'-[N-cyclopropylamino]-2'-oxo)-ethyloxy)paspalinine (LXIII)
Figure imgf000050_0002
LXIII
Compound prepared using similar procedure to that of (LX). LCMS m/e 547 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.93 (s, 1 H), 7.28 - 7.38 (m, 2 H), 6.95 - 7.06 (m, 2 H), 6.81 (s, 1 H), 5.83 (d, J=0.73 Hz, 1 H), 4.35 (d, ./=1.24 Hz, 1 H), 4.18 (d, ./=14.91 Hz, 1 H), 3.90 - 4.01 (m, 2 H), 3.65 (s, 1 H), 2.59 - 2.86 (m, 5 H), 2.42 (dd, ./=12.93, 10.38 Hz, 1 H), 2.18 - 2.25 (m, 1 H), 1.79 - 1.89 (m, 2 H), 1.41 (s, 3 H), 1.35 (s, 3 H), 1.17 (s, 3 H), 1.14 (s, 3 H), 0.63 - 0.74 (m, 2 H), 0.44 - 0.54 (m, 2 H).
Example 41 - 14-(5)-((2'-[N-pentylamino]-2'-oxo)-ethyloxy)paspalinine (LXTV)
Figure imgf000050_0003
LXIV
Compound prepared using similar procedure to that of (LX). LCMS m/e 599 (M+Na). 1H NMR (500 MHz, ACETONITJULE-d3) δ (ppm): 8.94 (s, 1 H), 7.33 (dd, J-19.26, 7.74 Hz, 2 H), 6.96 - 7.05 (m, 2 H), 6.87 (s, 1 H), 5.85 (s, 1 H), 4.35 (s, 1 H), 4.19 (d, J=14.72 Hz, 1 H), 4.00 (dd, J=10.60, 5.19 Hz, 1 H), 3.95 (d, J=14.72 Hz, 1 H), 3.64 (s, 1 H), 3.20 - 3.28 (m, 1 H), 3.09 - 3.17 (m, 1 H), 2.61 - 2.86 (m, 4 H), 2.42 (dd, J=12.97, 10.68 Hz, 1 H), 2.21 - 2.27 (m, 1 H), 1.81 - 1.91 (m, 2 H), 1.43 - 1.50 (m, 2 H), 1.41 (s, 3 H), 1.36 (s, 3 H), 1.24 - 1.34 (m, 4 H), 1.18 (s, 3 H), 1.14 (s, 3 H), 0.90 (t, J=7.10 Hz, 3 H).
Example 42 - 14-0S)-((2'-morpholin-4"-yl-2'-oxo)-ethyl oxy)paspalinine (LXVI)
Figure imgf000051_0001
LXVI
Compound prepared using similar procedure to that of (LX). LCMS m/e 599 (M+Na). 1H NMR (500 MHz, ACETONITRILE-d3) δ (ppm): 8.94 (s, 1 H), 7.33 (dd, J=I 8.20, 7.67 Hz, 2 H), 6.95 - 7.05 (m, 2 H), 6.41 (s, 1 H), 4.41 - 4.45 (m, 1 H), 4.31 - 4.35 (m, 2 H), 4.27 (dd, J=10.76, 5.26 Hz, 1 H), 4.02 (s, 1 H), 3.63 (t, J=4.88 Hz, 4 H), 3.49 - 3.55 (m, 2 H), 3.37 - 3.45 (m, 2 H), 2.74 - 2.83 (m, 2 H), 2.60 - 2.71 (m, 2 H), 2.43 (dd, J=12.97, 10.68 Hz, 1 H), 2.23 - 2.29 (m, 1 H), 1.80 - 1.91 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.19 (s, 3 H), 1.13 (s, 3 H).
Example 43 - 14-(,S)-((2'-[7V-pyridin-2"-ylmethyl]-2'-oxo)-ethyloxy)paspalinine (LXVII)
Figure imgf000051_0002
LXVII
Compound prepared using similar procedure to that of (LX). LCMS m/e 598 (M+H). 1H NMR (500 MHz, ACETONITRILE-d3) δ (ppm): 8.94 (s, 1 H), 8.49 (d, J=4.42 Hz, 1 H), 7.70 7.76 (m, 1 H), 7.59 (t, J=5.80 Hz, 1 H), 7.34 - 7.39 (m, 1 H), 7.32 (d, J-7.78 Hz, 1 H), 7.27 (d, J=7.86 Hz, 1 H), 7.22 (dd, J=7.25, 5.11 Hz, 1 H), 6.96 - 7.05 (m, 2 H), 5.92 (s, 1 H), 4.53 - 4.59 (m, 1 H), 4.41 - 4.47 (m, 1 H), 4.34 (s, 1 H), 4.31 (d, J=14.88 Hz, 1 H), 4.04 - 4.09 (m, 2 H), 3.65 (s, 1 H), 2.74 - 2.86 (m, 2 H), 2.62 - 2.71 (m, 2 H), 2.42 (dd, J=12.97, 10.68 Hz, 1 H), 2.24 - 2.30 (m, 1 H), 1.81 - 1.90 (m, 1 H), 1.41 (s, 3 H), 1.36 (s, 3 H), 1.20 (s, 3 H), 1.14 (s, 3 H).
Example 44 - 14-(5)-((2 ' -amino-2 ' -oxo)-ethyloxy)paspalinine (LXVIII)
Figure imgf000052_0001
LXVIII
Compound prepared using similar procedure to that of (LX). LCMS m/e 529 (M+Na). 1H NMR (400 MHz, DMSO-dβ) δ (ppm): 10.60 (s, 1 H), 7.67 (s, 1 H), 7.20 - 7.31 (m, 2 H), 6.87 - 6.98 (m, 2 H), 5.75 (d, J=0.73 Hz, 1 H), 5.33 (s, 1 H), 4.44 (d, J=1.02 Hz, 1 H), 4.10 (d, J=15.13 Hz, 1 H), 3.97 (dd, J=10.41, 4.93 Hz, 1 H), 3.84 (d, J=15.05 Hz, 1 H), 2.75 - 2.86 (m, 1 H), 2.58 - 2.65 (m, 1 H), 2.36 (dd, J=I 2.50, 10.38 Hz, 1 H), 2.12 - 2.19 (m, 1 H), 1.71 - 2.01 (m, 4 H), 1.37 (s, 3 H), 1.32 (s, 3 H), 1.14 (s, 3 H), 1.09 (s, 3 H).
Example 45 - 14-(5)-((2'-(4"-methyl-piperazin-l"-yl)-2'-oxo)-ethyloxy)paspalinine (LXX)
Figure imgf000052_0002
LXX
Compound prepared using similar procedure to that of (LX). LCMS m/e 590 (M+H). 1H NMR (500 MHz, DMSO-dβ) δ (ppm): 10.61 (s, 1 H), 7.24 - 7.30 (m, 2 H), 6.88 - 6.97 (m, 2 H), 6.38 (d, J=I.14 Hz, 1 H), 4.83 (s, 1 H), 4.32 - 4.42 (m, 3 H), 4.20 (dd, J=10.64, 5.00 Hz, 1 H), 2.72 - 2.81 (m, 1 H), 2.59 - 2.66 (m, 1 H), 2.37 (dd, J=12.74, 10.45 Hz, 1 H), 2.24 - 2.32 (m, 3 H), 2.18 (s, 3 H), 1.99 (s, 1 H), 1.91 - 1.97 (m, 1 H), 1.74 - 1.87 (m, 2 H), 1.36 (s, 3 H), 1.30 (s, 3 H), 1.13 (s, 3 H), 1.08 (s, 3 H).
Example 46 - 14-(5)-((2'-[N-cyclohexylamino]-2'-oxo)-ethyloxy)paspalinine (LXXIII)
Figure imgf000053_0001
LXXIII
Compound prepared using similar procedure to that of (LX). LCMS m/e 611 (M+Na). 1H NMR (500 MHz, ACETONITRILE-di) δ (ppm): 8.95 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.96 - 7.06 (m, 2 H), 6.60 (d, J=8.09 Hz, 1 H), 5.91 (s, 1 H), 4.35 (d, J=I .22 Hz, 1 H), 4.17 (d, J=14.88 Hz, 1 H), 4.00 (dd, J=10.68, 5.19 Hz, 1 H), 3.94 (d, J=14.80 Hz, 1 H), 3.66 - 3.75 (m, 2 H), 2.61 - 2.85 (m, 4 H), 2.42 (dd, J=I 3.01, 10.49 Hz, 1 H), 2.19 - 2.24 (m, 1 H), 1.69 - 1.91 (m, 6 H), 1.57 - 1.64 (m, 1 H), 1.41 (s, 3 H), 1.36 (s, 3 H), 1.21 - 1.32 (m, 2 H), 1.18 (s, 3 H), 1.14 (s, 3 H).
Example 47 - 14-(5)-((2'-[N-(2"-dimethylamino)]-ethylamino-2'-oxo)-ethyloxy)paspalinine (LXXV)
Figure imgf000053_0002
LXXV
Compound prepared using similar procedure to that of (LX). LCMS m/e 578 (M+H). 1H NMR (400 MHz, ACETONITRILE-di) δ (ppm): 8.95 (s, 1 H), 8.08 - 8.19 (m, 1 H), 7.28 - 7.38 (m, 2 H), 6.95 - 7.06 (m, 2 H), 5.83 (d, J=0.66 Hz, 1 H), 4.32 (d, J=I.17 Hz, 1 H), 4.20 (d, J=14.91 Hz, 1 H), 3.93 - 4.01 (m, 2 H), 3.32 - 3.47 (m, 3 H), 2.80 - 2.88 (m, 2 H), 2.60 - 2.71 (m, 5 H), 2.42 (dd, J=13.04, 10.56 Hz, 2 H), 2.18 - 2.26 (m, 2 H), 1.79 - 1.88 (m, 2 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.19 (s, 3 H), 1.13 (s, 3 H).
Example 48 - (5)-((2'-(2"-methoxy)-ethylamino-2'-oxo)-ethyloxy)paspalinine (LXXVI)
Figure imgf000054_0001
LXXVI
Compound prepared using similar procedure to that of (LX). LCMS m/e 565 (M+H). 1H NMR (500 MHz, ACETONITRJLE-^) δ (ppm): 8.94 (s, 1 H), 7.33 (dd, J=I 8.73, 7.44 Hz, 2 H), 6.97 - 7.04 (m, 2 H), 6.94 (s, 1 H), 5.86 (d, J=0.69 Hz, 1 H), 4.35 (d, J=I .14 Hz, 1 H), 4.20 (d, J=14.88 Hz, 1 H), 3.97 - 4.04 (m, 2 H), 3.65 (s, 1 H), 3.33 - 3.43 (m, 4 H), 3.28 (s, 3 H), 2.61 - 2.86 (m, 4 H), 2.42 (dd, J=13.08, 10.57 Hz, 1 H), 2.20 - 2.26 (m, 1 H), 1.79 - 1.91 (m, 2 H), 1.41 (s, 3 H), 1.36 (s, 3 H), 1.19 (s, 3 H), 1.14 (s, 3 H).
Example 49 - 14-(5)-((2'-[N-(2"-acetylamino)]-ethylamino-2'-oxo)-ethyloxy)paspalinine
(LXXVIII)
Figure imgf000054_0002
LXXVIII
Compound prepared using similar procedure to that of (LX). LCMS m/e 614 (M+Na). 1H NMR (500 MHz, ACETOMTRIlE-di) δ (ppm): 8.94 (s, 1 H), 7.78 (s, 1 H), 7.33 (dd, J=18.16, 7.48 Hz, 2 H), 6.96 - 7.05 (m, 2 H), 6.79 - 6.87 (m, 1 H), 5.75 (s, 1 H), 4.63 (s, 1 H), 4.33 (d, J=1.07 Hz, 1 H), 4.21 (d, J=14.57 Hz, 1 H), 3.97 (dd, J=10.60, 5.19 Hz, 1 H), 3.87 (d, J=14.57 Hz, 1 H), 3.35 - 3.43 (m, 1 H), 3.23 - 3.30 (m, 1 H), 3.13 - 3.21 (m, 2 H), 2.82 - 2.90 (m, 1 H), 2.74 - 2.81 (m, 1 H), 2.63 - 2.71 (m, 2 H), 2.43 (dd, J=13.05, 10.68 Hz, 1 H), 2.23 - 2.28 (m, 1 H), 1.88 - 1.92 (m, 1 H), 1.87 (s, 3 H), 1.80 - 1.85 (m, 1 H), 1.41 (s, 3 H), 1.39 (s, 3 H), 1.20 (s, 3 H), 1.14 (s, 3 H). Example 50- 14-(S)-((2'-[iV-cyclobutylamino]-2'-oxo)-ethyloxy)paspalinine (LXXX)
Figure imgf000055_0001
LXXX
Compound prepared using similar procedure to that of (LX). LCMS m/e 583 (M+Na).
1H NMR (500 MHz, ACETONITRILE-d3) δ (ppm): 8.94 (s, 1 H), 7.33 (dd, J=I 7.55, 7.48 Hz, 2
H), 6.96 - 7.05 (m, 2 H), 6.92 (d, J=7.32 Hz, 1 H), 5.90 (s, 1 H), 4.32 - 4.42 (m, 2 H), 4.17 (d,
J=14.88 Hz, 1 H), 4.01 (dd, ./=10.60, 5.19 Hz, 1 H), 3.93 (d, J=14.80 Hz, 1 H), 3.70 (s, 1 H),
2.73 - 2.87 (m, 2 H), 2.62 - 2.71 (m, 2 H), 2.42 (dd, J=13.08, 10.57 Hz, 1 H), 2.22 - 2.26 (m, 3
H), 1.79 - 1.90 (m, 2 H), 1.65 - 1.73 (m, 2 H), 1.41 (s, 3 H), 1.37 (s, 3 H), 1.20 (s, 3 H), 1.14 (s, 3
H).
Example 51 - 14-(S)-((2'-[7V-(propylamino)]-2'-oxo)-ethyloxy)paspalinine (LXXXI)
Figure imgf000055_0002
LXXXI
Compound prepared using similar procedure to that of (LX). LCMS m/e 571 (M+Na). 1H NMR (500 MHz, ACETONITRILE-d3) δ (ppm): 8.94 (s, 1 H), 7.33 (dd, J=19.45, 7.48 Hz, 2 H), 6.96 - 7.06 (m, 2 H), 6.88 (s, 1 H), 5.86 (d, J=0.53 Hz, 1 H), 4.35 (d, J=I.14 Hz, 1 H), 4.20 (d, J=14.72 Hz, 1 H), 4.00 (dd, J=10.60, 5.26 Hz, 1 H), 3.96 (d, J=14.80 Hz, 1 H), 3.64 (s, 1 H), 3.17 - 3.25 (m, 1 H), 3.07 - 3.15 (m, 1 H), 2.61 - 2.86 (m, 5 H), 2.42 (dd, J=13.05, 10.60 Hz, 1 H), 2.21 - 2.27 (m, 1 H), 1.81 - 1.91 (m, 2 H), 1.44 - 1.53 (m, 2 H), 1.41 (s, 3 H), 1.36 (s, 3 H), 1.19 (s, 3 H), 1.14 (s, 3 H), 0.88 (t, J=7.44 Hz, 3 H).
Example 52 - 14-(5)-((2'-(2"-hydroxy)-ethylamino-2'-oxo)-ethyloxy)paspalinine (LXXXTV)
Figure imgf000056_0001
LXXXIV
Compound prepared using similar procedure to that of (LX). LCMS m/e 573 (M+Na). 1H NMR (500 MHz, ACETONITRJLE-d2) δ (ppm): 8.93 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.96 - 7.07 (m, 3 H), 5.89 (d, J=0.76 Hz, 1 H), 4.35 (d, J=I.22 Hz, 1 H), 4.23 (d, J=14.88 Hz, 1 H), 3.97 - 4.05 (m, 2 H), 3.68 (s, 1 H), 3.51 - 3.55 (m, 2 H), 3.31 - 3.39 (m, 1 H), 3.22 - 3.29 (m, 1 H), 2.74 - 2.86 (m, 2 H), 2.62 - 2.71 (m, 2 H), 2.43 (dd, J=13.08, 10.57 Hz, 1 H), 2.23 - 2.28 (m, 1 H), 1.79 - 1.91 (m, 2 H), 1.41 (s, 3 H), 1.37 (s, 3 H), 1.20 (s, 3 H), 1.14 (s, 3 H).
Example 53 - 14-(5)-((2'-[N-(2"-(i?)-hydroxy-2"-phenyl-ethylamino)]-2'-oxo)- ethyloxy)paspalinine (XCII)
Figure imgf000056_0002
XCII
Compound prepared using similar procedure to that of (LX). LCMS m/e 649 (M+Na). 1U NMR (500 MHz, DMSO-d6) δ (ppm): 10.60 (s, 1 H), 8.26 (t, J=5.95 Hz, 1 H), 7.20 - 7.35 (m, 7 H), 6.87 - 6.99 (m, 2 H), 5.77 (s, 1 H), 5.45 (d, J=4.27 Hz, 1 H), 5.37 (s, 1 H), 4.60 - 4.67 (m, 1 H), 4.46 (d, J=0.92 Hz, 1 H), 4.14 (d, J=15.03 Hz, 1 H), 3.99 (dd, J=10.49, 5.00 Hz, 1 H), 3.95 (d, J=15.03 Hz, 1 H), 3.32 - 3.38 (m, 1 H), 3.10 - 3.17 (m, 1 H), 2.77 - 2.87 (m, 1 H), 2.58 - 2.72 (m, 2 H), 2.37 (dd, J=12.55, 10.57 Hz, 1 H), 2.11 - 2.18 (m, 1 H), 1.93 - 2.02 (m, 1 H), 1.84 - 1.91 (m, 1 H), 1.71 - 1.81 (m, 1 H), 1.38 (s, 3 H), 1.34 (s, 3 H), 1.14 (s, 3 H), 1.09 (s, 3 H).
Example 54 - 14-(5)-((2 '- [N-(I "-hydroxy-cyclohexylmethylamino)] -T -oxo)- ethyloxy)paspalinine (XCVI)
Figure imgf000057_0001
XCVI
Compound prepared using similar procedure to that of (LX). LCMS m/e 641 (M+Na). 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm): 7.71 (s, 1 H), 7.43 - 7.47 (m, 1 H), 7.29 - 7.33 (m, 1 H)3 7.06 - 7.16 (m, 2 H), 6.71 (dd, J=6.72, 4.97 Hz, 1 H), 5.94 (d, J=0.73 Hz, 1 H), 4.30 - 4.36 (m, 2 H), 4.08 (d, J=14.69 Hz, 1 H), 4.03 (dd, J=10.67, 5.26 Hz, 1 H), 3.58 (dd, JH 3.67, 7.53 Hz, 1 H), 3.06 - 3.13 (m, 2 H), 2.69 - 2.93 (m, 4 H), 2.47 - 2.55 (m, 1 H), 2.22 - 2.29 (m, 1 H), 1.98 - 2.15 (m, 3 H), 1.79 - 1.89 (m, 1 H), 1.44 (s, 3 H), 1.41 (s, 3 H), 1.27 (s, 5 H), 1.25 (s, 3 H), 1.20 (s, 3 H), 0.82 - 0.93 (m, 3 H).
Example 55 - 14-(S)-((2'-oxo-2'-[N-phenylamino])-ethyloxy)paspalinine (XCVII)
Figure imgf000057_0002
XCVII
Compound prepared using similar procedure to that of (LX). LCMS m/e 605 (M+Na). 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm): 8.17 (s, 1 H), 7.71 (s, 1 H), 7.53 (d, J=7.60 Hz, 2 H), 7.43 - 7.47 (m, 1 H), 7.29 - 7.37 (m, 3 H), 7.07 - 7.18 (m, 3 H), 5.90 (s, 1 H), 4.33 - 4.39 (m, 2 H), 4.19 (d, J=14.98 Hz, 1 H), 3.98 (dd, JH 0.67, 5.26 Hz, 1 H), 3.14 (s, 1 H), 2.85 - 2.95 (m, 1 H), 2.70 - 2.81 (m, 3 H), 2.46 - 2.56 (m, 1 H), 2.24 - 2.32 (m, 1 H), 2.00 - 2.13 (m, 2 H), 1.80 - 1.90 (m, 1 H), 1.46 (s, 3 H), 1.43 (s, 3 H), 1.23 (s, 3 H), 1.20 (s, 3 H).
Example - 56 14-(5)-((l'H-[l ',2',3']-triazol-4'-yl)-methyloxy)paspalinine (XCVIII)
m-xylene
Figure imgf000057_0003
XXXIV
Figure imgf000057_0004
A sealed tube was charged with the starting material (XXXIV) (20.5 mg, 0.046 mmol, 1 eq.) and 1 mL of Aw-xylene. The trimethylsilylazide (0.050 mL, 0.38 mmol, 8.3 eq.) reagent was then added, and the resulting mixture heated at 130 deg. C. After 16 hours, the reaction was checked by LCMS and appeared to be complete. The mixture was concentrated under a stream of nitrogen. The resulting residue was stirred vigorously with approximately 3 mL of methanol and then concentrated again under a stream of nitrogen. The residue was then purified by HPLC. LCMS m/e 553 (M+Na). 1H NMR (500 MHz, ACETONITRILE-d3) δ (ppm): 8.93 (s, 1 H), 7.74 (s, 1 H), 7.34 (dd, J=21.59, 7.55 Hz, 2 H), 6.95 - 7.06 (m, 2 H), 5.96 (s, 1 H), 4.94 (d, J=I 1.98 Hz, 1 H), 4.71 (d, J=I 1.90 Hz, 1 H), 4.31 (s, 1 H), 4.10 (dd, J=I 0.57, 5.30 Hz, 1 H), 3.49 (s, 1 H), 2.68 - 2.85 (m, 4 H), 2.59 - 2.66 (m, 1 H), 2.39 - 2.48 (m, 2 H), 1.78 - 1.90 (m, 2 H), 1.39 (s, 3 H), 1.36 (s, 3 H), 1.19 (s, 3 H), 1.13 (s, 3 H).
Example 57 - 14-(5)-((3'-methylisoxazol-5'-yl)-methyloxy)paspalinine (C)
Figure imgf000058_0001
C
A round bottom flask was charged with the starting material (XXXIV) (20 mg, 0.04 mmol, 1 eq.) and 0.25 mL toluene. A mixture of nitroethane (29.5 uL, 0.41 mmol, 10 eq) and triethylamine (29.5 uL, 0.21 mmol, 5 eq) in toluene (2 mL) was then added. The resulting suspension was then treated with a solution of phenyl isocyanate (81 uL, 0.75 mmol, 19 eq.) in toluene (2 mL). The mixture was then stirred vigorously for two minutes until reaction is homogeneous. After stirring the reaction for one hour a precipitate was observed and the reaction was heated to 75 deg. C. The reaction was stirred at 75 deg. C overnight. After this time the reaction was cooled to room temperature and additional nitroethane/triethylamine solution (0.25 mL) and phenyl isocyanate (0.25 mL) solution were added. The reaction was then stirred at room temperature for one hour and then heated to 95 deg. Celsius for three hours. The reaction was then cooled to room temperature and more nitroethane/triethylamine solution (0.25 mL) and phenylisocyanate solution (0.25 mL) was added. The reaction was once again stirred at room temperature for one hour and then at 95 deg. C for two hours and then cooled to room temperature. The reaction was then filtered and the solute was rinsed with toluene (1 mL). The combined filtrate was concentrated and purified by HPLC normal phase chromatography (1 g SPE cartridge, 0-5% EtOAc/DCM). LCMS m/e 567 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.93 (s, 1 H), 7.28 - 7.40 (m, 2 H), 6.96 - 7.06 (m, 2 H), 6.26 (s, 1 H), 5.96 (d, J=0.80 Hz, 1 H), 4.85 (d, J=13.08 Hz, 1 H), 4.66 (d, J=13.01 Hz, 1 H), 4.32 (d, J=1.32 Hz, 1 H), 4.09 (dd, J=10.60, 5.26 Hz, 1 H), 3.47 (s, 1 H), 2.58 - 2.85 (m, 4 H), 2.44 (dd, J-13.01, 10.52 Hz, 1 H), 2.30 - 2.37 (m, 1 H), 2.26 (s, 3 H), 1.79 - 1.91 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.18 (s, 3 H), 1.14 (s, 3 H).
Example 58 - 14-(S)-((2'-amino-2'-thioxo)-ethyloxy)paspalinine (CI) (hydrated)
Figure imgf000059_0001
Figure imgf000059_0002
XVII Cl
To a 100 mL round bottom flask was added the starting material (XVII) (60 mg, 0.123 mmol, 1 eq.), pyridine (0.1 mL, 1.24 mmol, 10 eq.), an excess of sodium hydrogen sulfide (hydrated) (150 mg), a catalytic amount of TBAB (approximately 0.1 eq.) and 10 mL THF. The reaction mixture was stirred at 50 deg. C for 16 hours. The reaction was allowed to cool and was diluted with brine. The resulting mixture was extracted with ethyl acetate x 2. The combined organic layers were washed with a dilute aqueous acetic acid solution (1%) followed by brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was then recrystallized from ethanol affording the desired product. LCMS m/e 545 (M+Na). 1H NMR (400 MHz, ACETONITRILE-di) δ (ppm): 8.95 (s, 1 H), 8.25 (d, J=I 1.77 Hz, 2 H), 7.33 (dd, J=16.70, 7.27 Hz, 2 H), 6.95 - 7.06 (m, 2 H), 5.76 (s, 1 H), 4.53 - 4.61 (m, 1 H), 4.34 - 4.41 (m, 2 H), 4.01 - 4.10 (m, 2 H), 3.59 (s, 1 H), 2.59 - 2.85 (m, 4 H), 2.41 (dd, J=12.97, 10.49 Hz, 1 H), 2.19 - 2.27 (m, 1 H), 1.79 - 1.90 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.18 (s, 3 H), 1.14 (s, 3 H).
Example 59 - 14-(S)-((4'-cyclopropyl-thiazol-2'-yl)-methyloxy)paspalinine (CII)
Figure imgf000059_0003
Cl CII To a 50 mL round bottom flask was added the starting material (CI) (10 mg, 0.02 mmol, 1 eq.), an excess of pyridine (0.020 mL, 12 eq.), and 2 mL of THF. An excess of 2-bromo-l- cyclopropyl-ethanone (0.050 mL) was then added and the reaction was heated to 55 deg. C. Heating was continued for 3 hours. A check by LCMS showed that the reaction was complete. The reaction was then allowed to cool and was subsequently diluted with brine to which a small amount of dilute acetic acid had been added. The resulting aqueous mixture was extracted with ethyl acetate, dried, and evaporated. Purification was performed by HPLC. LCMS m/e 587 (M+H). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.61 (s, 1 H), 7.23 - 7.31 (m, 3 H), 6.87 - 6.99 (m, 2 H), 6.09 (d, J=LlO Hz, 1 H), 4.96 (d, J=13.15 Hz, 1 H), 4.82 (d, J=13.08 Hz, 1 H), 4.74 (s, 1 H), 4.41 (d, J=1.24 Hz, 1 H), 4.19 (dd, J=10.52, 4.97 Hz, 1 H), 2.59 - 2.82 (m, 3 H), 2.39 (dd, J=12.72, 10.45 Hz, 1 H), 2.23 - 2.30 (m, 1 H), 1.79 - 2.1 1 (m, 4 H), 1.36 (s, 3 H), 1.32 (s, 3 H), 1.15 (s, 3 H), 1.09 (s, 3 H), 0.75 - 0.91 (m, 5 H).
Example 60 - 14-(5)-([6'-(2'-methyl-3'H-pyrimid-4'-onyl)]-methyloxy)paspalinine (CV)
Figure imgf000060_0001
To a 1-dram vial fitted with a magnetic stirbar was added the acetamidine hydrochloride (95.5 mg, 1 mmol, 50 eq.), potassium t-butoxide (1 12 mg, 1 mmol, 50 eq.), and 1 mL of ethanol. The mixture was agitated to give a fine suspension, and the resultant slurry was combined with the starting material (XXXV) (12 mg, 0.02 mmol, 1 eq.). The resulting mixture was heated with stirring at 75 deg. C for 16 hours. The reaction was allowed to cool and the solvent evaporated from the reaction. The resulting residue was dissolved in a small volume of methano I/water and purified by HPLC. LCMS m/e 558 (M+H). 1H NMR (500 MHz, ACETONE-d6) δ (ppm): 9.79 (s, 1 H), 7.28 - 7.37 (m, 2 H), 6.91 - 7.01 (m, 2 H), 6.36 (s, 1 H), 6.12 (s, 1 H), 4.66 (d, J=14.80 Hz, 1 H), 4.43 (d, J=14.72 Hz, 1 H), 4.33 (s, 1 H), 4.27 (d, J=I .14 Hz, 1 H), 4.22 (dd, J=10.57, 5.15 Hz, 1 H), 2.85 - 2.92 (m, 2 H), 2.63 - 2.75 (m, 2 H), 2.47 (dd, J=13.01, 10.72 Hz, 1 H), 2.40 (s, 3 H), 2.37 - 2.41 (m, 1 H), 1.85 - 2.01 (m, 2 H), 1.45 (s, 3 H), 1.39 (s, 3 H), 1.28 (s, 3 H), 1.11 (s, 3 H). Example 61 - 14(S)-((3'-ethoxycarbonyl-2'-oxo)-propyloxy)paspalinine (CVII)
Figure imgf000061_0001
CVII
A solution was prepared by the addition of potassium hydroxide (88 mg, 1.5 mmol, 30 eq.) into 1.5 mL of ethanol. To this solution was added the starting material (XXXV) (29 mg, 0.048 mmol, 1 eq.). The resulting suspension was heated with stirring at 75 deg. C for 3.5 hours. The reaction was allowed to cool and the solvent evaporated from the reaction. Addition of H2O (0.5 mL) followed by extraction with ethyl ether (3 x 1 mL) and evaporation of the combined organic phases provided a residue. Purification by chromatography with a 1 g SPE cartridge using hexanes: ethyl acetate provided the desired material. LCMS m/e 600 (M+Na).
1U NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.92 (s, 1 H), 7.28 - 7.39 (m, 2 H), 6.95 - 7.06 (m, 2 H), 6.38 (d, J=0.95 Hz, 1 H), 4.29 - 4.39 (m, 2 H), 3.98 - 4.05 (m, 1 H), 3.87 - 3.92 (m, 1 H), 3.50 - 3.72 (m, 2 H), 3.37 - 3.48 (m, 1 H), 2.52 - 2.94 (m, 7 H), 2.42 (dd, J=13.19, -• ■ - 10.56 Hz, -2 H), L72 -4:87 (m, 2 H), -1.40 (s, 3 H), 1.25 (s, 3 H), 1.21 (s,-3 H), 1.13 (s, 3 H), 0.96- (t, J=6.91 Hz, 3 H).
Example 62 - 14-(5)-([6'-(2'-/err-butyl-3'H-pyrimid-4'-onyl)]-methyloxy)paspalinine (CVIII)
Figure imgf000061_0002
CVIII Compound prepared using similar procedure to that of (CV). LCMS m/e 636 (M+Na).
1H NMR (400 MHz, ACETONE-d6) δ (ppm): 10.92 (s, 1 H), 9.78 (s, 1 H), 7.28 - 7.38 (m, 2 H), 6.92 - 7.03 (m, 2 H), 6.39 (s, 1 H), 6.00 (s, 1 H), 4.71 (dd, J=15.24, 0.91 Hz, 1 H), 4.50 (dd, J=I 5.24, 0.99 Hz, 1 H), 4.25 - 4.35 (m, 2 H), 2.84 - 2.96 (m, 2 H), 2.64 - 2.75 (m, 2 H), 2.49 (dd, J=13.08, 10.67 Hz, 1 H), 2.40 - 2.45 (m, 1 H), 1.85 - 2.03 (m, 2 H), 1.46 (s, 3 H), 1.40 (s, 9 H), 1.30 (s, 3 H), 1.16 (s, 3 H), 1.12 (s, 3 H).
Example 63 - 14(5)-(3'-oxypropyl phosphoric acid diphenyloxo)paspalinine (CIX)
Figure imgf000062_0001
Il CIX
To a 100 mL round bottom flask fitted with magnetic stirbar and under nitrogen atmosphere was added the starting material (II) (25 mg, 0.049 mmol, 1 eq.) and approximately 5 mL of anhydrous DCM followed by successive addition of titanium (IV) t-butoxide (1.6 mg, 0.0049 mmol, 0.1 eq.), triethylamine (0.010 mL, 0.074 mmol, 1.5 eq.), and diphenyl chlorophosphate (13.2 mg, 0.049 mmol, 1 eq.). The reaction mixture was stirred at room temperature for 16 hours. A check of the reaction by TLC (1 :1 EtO Ac/Heptane) showed the reaction to be nearly complete. The reaction mixture was filtered through a thin pad of silica gel, rinsed with approximately 200 mL of 1 : 1 EtO Ac/heptane, and the collected filtrate was then evaporated in vacuo. The resulting residue was subsequently purified by HPLC. LCMS m/e 740 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.94 (s, 1 H), 7.42 (t, J=7.66 Hz, 4 H), 7.29 - 7.37 (m, 2 H), 7.22 - 7~28 (m, 6 H), 6.96 - 7.05 (m, 2 H), 5.84 (d, J=I.07 Hz, 1 H), 4.27 - 4.47 (m, 3 H), 3.87 (dd, J=10.49, 5.32 Hz, 1 H), 3.78 - 3.84 (m, 1 H), 3.61 (s, 1 H), 3.47 - 3.54 (m, 1 H), 2.57 - 2.81 (m, 4 H), 2.37 (dd, J=12.98, 10.45 Hz, 1 H), 1.67 - 1.90 (m, 3 H), 1.40 (s, 3 H), 1.30 (s, 3 H), 1.16 (s, 3 H), 1.13 (s, 3 H).
Example 64 - 14-(iS)-((3'-oxy)-propyl ether-3 '-phosphoric acid mono-p- nitrophenyloxo)paspalinine (CXIII)
Figure imgf000062_0002
CXV
To a 1-dram vial fitted with a magnetic stirbar was added bis-PNP-phosphate (23.1 mg, 0.068 mmol, 2.3 eq.) and 2 mL of 1 ,4-dioxane. The mixture was heated sufficiently to dissolve the solid and was then allowed to cool. The N,iV-di-p-tolylcarbodiimide (6.6 mg, 0.03 mmol, 1 eq.) was added and the reaction mixture stirred for 15 minutes. The starting material (II) (15.0 mg, 0.03 mmol, 1 eq.) was then added and stirring was continued at room temperature for 40 hours. The reaction mixture was concentrated in vacuo and purified by HPLC. LCMS m/e 530 (M- PO4H2). 1H NMR (400 MHz, ACETONITRILE-di) δ (ppm): 9.01 (s, 1 H), 8.18 (d, J=8.49 Hz, 2 H), 7.34 - 7.41 (m, 3 H), 7.29 - 7.33 (m, 1 H), 6.95 - 7.06 (m, 2 H), 5.95 (s, 1 H), 5.66 - 5.72 (m, 1 H), 4.13 (s, 1 H), 3.85 - 3.95 (m, 2 H), 3.54 - 3.64 (m, 3 H), 3.47 (s, 1 H), 3.16 (dd, J=17.18, 2.05 Hz, 1 H), 3.03 (s, 1 H), 2.66 - 2.81 (m, 2 H), 2.61 (t, J=5.13 Hz, 1 H), 2.40 - 2.48 (m, 1 H), 2.29 - 2.35 (m, 1 H), 2.23 (dd, J=I 7.47, 6.25 Hz, 1 H), 1.82 - 1.90 (m, 1 H), 1.72 - 1.81 (m, 3 H), 1.32 (s, 3 H), 1.28 (s, 3 H), 1.23 (s, 3 H), 1.02 (s, 3 H).
Example 65 - 14(5)-(3'-oxypropyl phosphoric acid dibenzyloxo)paspalinine (CXVIII)
1 Dibenzyl dnsopropyl phosphoramidite / Tetrazole / THF
Figure imgf000063_0001
Figure imgf000063_0002
To a 250-mL round bottom flask fitted with a magnetic stir bar under nitrogen was added the starting material (II) (2.0 g, 4.0 mmol, 1 eq.) and 30 mL of anhydrous THF. The dibenzyl diisopropylamino phosphoramidite (5.4 g, 5.2 mL, 16 mmol, 4 eq.) was added followed by the tetrazole as a 3% (w/v) solution in acetonitrile (0.88 g, 30 mL, 13 mmol, 3.2 eq.). The reaction mixture was stirred for 16 hours at 25 deg. C. The reaction mixture was brought to -10 deg. C using a brine/ice bath, and the hydrogen peroxide solution was added dropwise with stirring (30% w/w, 3.35 g, 9.5 mL, 99 mmol, 25 eq.). The temperature was maintained at -10 deg. C for 15 minutes and was brought to 25 deg. C with stirring for an additional 45 minutes. The reaction mixture was diluted in 150 mL of dichloromethane and washed with approximately 100 mL each of 1 M aqueous sodium thiosulfate, saturated sodium bicarbonate solution, and water, respectively. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resulting residue was purified by HPLC. LCMS m/e (M+H = 768). 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.93 (br s, IH), 7.29-7.42 (m, 12H), 7.00 (dddd, J= 14.15, 7.13, 1.56, 1.56 Hz, 2H), 5.84 (d, J= 1.07 Hz, IH), 5.05 (ddd, J= 8.35, 2.34, 1.27 Hz, 4H), 4.31 (d, J= 1.32 Hz, IH), 4.02-4.19 (m, 2H), 3.89 (ddd, J= 10.49, 5.27, 5.27 Hz, IH), 3.76-3.84 (m, IH), 3.65 (s, IH), 3.50 (ddd, J= 1 1.52, 9.22, 5.71 Hz, IH), 2.57-2.83 (m, 4H), 2.39 (dd, J= 13.08, 10.54 Hz, IH), 2.20-2.27 (m, IH), 1.73-1.91 (m, 4H), 1.40 (s, 3H), 1.33 (s, 3H), 1.18 (s, 3H), 1.13 (s, 3H). Example 66 - 14(.S)-(S '-oxypropyl phosphorate bis-triethylammonium)paspalinine (CXIX)
Figure imgf000064_0001
CXVIII CXIX
To a 250-mL round bottom flask fitted with a magnetic stir bar was added the starting material (CXVIII) (1.0 g, 1.3 mmol, 1 eq.), palladium oxide (0.5 g, 4.2 mmol, 3.2 eq.), barium sulfate (1.7 g, 7.4 mmol, 5.7 eq.), triethylamine (5.2 mL, 3.76 g, 37 mmol, 28.5 eq.) and DMF (30 mL). Air was evacuated from the vessel and a hydrogen filled balloon was attached, and the reaction vessel was subsequently charged with hydrogen gas. The reaction was stirred at room temperature for 6 hours. The reaction was filtered through a 0.45 micron (nylon disc) syringe filter and injected directly onto the Chromeleon purification system using a Varian Dynamax HPLC 250 x 41.4 mm Compression Module Microsorb 60-8 C18 column. The purification method starts with 40:60 MeOH:H2O (0.1% TEA modifier) which is ramped up to 85:15 MeOH:H2O over 45 minutes. Flow rate is 35 mL/min. The column is then flushed with 100% MeOH for 15 minutes prior to re-equilibration back to 40:60 MeOH:H2O. Total run time is 70.1 minutes. Analytical HPLC using a base-modified method (0.1 % TEA) of 25 :75 to 100:0 MeOH:H2O over 3 min. (2 min. hold) shows a 100% pure compound. LCMS m/e 891.7 (M+H+TEA). 1H NMR (400 MHz, METHANOL-^) δ (ppm): 7.31 (ddd, J= 6.88, 3.86, 1.56 Hz, 2H), 6.96 (dddd, J= 15.28, 7.08, 1.32, 1.32 Hz, 2H), 5.98 (d, J= 1.07 Hz, IH), 4.33 (d, J= 1.12 Hz, IH), 3.88-4.03 (m, 4H), 3.62 (ddd, J= 9.08, 6.15, 6.15 Hz, IH), 3.19 (q, J= 7.32 Hz, 6H), 2.75-2.95 (m, 2H), 2.62-2.75 (m, 2H), 2.43 (dd, J= 12.93, 10.69 Hz, IH), 2.29-2.36 (m, IH), 1.87-2.02 (m, 5H), 1.43 (s, 3H), 1.40 (s, 3H), 1.32 (t, J= 7.32 Hz, 9H), 1.24 (s, 3H), 1.16 (s, 3H).
Example 67 - 10-(E/Z)-([(4'-methyl)-benzylimino]-14(5)-[N-(2'-cyclopropylamino)]-2'-oxo- ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXX)
Figure imgf000064_0002
LXIII CXX (E isomer) CXX (Z isomer) To a 1-dram vial with magnetic stirbar was added the starting material (LXIII) (15 mg, 0.027 mmol, 1 eq.) and 0.15 mL each of THF and methanol. 4-Methyl-benzylamine (0.1 mL, 0.87 mmol, 30 eq.) was then added. The vial was capped tightly and the reaction mixture heated with stirring at 45 deg. C for 16 hours. An additional aliquot of 4-methyl-benzylamine (0.1 mL, 0.87 mmol, 30 eq.) was added and heating was continued for an additional 24 hours. The reaction mixture was allowed to cool before taking it up into ethyl acetate. The solvent was evaporated in vacuo and the resulting residue was purified by HPLC. LCMS m/e 650 (M+H). 1H NMR (400 MHz, ACETONITRILE-d^) δ (ppm): 7.28 - 7.36 (m, 4 H), 7.11 - 7.25 (m, 12 H), 6.95 - 7.04 (m, 6 H), 6.91 (s, 2 H), 6.83 (s, 1 H), 6.50 (s, 2 H), 5.95 (s, 1 H), 5.14 (d, J=0.88 Hz, 1 H), 4.69 (d, J=15.71 Hz, 1 H), 4.58 (s, 4 H), 4.46 (d, J=15.86 Hz, 1 H), 4.43 (s, 2 H), 4.22 (d, J=14.91 Hz, 2 H), 4.17 (d, J=14.91 Hz, 1 H), 3.93 - 4.03 (m, 4 H), 3.88 (d, J=14.83 Hz, 1 H), 3.49 (s, 2 H), 3.43 (s, 1 H), 2.71 - 2.82 (m, 6 H), 2.55 - 2.69 (m, 12 H), 2.14 - 2.24 (m, 4 H), 1.74 - 1.90 (m, 10 H), 1.40 (s, 2 H), 1.35 (s, 6 H), 1.33 - 1.34 (m, 8 H), 1.18 (s, 8 H), 1.16 (s, 2 H), 1.10 (s, 6 H), 0.55 - 0.68 (m, 6 H), 0.40 - 0.48 (m, 6 H).
Example 68 - 10-(E/Z)-([iV-(propylimino)]-14(5)-[N-(2'-propylamino)]-2'-oxo- ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXXI)
Figure imgf000065_0001
CXXI (E isomer) CXXI (Z isomer)
Compound prepared using similar procedure to that of (CXX) using compound (LXXXI) as the starting material. LCMS m/e 590 (M+H). 1H NMR (500 MHz, ACETONITRILE-d3) δ (ppm): 8.92 (s, 3 H), 7.35 (dd, J=7.10, 1.30 Hz, 3 H), 7.31 (dd, J=7.17, 1.22 Hz, 3 H), 6.96 - 7.04 (m, 10 H), 6.92 (s, 1 H), 6.34 (d, J=0.76 Hz, 2 H), 5.93 (s, 1 H), 5.02 (d, J=0.92 Hz, 1 H), 4.37 (d, J=0.92 Hz, 2 H), 4.25 (d, J=14.80 Hz, 2 H), 4.21 (d, J=14.65 Hz, 1 H), 3.99 (dd, J=10.68, 5.19 Hz, 3 H), 3.95 (d, J=14.95 Hz, 3 H), 3.34 - 3.47 (m, 10 H), 3.16 - 3.28 (m, 6 H), 3.05 - 3.14 (m, 4 H), 2.72 - 2.81 (m, 9 H), 2.64 - 2.70 (m, 5 H), 2.56 - 2.63 (m, 4 H), 2.37 - 2.45 (m, 4 H), 2.18 - 2.26 (m, 4 H), 1.77 - 1.92 (m, 12 H), 1.62 - 1.71 (m, 2 H), 1.53 - 1.60 (m, 5 H), 1.44 - 1.53 (m, 8 H), 1.37 (s, 3 H), 1.36 (d, J=2.90 Hz, 19 H), 1.18 - 1.20 (m, 11 H), 1.15 (s, 3 H), 1.12 (s, 8 H), 0.95 (t, J=7.40 Hz, 3 H), 0.91 (t, J=7.32 Hz, 9 H), 0.88 (t, J=7.48 Hz, 11 H).
Example 69 - 14(5)-((2'-hydroxy)-ethyloxy)paspalinine (CX)
Figure imgf000066_0001
XLlV CX
To a 1-dram vial fitted with a magnetic stirbar was added the starting material (XLIV) (50 mg, 0.093 mmol, 1 eq.), anhydrous potassium carbonate (32.3 mg, 0.233 mmol, 2.5 eq.), 2.0 mL of 1 : 1 methanol/water mixture, and 1.0 mL of THF. The reaction was stirred at room temperature for approximately 3 hours. A check by TLC (1 :1 EtO Ac/Heptane) showed that the reaction was complete. The reaction mixture was diluted with a 1 :1 water/brine mixture and extracted three times with EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The resulting residue was purified by HPLC. LCMS m/e 516 (M+Na). (CX) was isolated: .1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.93 (s, 1 H), 7.28 - 7.38 (m, 2 H), 6.95 - 7.06 (m, 2 H), 6.01 (d, J=0.98 Hz, 1 H), 4.32 (d, J=I.37 Hz, 1 H), 3.95 (dd, J=10.49, 5.32 Hz, 1 H), 3.79 - 3.85 (m, 1 H), 3.60 - 3.66 (m, 2 H), 3.56 (s, 1 H), 3.50 - 3.55 (m, 1 H), 2.59 - 2.88 (m, 5 H), 2.42 (dd, J=13.08, 10.54 Hz, 1 H), 2.26 - 2.33 (m, 1 H), 1.76 - 1.89 (m, 2 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.19 (s, 3 H), 1.14 (s, 3 H).
Example 70 - 10-(E/Z)-([N-(cyclopentylimino)]-14(5)-[N-(2'-cyclopentylamino)]-2'-oxo- ethyloxy)paspalinine (ratio of E/ Z isomers = 1/0.4) (CXXIV)
Figure imgf000066_0002
CXXIV (E Isomer) CXXIV (Z Isomer)
Compound prepared using similar procedure to that of (CXX) using compound (LXXX) as the starting material. LCMS m/e 642 (M+H). 1H NMR (500 MHz, ACETONITRILE-d2) δ ppm 8.92 (s, 1 H), 7.27 - 7.38 (m, 2 H), 6.93 - 7.05 (m, 2 H), 6.39 (s, 1 H), 4.32 (d, J=I.07 Hz, 1 H), 4.11 - 4.26 (m, 2 H), 3.87 - 4.09 (m, 3 H), 3.48 (s, 1 H), 2.55 - 2.81 (m, 6 H), 2.36 - 2.47 (m, 2 H), 2.18 - 2.27 (m, 2 H), 1.50 - 1.92 (m, 12 H), 1.38 - 1.50 (m, 4 H), 1.36 (s, 6 H), 1.20 (s, 3 H), 1.09 - 1.14 (m, 3 H) Example 71 - Alternative procedure for the preparation of 14(S)-(3'-hydroxypropyloxy)- paspalinine (II).
Figure imgf000067_0001
To a 100 mL round bottom flask with magnetic stirbar under nitrogen atmosphere was added the starting material (LIX) (65 mg, 0.1 mmol, 1 eq.) and 3 mL of anhydrous THF at room temperature. Tetrabutylammonium fluoride (1 M in THF) (55 mg, 0.2 mL, 0.21 mmol, 2 eq.) was then added dropwise and stirring was continued for 90 minutes. The reaction was taken up into ethyl acetate and washed with water x 1 and brine x 1. The organic layer was evaporated to dryness in vacuo. The resulting residue was purified via HPLC. LCMS m/e 530 (M+Na). 1H NMR (400 MHz, ACETONJTRILE-d3) δ (ppm): 8.92 (br s, IH), 7.33 (ddd, J= 14.55, 7.03, 1.46 Hz, 2H), 7.05 (dddd, J= 14.35, 7.13, 1.37, 1.37 Hz, 2H), 5.88 (d, J= 0.74 Hz, IH), 4.33 (d, J= 1.17 Hz, IH), 3.92 (dd, J= 10.45, 5.27 Hz, IH), 3.83-3.88 (m, IH), 3.52-3.62 (m, 3H)5 3.51 (s, IH), 2.73-2.84 (m, 2H), 2.58-2.71 (m, 2H), 2.53 (dd, J= 5.17, 5.17 Hz, IH), 2.42 (dd, J= 13.08, 10.54 Hz, IH), 2.31 (ddd, J= 12.10, 5.47, 2.44.Hz, IH), 1.70-1 .91 (m, 4H), 1.40 (s, 3H), 1.35 (s, 3H), 1.19 (s, 3H), 1.14 (s, 3H).
Example 72 - 10-(E/Z)-([N-(2-methoxyethylimino)]-14(5)-[N-(2'-(2-methoxyethyl)amino)]-2'- oxo-ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXXVI)
Figure imgf000067_0002
CXXVII (E Isomer) CXXVII (Z Isomer)
Compound prepared using similar procedure to that of (CXX) using compound (LXXVI) as the starting material. LCMS m/e 622 (M+H). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 8.9 (s, 1 H), 7.3 - 7.4 (m, 2 H), 6.9 - 7.1 (m, 3 H), 6.4 (d, J=0.76 Hz, 1 H), 4.4 (d, J=0.84 Hz, 1 H),
4.2 (d, J=14.88 Hz, 1 H), 4.0 - 4.0 (m, 2 H), 3.5 - 3.6 (m, 3 H), 3.4 - 3.5 (m, 4 H), 3.2 - 3.3 (m, 7 H), 2.7 - 2.8 (m, 3 H), 2.5 - 2.7 (m, 2 H), 2.3 - 2.5 (m, 1 H), 2.2 - 2.3 (m, 1 H), 1.7 - 1.9 (m, 3 H),
1.3 - 1.4 (m, 6 H), 1.2 - 1.2 (m, 3 H), 1.1 (s, 3 H) Example 73 - 10-(E/Z)-([imino)]-14(5)-[jV-(2'-(cyclopropylamino)]-2'-oxo-ethyloxy)paspalinine (ratio of EIZ isomers = 1/1) (CXXVIII)
Figure imgf000068_0001
CXXVIII (E Isomer) CXXVIII (Z Isomer)
Compound prepared using similar procedure to that of (CXX) using compound (LXIII) as the starting material. LCMS m/e 546 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 10.6 (s, 1 H), 10.0 (d, J=42.34 Hz, 1 H), 7.9 (d, J=I 1.52 Hz, 1 H), 7.3 (d, J=8.55 Hz, 2 H), 6.8 - 7.0 (m, 2 H), 5.9 (s, 1 H), 5.1 (s, 1 H), 4.5 (d, J=50.81 Hz, 1 H), 3.7 - 4.2 (m, 3 H), 2.5 - 2.8 (m, 4 H), 2.4 - 2.5 (m, 1 H), 2.3 - 2.4 (m, 1 H), 2.1 (d, J=I 0.45 Hz, 1 H), 1.9 - 2.0 (m, 1 H), 1.6 - 1.9 (m, 2 H), 1.2 - 1.4 (m, 6 H), 1.0 - 1.2 (m, 6 H), 0.6 (s, 2 H), 0.5 (s, 2 H)
Example 74 - 10-(E/Z)-([N-(methylimino)]-14(5)-[N-(2'-propylamino)]-2'-oxo- ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.7) (CXXLX)
Figure imgf000068_0002
CXXIX (^ Isomer) CXXIX (Z Isomer)
Compound prepared using similar procedure to that of (CXX) using compound (LXXXI) as the starting material. LCMS m/e 562 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.7 - 7.8 (m, 1 H), 7.4 - 7.5 (m, 1 H), 7.3 - 7.3 (m, 1 H), 7.0 - 7.1 (m, 2 H), 6.4 (d, J=0.73 Hz, 1 H), 4.5 (s, 1 H), 4.3 (d, J=14.83 Hz, 1 H), 4.1 (d, J=14.76 Hz, 1 H), 3.9 - 4.1 (m, 1 H), 3.1 - 3.4 (m, 4 H),
2.6 - 2.9 (m, 4 H), 2.4 - 2.6 (m, 1 H), 2.2 - 2.3 (m, 1 H), 2.1 (s, 1 H), 2.0 (d, J-21.34 Hz, 3 H),
1.7 - 1.9 (m, 2 H), 1.5 - 1.6 (m, 2 H), 1.4 - 1.5 (m, 5 H), 1.2 - 1.3 (m, 5 H), 1.2 (s, 2 H), 0.9 - 1.0 (m, 3 H)
Example 75 - 10-(E/Z)-([N-(3-hydroxypropylimino)]-14(5)-[iV-(2'-isopropylamino)]-2'-oxo- ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXXX)
Figure imgf000069_0001
CXXX (E Isomer) CXXX (Z Isomer)
Compound prepared using similar procedure to that of (CXX) using compound (LXXI) as the starting material. LCMS m/e 606 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.7 (s, 1 H), 7.4 (dd, J=5.85, 2.63 Hz, 1 H), 7.3 - 7.3 (m, 1 H), 7.1 - 7.2 (m, 2 H), 6.4 (s, 1 H), 6.1 - 6.2 (m, 1 H), 4.5 (s, 1 H), 3.9 - 4.3 (m, 4 H), 3.8 - 3.8 (m, 2 H), 3.6 - 3.7 (m, 2 H), 2.6 - 2.9 (m, 4 H), 2.5 (d, J-2.92 Hz, 1 H), 2.2 - 2.3 (m, 1 H), 2.1 (s, 2 H), 1.9 - 2.0 (m, 2 H), 1.8 - 1.9 (m, 3 H), 1.4 - 1.5 (m, 6 H), 1.1 - 1.3 (m, 12 H)
Example 76 - 14(5)-(4'-Bromobenzoyloxy)paspalinine (CXXXII)
Figure imgf000069_0002
CXXXII
Method A: To a 2-dram vial fitted with a magnetic stir bar was added 14-hydroxypaspalinine (10 mg, 0.022 mmol, 1 eq.) in dry pyridine (0.5 mL). In a second vial, 4-bromobenzoyl chloride (53.4 mg, 0.24 mmol, 11 eq.) and acetone (0.5 mL) were combined. The pyridine solution was heated in an oil bath to 50 0C. The acetone solution was added to the heated pyridine solution in a drop-wise manner. The vial was capped and stirred at 50 0C for several hours. After this time, another aliquot of 4-bromobenzoyl chloride (54 mg, 0.24 mmol) was added in addition to N,N- dimethylaminopyridine (4 mg, 0.033 mmol, 1.5 eq.) and the reaction was stirred overnight at 50 0C. After this time the reaction was allowed to cool and transferred to a 20 mL scintillation vial. The solution was diluted with 6 mL water and then extracted three times with methylene chloride (5 mL portions). The organic fractions were combined and then dried over magnesium sulfate. The mixture was filtered, concentrated and purified by HPLC. The resulting residue was re- dissolved in a small volume of DMSO, filtered through a 0.45 micron (nylon disc) syringe filter, and purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 50:50 MeOHiH2O maintained for 0.5 minute and is ramped up to 100:0 Me0H:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 50:50 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 632 (M+H). 1H NMR (400 MHz, ACETONITRILE-Ci3) δ ppm 8.99 (s, 1 H), 8.03 (d, /=8.57 Hz, 2 H), 7.71 (d, J=8.57 Hz, 2 H), 7.35 (dd, J=I 1.54, 8.02 Hz, 2 H)5 6.97 - 7.09 (m, 2 H), 5.53 (dd, /=10.55, 5.49 Hz, 1 H), 5.45 (s, 1 H), 4.33 (s, 1 H), 3.78 (s, 1 H), 2.64 - 3.05 (m, 4 H), 2.43 (dd, /=13.30, 10.66 Hz, 1 H), 2.18 - 2.29 (m, 1 H), 1.96 - 2.05 (m, 1 H), 1.83 - 1.92 (m, 1 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.29 (s, 3 H), 1.12 (s, 3 H).
Example 77 - 14(5)-(2'-Hydroxy-ethoxy)-(21-bromo)-paspalinine (CCCXXI)
Figure imgf000070_0001
Compound CCCXXI was prepared in the same manner as compound II.
LCMS m/e 572 (M-H). Amount of CCCXXI isolated: 0.1572 g. 1H NMR (400 MHz, ACETOΗlTRILE-di) δ ppm 9.08 (s, 1 H), 7.46 (dd, /=1.24, 0.41 Hz, 1 H), 7.28 (d, J=8.40 Hz, 1 H), 7.11 (dd, J=8.40, 1.76 Hz, 1 H), 6.01 (s, 1 H), 4.32 (d, J=I.32 Hz, 1 H), 3.89 - 3.99 (m, 1 H), 3.77 - 3.85 (m, 1 H), 3.59 - 3.66 (m, 2 H), 3.48 - 3.58 (m, 2 H), 2.56 - 2.90 (m, 5 H), 2.37 - 2.45 (m, 1 H), 2.24 - 2.33 (m, I H), 2.09 - 2.12 (m, 1 H), 1.75 - 1.88 (m, 2 H), 1:40 (s, 3 H), O5 (s, 3 H), 1.15 - 1.19 (m, 3 H), 1.13 (s, 3 H).
Example 77 - 14(S)-(Morpholin-4-yl-acetoyloxy)paspalinine (CXXXV)
Figure imgf000070_0002
CXXXV
Scheme
Figure imgf000071_0001
CXXXIIl
Ethyl Morpholin-4-yl-acetic Acetate (CXXXIII):
Figure imgf000071_0002
Reference for the reaction: J. Med. Chem. 2000, 43, 1489-94
In a 50 mL round bottom flask ethyl bromoacetate (3.66 rnL, 0.033 mol, 1 eq.) and benzene (15 mL) were combined. While stirring vigorously, a solution of morpholine (5.50 mL, 0.630 mol, 1.9 eq.) in benzene (15 mL) was added. When the reagents were combined a precipitate formed. The reaction was stirred and refluxed for approximately 30 minutes. The reaction was cooled to room temperature and the precipitate was collected by filtration and rinsed with benzene. The material was dried and carried on to the next step without further purification.
Morpholin-4-yl-acetic Acid (CXXXTV):
Figure imgf000071_0003
Reference for the Reaction: J. Med. Chem. 2000, 43, 1489-94
In a 250 mL round bottom flask ethyl (2-morpholino)acetate (CXXXIII), (3.3 g, 0.0191 mol, 1 eq) and water (75 mL) were combined. The mixture was refluxed for approximately 44 hours. After this time, the reaction was cooled to room temperature and concentrated by rotary evaporation. Crude product was isolated as a brownish yellow solid. Product was purified by recrystallization from ethanol-heptane. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.55 - 3.62 (m, 4 H), 3.14 (s, 2 H), 2.49 - 2.58 (m, 4 H).
Method B: To a one dram vial fitted with a magnetic stir bar was added N- cyclohexylcarbodiimide, N5 -methyl polystyrene HL (PoIy-DCC, 200-400 mesh, 2.3 mmol/g loading) (130 mg, 0.22 mmol, 10 eq), 2-morpholino acetic acid (33.1 mg, 0.23 mmol, 10.45 eq), N,N-dimethylaminopyridine ( 5.7 mg, 0. 047 mmol, 2.1 eq), toluene (0.5 mL) and 1,2- dichloroethane (0.5 mL). The solution was stirred at room temperature for 30 minutes followed by the addition of 14-hydroxypaspalinine (10 mg, 0.022 mmol, 1 eq). The vial was recapped and stirred at room temperature overnight. After this time, the reaction was filtered to remove the resin, concentrated and purified by HPLC. The resulting residue was re-dissolved in a small volume of DMSO, filtered through a 0.45 micron (nylon disc) syringe filter, and purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 50:50 MeOH:H2O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 50:50 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 577 (M+H). 1H NMR (400 MHz, ACETONITRILE-d^) δ ppm 8.96 (s, 1 H), 7.34 (dd, J=13.24, 7.53 Hz, 2 H), 6.96 - 7.08 (m, 2 H), 5.45 (s, 1 H), 5.31 (dd, J=I 0.55, 5.49 Hz, 1 H), 4.36 (s, 1 H), 3.61 - 3.70 (m, 5 H), 3.18 - 3.32 (m, 2 H), 2.59 - 2.97 (m, 4 H), 2.51 - 2.59 (m, 4 H), 2.41 (dd, J=13.29, 10.66 Hz, 1 H), 1.97 - 2.14 (m, 2 H), 1.80 - 1.92 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.23 (s, 3 H), 1.13 (s, 3 H).
Example 78 -14(5)-Isonicotinoyloxy-paspalinine (CXXXVI)-
Figure imgf000072_0001
CXXXVI
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 555 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.98 (s, 1 H), 8.79 (d, J=6.04 Hz, 2 H), 7.95 (d, J=6.04 Hz, 2 H), 7.28 - 7.39 (m, 2 H), 6.96 - 7.08 (m, 2 H), 5.56 (dd, J=10.49, 5.55 Hz, 1 H), 5.45 (s, 1 H), 4.34 (d, J=1.32 Hz, 1 H), 3.83 (s, 1 H), 2.65 - 3.04 (m, 4 H), 2.44 (dd, J=13.24, 10.60 Hz, 1 H), 2.16 - 2.32 (m, 2 H), 1.96 - 2.12 (m, 2 H), 1.84 - 1.92 (m, 1 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.30 (s, 3 H), 1.12 (s, 3 H).
Example 79 -14(S)-(Methoxy-acetoxy)paspalinine (CXXXLX)
Figure imgf000073_0001
CXXXIX
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 522 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.95 (s, 1 H), 7.29 - 7.39 (m, 2 H), 6.95 - 7.07 (m, 2 H), 5.42 (s, 1 H), 5.35 (dd, J=10.58, 5.58 Hz, 1 H), 4.36 (d, J=1.26 Hz, 1 H), 3.98 - 4.14 (m, 2 H), 3.63 (s, 1 H), 3.37 - 3.43 (m, 3 H), 2.59 - 2.98 (m, 4 H), 2.41 (dd, J=13.27, 10.58 Hz, 1 H), 2.16 (dd, J=5.63, 2.61 Hz, 1 H), 1.96 - 2.11 (m, 3 H), 1.80 - 1.91 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.24 (s, 3 H), 1.13 (s, 3 H).
Example 80 -14(S)-(Dimethylammo-acetoxy)paspalinine (CXL)
Figure imgf000073_0002
CXL
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 535 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.95 (s, 1 H), 7.28 - 7.39 (m, 2 H), 6.94 - 7.07 (m, 2 H), 5.44 (d, J=0.68 Hz, 1 H), 5.32 (dd, J=I 0.54, 5.56 Hz, 1 H), 4.35 (d, J=I.27 Hz, 1 H), 3.67 (s, 1 H), 3.20 (q, J=16.60 Hz, 2 H), 2.59 - 2.97 (m, 4 H), 2.41 (dd, J=13.23, 10.59 Hz, 1 H), 2.31 (s, 6 H), 1.97 - 2.13 (m, 2 H), 1.80 - 1.92 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.24 (s, 3 H), 1.13 (s, 3 H).
Example 81 - 14(5)-Propionoyloxypaspalinine (CXLII)
Figure imgf000074_0001
CXLII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 506 (M+H). 1H NMR (400 MHz, ACETONITRILE-di) δ ppm 8.96 (s, 1 H), 7.27 - 7.38 (m, 2 H), 6.93 - 7.07 (m, 2 H), 5.41 (d, J=0.66 Hz, 1 H), 5.27 (dd, J=10.49, 5.55 Hz, 1 H), 4.35 (d, J=1.21 Hz, 1 H), 3.63 (s, 1 H), 2.60 - 2.97 (m, 4 H), 2.33 - 2.45 (m, 3 H), 2.07 - 2.14 (m, 1 H), 1.96 - 2.05 (m, 2 H), 1.80 - 1.92 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.23 (s, 3 H), 1.09 - 1.16 (m, 6 H).
Example 82 -14(5)-Cyclopentanecarbonyloxypaspalinine (CXLVI)
Figure imgf000074_0002
CXLVI
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 546 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.96 (s, 1 H), 7.28 - 7.38 (m, 2 H), 6.94 - 7.06 (m, 2 H), 5.41 (d, J=0.88 Hz, 1 H), 5.27 (dd, J=10.44, 5.66 Hz, 1 H), 4.35 (d, J=1.26 Hz, 1 H), 3.58 (s, 1 H), 2.60 - 2.95 (m, 5 H), 2.40 (dd, J=13.24, 10.60 Hz, 1 H), 1.96 - 2.13 (m, 3 H), 1.53 1.92 (m, 9 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.23 (s, 3 H), 1.13 (s, 3 H).
Example 83 -14(5)-(3',3',3'-Trifluoropropionoyloxy)paspalinine (CXLVII)
Figure imgf000074_0003
CXLVII Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 560 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.96 (s, 1 H), 7.28 - 7.40 (m, 2 H), 6.94 - 7.08 (m, 2 H), 5.42 (s, 1 H), 5.37 (dd, J=10.55, 5.60 Hz, 1 H), 4.37 (d, J=I .21 Hz, 1 H), 3.64 (s, 1 H), 3.39 - 3.51 (m, 2 H), 2.59 - 2.97 (m, 4 H), 2.42 (dd, J=13.24, 10.60 Hz, 1 H), 2.16 - 2.22 (m, 1 H), 1.96 - 2.13 (m, 2 H), 1.82 - 1.92 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.23 (s, 3 H), 1.13 (s, 3 H).
Example 84 - 14(S)-(Furan-2'-carbonyloxy)paspalinine (CXLIX)
Figure imgf000075_0001
CXLIX
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 598 (M+Na+MeOH). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.97 (s, 1 H), 7.77 (dd, J=1.65, 0.66 Hz, 1 H), 7.41 (dd, J=3.57, 0.55 Hz, 1 H), 7.28 - 7.39 (m, 2 H), 6.93 - 7.10 (m, 2 H), 6.63 (dd, J=3.52, 1.70 Hz, 1 H), 5.43 - 5.53 (m, 2 H), 4.34 (d, J=I .21 Hz, 1 H), 3.68 (s, 1 H), 2.65 - 3.03 (m, 4 H), 2.43 (dd, J=13.24, 10.60 Hz, 1 H), 2.14 - 2.28 (m, 2 H), 1.95 - 2.13 (m, 2 H), 1.84 - 1.92 (m, 1 H), 1.41 (s, 3 H), 1.40 (s, 3 H), 1.28 (s, 3 H), 1.13 (s, 3 H).
Example 85 - 14(5)-Methylsulfanyl-acetoxypaspalinine (CLI)
Figure imgf000075_0002
CLI
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 560 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.95 (s, 1 H), 7.26 - 7.40 (m, 2 H), 6.92 - 7.08 (m, 2 H), 5.52 (d, J=0.71 Hz, 1 H), 5.30 (dd, J=10.55, 5.55 Hz, 1 H), 4.35 (d, J=I .26 Hz, 1 H), 3.62 (s, 1 H), 3.26 (s, 2 H), 2.56 - 2.98 (m, 4 H), 2.42 (dd, J=13.27, 10.58 Hz, 1 H), 2.21 (s, 3 H), 2.14 - 2.19 (m, 1 H), 1.95 - 2.09 (m, 2 H), 1.82 - 1.92 (m, 1 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.24 (s, 3 H), 1.13 (s, 3 H).
Example 86 - 14(5)-((S)-2'-Dimethylamino-3'-phenyl-propionoyloxy)paspalinine (CLII)
Figure imgf000076_0001
CLII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 625 (M+H). 1B. NMR (400 MHz, ACETONITRILE-ds) δ ppm 8.95 (s, 1 H), 7.15 - 7.40 (m, 7 H), 6.92 - 7.08 (m, 2 H), 5.39 (d, J=0.71 Hz, 1 H), 5.32 (dd, J=10.44, 5.66 Hz, 1 H), 4.34 (d, J=1.26 Hz, 1 H), 3.69 (dd, J=8.16, 7.22 Hz, 1 H), 3.49 (s, 1 H), 2.59 - 3.08 (m, 6 H), 2.34 - 2.45 (m, 7 H), 1.96 - 2.13 (m, 3 H), 1.79 - 1.91 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.22 (s, 3 H), 1.12 (s, 3 H).
Example 87 - 14(5)-(r-Methyl-cyclopropanecarbonyloxy)paspalinine (CLVII)
Figure imgf000076_0002
CLVII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 554 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.95 (s, 1 H), 7.29 - 7.37 (m, 2 H), 6.95 - 7.06 (m, 2 H), 5.40 (s, 1 H), 5.25 (dd, J=IO.14, 5.85 Hz, 1 H), 4.36 (d, J=I.26 Hz, 1 H), 3.30 (s, 1 H), 2.75 - 2.95 (m, 2 H), 2.61 - 2.74 (m, 2 H), 2.40 (dd, J=13.24, 10.60 Hz, 1 H), 2.11 (s, 3 H), 1.95 - 2.07 (m, 2 H), 1.81 - 1.91 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.29 (s, 3 H), 1.24 (s, 3 H), 1.21 (d, J=UO Hz, 2 H), 1.13 (s, 3 H).
Example 88 - 14(S)-(Benzyloxycarbonyl-methyl-amino)-acetoxypaspalinine (CLX)
Figure imgf000077_0001
CLX
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 677 (M+Na). 1H NMR (400 MHz, ACETONITJULE-CI3) δ ppm 8.96 (s, 1 H), 7.29 - 7.43 (m, 7 H), 6.96 - 7.06 (m, 2 H), 5.48 (d, J=3.96 Hz, 1 H), 5.20 - 5.36 (m, 2 H), 5.09 - 5.15 (m, 1 H), 4.35 (d, J=1.21 Hz, 1 H), 3.96 - 4.13 (m, 2 H), 3.63 (d, J=5.33 Hz, 1 H), 2.99 (s, 1 H), 2.96 (s, 2 H), 2.75 - 2.92 (m, 2 H), 2.60 - 2.74 (m, 2 H), 2.36 - 2.45 (m, 1 H), 1.96 - 2.16 (m, 2 H), 1.80 - 1.92 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 1 H), 1.35 (s, 2 H), 1.36 (d, J=8.74 Hz, 3 H), 1.22 (d, J=I.87 Hz, 3 H), 1.12 (d, J=4.23 Hz, 3 H).
Example 89 - 14(S)-((i?)-Tetrahydro-furan-2'-carbonyloxy)paspalinine (CLXIII)
Figure imgf000077_0002
CLXIII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 570 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.95 (s, 1 H), 7.33 (dd, J=13.13, 7.91 Hz, 1 H), 6.95 - 7.05 (m, 1 H), 5.37 (s, 1 H), 5.29 (dd, J=10.41, 5.52 Hz, 1 H), 4.45 (dd, J=8.19, 4.56 Hz, 1 H), 4.36 (d, J=1.04 Hz, 1 H), 3.89 - 3.98 (m, 1 H), 3.81 - 3.89 (m, 1 H), 3.57 (s, 1 H), 2.61 - 2.95 (m, 4 H), 2.41 (dd, J=13.24, 10.55 Hz, 1 H), 2.15 - 2.24 (m, 1 H), 1.97 - 2.09 (m, 3 H), 1.80 - 1.90 (m, 2 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.23 (s, 3 H), 1.13 (s, 3 H).
Example 90 - 14(5)-(Methyl acetate)-21-(bromo)-paspalinine (CCCXXII)
Figure imgf000078_0001
Compound (CCCXXII) was prepared in the same manner as compound II. LCMS m/e 599 (M- H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 9.09 (s, 1 H), 7.47 (d, J=I.76 Hz, 1 H), 7.27 (d, J=8.44 Hz, 1 H), 7.11 (dd, J=8.40, 1.81 Hz, 1 H), 6.41 (d, J=1.03 Hz, 1 H), 4.28 - 4.34 (m, 3 H), 4.21 (dd, J=10.74, 5.32 Hz, 1 H), 3.73 (s, 3 H), 3.58 (s, 1 H), 2.71 - 2.81 (m, 2 H), 2.57 - 2.70 (m, 2 H), 2.42 (dd, J=I 3.25, 10.57 Hz, 1 H), 2.19 - 2.26 (m, 1 H), 2.11 (d, J=4.93 Hz, 1 H), 1.74 - 1.92 (m, 3 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.18 (s, 3 H), 1.14 (s, 3 H).
Example 91 - 14(,S)-Benzoyloxypaspalinine (CLXIX)
Figure imgf000078_0002
CLXIX
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 576 (M+Na). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 8.98 (s, 1 H), 8.10 - 8.16 (m, 2 H), 7.64 - 7.71 (m, 1 H), 7.49 - 7.56 (m, 2 H), 7.31 - 7.39 (m, 2 H), 6.96 - 7.07 (m, 2 H), 5.53 (dd, J=I 0.56, 5.43 Hz, 1 H), 5.47 (d, J=0.67 Hz, 1 H), 4.32 (d, J=I.22 Hz, 1 H), 3.75 (s, 1 H), 2.94 - 3.04 (m, 1 H), 2.81 - 2.91 (m, 1 H), 2.67 - 2.77 (m, 2 H), 2.44 (dd, J=I 3.24, 10.62 Hz, 1 H), 2.15 - 2.29 (m, 2 H), 1.96 - 2.05 (m, 1 H), 1.85 - 1.92 (m, 1 H), 1.43 (s, 3 H), 1.40 (s, 3 H), 1.30 (s, 3 H), 1.12 (s, 3 H).
Example 92 14(5)-((5)-2 ' -(9 'H-Fluoren-9 ' -ylmethoxycarbonylamino)-3 ' -methyl- butyroyloxy)paspalinine (CLXX)
Figure imgf000079_0001
CLXX
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 793 (M+Na). 1H NMR (500 MHz, ACETONITRILE-di) δ ppm 8.96 (s, 1 H), 7.84 (t, J=7.20 Hz, 2 H), 7.70 (d, J=7.39 Hz, 2 H), 7.28 - 7.47 (m, 6 H), 6.95 - 7.05 (m, 2 H), 6.15 (d, J=9.22 Hz, 1 H), 5.38 - 5.43 (m, 1 H), 5.30 (dd, J=10.41, 5.34 Hz, 1 H), 4.18 - 4.37 (m, 4 H), 4.11 (dd, J=9.12, 6.20 Hz, 1 H), 3.62 (s, 1 H), 3.04 - 3.10 (m, 1 H), 2.75 - 2.95 (m, 2 H), 2.57 - 2.75 (m, 2 H), 2.41 (dd, J=12.94, 10.74 Hz, 1 H), 2.16 - 2.25 (m, 1 H), 1.97 - 2.12 (m, 2 H), 1.79 - 1.92 (m, 1 H), 1.54 - 1.64 (m, 1 H), 1.37 (s, 6 H), 1.37 (s, 3 H), 1.23 (s, 4 H), 1.10 (s, 3 H), 0.88 - 1.02 (m, 6 H).
Example 93 - 14(S)-([2-(2-Methoxy-ethoxy)-ethoxy]-acetoxy)paspalinine (CLXXII)
Figure imgf000079_0002
CLXXII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 632 (M+Na). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 8.95 (s, 1 H), 7.30 - 7.37 (m, 2 H), 6.96 - 7.05 (m, 2 H), 5.42 (s, 1 H), 5.35 (dd, J=10.59, 5.58 Hz, 1 H), 4.36 (d, J=1.22 Hz, 1 H), 4.12 - 4.21 (m, 2 H), 3.78 (s, 1 H), 3.56 - 3.70 (m, 6 H), 3.46 - 3.51 (m, 2 H), 3.30 (s, 3 H), 2.77 - 2.95 (m, 2 H), 2.62 ■- 2.74 (m, 2 H), 2.42 (dd, J=13.18, 10.62 Hz, 1 H), 2.14 - 2.19 (m, 1 H), 1.95 - 2.11 (m, 2 H), 1.82 - 1.91 (m, 1 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.24 (s, 3 H), 1.13 (s, 3 H). Example 94 - 14(5)-Cycloheptanecarbonyloxypaspalinine (CLXXIII)
Figure imgf000080_0001
CLXXIII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 628 (M+Na+MeOH). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 8.95 (s, 1 H), 7.29 - 7.37 (m, 2 H), 6.96 - 7.06 (m, 2 H), 5.40 (d, J=0.67 Hz, 1 H), 5.26 (dd, J=IOM, 5.62 Hz, 1 H), 4.35 (d, J=I.28 Hz, 1 H), 3.55 (s, 1 H), 2.76 - 2.94 (m, 2 H), 2.52 - 2.73 (m, 3 H), 2.40 (dd, J=13.24, 10.62 Hz, 1 H), 1.95 - 2.10 (m, 3 H), 1.82 - 1.93 (m, 3 H), 1.44 - 1.78 (m, 12 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.23 (s, 3 H), 1.13 (s, 3 H). Example 95 - 14(5)-Diphenyl-acetoxypaspalinine (CLXXIV)
Figure imgf000080_0002
CLXXIV
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 666 (M+Na). 1H NMR (500 MHz, ΛCETONITRILE-dJδ ppm 8.94 (s, 1 H), 7.28 - 7.41 (m, 14 H), 6.95 - 7.04 (m, 2 H), 5.35 (q, J=5.53 Hz, 2 H), 5.22 (s, 1 H), 4.32 (d, J=1.22 Hz, 1 H), 3.46 (s, 1 H), 2.83 - 2.94 (m, 1 H), 2.58 - 2.81 (m, 3 H), 2.39 (dd, J= 13.24, 10.56 Hz, I H), 1.95 - 1.99 (m, 1 H), 1.78 - 1.92 (m, 2 H), 1.38 (s, 3 H), 1.33 (s, 3 H), 1.21 (s, 3 H), 1.10 (s, 3 H).
Example 96 - 14(5)-[(4'-(r-Methoxycarbonyl)-piperidinyl)-carbonyloxy]-paspalinine (CLXXVI)
Figure imgf000081_0001
CLXXVI
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 641 (M+Na). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 8.95 (s, 1 H), 7.29 - 7.37 (m, 2 H), 6.96 - 7.05 (m, 2 H), 5.38 (d, J=0.73 Hz, 1 H), 5.28 (dd, J=10.50, 5.55 Hz, 1 H), 4.36 (d, J=I.28 Hz, 1 H), 3.99 (d, J=9.22 Hz, 2 H), 3.63 (s, 3 H), 3.59 (s, 1 H), 2.76 - 2.94 (m, 4 H), 2.54 - 2.73 (m, 3 H), 2.40 (dd, J=13.24, 10.62 Hz, 1 H), 1.95 - 2.12 (m, 3 H), 1.82 - 1.92 (m, 3 H), 1.48 - 1.64 (m, 2 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.23 (s, 3 H), 1.13 (s, 3 H).
Example 97 - 14(S)-((S)-2'-Dimethylamino-propionoyloxy)paspalinine (CLXXVII)
Figure imgf000081_0002
CLXXVII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 571 (M+Na). 1H NMR (500 MHz, ACETONITRILE-d^) δ ppm 8.95 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.96 - 7.06 (m, 2 H), 5.39 (d, J=0.67 Hz, 1 H), 5.32 (dd, J=10.53, 5.58 Hz, 1 H), 4.36 (d, J=1.34 Hz, 1 H), 3.67 (s, 1 H), 3.34 (q, J=7.08 Hz, 1 H), 2.61 - 2.95 (m, 4 H), 2.41 (dd, J=13.21, 10.59 Hz, 1 H), 2.29 - 2.34 (m, 6 H), 1.95 - 2.13 (m, 3 H), 1.82 - 1.91 (m, 1 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.23 (d, J=4.88 Hz, 4 H), 1.21 (s, 1 H), 1.13 (s, 3 H). Example 98 - 14(5)-((5)-2'-Methoxy-3'-phenyl-propionoyloxy)paspalinine (CLXXVIII)
Figure imgf000082_0001
CLXXVIII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 634 (M+Na). 1H NMR (500 MHz, ΛCETONITRILE-d3) δ ppm 8.96 (s, 1 H), 7.21 - 7.37 (m, 7 H), 6.97 - 7.06 (m, 2 H), 5.46 (d, J=0.79 Hz, 1 H), 5.35 (dd, J=10.56, 5.55 Hz, 1 H), 4.36 (d, J=I .28 Hz, 1 H), 4.12 (dd, J=9.06, 4.61 Hz, 1 H), 3.51 (s, 1 H), 3.31 (s, 3 H), 3.06 (dd, J=14.28, 4.64 Hz, 1 H), 2.77 - 2.94 (m, 3 H), 2.62 - 2.74 (m, 2 H), 2.41 (dd, J=13.21 , 10.65 Hz, I H), 1.95 - 2.12 (m, 4 H), 1.82 - 1.91 (m, I H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.24 (s, 3 H), 1.14 (s, 3 H).
Example 99 - 14(5)-(r-Methoxy-cyclopropanecarbonyloxy)paspalinine (CLXXIX)
Figure imgf000082_0002
CLXXIX
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 570 (M+Na). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 8.95 (s, 1 H), 7.29 - 7.37 (m, 2 H), 6.96 - 7.05 (m, 2 H), 5.41 (d, J=0.55 Hz, 1 H), 5.34 (dd, J=10.44, 5.62 Hz, 1 H), 4.37 (d, J=I.28 Hz, 1 H),
3.36 - 3.39 (m, 3 H), 3.30 (s, 1 H), 2.86 - 2.95 (m, 1 H), 2.75 - 2.84 (m, 1 H), 2.62 - 2.74 (m, 2 H), 2.41 (dd, J=13.24, 10.62 Hz, 1 H), 1.95 - 2.12 (m, 3 H), 1.82 - 1.91 (m, 1 H), 1.40 (s, 3 H),
1.37 (s, 3 H), 1.28 - 1.31 (m, 2 H), 1.24 (s, 3 H), 1.16 - 1.18 (m, 1 H), 1.11 - 1.16 (m, 4 H).
Example 100 - 14(5)-((i?)-2'-Dimethylamino-propionoyloxy)paspalinine (CLXXXII)
Figure imgf000083_0001
CLXXXII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 549 (M+H). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 8.97 (s, 1 H), 7.30 - 7.37 (m, 2 H), 6.96 - 7.05 (m, 2 H), 5.51 (d, J=0.73 Hz, 1 H), 5.30 (dd, J=10.47, 5.52 Hz, 1 H), 4.35 (d, J=I .28 Hz, 1 H), 3.99 (s, 1 H), 3.24 - 3.29 (m, 1 H), 2.77 - 2.97 (m, 2 H), 2.62 - 2.73 (m, 2 H), 2.38 - 2.45 (m, 1 H), 1.97 - 2.13 (m, 3 H), 1.79 - 1.91 (m, 2 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.26 (d, J=7.08 Hz, 2 H), 1.24 (s, 3 H), 1.13 (s, 3 H).
Example 101 - 14(<S)-(2'-Methyl-5'-trifluoromethyl-oxazole-4'-carbonyloxy)paspalinine (CLXXXIII)
Figure imgf000083_0002
CLXXXIII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 649 (M+Na). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 8.98 (s, 1 H), 7.31 - 7.38 (m, 2 H), 6.97 - 7.06 (m, 2 H), 5.59 (dd, J=10.59, 5.58 Hz, 1 H), 5.46 (s, 1 H), 4.35 (d, J=1.28 Hz, 1 H), 3.31 (s, 1 H), 2.92 - 3.00 (m, 1 H), 2.78 - 2.87 (m, 1 H), 2.65 - 2.76 (m, 2 H), 2.38 - 2.55 (m, 6 H), 2.22 - 2.28 (m, 1 H), 2.10 - 2.17 (m, 1 H), 1.95 - 2.02 (m, 1 H), 1.86 - 1.92 (m, 1 H), 1.40 (d, J=1.46 Hz, 6 H), 1.28 (s, 3 H), 1.13 (s, 3 H).
Example 102 - 14(5)-(Pyrimidine-5'-carbonyloxy)paspalinine (CLXXXIV)
Figure imgf000084_0001
CLXXXIV
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 578 (M+Na). 1H NMR (500 MHz, ACETONITRILE-di) δ ppm 9.33 - 9.37 (m, 2 H), 8.99 (s, 1 H), 7.31 - 7.38 (m, 2 H), 6.97 - 7.07 (m, 2 H), 5.60 (dd, J=10.50, 5.55 Hz, 1 H), 5.50 (d, J=0.61 Hz, 1 H), 4.34 (d, J=1.22 Hz, 1 H), 3.86 (s, 1 H), 2.93 - 3.03 (m, 1 H), 2.81 - 2.90 (m, 1 H), 2.67 - 2.78 (m, 2 H), 2.44 (dd, J=13.21, 10.65 Hz, 1 H), 2.16 - 2.31 (m, 3 H), 2.00 (dd, J=13.09, 8.70 Hz, 1 H), 1.86 - 1.93 (m, 1 H), 1.43 (s, 3 H), 1.40 (s, 3 H), 1.30 (s, 3 H), 1.13 (s, 3 H).
Example 103 - 14(S)-(2'-Bromo-3'-methyl-butyroyloxy)paspalinine (CLXXXVI)
Figure imgf000084_0002
CLXXXVI
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 654 (M+Na). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 8.96 (s, 1 H), 7.30 - 7.37 (m, 2 H), 6.96 - 7.06 (m, 2 H), 5.54 (d, J=0.49 Hz, 1 H), 5.35 (dd, J=10.56, 5.55 Hz, 1 H), 4.34 - 4.38 (m, .1 H), 4.23 - 4.27 (m, 1 H), 3.68 (s, 1 H), 2.62 - 2.94 (m, 5 H), 2.38 - 2.46 (m, 1 H), 2.24 - 2.31 (m, 2 H), 1.95 - 2.10 (m, 3 H), 1.83 - 1.92 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.24 (s, 3 H), 1.14 (s, 3 H), 1.11 (d, J=6.65 Hz, 3 H), 1.05 (d, J=6.65 Hz, 3 H).
Example 104 - 14(S)-(2'-Methyl-imidazo[l',2'-α]pyridine-3'-carbonyloxy)paspalinine (CXCII)
Figure imgf000085_0001
CXCII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 608 (M+H). 1H NMR (400 MHz, ACETONITRILE-d^) δ ppm 9.31 (d, J=8.05 Hz, 1 H), 8.98 (s, 1 H), 7.58 - 7.66 (m, 1 H), 7.51 (dd, J=I 0.18, 7.05 Hz, 1 H), 7.29 - 7.40 (m, 2 H), 7.08 - 7.15 (m, 1 H), 6.95 - 7.07 (m, 2 H), 5.64 - 5.74 (m, 2 H), 4.32 (s, 1 H), 3.36 (s, 1 H), 2.68 - 3.11 (m, 4 H), 2.62 - 2.68 (m, 3 H), 2.38 - 2.54 (m, 1 H), 2.21 - 2.32 (m, 2 H), 1.45 (s, 3 H), 1.40 (s, 3 H), 1.33 (s, 3 H), 1.14 (s, 3 H).
Example 105 - 14(5)-(Benzo[6]furan-2'-carbonyloxy)paspalinine (CXCIII)
Figure imgf000085_0002
CXCIII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 616 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.98 (s, 1 H), 7.76 - 7.84 (m, 2 H), 7.63 - 7.70 (m, 1 H), 7.50 - 7.59 (m, 1 H), 7.30 - 7.42 (m, 3 H), 6.96 - 7.08 (m, 2 H), 5.51 - 5.60 (m, 2 H), 4.34 (s, 1 H), 3.79 (s, 1 H), 2.80 - 3.06 (m, 2 H), 2.67 - 2.79 (m, 2 H), 2.44 (dd, J=13.20, 10.66 Hz, 1 H), 2.16 - 2.35 (m, 2 H), 1.97 - 2.06 (m, 1 H), 1.85 - 1.92 (m, 1 H), 1.43 (s, 3 H), 1.40 (s, 3 H), 1.30 (s, 3 H), 1.13 (s, 3 H).
Example 106 - 14(5)-(3-Hydroxypropyloxy)-21 -(cy
Figure imgf000085_0004
Figure imgf000085_0003
CCCXXXIII CCCXXXIX
Compound CCCXXXIX was prepared in the same manner as compound II. LCMS m/e 555 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 9.45 (s, 1 H), 7.70 (s, 1 H), 7.47 (d, J=8.35 Hz, 1 H), 7.28 (dd, J=8.25, 1.32 Hz, 1 H), 5.89 (s, 1 H), 4.33 (d, J=1.22 Hz, 1 H), 3.81 - 3.94 (m, 2 H), 3.51 - 3.62 (m, 4 H), 2.41 - 2.86 (m, 6 H), 2.28 - 2.36 (m, 1 H), 1.71 - 1.90 (m, 4 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.17 (s, 3 H), 1.14 (s, 3 H).
Example 107 - 14(5)-(Adamantane-r-carbonyloxy)paspalinine (CXCVII)
Figure imgf000086_0001
CXCVII
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 634 (M+Na). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 8.97 (s, 1 H), 7.31 - 7.38 (m, 1 H), 6.98 - 7.07 (m, 2 H), 5.39 (d, J=0.73 Hz, 1 H), 5.28 (dd, J=I 0.28, 5.77 Hz, 1 H), 4.37 (d, J=I.28 Hz, 1 H), 3.60 (s, 3 H), 3.40 (s, 1 H), 2.79 - 2.95 (m, 4 H), 2.64 - 2.75 (m, 4 H), 2.42 (dd, J=13:21, 10.65 " Hz, 1 H), 1.97 - 2.07 (m, 7 H), 1.90 - 1.95 (m, 10 H), 1.86 - 1.89 (m, 4 H), 1.69 - 1.81 (m, 14 H), 1.40 - 1.43 (m, 3 H), 1.39 - 1.41 (m, 3 H), 1.24 - 1.26 (m, 3 H), 1.13 - 1.16 (m, 3 H).
Example 108 - 14(5)-((i?)-2'-Methoxy-3' -phenyl -propionoyloxy)paspalinine (CCI)
Figure imgf000086_0002
CCI
Compound prepared in a similar manner as for (CXXXV) (Method B). LCMS m/e 634 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.96 (s, 1 H), 7.20 - 7.38 (m, 7 H), 6.95 - 7.06 (m, 2 H), 5.48 (s, 1 H), 5.31 (dd, J=10.54, 5.61 Hz, 1 H), 4.36 (d, J=1.22 Hz, 1 H), 4.12 - 4.18 (m, 1 H), 3.54 (s, 1 H), 3.31 (s, 3 H), 3.03 (d, J=6.88 Hz, 2 H), 2.75 - 2.91 (m, 2 H), 2.60 - 2.72 (m, 2 H), 2.38 (dd, J-13.23, 10.59 Hz, 1 H), 1.96 - 2.01 (m, 1 H), 1.74 - 1.92 (m, 3 H), 1.40 (s, 3 H), 1.33 (s, 3 H), 1.22 (s, 3 H), 1.13 (s, 3 H).
Example 109 - 14(S)-(3'-Hydroxy-propoxy-phosphono-oxy(bis-triemylammonium))- propyloyloxy)-21 -(cyano)-paspalinine (CCCXL)
Figure imgf000087_0001
CCCXXXIX CCCXL
Compound CCCXL was prepared in the same manner as CXIX. LCMS m/e 714 (M+EtβN). 1H NMR (400 MHz, METHANOL-^) δ ppm 7.97 (s, 1 H), 7.65 (d, J=0.73 Hz, 1 H), 7.43 (d, J=8.25 Hz, 1 H), 7.21 (dd, J=8.22, 1.34 Hz, 1 H), 5.96 (s, 1 H), 4.31 (s, 1 H), 3.85 - 4.02 (m, 4 H), 3.55 - 3.64 (m, 1 H), 3.13 (q, J=7.32 Hz, 9 H), 2.98 (s, 3 H), 2.85 (s, 4 H), 2.60 - 2.77 (m, 2 H), 2.46 (dd, J=13.15, 10.81 Hz, 1 H), 2.28 - 2.37 (m, 1 H), 1.86 - 2.01 (m, 15 H), 1.41 (d, J=3.95 Hz, 6 H), 1.28 (t, J=7.30 Hz, 6 H), 1.21 (s, 3 H), 1.10 - 1.17 (m, 3 H).
Example 110 - 14(5)-(4'-bromo-phenyl)carbamoyloxypaspalinine (CCIX)
Figure imgf000087_0002
CCIX
To a two dram vial fitted with a magnetic stir bar was added 14-hydroxypaspalinine (10 mg, 0.022 mmol, 1 eq.) in methylene chloride (1.5 mL). Pyridine (0.210 mL, 0.0027 mol, 120 eq) and DMAP (33 mg, 0.27 mmol, 12 eq) was added to the solution and stirred. 4-Bromophenyl isocyanate (53 mg, 0.27 mmol, 12 eq) was added to the reaction vial last. The vial was capped and stirred at 50 0C for 24 hours. After this time, the reaction was cooled to room temperature and diluted with another 2 mL of methylene chloride. The reaction was filtered through a 0.45 micron (nylon disc) syringe filter. The sample was then washed one time with a 10% HCl solution, one time with a saturated sodium bicarbonate solution and concentrated under nitrogen. The sample was then taken up in DMSO and purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 40:60 MeOH:H2O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH :H2θ. Total run time is 8 minutes. LCMS m/e 648 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.97 (s, 1 H), 7.91 (s, 1 H), 7.49 (d, 2 H), 7.41 (d, 2 H), 7.35 (dd, J=13.73, 7.64 Hz, 2 H), 6.92 - 7.11 (m, 2 H), 5.57 (s, 1 H), 5.25 (dd, J=10.55, 5.66 Hz, 1 H), 4.36 (s, 1 H), 3.41 (s, 1 H), 2.88 - 3.01 (m, 1 H), 2.77 - 2.88 (m, 1 H), 2.63 - 2.76 (m, 2 H), 2.43 (dd, J=13.24, 10.71 Hz, 1 H), 2.19 - 2.28 (m, 1 H), 2.09 - 2.12 (m, 1 H), 2.04 - 2.08 (m, 1 H), 1.96 - 2.02 (m, 1 H), 1.83 - 1.91 (m, 1 H), 1.40 (s, 3 H), 1.39 (s, 3 H), 1.26 (s, 3 H), 1.13 (s, 3 H).
Example 111 - 14(5)-(3'-chloropropyl)carbamoyloxypaspalinine (CCX)
Figure imgf000088_0001
CCX
Compound (CCX) was prepared in the same manner as compound (CCIX). LCMS m/e 569 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.95 (s, 1 H), 7.22 - 7.43 (m, 2 H), 6.89 - 7.12 (m, 2 H), 5.66 (t, J=5.99 Hz, 1 H), 5.52 (s, 1 H), 5.12 (dd, J=10.49, 5.66 Hz, 1 H), 4.35 (d, J=I .26 Hz, 1 H), 3.63 (t, J=6.48 Hz, 2 H), 3.20 - 3.37 (m, 2 H), 2.75 - 2.95 (m, 2 H), 2.58 - 2.74 (m, 2 H), 2.41 (dd, J=13.27, 10.58 Hz, 1 H), 2.08 - 2.12 (m, 1 H), 1.96 - 2.06 (m, 2 H), 1.81 - 1.91 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.23 (s, 3 H), 1.13 (s, 3 H).
Example 1 12 - 14(SΗallyl)carbamoyloxypaspalinine (CCXffl)
Figure imgf000088_0002
CCXIII
Prepared in the same manner as compound (CCIX). LCMS m/e 533 (M+H). 1H NMR (400 MHz, ACETONITRILE-ds) δ ppm 8.94 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.94 - 7.07 (m, 2 H), 5.82 - 5.94 (m, 1 H), 5.67 (t, J=6.13 Hz, 1 H), 5.55 (s, 1 H), 5.20 (d, J=I .43 Hz, 1 H), 5.08 - 5.17 (m, 2 H), 4.35 (d, J=I.21 Hz, 1 H), 3.68 - 3.85 (m, 2 H), 3.68 - 3.85 (m, 2 H), 2.75 - 2.95 (m, 2 H), 2.59 - 2.74 (m, 2 H), 2.41 (dd, JH 3.27, 10.63 Hz, 1 H), 1.96 - 2.12 (m, 3 H), 1.80 - 1.91 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.23 (s, 3 H), 1.13 (s, 3 H).
Example 113 - 14(5)-((iS)-propionoyloxy methyl)carbamoyloxypaspalinine (CCXVI)
Figure imgf000089_0001
CCXVI
Prepared in the same manner as compound (CCIX). LCMS m/e 579 (M+H). 1H NMR (400 MHz, ACETONITRJLE-Ci3) δ ppm 8.94 (s, 1 H), 7.26 - 7.39 (m, 2 H), 6.94 - 7.08 (m, 2 H), 5.94 (d, J-7.58 Hz, 1 H), 5.53 (s, 1 H), 5.12 (dd, JM 0.38, 5.66 Hz, 1 H), 4.36 (d, J=I .26 Hz, 1 H), 4.19 - 4.31 (m, 1 H), 3.72 (s, 3 H), 2.76 - 2.95 (m, 2 H), 2.60 - 2.74 (m, 2 H), 2.42 (dd, J=I 3.24, 10.60 Hz, 1 H), 2.07 - 2.11 (m, 1 H), 1.96 - 2.06 (m, 2 H), 1.81 - 1.91 (m, 1 H), 1.40 (s, 3 H), 1.37 (t, J=3.57 Hz, 6 H), 1.23 (s, 3 H), 1.13 (s, 3 H).
Example 114- 14(5)-(4'-dimethylaminophenyl)carbamoyloxypaspalinine (CCXX)
Figure imgf000089_0002
CCXX
Prepared in the same manner as compound (CCIX). LCMS m/e 612 (M+H). 1H NMR (400 MHz, ACETONITRILE-CI3) δ ppm 8.96 (s, 1 H), 7.44 (s, 1 H), 7.29 - 7.38 (m, 2 H), 7.24 (d, J=8.68 Hz, 2 H), 6.95 - 7.07 (m, 2 H), 6.74 (d, J=9.01 Hz, 2 H), 5.60 (d, J=0.38 Hz, 1 H), 5.21 (dd, JM 0.52, 5.63 Hz, 1 H), 4.36 (d, J=LlO Hz, 1 H), 3.37 - 3.48 (m, 1 H), 2.77 - 3.00 (m, 8 H), 2.61 - 2.76 (m, 2 H), 2.43 (dd, JH 3.24, 10.60 Hz, 1 H), 2.17 - 2.25 (m, 1 H), 2.05 - 2.13 (m, 1 H), 1.96 - 2.04 (m, 1 H), 1.83 - 1.91 (m, 1 H), 1.40 (s, 3 H), 1.39 (s, 3 H), 1.26 (s, 3 H), 1.14 (s, 3 H).
Example 1 15 - 14(5)-(3',4'-methylenedioxyphenyl)carbamoyloxypaspalinine (CCXXII)
Figure imgf000090_0001
CCXXII
Prepared in the same manner as compound (CCIX). LCMS m/e 613 (M+H). 1H NMR (400 MHz, ACETONITRILE-Ci2) δ ppm 8.96 (s, 1 H), 7.65 (s, 1 H), 7.29 - 7.39 (m, 2 H), 7.10 (s, 1 H), 6.94 - 7.07 (m, 2 H), 6.79 (d, J=LlO Hz, 2 H), 5.92 - 5.99 (m, 2 H), 5.57 (d, J=0.88 Hz, 1 H), 5.21 (dd, J=10.52, 5.58 Hz, 1 H), 4.36 (d, J=1.32 Hz, 1 H), 3.38 (s, 1 H), 2.61 - 2.99 (m, 4 H), 2.43 (dd, J=13.27, 10.58 Hz, 1 H), 2.17 - 2.26 (m, 1 H), 1.96 - 2.12 (m, 2 H), 1.83 - 1.91 (m, 1 H), 1.40 (s, 3 H), 1.39 (s, 3 H), 1.26 (s, 3 H), 1.14 (s, 3 H).
Example 116 - 14(5}-moφholinocarbamoyloxypaspalinine (CCXXIII)
Figure imgf000090_0002
CCXXIII
Prepared in the same manner as compound (CCIX). LCMS m/e 563 (M+H). 1H NMR (400 MHz, ACETONITRILE-CI3) δ ppm 9.02 (s, 1 H), 7.20 - 7.42 (m, 2 H), 6.87 - 7.11 (m, 2 H), 5.71 - 5.75 (m, 1 H), 5.69 (s, 1 H), 5.22 (dd, J-8.96, 7.00 Hz, 1 H), 4.13 (s, 1 H), 3.52 - 3.63 (m, 4 H), 3.20 (d, J=16.11 Hz, 1 H), 2.82 - 2.93 (m, 1 H), 2.71 (dd, J=13.28, 6.39 Hz, 1 H), 2.43 (dd, J-13.28, 10.74 Hz, 1 H), 2.25 (dd, J=17.55, 6.22 Hz, 1 H), 2.12 - 2.17 (m, 2 H), 2.10 - 2.11 (m, 1 H), 2.05 - 2.07 (m, 1 H), 1.71 - 1.84 (m, 2 H), 1.37 - 1.46 (m, 1 H), 1.34 (s, 3 H), 1.29 (s, 3 H), 1.22 (s, 3 H), 1.08 (s, 3 H), 0.87 - 1.00 (m, 2 H).
Example 117 - 14(5)-(Ethylcarbamyl)carbamoyloxypaspalinine (CCXXVIII)
Figure imgf000091_0001
CCXXVIII
Prepared in the same manner as compound (CCIX). LCMS m/e 565 (M+H). 1H NMR (400 MHz, ACETONITRILE-di) δ ppm 8.96 (s, 1 H), 8.15 (s, 1 H), 7.26 - 7.42 (m, 2 H), 6.92 - 7.14 (m, 2 H), 5.47 (d, J=0.77 Hz, 1 H), 5.22 (dd, J-10.55, 5.66 Hz, 1 H), 4.37 (d, J-1.26 Hz, 1 H), 4.17 (q, J=IA 1 Hz, 2 H), 3.46 (s, 1 H), 2.57 - 2.98 (m, 4 H), 2.42 (dd, J=13.27, 10.58 Hz, 1 H), 2.22 - 2.30 (m, 1 H), 1.95 - 2.11 (m, 3 H), 1.81 - 1.92 (m, 1 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.21 1.28 (m, 6 H), 1.14 (s, 3 H).
Example 118 - 14(S)-(2'-Hydroxyethyloxy)-
Figure imgf000091_0003
Figure imgf000091_0002
CCCXXXII CCCXLI
Compound CCCXLI was prepared in the same manner as compound (II). LCMS m/e 541 (M+Na). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 7.72 (d, J=0.68 Hz, 1 H), 7.49 (d, J=8.20 Hz, 1 H), 7.30 (dd, J=8.20, 1.37 Hz, 1 H), 6.04 (s, 1 H), 4.35 (d, J=I.17 Hz, 1 H), 3.97 (s, 1 H), 3.79 - 3.87 (m, 1 H), 3.48 - 3.72 (m, 3 H), 2.98 (s, 3 H), 2.88 - 2.95 (m, 1 H), 2.85 (s, 3 H), 2.58 - 2.82 (m, 2 H), 2.44 - 2.54 (m, 1 H), 2.27 - 2.38 (m, 1 H), 1.76 - 1.93 (m, 1 H), 1.38 - 1.45 (m, 6 H), 1.19 (s, 3 H), 1.13 - 1.17 (m, 3 H).
Example 119 - 14(5)-[(4'-ter/-Butoxycarbonylpiperazin-r-yl)-carbonyloxy]-paspalinine (CCXXXIX)
Figure imgf000092_0001
CCXXXIX
Prepared in the same manner as compound (CCIX). LCMS m/e 662 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.96 (s, 1 H), 7.22 - 7.45 (m, 2 H), 6.85 - 7.15 (m, 2 H), 5.58 (s, 1 H), 5.12 - 5.34 (m, 1 H), 4.37 (d, J=1.27 Hz, 1 H), 3.10 - 3.64 (m, 9 H), 2.56 - 2.99 (m, 4 H), 2.42 (dd, J=13.18, 10.79 Hz, 1 H), 1.97 - 2.12 (m, 4 H), 1.75 - 1.94 (m, 3 H), 1.45 (s, 9 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.26 (s, 3 H), 1.15 (s, 3 H).
Example 120 - 14(5)-(2'-Aminobenzyl)carbamoyloxypaspalinine (CCXLVI)
Figure imgf000092_0002
CCXLVI
Prepared in the same manner as compound (CCIX). LCMS m/e 598 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.97 (s, 1 H), 7.95 (s, 1 H), 7.35 (dd, J=14.37, 7.25 Hz, 2 H), 6.92 - 7.17 (m, 5 H), 6.58 - 6.80 (m, 2 H), 5.89 (t, J=5.95 Hz, 1 H), 5.62 (s, 1 H), 5.19 (dd, J=10.40, 5.95 Hz, 1 H), 4.37 (s, 2 H), 4.16 - 4.35 (m, 2 H), 2.59 - 2.99 (m, 4 H), 2.43 (dd, J=13.08, 10.64 Hz, 1 H), 1.98 - 2.14 (m, 4 H), 1.78 - 1.94 (m, 2 H), 1.42 (s, 3 H), 1.38 (s, 3 H), 1.25 (s, 3 H), 1.16 (s, 3 H).
Example 121 - (CCL)
Figure imgf000092_0003
Prepared in the same manner as compound (CCIX). LCMS m/e 592 (M+H). 1H NMR (400 MHz, ACETONITRILE-di) δ ppm 8.97 (s, 1 H), 7.26 - 7.45 (m, 2 H), 6.91 - 7.11 (m, 2 H), 5.70 (t, J=5.59 Hz, 1 H), 5.56 (s, 1 H), 5.13 (dd, J=10.57, 5.64 Hz, 1 H), 4.36 (d, J=1.27 Hz, 1 H), 3.20 (s, 2 H), 2.62 - 2.98 (m, 4 H), 2.54 (q, J=7.11 Hz, 4 H), 2.43 (dd, J=I 3.23, 10.59 Hz, 1 H), 1.97 - 2.16 (m, 4 H), 1.82 - 1.94 (m, 1 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.25 (s, 3 H), 1.15 (s, 3 H), 0.98 - 1.04 (m, 6 H).
Example 122 - 14(S)-(4'-Benzylpiperidine)carbamoyloxypaspalinine (CCLIII)
Figure imgf000093_0001
CCLIII
Prepared in the same manner as compound (CCIX). LCMS m/e 651 (M+H). 1H NMR (400 MHz, ACETONITRILE-di) δ ppm 8.96 (s, 1 H), 7.26 - 7.43 (m, 4 H), 7.14 - 7.26 (m, 3 H), 6.93 - 7.11 (m, 2 H), 5.59 (s, 1 H), 5.20 (dd, J=9.47, 6.44 Hz, 1 H), 4.27 - 4.49 (m, 1 H), 4.02 - 4.21 (m, 2 H), 2.35 - 3.00 (m, 9 H), 1.97 - 2.14 (m, 4 H), 1.71 - 1.93 (m, 2 H), 1.43 (s, 3 H), 1.39 (s, 3 H), 1.26 (s, 3 H), 1.10 - 1.20 (m, 4 H).
Example 123 - 14(5)-[(4'-Methoxycarbonylpiperidin-r-yl)-carbonyloxy]-paspalinine (CCLIV)
Figure imgf000093_0002
CCLIV
Prepared in the same manner as compound (CCIX). LCMS m/e 619 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.97 (s, 1 H), 7.27 - 7.43 (m, 2 H), 6.94 - 7.10 (m, 2 H), 5.58 (s, 1 H), 5.21 (dd, J=9.98, 6.13 Hz, 1 H), 4.37 (d, J=1.03 Hz, 1 H), 3.97 - 4.18 (m, 2 H), 3.67 (s, 3 H), 2.51 - 3.06 (m, 8 H), 2.43 (dd, J=I 3.25, 10.62 Hz, 1 H), 1.99 - 2.15 (m, 4 H), 1.82 - 1.93 (m, 2 H), 1.49 - 1.62 (m, 1 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.26 (s, 3 H), 1.15 (s, 3 H). Example 124 - 14(S)-(OS)- l'-Hydroxymethyl-3' -methyl-butyl) carbamoyloxypaspalinine (CCLV)
Figure imgf000094_0001
CCLV
Prepared in the same manner as compound (CCIX). LCMS m/e 593 (M+H). 1H NMR (400 MHz, ACETONITRlLE-dτ) δ ppm 8.97 (s, 1 H), 8.30 (s, 1 H), 7.27 - 7.43 (m, 2 H), 6.92 - 7.11 (m, 2 H), 5.59 (s, 1 H), 5.47 (d, J=9.62 Hz, 1 H), 5.14 (dd, J=10.49, 5.66 Hz, 1 H), 4.37 (d, JH .03 Hz, 1 H), 3.61 - 3.79 (m, 1 H), 3.40 - 3.55 (m, 2 H), 2.61 - 2.99 (m, 4 H), 2.43 (dd, J-13.28, 10.64 Hz, 1 H), 1.98 - 2.18 (m, 4 H), 1.82 - 1.94 (m, 2 H), 1.57 - 1.75 (m, 2 H), 1.44 - 1.51 (m, 1 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.29 - 1.38 (m, 3 H), 1.25 (s, 3 H), 1.15 (s, 3 H), 0.96 (dd, J-6.56, 1.83 Hz, 6 H), 0.88 - 0.94 (m, 3 H).
Example - 148 l-Allyl-14(S)-propyloxypaspalinine (CCCL)
Figure imgf000094_0002
CCCL To a one dram vial fitted with a magnetic stir bar was added 14-propyloxypaspalinine (IV) (20 mg, 0.03762 mmol, 1 eq.) in THF (3 mL), sodium hydride (60% dispersion in mineral oil, 30 mg, 0.75 mmol, 20 eq) and allyl bromide (0.050 mL, 0.58 mmol, 15 eq). The reaction was stirred at 60 0C for three hours. After this time, the reaction was quenched by adding water (1 mL) and concentrated under nitrogen. The reaction was then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 40:60 MeOH:H2θ maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 532 (M+H). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 7.39 (dd, J=7.72, 0.58 Hz, 1 H), 7.24 - 7.32 (m, 2 H), 7.10 - 7.16 (m, 1 H), 5.88 (d, J=Q.19 Hz, 1 H), 5.07 - 5.17 (m, 1 H), 4.80 (d, J-3.17 Hz, 1 H), 4.77 (s, 1 H), 4.32 (d, J=1.28 Hz, 1 H)5 3.98 (dd, J=10.28, 5.40 Hz, 1 H), 3.70 - 3.78 (m, 1 H), 3.40 - 3.47 (m, 1 H), 3.09 - 3.19 (m, 1 H), 2.67 - 2.81 (m, 3 H), 2.46 (dd, J=14.04, 7.02 Hz, 1 H), 2.23 - 2.30 (m, 1 H), 2.01 (dd, J=I 1.51, 4.67 Hz, 1 H), 1.88 - 1.93 (m, 1 H), 1.55 - 1.72 (m, 4 H), 1.42 - 1.53 (m, 2 H), 1.38 (d, J=7.08 Hz, 6 H), 1.33 (s, 3 H), 1.22 - 1.31 (m, 1 H), 1.15 (s, 3 H), 0.94 (t, J=7.39 Hz, 3 H).
Example 125 - 14(5)-((5)-r-Hydroxymethyl-3'-methylsulfanyl-propyl)carbamoyloxypaspalinine (CCLVI)
Figure imgf000095_0001
CCLVI
Prepared in the same manner as compound (CCIX). LCMS m/e 611 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.97 (s, 1 H), 7.95 (s, 1 H), 7.29 - 7.44 (m, 2 H), 6.94 - 7.12 (m, 2 H), 5.57 (s, 1 H), 5.07 - 5.19 (m, 1 H), 4.38 (d, J=I.17 Hz, 1 H), 3.68 - 3.84 (m, 1 H), 3.36 - 3.60 (m, 2 H), 2.37 - 3.00 (m, 10 H), 2.13 (s, 3 H), 1.98 - 2.12 (m, 4 H), 1.76 - 1.93 (m, 3 H), , 1.62 - 1.74 (m, 1 H), 1.39 (s, 3 H), 1.25 (s, 3 H), 1.16 (s, 3 H).
Example 126 - 14(lS)-(2'-(N,N-Dimethylamino)ethyl)carbamoyloxypaspalim'ne (CCLIX)
Figure imgf000095_0002
CCLIX
Prepared in the same manner as compound (CCIX). LCMS m/e 564 (M+H). 1H NMR (400 MHz, ACETOΗITRILE-di) δ ppm 8.96 (s, 1 H), 8.25 (s, 1 H), 7.27 - 7.42 (m, 2 H), 6.94 - 7.09 (m, 2 H), 6.10 - 6.24 (m, 1 H), 5.52 (s, 1 H), 5.12 (dd, J=10.49, 5.71 Hz, 1 H), 4.35 (d, J=I .12 Hz, 1 H), 3.20 - 3.41 (m, 2 H), 2.38 - 2.97 (m, 7 H), 2.31 (s, 6 H), 1.99 - 2.21 (m, 4 H), 1.79 - 1.93 (m, 2 H), 1.41 (s, 3 H), 1.38 (s, 3 H), 1.23 - 1.25 (m, 3 H), 1.14 (s, 3 H). Example 127 - 14(5)-(r-Hydroxymethyl-cyclopentyl)carbamoyloxypaspalinine (CCLXI)
Figure imgf000096_0001
CCLXI
Prepared in the same manner as compound (CCIX). LCMS m/e 591 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.96 (s, 1 H), 7.35 (dd, J=13.54, 7.54 Hz, 2 H), 6.88 - 7.14 (m, 2 H), 5.63 (s, 1 H), 5.56 (s, 1 H), 5.11 (dd, J=10.05, 5.66 Hz, 1 H), 4.37 (s, 1 H), 3.51 - 3.65 (m, 2 H), 2.61 - 2.98 (m, 4 H), 2.43 (dd, J=13.06, 10.76 Hz, 1 H), 1.98 - 2.15 (m, 4 H), 1.85 - 1.93 (m, 2 H), 1.57 - 1.83 (m, 8 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.25 (s, 3 H), 1.16 (s, 3 H).
Example 128 - 14(5)-((5)-r-Hydroxymethyl-3'-methyl-butyl)carbamoyloxypaspalim'ne
(CCLXVI)
Figure imgf000096_0002
CCLXVI
Prepared in the same manner as compound (CCIX). LCMS m/e 579 (M+H). 1H NMR (400 MHz, ACETONITRILE-Ci3) δ ppm 8.96 (s, 1 H), 7.24 - 7.48 (m, 2 H), 6.91 - 7.18 (m, 2 H), 5.60 (s, 1 H), 5.51 (d, J=10.59 Hz, 1 H), 5.13 (dd, J=10.76, 5.83 Hz, 1 H), 4.38 (d, J=1.03 Hz, 1 H), 3.55 (d, J=5.27 Hz, 2 H), 3.39 - 3.47 (m, 1 H), 2.62 - 2.96 (m, 4 H), 2.43 (dd, J=13.06, 10.66 Hz, 1 H), 1.98 - 2.13 (m, 4 H), 1.83 - 1.94 (m, 2 H), 1.79 (s, 1 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.24 - 1.27 (m, 3 H), 1.15 (s, 3 H), 0.97 (d, J=6.78 Hz, 3 H), 0.91 (d, J=6.78 Hz, 3 H), 0.84 - 0.90 (m, 1 H).
Example 129 -14(S)-(I' -Hy droxymethyl-benzyl)carbamoyloxypaspalinine (CCLXVII)
Figure imgf000097_0001
CCLXVII
Prepared in the same manner as compound (CCIX). LCMS m/e 613 (M+H). 1H NMR (400 MHz, ACETOΗITRlLE-di) δ ppm 8.95 (s, 1 H), 7.18 - 7.47 (m, 7 H), 6.91 - 7.08 (m, 2 H), 6.25 (d, J=9.03 Hz, 1 H), 6.00 (s, 1 H), 5.52 (s, 1 H), 5.10 (dd, J=10.47, 6.71 Hz, 1 H), 4.66 - 4.80 (m, 1 H), 4.39 (s, 1 H), 3.74 - 3.85 (m, 1 H), 3.61 - 3.72 (m, 1 H), 2.55 - 2.96 (m, 4 H), 2.40 - 2.51 (m, 1 H), 1.99 - 2.1 1 (m, 4 H), 1.84 - 1.93 (m, 1 H), 1.76 - 1.81 (m, 1 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.23 (s, 3 H), 1.13 (s, 3 H).
Example 130 - 14(S)-(I ' -Benzyl -piperidin-4'-yl)carbamoyloxypaspalinine (CCLXXV)
Figure imgf000097_0002
CCLXXV
Prepared in the same manner as compound (CCIX). LCMS m/e 666 (M+H). 1H NMR (400 MHz, ACETOΗITRILE-di) δ ppm 8.94 (s, 1 H), 8.12 (s, 1 H), 7.17 - 7.42 (m, 7 H), 6.89 - 7.11 (m, 2 H), 5.38 - 5.63 (m, 2 H), 5.10 (dd, J=10.52, 5.20 Hz, 1 H), 4.35 (d, J=I.12 Hz, 1 H), 3.35 - 3.57 (m, 3 H), 2.58 - 2.95 (m, 7 H), 2.41 (dd, J=13.30, 10.47 Hz, 1 H), 1.98 - 2.14 (m, 5 H), 1.80 - 1.90 (m, 2 H), 1.34 - 1.51 (m, 8 H), 1.23 (s, 3 H), 1.13 (s, 3 H).
Example 131 - 14(S)-(T, 2 '-Dimethoxy-ethy^carbamoyloxypaspalinine (CCLXXVI)
Figure imgf000098_0001
CCLXXVI
Prepared in the same manner as compound (CCIX). LCMS m/e 581 (M+H). 1H NMR (400 MHz, ACETONITRILE-di) δ ppm 8.95 (s, 1 H), 7.28 - 7.39 (m, 2 H), 6.94 - 7.07 (m, 2 H), 5.58 (t, J=6.03 Hz, 1 H), 5.53 (s, 1 H), 5.12 (dd, ./=10.49, 5.61 Hz, 1 H), 4.32 - 4.41 (m, 2 H), 3.16 - 3.38 (m, 9 H), 2.59 - 2.94 (m, 4 H), 2.41 (dd, ./=13.23, 10.59 Hz, 1 H), 1.95 - 2.14 (m, 4 H), 1.80 - 1.92 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.23 (s, 3 H), 1.13 (s, 3 H).
Example 132 - 14(S)-((i?)-r-phenyl-ethyl)carbamoyloxypaspalinine (CCLXXIX)
Figure imgf000098_0002
CCLXXIX
Prepared in the same manner as compound (CCIX). LCMS m/e 597 (M+H). 1H NMR (400 MHz, ACETONITRILE-CI3) δ ppm 8.97 (s, 1 H), 7.18 - 7.51 (m, 7 H), 6.84 - 7.10 (m, 2 H), 6.05 (d, J=7.42 Hz, 1 H), 5.49 (s, 1 H), 5.06 (dd, ./=10.49, 5.61 Hz, 1 H), 4.65 - 4.85 (m, 1 H), 4.36 (s, 1 H), 2.58 - 2.92 (m, 4 H), 2.41 (dd, ./=13.06, 10.76 Hz, 1 H), 1.95 - 2.18 (m, 3 H), 1.79 - 1.91 (m, 1 H), 1.33 - 1.45 (m, 9 H), 1.20 (s, 3 H), 1.10 (s, 3 H).
Example 133 - 14(5)-(2',2'-Dimethyl-[l ',3']dioxolan-4'-ylmethyl)carbamoyloxypaspalinine (CCLXXX)
Figure imgf000098_0003
CCLXXX
Prepared in the same manner as compound (CCIX). LCMS m/e 607 (M+H). 1H NMR (400 MHz, ACETOMTRILE-di) δ ppm 8.95 (s, 1 H), 7.23 - 7.44 (m, 2 H), 6.87 - 7.14 (m, 2 H), 5.66 (t, J=6.59 Hz, 1 H), 5.53 (s, 1 H), 5.03 - 5.23 (m, 1 H), 4.36 (s, 1 H), 4.10 - 4.22 (m, 1 H), 3.97 - 4.09 (m, 1 H), 3.60 - 3.70 (m, 1 H), 3.19 - 3.40 (m, 2 H), 2.59 - 2.96 (m, 4 H), 2.42 (dd, J=13.25, 10.71 Hz, 1 H), 1.96 - 2.14 (m, 3 H), 1.81 - 1.92 (m, 1 H), 1.41 (s, 3 H), 1.35 - 1.39 (m, 6 H), 1.31 (s, 3 H), 1.24 (s, 3 H), 1.14 (s, 3 H).
Example 134 - 14(5)-(Furan-2'-yl-methyl)carbamoyloxypaspalinine (CCLXXXIII)
Figure imgf000099_0001
CCLXXXIII
Prepared in the same manner as compound (CCIX). LCMS m/e 573 (M+H). 1H NMR (400 MHz, ACETONITRILE-di) δ ppm 8.94 (s, 1 H), 7.46 (s, 1 H), 7.33 (dd, J=14.08, 7.39 Hz, 2 H), 6.90 - 7.09 (m, 2 H), 6.38 (d, J=2.10 Hz, 1 H), 6.25 (d, J=2.88 Hz, .1 H), 5.92 (t, J=6.10 Hz, 1 H), 5.56 (s, 1 H), 5.15 (dd, J=10.62, 5.59 Hz, 1 H), 4.21 - 4.46 (m, 3 H), 2.56 - 2.98 (m, 4 H), 2.41 (dd, J=13.25, 10.62 Hz, 1 H), 1.98 - 2.12 (m, 3 H), 1.82 - 1.92 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.23 (s, 3 H), 1.13 (s, 3 H).
Example 135 -14(5)-((5)-2'-Methoxymethyl-pyrrolidine)carbamoyloxypaspalinine (CCXCI)
Figure imgf000099_0002
CCXCI
Prepared in the same manner as compound (CCIX). LCMS m/e 591 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.95 (s, 1 H), 7.34 (dd, J=12.35, 7.76 Hz, 2 H), 6.87 - 7.12 (m, 2 H), 5.57 (s, 1 H), 5.05 - 5.31 (m, 1 H), 4.51 (s, 1 H), 4.33 (s, 1 H), 3.98 - 4.16 (m, 1 H), 3.46 - 3.58 (m, 1 H), 3.11 - 3.40 (m, 7 H), 2.60 - 2.97 (m, 4 H), 2.41 (dd, J=13.18, 10.49 Hz, 1 H), 1.96 - 2.11 (m, 3 H), 1.75 - 1.91 (m, 2 H), 1.53 - 1.67 (m, 1 H), 1.39 (d, J=4.83 Hz, 6 H), 1.23 (s, 3 H), 1.13 (s, 3 H), 0.78 - 0.99 (m, 1 H).
Example 136 - 14(5)-(3',6'-Dihydro-2'H-pyridine)carbamoyloxypasρalinine (CCXCV)
Figure imgf000100_0001
CCXCV
Prepared in the same manner as compound (CCIX). LCMS m/e 559 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.95 (s, 1 H), 7.25 - 7.40 (m, 2 H), 6.93 - 7.07 (m, 2 H), 5.81 5.91 (m, 1 H), 5.62 - 5.79 (m, 1 H), 5.56 (s, 1 H), 5.15 - 5.26 (m, 1 H), 4.35 (s, 1 H), 3.81 - 4.11 (m, 2 H), 3.35 - 3.74 (m, 3 H), 2.60 - 2.97 (m, 4 H), 2.41 (dd, J-13.23, 10.59 Hz, 1 H), 1.96 - 2.13 (m, 4 H), 1.80 - 1.92 (m, 1 H), 1.39 (d, J=8.3O Hz, 6 H), 1.25 (s, 3 H), 1.13 (s, 3 H).
Example 137 - 14(S)-(2 '-(! ', 3 '-Dihydro-isoindole))carbamoyloxypaspalinine (CCXCVI)
Figure imgf000100_0002
CCXCVI
Prepared in the same manner as compound (CCIX).
LCMS m/e 595 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.97 (s, 1 H), 7.20 -
7.45 (m, 6 H), 6.87 - 7.12 (m, 2 H), 5.67 (s, 1 H), 5.25 (dd, J=10.37, 5.69 Hz, 1 H), 4.54 - 4.88
(m, 4 H), 4.34 (d, J=1.22 Hz, 1 H), 2.79 - 2.98 (m, 2 H), 2.63 - 2.77 (m, 2 H), 2.42 (dd, J=13.28,
10.64 Hz, 1 H), 1.96 - 2.13 (m, 3 H), 1.83 - 1.91 (m, 1 H), 1.41 (s, 6 H), 1.27 (s, 3 H), 1.13 (s, 3
H).
Example 138 - 14(5)-Toluene-4'-sulfonoyloxypaspalinine (CCXCIX)
Figure imgf000101_0001
I CCXCIX
To an HPLC vial fitted with a magnetic stir bar was added 14-hydroxypaspalinine I (10 mg, 0.022 mmol, 1 eq.) and dibutyl tin oxide (99.6 mg, 0.04 mmol, 1.8 eq) in dry THF (0.5 mL) and dry toluene (0.5 mL). The reaction was heated to 75 0C and stirred for two hours. After this time the reaction was cooled to room temperature. Tetrabutylammonium bromide (10 mg, 0.03 mmol, 1.4 eq) and/»-toluenesulfonyl chloride (50 mg, 0.26 mmol, 12 eq) were added to the vial. The reaction was stirred at room temperature for one hour and then at 75 0C for approximately 14 hours. After this time the reaction was cooled to room temperature and filtered. The reaction was concentrated under a stream of nitrogen. The crude material was dissolved in methanol and purified by HPLC. LCMS m/e 604 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.93 (s, 1 H), 7.86 (d, J=7.53 Hz, 2 H), 7.47 (d, J=8.02 Hz, 2 H), 7.32 (dd, J=12.94, 7.55 Hz, 2 H), 6.95 - 7.06 (m, 2 H), 6.16 (s, 1 H), 5.31 (dd, J=10.49, 5.44 Hz, 1 H), 4.35 (s, 1 H), 3.69 (s, 1 H), 2.57 - 2.89 (m, 4 H), 2.21 - 2.40 (m, 2 H), 2.03 - 2.12 (m, 1 H), 1.78 - 1,92 (m, 2 H), 1.40 (s, 3 H), 1.30 (s, 3 H), 1.22 (s, 3 H), 1.16 (s, 2 H).
Example 139 - 14(5)-terM3utoxycarbonyloxypaspalinine (CCC)
Figure imgf000101_0002
I CCC
In a 100 mL round bottom flask was combined di-tert-butyl dicarbonate (73 mg, 0.33 mmol, 1.5 eq), dimethylaminopyridine (catalytic) and 14-hydroxy paspalinine I (100 mg, 0.22 mmol, 1 eq) in acetonitrile (10 mL). The reaction was stirred at room temperature for one hour and the reaction progress was monitored by TLC (1:1 Hept/EtOAC). The mixture was then partitioned between a saturated ammonium chloride solution and ethyl acetate. The aqueous layer was washed three times with ethyl acetate. The organic fractions were combined, washed one time with a saturated sodium bicarbonate solution. The organic layer was then dried over magnesium sulfate, filtered and concentrated. The material was then purified by HPLC. LCMS m/e 550 (M+H). 1H NMR (400 MHz, ACETONJTRILE-d3) δ ppm 8.95 (s, 1 H), 7.29 - 7.38 (m, 2 H), 6.96 - 7.06 (m, 2 H), 5.50 (s, 1 H), 5.10 (dd, J=10.27, 5.83 Hz, 1 H), 4.36 (d, J=1.22 Hz, 1 H), 3.46 (s, 1 H), 2.60 - 2.95 (m, 4 H), 2.42 (dd, J=13.28, 10.64 Hz, 1 H), 1.98 - 2.10 (m, 3 H), 1.73 1.91 (m, 2 H), 1.50 (s, 9 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.24 (s, 3 H), 1.14 (s, 3 H).
Example 140 - 14(5>(2'-(Pyridin-2'-yloxy)paspalinine (CCCI)
Figure imgf000102_0001
I CCCI In a 25 mL round bottom flask 14-hydroxypaspalinine I (30 mg, 0.067 mmol, 1 eq.) was dissolved in THF (10 mL). Sodium hydride (60% suspension in mineral oil, 10 mg, 0.25 mmol, 3.7 eq) was added and the mixture was heated to 60 0C. The 2-fluoropyridine (0.060 mL, 0.70 mmol, 10.4 eq.) was added and the reaction was heated overnight at 60 0C. After this time the reaction was cooled to room temperature and partitioned between a saturated ammonium chloride solution and ethyl acetate. The aqueous layer was washed two times with ethyl acetate. The organic fractions were combined and washed one time with a brine solution. The organic layer was then dried over magnesium sulfate, filtered and concentrated. The material was then purified by HPLC. LCMS m/e 550 (M+H). 1H NMR (400 MHz, ACETONE-d6) δ ppm 9.81 (s, 1 H), 8.22 - 8.28 (m, 1 H), 7.71 - 7.79 (m, 1 H), 7.29 - 7.38 (m, 2 H), 6.86 - 7.06 (m, 4 H), 5.70 (dd, J=I 0.41, 5.37 Hz, 1 H), 5.56 (d, J=0.58 Hz, 1 H), 4.55 (s, 1 H), 4.27 (d, J=I .17 Hz, 1 H), 2.86 - 3.08 (m, 2 H), 2.68 - 2.75 (m, 2 H), 2.45 (dd, J=13.15, 10.67 Hz, 1 H), 2.31 - 2.39 (m, 1 H), 2.10 - 2.24 (m, 1 H), 1.86 - 2.03 (m, 2 H), 1.50 (s, 3 H), 1.35 - 1.43 (m, J=5.44, 5.44 Hz, 6 H), 1.10 (s, 3 H).
Example 141 - Paspalin-14-one (CCCII)
Figure imgf000102_0002
CCCII 14-Hydroxypaspalinine I (30 mg, 0.066 mmol, 1 eq.), tetrapropyl ammonium perruthenate (TPAP, 7.2 mg, 0.020 mmol, 0.3 eq.), 4-Methylmorpholine N-oxide (15.6 mg, 0.13 mmol, 2 eq.) and 4 angstroms powdered sieves (0.075 g) were combined in a 1 dram vial. A stir bar was added along with dry methylene chloride (2 mL). The vial was capped and stirred at room temperature. The reaction was monitored by TLC (1 :1 Hept./EtOAc) which indicated the reaction was complete after 16 hours. The reaction was filtered through a plug of silica gel and rinsed with methylene chloride. The organic solvent was removed under vacuum and the reaction was purified by HPLC. LCMS m/e 448 (M+H). 1H NMR (400 MHz, DICHWROMETHANE-CI2) δ ppm 7.87 (s, 1 H), 7.39 - 7.43 (m, 1 H), 7.33 (dd, J=7.14, 1.43 Hz, 1 H), 7.01 - 7.12 (m, 2 H), 6.82 (d, J=0.66 Hz, 1 H), 4.30 (d, J=1.21 Hz, 1 H), 3.57 (dd, J=15.46, 12.22 Hz, 1 H), 3.01 - 3.11 (m, 1 H), 2.71 - 2.84 (m, 3 H), 2.59 (dd, J=13.29, 10.44 Hz, 1 H), 2.48 (dd, J=12.20, 2.75 Hz, 1 H), 2.44 (s, 1 H), 2.02 - 2.12 (m, 1 H), 1.86 - 1.97 (m, 1 H), 1.57 (s, 3 H), 1.43 (s, 3 H), 1.19 (s, 3 H), 1.17 (s, 3 H).
Example 142 - 14(i?)-Hydroxypaspalinine (CCCIII)
Figure imgf000103_0001
CCCII CCCIII
Paspalin-14-one (CCCII) (100.7 mg, 0.225 mmol, 1 eq.) and sodium cyanoborohydride (150.7 mg, 2.36 mmol, 10.5 eq) were combined in a 1 dram vial containing 2 mL of a 3% acetic acid/acetonitrile solution. The vial was capped and stirred at room temperature overnight. After this time the reaction was quenched by adding it slowly to a solution of saturated sodium bicarbonate. The mixture was then extracted three times with ethyl acetate. The organic fractions were combined and concentrated in vacuo. The crude material was purified by HPLC. LCMS m/e 450 (M+H). 1H NMR (400 MHz, ACETONITRILE-di) δ ppm 8.98 (br. s., 1 H) 7.25 - 7.44 (m, 2 H) 6.91 - 7.11 (m, 2 H) 6.04 (d, J=0.68 Hz, 1 H) 4.32 (d, J=I.17 Hz, 1 H) 4.17 (d, J=2.15 Hz, 1 H) 3.25 - 3.45 (m, 1 H) 3.15 (s, 1 H) 3.07 (d, J=3.12 Hz, 1 H) 2.57 - 2.76 (m, 3 H) 2.30 - 2.49 (m, 2 H) 1.98 - 2.09 (m, 1 H) 1.67 - 1.85 (m, 2 H) 1.43 (s, 3 H) 1.35 (s, 3 H) 1.31 (s, 3 H) 1.17 (s, 3 H).
Example 143 - 13,14-(Dioxanoyloxypaspalinine (CCCIV)
Figure imgf000104_0001
CCC CCCIV
14(S)-tert-Butoxycarbonyloxypaspalinine (CCC) (10 mg, 0.0182 mmol, 1 eq.) and cyclopropyl amine (0.063 mL, 0.094 mmol, 50 eq.) were added to a 1-dram vial containing DMF (1 mL). The vial was capped and stirred at 50 0C for 96 hours. After this time the reaction was cooled to room temperature, filtered and purified by HPLC. LCMS m/e 476 (M+H). 1H NMR (400 MHz, ACETONITRILE-ds) δ ppm 9.04 (s, 1 H), 7.36 (dd, J=I 8.28, 8.18 Hz, 2 H), 6.98 - 7.10 (m, 2 H), 5.97 (s, 1 H), 5.17 (dd, J=9.22, 7.57 Hz, 1 H), 4.44 (d, J-1.12 Hz, 1 H), 2.62 - 2.91 (m, 4 H), 2.40 - 2.60 (m, 3 H), 1.96 - 2.11 (m, 3 H), 1.43 (s, 3 H), 1.25 (s, 3 H), 1.23 (s, 3 H), 1.16 (s, 3 H).
Example 1 (CCC
Figure imgf000104_0002
Figure imgf000104_0003
A mixture of 14(5)-hydroxypaspalinine (I) (100 mg, 0.22 mmol, 1 eq) and zinc powder (220 mg, 3.36 mmol, 15.3 eq) in absolute ethanol (5 mL) was treated with glacial acetic acid (1 mL). The mixture was then stirred and heated at 45 0C for 2 hours. The mixture was then cooled to room temperature and decanted into a saturated brine solution (10 mL). The remaining solid was then washed with ethyl acetate (10 mL). The liquids were then combined and made basic by the careful addition of a 1 M sodium bicarbonate solution. The aqueous phase was then washed three times with ethyl acetate (10 mL each wash). The organic fractions were combined and dried over sodium sulfate. The solution was filtered and concentrated in vacuo. The crude product was then subjected to purification using a 2 g silica SPE cartridge eluted with 9:1, 7:1, 4:1, 3:1, 2:1, 1 :1 and 0:1 hexane/ethyl acetate. Purification resulted in the isolation of compound CCCV. 1H NMR (300 MHz, ACETONITRILE-di) δ ppm 8.96 (s, 1 H), 7.26 - 7.36 (m, 2 H), 6.92 - 7.04 (m, 2 H), 4.45 - 4.57 (m, 1 H), 3.94 - 4.08 (m, 4 H), 3.39 - 3.50 (m, 1 H), 3.03 (d, J=5.92 Hz, 1 H), 2.88 - 3.01 (m, 1 H), 2.65 (dd, J=13.43, 6.52 Hz, 1 H), 2.17 - 2.39 (m, 3 H), 1.95 - 2.15 (m, 2 H), 1.77 - 1.93 (m, 3 H), 1.31 (s, 3 H), 1.13 - 1.21 (m, 8 H), 0.89 - 0.93 (m, 3 H).
It was found that compound CCCV was not stable and had to be carried on to the next step directly. Compound CCCV (25 mg, 0.058 mmol, 1 eq) was dissolved in dichloromethane (2 mL) and triethylamine (0.023 mL, 0.165 mmol, 2.8 eq) was added. The mixture was stirred and methanesulfonyl chloride (0.0085 mL, 0.11 mmol, 1.9 eq) was added. Stirring was continued at room temperature for one hour. The reaction was then concentrated under a stream of nitrogen. The crude material was purified using a 1 g silica SPE cartridge loaded with methylene chloride/hexane. The column was eluted with 7:1 hexane/ethyl acetate. LCMS m/e 416 (M+H). 1H NMR (300 MHz, ΛCETONITRILE-d3) δ ppm 9.12 (s, 1 H), 7.31 - 7.42 (m, 2 H), 6.96 - 7.09 (m, 2 H), 6.43 (dd, J=5.20, 2.76 Hz, 1 H), 6.06 (d, J=0.44 Hz, 1 H), 4.33 (d, J=I.22 Hz, 1 H), 2.90 - 3.04 (m, 1 H), 2.73 - 2.84 (m, 1 H), 2.26 - 2.59 (m, 4 H), 2.08 - 2.13 (m, 1 H), 1.96 - 2.05 (m, 1 H), 1.76 - 1.91 (m, 1 H), 1.42 (s, 3 H), 1.18 - 1.23 (m, J=3.43 Hz, 6 H), 1.04 (s, 3 H).
Example 145
Figure imgf000105_0001
I CCCVII
Additional literature references: Tet. 55 (1999) 11095-11108; JOC (1999) 64, 4607-4609. In a 50 mL round bottom flask with stirring was added 14-hydroxypaspalinine (I) (200 mg, 0.44 mmol, 1 eq) and a 1,4-dioxane/water mixture (10 mL, 95:5). The flask was flushed with nitrogen, hi a 25 mL round bottom flask was combined 2,3-dichloro-5,6-dicyano-p- benzoquinone (DDQ) (200 mg, 0.89 mmol, 2 eq) and dry 1,4-dioxane (3 mL) under nitrogen. The DDQ solution was then added dropwise over a period of approximately 20 minutes to the flask containing the starting material. After the addition of the DDQ solution was complete, the reaction was allowed to stir overnight at room temperature. After this time the reaction mixture was filtered through a pad of silica gel and rinsed with ethyl acetate (150 mL). The organic filtrate was washed two times with a saturated sodium bicarbonate solution and one time with a saturated brine solution. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. The material was purified by HPLC. LCMS m/e 464 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 7.64 - 7.70 (m, 1 H), 7.44 - 7.50 (m, 1 H), 7.15 - 7.26 (m, 2 H), 6.16 (d, J=1.27 Hz, 1 H), 4.32 (d, J=1.32 Hz, 1 H), 4.17 (dd, J=10.45, 5.56 Hz, 1 H), 3.69 (s, 1 H), 3.31 (dd, J=13.11, 1.93 Hz, 1 H), 2.71 - 2.83 (m, 1 H), 2.55 - 2.65 (m, 1 H), 2.25 (dd, J=5.54, 2.37 Hz, 1 H), 1.96 - 2.01 (m, 1 H), 1.77 - 1.92 (m, 2 H), 1.60 (s, 3 H), 1.40 (s, 3 H), 1.22 (s, 3 H), 1.13 (s, 3 H).
Example 146 - 14(5)-Hydroxypaspalin-10-exo-ene (CCCVIII)
Figure imgf000106_0002
Figure imgf000106_0001
I CCCVII
In a 100 mL round bottom flask was added 14-hydroxypaspalinine I (45 mg, 0.1 mmol, 1 eq) and methyl triphenylphosphonium bromide (143 mg, 0.4 mmol, 4 eq) and THF (2 mL). The mixture was treated with potassium tert-butoxϊde (45 mg, 0.4 mmol, 4 eq). The resulting mixture was stirred at 50 0C for one hour. The reaction was cooled to room temperature and concentrated under a stream of nitrogen. The residue was taken up in water and extracted three times with ether (1 mL aliquots). The ether fractions were combined and concentrated under a stream of nitrogen. The crude material was purified using a 1 g silica SPE cartridge eluted with 5:1 hexane/ethyl acetate. The isolated product, following concentration, was triturated with acetonitrile (2 mL). LCMS m/e 470 (M+Na). 1H NMR (400 MHz, ACETONE-d6) δ ppm 9.69 (s, 1 H), 7.27 - 7.36 (m, 2 H), 6.90 - 7.00 (m, 2 H), 6.50 (s, 1 H), 4.97 - 5.03 (m, 1 H), 4.90 - 4.95 (m, 1 H), 4.50 (s, 1 H), 4.19 - 4.31 (m, 1 H), 3.35 (d, J=2.19 Hz, 1 H), 2.52 - 2.96 (m, 6 H), 2.40 (dd, J=13.04, 10.71 Hz, 1 H), 1.96 - 2.03 (m, 2 H), 1.73 - 1.93 (m, 2 H), 1.39 (s, 3 H), 1.30 (s, 3 H), 1.28 (s, 3 H), 1.15 (s, 3 H).
Example 147 - 10(S)-(Oxaspiro)-14(S)-hydroxypaspalinine (CCCIX)
Figure imgf000106_0003
I CCCIX In a 1-dram vial was added trimethylsulphoxonium iodide (16.5 mg, 0.075 mmol, 1.5 eq) and THF (1 mL). Potassium tert-butoxide (8.4 mg, 0.075 mmol, 1.5 eq) was added to the solution. 14-Hydroxypaspalinine I (22 mg, 0.05 mmol, 1 eq) was then added to the mixture and the reaction was stirred at room temperature for 72 hours. After this time the reaction was treated with a mixture of water (0.75 mL) and acetic acid (1 drop). The reaction was then extracted two times with hexanes (1.5 mL aliquots). The combined hexanes fractions were then washed one time with water (1 mL) and then concentrated under a stream of nitrogen. The crude product was then triturated with acetonitrile (2 mL). LCMS m/e 486 (M+Na). 1H NMR (500 MHz, ACETONE-de) δ ppm 9.69 (s, 1 H), 7.27 - 7.34 (m, 2 H), 6.91 - 6.99 (m, 2 H), 5.65 (s, 1 H), 4.21 - 4.28 (m, 2 H), 3.66 (d, J=LQl Hz, 1 H), 3.39 - 3.42 (m, 1 H), 2.85 - 2.95 (m, 2 H), 2.71 - 2.81 (m, 2 H), 2.63 - 2.70 (m, 2 H), 2.57 (dd, J=12.59, 10.38 Hz, 1 H), 2.40 (dd, J=12.97, 10.76 Hz, 1 H), 1.95 - 2.03 (m, 2 H), 1.83 - 1.93 (m, 1 H), 1.79 (dd, J=I 2.55, 8.66 Hz, 1 H), 1.43 (s, 3 H), 1.38 (s, 3 H), 1.31 (s, 3 H), 1.24 (s, 3 H).
Example 148 - 10-(Carbomethoxymethylene)-14-(5)-hydroxypaspalinine (CCCX)
Figure imgf000107_0001
I CCCX
14-Hydroxypaspalinine (I) (60 mg, 0.134 mmol, 1 eq) and (carbomethoxymethylene)- triphenylphosphorane (80 mg, 0.239 mmol, 2 eq) were added to a one dram vial containing xylene (1 mL). The vial was capped and the reaction was stirred at 130 0C for 6 hours. The reaction was then cooled to room temperature and the reaction was directly purified using a 2 g SPE cartridge and eluting with 4:1, 3:1 and then 2:1 hexanes/ethyl acetate. The material was then re-purified, this time by HPLC. The clean product was then crystallized from acetonitrile (0.5 mL). LCMS m/e 506(M+H). 1H NMR (400 MHz, ACETONITRILE-di) δ ppm 8.89 (s, 1 H), 7.28 - 7.37 (m, 2 H), 6.95 - 7.04 (m, 2 H), 6.45 (s, 1 H), 5.82 (s, 1 H), 5.74 (s, 1 H), 4.14 - 4.22 (m, 1 H), 3.68 (s, 3 H), 3.25 (s, 1 H), 2.78 - 2.90 (m, 1 H), 2.52 - 2.75 (m, 3 H), 2.39 (dd, J-13.15, 10.67 Hz, 1 H), 2.10 (s, 1 H), 1.72 - 1.92 (m, 2 H), 1.40 (s, 3 H), 1.32 (s, 3 H), 1.19 (s, 3 H), 1.12 (s, 3 H).
Example 149 - 10(5)-Methyl-14(5)-hydroxypaspalinine
Figure imgf000107_0003
Figure imgf000107_0002
CCCVIII CCCXI To a solution of 14(5)-Hydroxypaspalin-10-exo-ene (14 mg, 0.031 mmol, 1 eq) (CCCVIII) in ethanol (5 mL) was added 10% Palladium on Carbon (3 mg, 0.2 eq) and ammonium formate (10 mg, 0.16 mmol, 5 eq). The reaction was heated to reflux and stirred overnight. After this time the reaction was cooled to room temperature and filtered. The reaction was purified by HPLC. LCMS m/e 448(M-H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 6.84 - 6.96 (m, 2 H), 6.50 (t, J=7.15 Hz, 1 H), 6.42 (d, J=7.76 Hz, 1 H), 6.01 (s, 1 H), 5.45 (s, 1 H), 4.33 (s, 1 H), 4.12 (d, J=I 1.23 Hz, 1 H), 3.92 - 4.06 (m, 2 H), 3.67 - 3.80 (m, 1 H), 3.28 (d, J=5.08 Hz, 3 H), 2.99 - 3.13 (m, 1 H), 2.82 (d, J=5.17 Hz, 1 H), 2.65 (s, 1 H), 2.27 - 2.37 (m, 1 H), 2.17 - 2.23 (m, 1 H), 1.97 - 2.08 (m, 2 H), 1.72 - 1.83 (m, 1 H), 1.48 - 1.68 (m, 2 H), 1.43 (s, 3 H), 1.32 - 1.42 (m, 2 H), 1.28 - 1.32 (m, 3 H), 1.21 - 1.24 (m, 3 H), 1.15 (d, J=7.96 Hz, 3 H), 0.88 (none, 1 H).
Example 150 -
Figure imgf000108_0001
I CCCXII To a solution of 14-hydroxypaspalinine (50 mg, 0.1 mmol, 1 eq) (I) in a mixture of acetone (1 mL) and toluene (1 mL) was added l,l '-thiocarbonyldiimidazole (90% solution) (0.15 mL, 0.75 mmol, 6.8 eq). The reaction was then refluxed for 48 hours. After this time the reaction was then cooled to room temperature and concentrated in vacuo. The crude material was purified by HPLC. LCMS m/e 446(M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 9.20 (s, 1 H), 7.31 - 7.44 (m, 2 H), 6.98 - 7.11 (m, 2 H), 4.46 (s, 1 H), 3.33 - 3.45 (m, 1 H), 3.28 (d, J=2.73 Hz, 1 H), 3.06 - 3.15 (m, 1 H), 2.86 - 3.00 (m, 2 H), 2.63 - 2.76 (m, 1 H), 2.57 (dd, J=13.57, 10.35 Hz, 1 H), 2.36 - 2.45 (m, 1 H), 2.09 - 2.14 (m, 1 H), 1.92 (s, 1 H), 1.47 (s, 3 H), 1.33 (s, 3 H), 1.16 (s, 3 H), 0.85 (s, 3 H).
Example 151 - 14(5)-Hydroxyl-21-bromopaspalinine (CCCXIII)
Figure imgf000108_0002
I CCCXIII
To a 500 mL round bottom flask containing 14-hydroxypaspalinine (I) (5.3 g, 0.0118 mol, 1 eq.) in pyridine (65 mL) was added bromine (0.66 mL, 0.013 mol, 1.1 eq) in a dropwise manner. The reaction was stirred at room temperature overnight. After this time silica gel (75 g) was added and the reaction was concentrated in vacuo. Once completely dry the sample was then placed on a bed of silica gel in a fritted funnel and covered with another layer of silica gel. The sample was then washed with heptane (800 mL). This was followed by a washing with a mixture of 25% acetone/heptane (1.8 L). The organic fractions were combined and concentrated to give crude product (CCCXIII). The crude material was recrystallized from acetone/heptane to provide product. 1H NMR indicated a small (~7%) impurity, the 23-Br regio-isomer. The 23-Br regio- isomer was removed by HPLC (Dynamax C-18 prep column, pore=60 A, L=25 cm, ID=41.4 mm) (isocratic 65% methanol, 160 minute run, 35 mL/min, 10% THF added to water and methanol source, 0.5 g injection in 4 mL to provide pure product (CCCXIH). 1H NMR (400 MHz, ACETONITRILE-di) δ ppm 9.07 (s, 1 H), 7.46 (d, J=I.76 Hz, 1 H), 7.27 (d, J=8.40 Hz, 1 H), 7.11 (dd, J=8.40, 1.81 Hz, 1 H), 6.16 (s, 1 H), 4.31 (d, J=I.32 Hz, 1 H), 4.18 - 4.26 (m, 1 H), 3.53 (s, 1 H), 3.42 (d, J=3.76 Hz, 1 H), 2.56 - 2.89 (m, 5 H), 2.39 (dd, J=13.30, 10.71 Hz, 1 H), 1.75 - 1.87 (m, 2 H), 1.40 (s, 3 H), 1.33 (s, 3 H), 1.17 (s, 3 H), 1.13 (s, 3 H).
Example 152 - (14(5r)-7V-(3-Hydroxy-2,2-dimethyl-propyl))-(21-bromo)-acetamide-paspalinine (CCCXV)
Figure imgf000109_0001
Preparation of compound CCCXIV proceeded by combining compound CCCXIII (200 mg, 0.38 mmol, 1 eq), dibutyl tin oxide (0.28 g, 1.1 mmol, 3 eq) and 4 Angstrom powdered molecular sieves (400 mg, based on 2 x wt. of starting material) in a 40 mL vial containing a magnetic stir bar. Anhydrous THF (8 mL) and anhydrous toluene (8 mL) were added to the vial. The reaction vial was capped and stirred at 75 0C for three hours. After this time methyl bromoacetate (0.18 mL, 1.9 mmol, 5 eq) and tetrabutylammonium bromide (370 mg, 1.1 mmol, 3 eq) were added to the reaction. The reaction was stirred at 75 0C overnight. After this time the reaction was transferred to a 125 mL separatory funnel and diluted with ethyl acetate (100 mL). The solution was washed twice with a 1 : 1 saturated brine/water mixture (50 mL). The organic solution was then washed with a saturated potassium fluoride solution (30 mL). The organic fraction was then concentrated. The residue was then purified by HPLC. LCMS m/e 599 (M-H). 1H NMR (400 MHz, ACETONJTRILE-d3) δ ppm 9.10 (s, 1 H), 7.47 (d, J=I.76 Hz, 1 H), 7.27 (d, J=8.40 Hz, 1 H), 7.11 (dd, J=8.40, 1.81 Hz, 1 H), 6.41 (d, J=1.07 Hz, 1 H), 4.27 - 4.34 (m, 3 H), 4.21 (dd, J=10.74, 5.32 Hz, 1 H), 3.73 (s, 3 H), 3.58 (s, 1 H), 2.71 - 2.81 (m, 2 H), 2.57 - 2.70 (m, 2 H), 2.37 - 2.46 (m, 1 H), 2.19 - 2.27 (m, 1 H), 1.74 - 1.88 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.18 (s, 3 H), 1.14 (s, 3 H). hi a 2 dram vial with a stir bar was added compound CCCXIV (40 mg, 0.067 mmol, 1 eq) and THF (1.5 mL). Neopentanolamine (0.34 g, 3.3 mmol, 50 eq) was then added to the reaction vial and the capped vial was then heated to 45 0C and stirred overnight.
After this time the reaction was cooled to room temperature and diluted with ethyl acetate (5 mL). The reaction was then concentrated and purified by HPLC. LCMS m/e 673 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 9.11 (s, 1 H), 7.47 (d, J=I.56 Hz, 1 H), 7.28 (d, J=8.40 Hz, 1 H), 7.17 - 7.25 (m, 1 H), 7.12 (dd, J=8.42, 1.78 Hz, 1 H), 5.86 (d, J=I.12 Hz, 1 H), 4.34 (d, J=I.12 Hz, 1 H), 4.26 (d, J=14.98 Hz, 1 H), 3.99 - 4.07 (m, 2 H), 3.65 (s, 1 H), 3.03 - 3.21 (m, 3 H), 2.95 (dd, J=13.64, 6.32 Hz, 1 H), 2.58 - 2.87 (m, 4 H), 2.41 (dd, J=13.20, 10.57 Hz, 1 H), 2.19 - 2.29 (m, 2 H), 2.10 (d, J=2.00 Hz, 1 H), 1.74 - 1.92 (m, 2 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.17 (s, 3 H), 1.14 (s, 3 H), 0.83 (s, 3 H), 0.78 (s, 3 H).
Example 153 - 14(5)-Hydroxy-21-methoxycarbonylpaspalinine (CCCXVI)
Figure imgf000110_0001
CCCXIII CCCXVI
21-Bromo-14-hydroxypaspalinine (CCCXIII) (100 mg, 0.189 mmol, 1 eq), triethylamine (0.034 mL, 0.246 mmol, 1.3 eq), [(i?)-(+)-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl]palladium(II) chloride (4.5 mg, 0.006 mmol, 0.03 eq) and methanol (7 mL) were combined in a 22 mL steel pressure vessel with a magnetic stir bar. The system was closed, evacuated under vacuum and then charged with carbon monoxide (50 psi). This step was repeated two more times. The reaction was then stirred under an atmosphere of carbon monoxide (50 psi) at room temperature overnight. After this time the reaction was filtered, concentrated, and purified by HPLC. LCMS m/e 508 (M+H). 1H NMR (400 MHz, ACETONITRILE-d^) δ ppm 9.28 (s, 1 H), 7.96 - 8.00 (m, 1 H), 7.66 (dd, J=8.35, 1.51 Hz, 1 H), 7.40 (d, J=8.35 Hz, 1 H), 6.16 (d, J=I .03 Hz, 1 H), 4.32 (d, J=I.37 Hz, 1 H), 4.16 - 4.24 (m, 1 H), 3.86 (s, 3 H), 3.55 (s, 1 H), 2.59 - 2.90 (m, 4 H), 2.44 (dd, J=13.30, 10.71 Hz, I H), 1.79 - 1.91 (m, 2 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.16 (s, 3 H), 1.14 (s, 3 H).
Example 154 - 14(5)-(Acetamide-N-(3'-hydroxy-2',2'-dimethyl-propyl)-3'-phosphonooxy (bis- triethylammoni
Figure imgf000111_0001
Compound CCCXVII was prepared in the same manner as CXVIII. LCMS m/e 854 (M+H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.27 - 7.41 (m, 12 H), 6.90 - 7.00 (m, 2 H), 5.85 (d, J=1.27 Hz, 1 H), 5.04 - 5.11 (m, 4 H), 4.33 (d, ./=15.03 Hz, 1 H), 4.21 (d, ./=1.27 Hz, 1 H), 3.98 - 4.06 (m, 2 H), 3.67 (d, J=7.86 Hz, 2 H), 3.18 (d, J=13.72 Hz, 1 H), 2.78 - 2.99 (m, 3 H), 2.64 - 2.74 (m, 2 H), 2.43 (dd, ./=13.01, 10.66 Hz, 1 H), 2.21 - 2.29 (m, 1 H), 1.89 - 2.07 (m, 3 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.25 (s, 3 H), 1.14 (s, 3 H), 0.84 (d, J=4.34 Hz, 6 H). Compound CCCXVIII was prepared in the same manner as CXIX. Purification was performed by reverse-phase HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The aqueous phase contained 0.1% EtβN in H2θ. The initial gradient of 5% MeOH:aqueous phase was maintained for 1 minute then ramped up to 100% MeOH:0% aqueous phase over 4.1 minutes. 100% MeOH was maintained for 3.3 more minutes. A flow rate of 28 mL/min. Under these conditions, compound (CCCXVIII) eluted at a retention time of 3.3 minutes. 1H NMR (400 MHz, METHANOL-^) δ ppm 7.98 (s, 1 H), 7.27 - 7.33 (m, 2 H), 6.90 - 7.01 (m, 2 H), 5.85 (d, J=I.17 Hz, 1 H), 4.27 - 4.38 (m, 2 H), 3.92 - 4.07 (m, 2 H), 3.49 - 3.56 (m, 1 H), 3.42 (dd, ./=10.35, 5.81 Hz, 1 H), 3.34 (s, 1 H), 3.12 (q, J=7.35 Hz, 8 H), 2.99 (s, 3 H), 2.90 - 2.98 (m, 1 H), 2.86 (d, J=0.54 Hz, 3 H), 2.62 - 2.83 (m, 3 H), 2.41 (dd, ./=12.84, 10.59 Hz, 1 H), 2.15 - 2.25 (m, 1 H), 1.87 - 2.05 (m, 3 H), 1.43 (s, 3 H), 1.40 (s, 3 H), 1.28 (t, J=7.32 Hz, 9 H), 1.20 (s, 3 H), 1.16 (s, 3 H), 0.93 (s, 3 H), 0.86 (s, 3 H).
Example 155 - 14(5)-(2'-Hydroxy-ethoxy-phosphonooxy (bis-triethylammonium))- ethyloyloxy)paspalinine (CCCXX)
Figure imgf000112_0001
Compound CCCXIX was prepared in the same manner as compound CXVIII. Compound CCCXX was prepared in the same manner as CXIX. LCMS m/e 572 (M-H). 1H NMR (400 MHz, METHANOL-^) δ ppm 7.96 - 7.99 (m, 1 H), 7.27 - 7.33 (m, 2 H), 6.89 - 7.00 (m, 2 H), 6.17 (d, J=1.27 Hz, 1 H), 4.32 (d, J=1.27 Hz, 1 H), 3.94 - 4.08 (m, 4 H), 3.65 - 3.72 (m, 1 H), 3.32 - 3.35 (m, 1 H), 3.10 (q, J=7.29 Hz, 12 H), 2.78 - 2.94 (m, 2 H)3 2.61 - 2.73 (m, 2 H), 2.42 (dd, J=12.93, 10.69 Hz, 1 H), 2.27 - 2.35 (m, 1 H), 1.94 (s, 12 H), 1.90 (s, 2 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.21 - 1.31 (m, 18 H), 1.13 - 1.17 (m, 3 H). Example 15
Figure imgf000112_0002
In a 2-dram vial fitted with a magnetic stir bar was added Pd(dba)2 (9 mg, 0.016 mmol, 0.03 eq) and tncyclohexylphosphine (10 mg, 0.036 mmol, 0.08 eq) in dioxane (3 mL). The reagents were stirred under nitrogen for 30 minutes. Bis-pinacolato borane (140 mg, 0.55 mmol, 1.2 eq), potassium acetate (74 mg, 0.75 mmol, 1.7 eq) and compound CCCXIII (240 mg, 0.45 mmol, 1 eq) were then added and the reaction heated to 80 0C and stirred overnight. The reaction was cooled to room temperature and filtered through a 0.45 micron (nylon disc) syringe filter. The reaction was then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 40:60 MeOHiH2O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re- equilibrated back to 40:60 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 466 (M+H). 1H NMR (400 MHz, ACETONITRILE-Ci3) δ ppm 8.66 (s, 1 H), 7.14 (d, J=8.44 Hz, 1 H), 6.72 (d, J=2.05 Hz, 1 H), 6.53 (dd, J=8.42, 2.22 Hz, 1 H), 6.15 (d, J=0.98 Hz, 1 H), 4.31 (d, J=I.37 Hz, 1 H), 4.15 - 4.25 (m, 1 H), 3.30 - 3.52 (m, 1 H), 2.69 - 2.86 (m, 2 H), 2.55 - 2.65 (m, 2 H), 2.33 (dd, J=13.23, 10.64 Hz, 1 H), 2.06 - 2.14 (m, 2 H), 1.90 (s, 1 H), 1.67 - 1.84 (m, 1 H), 1.39 (s, 3 H), 1.30 (s, 3 H), 1.18 (s, 3 H), 1.13 (s, 3 H)
Example 157 - 14(S)-Hydroxy-21-vinyl-paspalinine (CCCXXVIII)
Figure imgf000113_0001
CCCXIII CCCXXVIII hi a 1-dram vial fitted with a magnetic stir bar was added Pd(dba)2 (5 mg, 0.009 mmol, 0.09 eq) and tricyclohexyl phosphine (5 mg, 0.018 mmol, 0.04 eq) in dioxane (1 mL). The reagents were stirred under nitrogen for 30 minutes. Compound CCCXIII (50 mg, 0.095 mmol, 1 eq) and tributyl(vinyl)tin (0.092 mL, 0.32 mmol, 3.3 eq) were then added to the vial. The reaction vial was sealed and then stirred at 80 0C overnight. The reaction was then cooled to room temperature and filtered through a 0.45 micron (nylon disc) syringe filter. The reaction was then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 40:60 MeOH:H2θ maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 476 (M+H). 1H NMR (400 MHz, ACETONITRlLE-di) δ ppm 8.95 (s, 1 H), 7.26 - 7.37 (m, 2 H), 7.16 (dd, J=8.25, 1.46 Hz, 1 H), 6.80 (dd, J=I 7.62, 10.93 Hz, 1 H), 6.15 (d, J=0.78 Hz, 1 H), 5.69 (dd, J=I 7.60, 1.05 Hz, 1 H), 5.09 (dd, J=10.91, 1.05 Hz, 1 H), 4.31 (d, J=1.37 Hz, 1 H), 4.15 - 4.26 (m, 1 H), 2.54 - 2.89 (m, 4 H), 2.38 (dd, J=13.28, 10.69 Hz, 1 H), 1.89 - 2.00 (m, 3 H), 1.74 - 1.89 (m, 2 H), 1.39 (s, 3 H), 1.33 (s, 3 H), 1.17 (s, 3 H), 1.13 (s, 3 H)
Example 158 - 14(5)-Hydroxy-21 -phenylpaspalinine (CCCXXTX)
Figure imgf000114_0001
CCCXXIX
In a 1-dram vial fitted with a magnetic stir bar was added Pd(dba)2 (5 mg, 0.009 mmol, 0.09 eq) and tricyclohexyl phosphine (5 mg, 0.018 mmol, 0.04 eq) in dioxane (1 mL). The reagents were stirred under nitrogen for 30 minutes. Compound CCCXIII (50 mg, 0.095 mmol, 1 eq) and phenyl boronic acid (0.050 mL, 0.41 mmol, 4.3 eq) and potassium carbonate (13 mg, 0.095 mmol, 1 eq) were then added to the vial. The reaction vial was sealed and then stirred at 80 0C overnight. The reaction was then cooled to room temperature and filtered through a 0.45 micron (nylon disc) syringe filter. The reaction was then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 40:60 MeOHiH2O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 526 (M+H). 1H NMR (400 MHz, ACETONITRILE-di) δ ppm 9.05 (s, 1 H), 7.64 (dd, J=8.30, 1.17 Hz, 2 H), 7.55 (d, J=1.46 Hz, 1 H), 7.38 - 7.46 (m, 4 H), - 7.26 - 7.33 (m, 2 H), 6.18 (s, 1 H), 4.30 (d, J=I.22 Hz, 1 H), 4.22 (dd, J=8.96, 7.10 Hz, I H), 2.58 - 2.96 (m, 4 H), 2.41 (dd, J=13.23, 10.74 Hz, 1 H), 1.94 - 2.00 (m, 3 H), 1.80 - 1.90 (m, 2 H), 1.39 (s, 3 H), 1.35 (s, 3 H), 1.20 (s, 3 H), 1.13 (s, 3 H)
Example 159 - 14(5)-Hydroxy-21 -methoxypaspalinine
Figure imgf000114_0003
Figure imgf000114_0002
CCCXXVII CCCXXX
In a 25 mL round bottom flask fitted with a magnetic stir bar was dissolved compound CCCXXVII (20 mg, 0.043 mmol, 1 eq) in acetone (4 mL). Potassium carbonate (140 mg, 1.01 mmol, 23 eq) and methyl iodide (0.700 mL, 1 1.24 mmol, 261 eq) was added and the reaction was stirred at room temperature for one hour. The reaction was then heated to 60 0C and stirred for four hours. The reaction was concentrated under nitrogen and filtered through a 0.45 micron (nylon disc) syringe filter. The reaction was then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 40:60 MeOH:H2O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 480 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.78 (s, 1 H), 7.23 (d, J=8.59 Hz, 1 H), 6.86 (d, J=2.25 Hz, 1 H), 6.66 (dd, J=8.59, 2.34 Hz, 1 H), 6.17 (s, 1 H), 4.32 (d, J=1.37 Hz, 1 H), 4.19 - 4.27 (m, 1 H), 3.79 (s, 3 H), 2.72 - 2.89 (m, 2 H), 2.57 - 2.68 (m, 2 H), 2.36 (dd, J=13.28, 10.64 Hz, 1 H), 1.91 - 1.99 (m, 3 H), 1.76 - 1.87 (m, 1 H), 1.41 (s, 3 H), 1.32 (s, 3 H), 1.20 (s, 3 H), 1.15 (s, 3 H)
Example 160 - 14(5>Hydroxy-21 -nitropaspalinine (CCCXXXI)
Figure imgf000115_0001
CCCXXXI
In a 15 mL round bottom flask fitted with a magnetic stir bar was added 14-hydroxypaspalinine (I) (200 mg, 0.445 mmol, 1 eq), potassium carbonate (100 mg, 0.0724 mmol, 1.6 eq) and methylene chloride (3 mL). The reaction was purged under nitrogen and cooled to -70 0C. Nitronium tetrafluoroborate (0.5 M solution, 0.3 mL, 0.15 mmol, 0.34 eq) was added and the reaction was stirred under nitrogen at -70 0C for 2.5 hours. After this time ethyl acetate (5 mL) and water (10 mL) were added to the reaction. The organic layer was separated and concentrated. The residue was then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 40:60 MeOH:H2O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 495 (M+H). 1H NMR (400 MHz, ACETOMTRILE-di) δ ppm 9.64 (s, 1 H), 8.24 (d, J=2.05 Hz, 1 H), 7.92 (dd, J=8.83, 2.15 Hz, 1 H), 7.45 (d, J=8.83 Hz, 1 H), 6.17 (s, 1 H), 4.32 (s, 1 H), 4.18 - 4.30 (m, 1 H), 2.60 - 2.96 (m, 4 H), 2.47 (dd, J=13.54, 10.86 Hz, 1 H), 1.96 - 2.21 (m, 3 H), 1.74 - 1.91 (m, 1 H), 1.40 (s, 6 H), 1.19 (s, 3 H), 1.14 (s, 3 H)
Example 161 - 14(5)-Hydroxy-21-cyanopaspalinine (CCCXXXII)
Figure imgf000116_0001
In a 2-dram vial was combined 21-bromo-14-hydroxypaspalinine CCCXIII (99.2 mg, 0.188 mmol, 1 eq), tris(dibenzylideneacetone)dipalladium (3.4 mg, 0.004 mmol, 0.02 eq), (diphenylphosphino)ferrocene (4.2 mg, 0.008 mmol, 0.04 eq), zinc dust (1.5 mg, 0.023 mmol, 0.12 eq) and zinc cyanide (13.2 mg, 0.113 mmol, 0.6 eq) in dimethyl acetamide (2.5 mL). Nitrogen was bubbled through the reaction solution for several minutes and then the vial was capped. The reaction was stirred at 120 0C overnight. After this time the reaction was filtered and purified by HPLC. LCMS m/e 475 (M+H). 1H NMR (400 MRz, ACETONITRILE-CI3) δ ppm 9.45 (s, 1 H), 7.70 (s, 1 H), 7.47 (d, J=8.20 Hz, 1 H), 7.28 (dd, J=8.20, 1.32 Hz, 1 H), 6.16 (s, 1 H), 4.32 (d, J=1.03 Hz, 1 H), 4.17 - 4.25 (m, 1 H), 3.55 (s, 1 H), 3.45 (s, 1 H), 2.58 - 2.92 (m, 4 H), 2.44 (dd, J=13.40, 10.76 Hz, 1 H), 1.78 - 1.91 (m, 1 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.16 (s, 3 H), 1.13 (s, 3 H).
Example
Figure imgf000116_0002
Compound (CCCXXXIII) was made in the same manner as compound (II). LCMS m/e 547 (M+H). 1H NMR (400 MHz, ACETOΗITRILE-di) δ ppm 9.48 (s, 1 H), 7.70 (d, J=0.68 Hz, 1 H), 7.47 (d, J=8.20 Hz, 1 H), 7.28 (dd, J=8.20, 1.37 Hz, 1 H), 6.42 (s, 1 H), 4.28 - 4.35 (m, 3 H), 4.18 - 4.27 (m, 1 H), 3.73 (s, 3 H), 3.60 (d, J=I .07 Hz, 1 H), 2.58 - 2.91 (m, 5 H), 2.42 - 2.48 (m, 1 H), 2.20 - 2.28 (m, 1 H), 1.79 - 1.91 (m, 2 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 1.17 (s, 3 H), 1.14 (s, 3 H).
Example 163 - 14(5)-(2'-Methyl-allyloxy)-21-cyano-paspalinine (CCCXLV)
Figure imgf000117_0001
CCCXXXII CCCXLV
Compound CCCXLV was prepared in the same manner as compound II. LCMS m/e 527 (M- H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 9.47 (s, 1 H)5 7.70 (s, 1 H), 7.47 (d, J=8.15 Hz, 1 H), 7.28 (dd, J=8.20, 1.42 Hz, 1 H), 5.91 (s, 1 H), 5.00 (s, 1 H), 4.88 (s, 1 H), 4.33 (d, J=I .32 Hz, 1 H), 4.23 (d, J=UAO Hz, 1 H), 3.89 - 4.04 (m, 2 H), 3.48 (s, 1 H), 2.57 - 2.90 (m, 4 H), 2.48 (d, J=I 0.64 Hz, 1 H), 2.27 - 2.39 (m, 1 H), 2.06 - 2.12 (m, 1 H), 1.80 - 1.92 (m, 2 H), 1.72 - 1.80 (m, 3 H), 1.40 (d, J=4.64 Hz, 6 H), 1.18 (s, 3 H), 1.13 (s, 3 H).
Example 164 - l-«-Butylcarbamoyl-14(<S)-[(«-butyl)carbamoyloxy]-paspalinine (CCCXLVI)
Figure imgf000117_0002
CCCXLVI
To a 100 mL round bottom flask fitted with a magnetic stir bar was added 14-hydroxypaspalinine (I) (10 mg, 0.0222 mmol, 1 eq.) in THF/toluene (35 mL total, 1 :1 ratio). Dibutyltin oxide (6.6 mg, 0.0267 mmol, 1.2 eq) was added and the mixture was stirred at 75 0C for one hour. The reaction was then cooled to room temperature and tetrabutyl ammonium bromide (3.6 mg, 0.0111 mmol, 0.5 eq) and «-Butyl isocyanate (0.050 mL, 0.00044 mol, 20 eq) were added to the flask. The reaction was stirred at room temperature overnight. After this time the reaction was filtered through a 0.45 micron (nylon disc) syringe filter and concentrated under nitrogen. The sample was then taken up in DMSO and purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 40:60 MeOHiH2O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH:H2θ. Total run time is 8 minutes. LCMS m/e 648 (M+H). 1H NMR (400 MHz, ACETONITRILE-di) δ ppm
7.37 - 7.43 (m, 2 H), 7.06 - 7.21 (m, 2 H), 5.50 - 5.56 (m, 2 H), 5.08 (dd, J=IOAl, 5.80 Hz, 1 H), 4.33 (d, J=I .21 Hz, 1 H), 3.34 - 3.53 (m, 3 H), 3.05 - 3.22 (m, 2 H), 2.87 - 2.99 (m, 1 H), 2.66 - 2.83 (m, 2 H), 2.57 (dd, J=13.76, 9.97 Hz, 1 H), 2.41 (dd, J=13.57, 10.99 Hz, 1 H), 1.96 - 2.12 (m, 4 H), 1.82 - 1.91 (m, 1 H), 1.62 - 1.79 (m, 3 H), 1.41 - 1.53 (m, 5 H), 1.29 - 1.41 (m, 5 H), 1.27 (s, 3 H), 1.13 (s, 3 H), 1.00 (t, J=7.33 Hz, 3 H), 0.93 (t, J=7.28 Hz, 3 H).
Example 165 - l-Bromo-14(5)-hydroxypaspalinine (CCCXLVIII)
Figure imgf000118_0001
CCCXLVIII
To a 1-dram vial fitted with a magnetic stir bar was added 14-hydroxypaspalinine (I) (50 mg, 0.111 mmol, 1 eq.) in methylene chloride (1 mL). 7V-Bromosuccinimide (NBS) (100 mg, 0.56 mmol, 5 eq) and silica gel (0.100 g) were added to the reaction. The reaction was then stirred at room temperature for 6 hours and then concentrated under nitrogen. The sample was then taken up in DMSO, filtered through a 0.45 micron (nylon disc) syringe filter, and purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 40:60 MeOHrH2O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 528 (M+H). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 7.52 - 7.59 (m, 1 H), 7.38 - 7.44 (m, 1 H), 7.32 - 7.38 (m, 1 H), 7.19 - 7.27 (m, 1 H), 6.18 (d, J=I.04 Hz, 1 H), 4.26 - 4.37 (m, 2 H), 3.56 (s, 1 H), 3.52 (d, J=4.09 Hz, 1 H), 3.39 - 3.49 (m, 1 H), 2.68 - 2.83 (m, 2 H), 2.42 (dd, J=13.89, 4.36 Hz, 1 H), 1.96 - 2.03 (m, 2 H), 1.82 - 1.93 (m, 1 H), 1.68 - 1.77 (m, 2 H), 1.52 (s, 3 H), 1.39 (s, 3 H), 1.38 (s, 3 H), 1.16 (s, 3 H).
Example 166 - l-Allyl-14(5)-allylo
Figure imgf000118_0002
CCCXLIX
To a 2-dram vial fitted with a magnetic stir bar was added 14-hydroxypaspalinine (I) (20 mg, 0.0444 mmol, 1 eq.) in THF (3 mL) followed by sodium hydride (60% dispersion in mineral oil, 30 mg, 0.75 mmol, 20 eq) and allyl bromide (0.050 mL, 0.58 mmol, 15 eq). The reaction was stirred at 75 0C for one hour and then at room temperature overnight. After this time, the reaction was quenched by adding water (1 mL) and the reaction was then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 40:60 MeOH:H2O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2θ over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 40:60 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 530 (M+H). 1H NMR (500 MHz, ACETOMTRILE-di) δ ppm 7.36 - 7.45 (m, 1 H), 7.24 - 7.33 (m, 2 H), 7.07 - 7.17 (m, 1 H), 5.92 - 6.05 (m, 1 H), 5.88 - 5.92 (m, 1 H), 5.26 - 5.37 (m, 1 H), 5.04 - 5.21 (m, 2 H), 4.74 - 4.84 (m, 2 H), 4.26 - 4.37 (m, 2 H), 4.01 - 4.12 (m, 2 H), 3.09 - 3.21 (m, 1 H), 2.67 - 2.83 (m, 3 H), 2.46 (dd, J=14.07, 7.11 Hz, 1 H), 2.22 - 2.33 (m, 1 H), 2.06 - 2.11 (m, 1 H), 2.02 (dd, J=I 1.57, 4.61 Hz, 1 H), 1.87 - 1.92 (m, 1 H), 1.62 - 1.74 (m, 2 H), 1.45 - 1.55 (m, 1 H), 1.38 (d, J=3.72 Hz, 6 H), 1.34 (s, 3 H), 1.19 - 1.31 (m, 1 H), 1.15 (s, 3 H), 0.91 (dd, J=14.53, 6.59 Hz, 2 H).
Example 167 - 1 -Propyl- 14(5)-allyloxypaspalinine (CCCLI)
Figure imgf000119_0001
CCCLI
Compound (CCCLI) was prepared in the same manner as compound (CCCL). LCMS m/e 676 (M+H). 1H NMR (500 MHz, ACETONITRILE-d3) δ ppm 7.29 - 7.39 (m, 2 H), 7.04 - 7.13 (m, 1 H), 6.94 - 7.04 (m, 1 H), 5.87 (d, J=I.28 Hz, 1 H), 4.34 (d, J=I.34 Hz, 1 H), 4.14 (t, J=8.24 Hz, 2 H), 3.90 (dd, J=10.65, 5.34 Hz, 1 H), 3.72 - 3.79 (m, 1 H), 3.38 - 3.46 (m, 1 H), 2.72 - 2.91 (m, 3 H), 2.68 (dd, J=13.24, 6.53 Hz, 1 H), 2.35 (dd, J=13.28, 10.96 Hz, 1 H), 2.24 - 2.31 (m, 1 H), 2.06 - 2.10 (m, 1 H), 1.74 - 1.92 (m, 4 H), 1.54 - 1.64 (m, 2 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.27 (s, 3 H), 1.14 (s, 3 H), 1.02 (t, J=7.42 Hz, 3 H), 0.94 (t, J=7.42 Hz, 3 H).
Example 168 - l-Methoxymethyl-14(5)-propyloxypaspalinine (CCCLII)
Figure imgf000119_0002
CCCLII Compound (CCCLII) was prepared in the same manner as compound (CCCL). LCMS m/e 536 (M+H). 1H NMR (500 MHz, ACETONITRILE-d^) δ ppm 7.49 (d, J=8.35 Hz, 1 H), 7.35 - 7.42 (m, 1 H), 7.09 - 7.16 (m, 1 H), 7.01 - 7.09 (m, 1 H), 5.86 (d, J=0.80 Hz, 1 H), 5.42 - 5.53 (m, 2 H), 4.33 (d, J=1.38 Hz, 1 H), 3.89 (dd, J=10.63, 5.26 Hz, 1 H), 3.71 - 3.79 (m, 1 H), 3.37 - 3.46 (m, 1 H), 3.23 (s, 3 H), 2.77 - 2.89 (m, 2 H), 2.64 - 2.74 (m, 2 H), 2.36 (dd, J=13.48, 10.97 Hz, 1 H), 2.24 - 2.32 (m, 1 H), 1.99 - 2.08 (m, 1 H), 1.76 - 1.92 (m, 2 H), 1.55 - 1.64 (m, 2 H), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.25 (s, 3 H), 1.14 (s, 3 H), 0.94 (t, J=7.42 Hz, 3 H)
Example 169 - 1 -Acetyl- Mrø-propyloxypaspalinine (CCCLIII)
Figure imgf000120_0001
CCCLIII
To a 50 mL round bottom flask under nitrogen fitted with a magnetic stir bar was added 14(5)- propyloxypaspalinine (IV) (25 mg, 0.051 mmol, 1 eq) and anhydrous THF (2.5 mL). While stirring vigorously, potassium t-butoxide (17 mg, 0.14 mmol, 3 eq) was added to the flask followed by the addition of acetyl chloride (0.011 mL, 0.15 mmol, 3 eq). The reaction was stirred at room temperature for 4 hours and then quenched by the addition of saturated solution of ammonium chloride (5 mL). The solution was extracted three times with ethyl acetate (10 mL). The organic fractions were combined and concentrated. The residue was then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 70:30 MeOH:H2O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 70:30 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 534 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 7.62 (dd, J=7.27, 1.17 Hz, 1 H), 7.40 - 7.45 (m, 1 H), 7.16 - 7.26 (m, 2 H), 5.81 (d, J=0.78 Hz, 1 H), 4.29 (d, J=1.32 Hz, 1 H), 3.81 (dd, J=10.59, 5.37 Hz, 1 H), 3.69 - 3.77 (m, 1 H), 3.35 - 3.44 (m, 1 H), 2.54 - 2.83 (m, 7 H), 2.39 - 2.48 (m, 1 H), 2.19 - 2.26 (m, 1 H), 1.77 - 1.90 (m, 3 H), 1.46 - 1.63 (m, 6 H), 1.37 (s, 3 H), 1.15 (s, 3 H), 1.10 (s, 3 H), 0.88 - 0.96 (m, 3 H)
Example - 170 l-(3-Hydroxypropyloxycarbonyl)-14(5)-propyloxypaspalinine (CCCLVII)
Figure imgf000121_0001
CCCLVII
To a 1-dram vial fitted with a magnetic stir bar was added a solution of phosgene (20% in toluene) in CH2Cl2 (0.140 mL, 0.26 mmol, 5 eq). Pyridine (0.05 mL, 0.62 mmol, 12 eq) was then added, followed by H^-propyloxypaspalinine (IV) (25 mg, 0.051 mmol, 1 eq). The reaction was stirred at room temperature overnight. 1,3 -propanediol (0.037 mL, 0.52 mmol, 10 eq) was then added and the reaction was stirred at 45 0C for 3 h. The reaction was then concentrated under nitrogen and then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 50:50 MeOHiH2O maintained for 0.5 minutes and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 50:50 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 594 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 7.51 (d, J=7.76 Hz, 1 H), 7.31 - 7.41 (m, 2 H), 7.14 - 7.20 (m, 1 H), 5.85 (s, 1 H), 4.32 (d, J=0.98 Hz, 1 H), 4.00 - 4.08 (m, 1 H), 3.92 (dd, J=10.35,.5.37 Hz, 1 H), 3.79 - 3.87 (m, 1 H), 3.68 - 3.77 (m, 1 H), 3.51 (s, 1 H), 3.37 - 3.46 (m, 1 H), 3.12 (q, J=6.05 Hz, 2 H), 2.70 - 2.83 (m, 3 H), 2.58 - 2.69 (m, 1 H), 2.40 (t, J=5.37 Hz, 1 H), 2.26 - 2.34 (m, 1 H), 2.15 (s, 2 H), 1.87 - 1.92 (m, 1 H), 1.55 - 1.75 (m, 4 H), 1.44 - 1.54 (m, 3 H), 1.42 (s, 3 H), 1.38 (s, 3 H) 1.26 (s, 3 H), 1.13 (s, 3 H), 0.92 (t, J=7.42 Hz, 3 H).
Example 171 - l-[(3'-(7V,N-Dimethylaminoacetoxy)-propyloxy)-carbonyl]-14(S)- propyloxypaspalinine (CCCLVIII)
Figure imgf000121_0002
CCCLVIII
To a 1-dram vial fitted with a magnetic stir bar was added l-(3-Hydroxypropyloxycarbonyl)- 14(S)-PrOPyIoXyPaSPaI inine (CCCLVII) (35 mg, 0.059 mmol, 1 eq) and 1, 4-dioxane (2 mL). Dicyclohexylcarbodiimide (70 mg, 0.34 mmol, 6 eq), dimethyl aminopyridine (15 mg, 0.13 mmol, 2 eq), and ΛyV-dimethyl glycine (13 mg, 0.13 mmol, 2 eq) was added to the vial. The reaction was stirred at room temperature for 72 hours. The reaction was then concentrated under nitrogen and then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 Cg column. The purification method starts with 60:40 MeOH:H2O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re- equilibrated back to 60:40 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 679 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 7.50 (d, J=7.76 Hz, 1 H), 7.31 - 7.40 (m, 2 H), 7.11 - 7.20 (m, 1 H), 5.85 (d, J=1.03 Hz, 1 H), 4.32 (d, J=I.37 Hz, 1 H), 4.01 - 4.10 (m, 1 H), 3.93 (dd, J=10.30, 5.37 Hz, 1 H), 3.77 - 3.85 (m, 1 H), 3.66 - 3.76 (m, 3 H), 3.37 - 3.47 (m, 1 H), 3.05 (s, 2 H), 2.56 - 2.84 (m, 4 H), 2.27 - 2.36 (m, 1 H), 2.23 (s, 6 H), 1.87 - 1.93 (m, 1 H), 1.46 - 1.77 (m, 7 H), 1.42 (s, 3 H), 1.38 (s, 3 H), 1.25 (s, 3 H), 1.13 (s, 3 H), 0.92 (t, J=7.39 Hz, 3 H)
Example 172 - 14-(S>((4'-cyano)-butyloxy)-21-bromopaspalinine (CCCXCI)
Figure imgf000122_0001
CCCXCI
Compound (CCCXCI) was prepared from I in the same manner as compound (XXVII) and isolated as a byproduct. LCMS m/e 609 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 9.1 (s, 1 H), 7.5 (d, J=I.66 Hz, 1 H), 7.3 (d, J=8.40 Hz, 1 H), 7.1 (dd, J=8.40, 1.85 Hz, 1 H), 5.8 (d, J=0.98 Hz, 1 H), 4.3 (d, J=I .27 Hz, 1 H), 3.7 - 3.9 (m, 2 H), 3.4 - 3.6 (m, 2 H), 2.5 - 2.9 (m, 4 H), 2.3 - 2.5 (m, 3 H), 2.2 - 2.3 (m, 1 H), 1.6 - 1.9 (m, 6 H), 1.4 (s, 3 H), 1.3 (s, 3 H), 1.1 - 1.2 (m, J=2.15 Hz, 6 H)
Example 173 - 14(5)-Isopropylcarbamoyloxy-21-bromopaspalinine (CCCXCII)
Figure imgf000122_0002
CCCXCH Compound (CCCXCII) was prepared from (CCCXIII) in the same manner as compound CCXIV. LCMS m/e 613 (M+H). 1H NMR (400 MHz, ACETOΗlTBJLE-di) δ ppm 9.1 (s, 1 H), 7.4 - 7.5 (m, 1 H), 7.3 (d, J=8.40 Hz, 1 H), 7.1 (dd, J=8.40, 1.81 Hz, 1 H), 5.5 (s, 1 H), 5.4 (s, 1 H), 5.1 (s, 1 H), 4.4 (s, 1 H), 3.7 (s, 1 H), 3.4 (s, 1 H), 2.5 - 3.0 (m, 4 H), 2.4 (dd, 1 H), 1.7 - 1.9 (m, 1 H), 1.3 - 1.5 (m, J=14.35 Hz, 6 H), 1.2 (s, 3 H), 1.1 - 1.2 (m, 9 H).
Example 174 - l-(Hydroxymethyl)-14-(S)-propyloxy paspalinine (CCCXCVII)
Figure imgf000123_0001
CCCXCVII
To a solution of 14(5)-propyloxy paspalinine (IV) (0.200 g, 0.407 mmol, 1 eq.) in THF (20 mL) was added formaldehyde (0.200 mL, 37% in water) and 5 drops of 50% aqueous NaOH solution. The mixture was stirred at room temperature overnight. More formaldehyde (0.200 mL, 37% in water) was added and the reaction mixture was stirred at room temperature for an additional 48 h. The reaction was then concentrated under nitrogen and then purified via chromatography on silica gel (gradient: 0 to 25% ethyl acetate in heptane). LCMS m/e 492 (M-CHO); 1H NMR (400 MHz, ACETONITRILE-di) δ ppm 7.43 (d, J=8.24 Hz, 1 H), 7.38 (d, J=7.68 Hz, 1 H), 7.09 - 7.16 (m, 1 H), 7.02 - 7.08 (m, 1 H), 5.86 (d, J=0.76 Hz, 1 H), 5.66 (dd, J=I 1.89, 5.71 Hz, 1 H), 5.49 (dd, J=I 1.88, 7.84 Hz, 1 H), 4.33 (d, J=I .32 Hz, 1 H), 4.24 (dd, J=7.81, 5.72 Hz, 1 H), 3.89 (dd, J=10.62, 5.29 Hz, 1 H), 3.71 - 3.79 (m, 1 H), 3.52 (s, 1 H), 3.38 - 3.46 (m, 1 H), 2.78 - 2.91 (m, 2 H), 2.65 - 2.75 (m, 2 H), 2.36 (dd, J=13.40, 10.98 Hz, 1 H), 2.24 - 2.31 (m, 1 H), 2.05 - 2.13 (m, 1 H), 1.75 - 1.92 (m, 2 H), 1.54 - 1.65 (m, 2 H), 1.41 (s, 3 H), 1.37 (s, 3 H), 1.28 (s, 3 H), 1.14 (s, 3 H), 0.94 (t, J=7.41 Hz, 3 H).
Example 175 - l-(«-Propylcarbamoyloxymethyl)-14-(5)-propyloxypaspalinine (CCCXCVIII)
Figure imgf000123_0002
CCCXCVIII
To a solution of l-(Hydroxymethyl)-14-(S)-propyloxypaspalinine (CCCXCVII) (64 mg, 0.123 mmol, 1 eq.) in THF (10.00 niL) was added DMAP (0.7 mg, 0.006 mmol, 0.05 eq.) and propyl isocyanate (0.023 mL, 0.246 mmol, 2.0 eq.). The mixture was refluxed for 48 h. The reaction was then concentrated under nitrogen and then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 Cg column. The purification method starts with 60:40 MeOH:H2O maintained for 0.5 minute and is ramped up to 100:0 MeOH:H2θ over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 60:40 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 607 (M+H). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 7.52 (d, J=8.15 Hz, 1 H), 7.36 - 7.40 (m, 1 H), 7.11 - 7.17 (m, 1 H), 7.05 - 7.10 (m, 1 H), 6.11 (s, 2 H), 5.85 (d, J=I.17 Hz, 1 H), 5.72 (s, 1 H), 4.33 (d, J=I .17 Hz, 1 H), 3.87 (dd, J=I 0.62, 5.25 Hz, 1 H), 3.71 - 3.79 (ra, 1 H), 3.54 (s, 1 H), 3.38 - 3.46 (m, 1 H), 2.96 - 3.09 (m, 2 H), 2.65 - 2.89 (m, 4 H), 2.36 (dd, J=13.47, 11.03 Hz, 1 H), 2.24 - 2.31 (m, 1 H), 1.75 - 1.92 (m, 3 H), 1.54 - 1.65 (m, 2 H), 1.42 - 1.50 (m, 2 H), 1.37 - 1.42 (m, 6 H), 1.27 (s, 3 H), 1.14 (s, 3 H), 0.94 (t, J=7.39 Hz, 3 H), 0.86 (t, J=7.42 Hz, 3 H).
Example 176 - 14-(5)-((4'-cyano)-butyloxy)paspalimne (XXVII)
Figure imgf000124_0001
XXVII
Compound prepared using similar procedure to that of (II). LCMS m/e 553 (M+Na). (XXVII) isolated. 1H NMR (400 MHz, ACETONITRILE-d3) δ (ppm): 8.92 (s, 1 H), 7.29 - 7.37 (m, 2 H), 6.96 - 7.05 (m, 2 H), 5.83 (d, J=I.02 Hz, 1 H), 4.33 (d, J=I.27 Hz, 1 H), 3.90 (dd, J=10.47, 5.34 Hz, 1 H), 3.77 - 3.84 (m, 1 H), 3.49 - 3.54 (m, 1 H), 3.48 (s, 1 H), 2.58 - 2.84 (m, 4 H), 2.38 - 2.46 (m, 3 H), 2.26 - 2.32 (m, 1 H), 1.77 - 1.91 (m, 3 H), 1.67 - 1.74 (m, 2 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.27 (s, 2 H), 1.18 (s, 3 H), 1.14 (s, 3 H).
Example 177 - 14(5>[2'-(Methoxycarbonyl)-ethyloxy]-21-bromo-paspalinine (CCCXXII)
Compound (CCCXXII) was prepared in the same manner as compound (II). LCMS m/e 599 (M-H). CCCXXII isolated. 1H NMR (400 MHz, ΛCETONITRILE-di) δ ppm 9.09 (s, 1 H), 7.47 (d, J=I.76 Hz, 1 H), 7.27 (d, J=8.44 Hz, 1 H), 7.1 1 (dd, J=8.40, 1.81 Hz, 1 H), 6.41 (d, J=I .03 Hz, 1 H), 4.28 - 4.34 (m, 3 H), 4.21 (dd, J=10.74, 5.32 Hz, 1 H), 3.73 (s, 3 H), 3.58 (s, 1 H), 2.71 - 2.81 (m, 2 H), 2.57 - 2.70 (m, 2 H), 2.42 (dd, J=13.25, 10.57 Hz, 1 H), 2.19 - 2.26 (m, 1 H), 2.11 (d, J=4.93 Hz, 1 H), 1.74 - 1.92 (m, 3 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.18 (s, 3 H), 1.14 (s, 3 H).
Example 178 - 14(5)-(2'-Hydroxy-ethoxy-phosphono-oxy (bis-triethylammonium))- ethyloyloxy)-21 -(cyano)-paspalinine (CCCXLIII)
Figure imgf000125_0002
Compound (CCCXLII) was prepared in the same manner as compound (CXVIII). LCMS m/e 779 (M+H). Amount of (CCCXLII) isolated: 0.1355 g (0.174 mmol, yield = 60%). 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 9.47 (s, 1 H), 7.68 - 7.72 (m, 1 H), 7.25 - 7.50 (m, 12 H), 5.95 (s, 1 H), 4.89 - 5.09 (m, 6 H), 4.26 - 4.33 (m, 1 H), 4.08 - 4.25 (m, 3 H), 4.05 (s, 1 H), 3.98 (dd, J=10.35, 5.22 Hz, 1 H), 3.85 - 3.94 (m, 1 H), 3.39 - 3.71 (m, 2 H), 2.56 - 2.88 (m, 5 H), 2.43 (dd, J=13.11, 10.62 Hz, 1 H), 2.21 - 2.30 (m, 1 H), 2.00 (d, J=2.15 Hz, 1 H), 1.74 - 1.93 (m, 2 H), 1.39 (s, 3 H), 1.36 (s, 3 H), 1.16 (s, 3 H), 1.10 - 1.14 (m, 3 H). Compound (CCCXLIII) was prepared in the same manner as (CXIX). LCMS m/e 597 (M-H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.66 (d, J=0.78 Hz, 1 H), 7.44 (d, J=8.15 Hz, 1 H), 7.22 (dd, J=8.22, 1.39 Hz, 1 H), 6.18 (d, J=I .27 Hz, 1 H), 4.33 (d, J=I .17 Hz, 1 H), 3.93 - 4.08 (m, 5 H), 3.65 - 3.73 (m, 1 H), 3.19 (q, J=7.34 Hz, 12 H), 2.82 - 2.93 (m, 2 H), 2.62 - 2.78 (m, 2 H), 2.47 (dd, J=I 3.13, 10.74 Hz, 1 H), 2.28 - 2.37 (m, 1 H), 1.89 - 2.03 (m, 4 H), 1.40 - 1.45 (m, J=6.44 Hz, 6 H), 1.31 (t, J=7.32 Hz, 18 H), 1.23 (s, 3 H), 1.14 (s, 3 H).
Example 179 - l-(Hydroxymethyl)-14-(S)-propyloxy paspalinine (CCCXCVII)
Figure imgf000126_0001
CCCXCVII
To a solution of 14(5)-propyloxy paspalinine (IV) (0.200 g, 0.407 mmol, 1 eq.) in THF (20 mL) was added formaldehyde (0.200 mL, 37% in water) and 5 drops of 50% aqueous NaOH solution. The mixture was stirred at room temperature overnight. More formaldehyde (0.200 mL, 37% in water) was added and the reaction mixture was stirred at room temperature for an additional 48 hours. The reaction was then concentrated under nitrogen and then purified via chromatography on silica gel (gradient: 0 to 25% ethyl acetate in heptane) to provide (CCCXCVII): LCMS m/e 492 (M-CHO); 1R NMR (400 MHz, ACETONITIULE-ds) δ ppm 7.43 (d, J=8.24 Hz, 1 H), 7.38 (d, J=7.68 Hz, 1 H), 7.09 - 7.16 (m, 1 H), 7.02 - 7.08 (m, 1 H), 5.86 (d, J=0.76 Hz, 1 H), 5.66
(dd, J=I 1.89, 5.71 Hz,"l H), 5.49 (dd, J=I 1.88, 7.84 Hz, 1 H), 4.33 (d, J=I .32 Hz, 1 H), 4.24 (dd, J=7.81, 5.72 Hz, 1 H), 3.89 (dd, J=10.62, 5.29 Hz, 1 H), 3.71 - 3.79 (m, 1 H), 3.52 (s, 1 H), 3.38 - 3.46 (m, 1 H), 2.78 - 2.91 (m, 2 H), 2.65 - 2.75 (m, 2 H), 2.36 (dd, J=13.40, 10.98 Hz, 1 H), 2.24 - 2.31 (m, 1 H), 2.05 - 2.13 (m, 1 H), 1.75 - 1.92 (m, 2 H), 1.54 - 1.65 (m, 2 H), 1.41 (s, 3 H), 1.37 (s, 3 H), 1.28 (s, 3 H), 1.14 (s, 3 H), 0.94 (t, J=7.41 Hz, 3 H).
Example 180 - l-(«-Propylcarbamoyloxymethyl)-14-(5)-propyloxypaspalinine (CCCXCVIII)
Figure imgf000126_0002
CCCXCVIII To a solution of l-(hydroxymethyl)-14-(S)-propyloxy paspalinine (CCCXCVII) (64 mg, 0.123 mmol, 1 eq.) in THF (10.00 mL) was added DMAP (0.7 mg, 0.006 mmol, 0.05 eq.) and propyl isocyanate (0.023 mL, 0.246 mmol, 2.0 eq.). The mixture was refluxed for 48 h. The reaction was then concentrated under nitrogen and then purified via HPLC using a 50 mm Varian Dynamax HPLC 21.4 mm Microsorb Guard-8 C8 column. The purification method starts with 60:40 MeOHiH2O maintained for 0.5 minute and is ramped up to 100:0 MeOHiH2O over approximately 5 minutes (i.e.; total time to 100% MeOH is 5.2 minutes). 100% MeOH is maintained for 2 more minutes before it is re-equilibrated back to 60:40 MeOH:H2O. Total run time is 8 minutes. LCMS m/e 607 (M+H). 1H NMR (400 MHz, AC ETONITRILE-d3) δ ppm 7.52 (d, J=8.15 Hz, 1 H), 7.36 - 7.40 (m, 1 H), 7.11 - 7.17 (m, 1 H), 7.05 - 7.10 (m, 1 H), 6.11 (s, 2 H), 5.85 (d, J=I.17 Hz, 1 H), 5.72 (s, 1 H), 4.33 (d, J=I .17 Hz, 1 H), 3.87 (dd, J=10.62, 5.25 Hz, 1 H), 3.71 - 3.79 (m, 1 H), 3.54 (s, 1 H), 3.38 - 3.46 (m, 1 H), 2.96 - 3.09 (m, 2 H), 2.65 - 2.89 (m, 4 H), 2.36 (dd, J=13.47, 11.03 Hz5 1 H), 2.24 - 2.31 (m, 1 H), 1.75 - 1.92 (m, 3 H), 1.54 - 1.65 (m, 2 H), 1.42 - 1.50 (m, 2 H), 1.37 - 1.42 (m, 6 H), 1.27 (s, 3 H), 1.14 (s, 3 H), 0.94 (t, J=7.39 Hz, 3 H), 0.86 (t, J=7.42 Hz, 3 H).
FUNCTIONAL ASSAYS
A. Maxi-K Channel
The activity of the compounds can also be quantified by the following assay. The identification of inhibitors of the Maxi-K channel is based on the ability of expressed Maxi-K channels to set cellular resting potential after transfection of both alpha and betal subunits of the channel in HEK-293 cells and after being incubated with potassium channel blockers that selectively eliminate the endogenous potassium conductances of HEK-293 cells. In the absence of Maxi-K channel inhibitors, the transfected HEK-293 cells display a hyperpolarized membrane potential, negative inside, close to EK (-80 mV) which is a consequence of the activity of the Maxi-K channel. Blockade of the Maxi-K channel by incubation with Maxi-K channel blockers will cause cell depolarization. Changes in membrane potential can be determined with voltage-sensitive fluorescence resonance energy transfer (FRET) dye pairs that use two components, a donor coumarin (CC2DMPE) and an acceptor oxanol (DiSBAC2(3)).
Oxanol is a lipophilic anion and distributes across the membrane according to membrane potential. Under normal conditions, when the inside of the cell is negative with respect to the outside, oxanol is accumulated at the outer leaflet of the membrane and excitation of coumarin will cause FRET to occur. Conditions that lead to membrane depolarization will cause the oxanol to redistribute to the inside of the cell, and, as a consequence, to a decrease in FRET. Thus, the ratio change (donor/acceptor) increases after membrane depolarization, which determines if a test compound actively blocks the Maxi-K channel.
The HEK-293 cells were obtained from the American Type Culture Collection , 12301 Parklawn Drive, Rockville, Maryland, 20852 under accession number ATCC CRL-1573. Any restrictions relating to public access to the microorganism shall be irrevocably removed upon patent issuance.
Transfection of the alpha and betal subunits of the Maxi-K channel in HEK-293 cells was carried out as follows: HEK-293 cells were plated in 100 mm tissue culture treated dishes at a density of 3x106 cells per dish, and a total of five dishes were prepared. Cells were grown in a medium consisting of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% Fetal Bovine serum, IX L-Glutamine, and IX Penicillin/Streptomycin, at 370C, 10% CO2. For transfection with Maxi-K hα(pCIneo) and Maxi-K hβ 1 (pIRESpuro) DNAs, 150 μl FuGENEό™ was added dropwise into 10 mL of serum free/phenol-red free DMEM and allowed to incubate at room temperature for 5 minutes. Then, the FuGENEό™ solution was added dropwise to a DNA solution containing 25 μg of each plasmid DNA, and incubated at room temperature for 30 minutes. After the incubation period, 2 mL of the FuGENE6™/DNA solution was added dropwise to each plate of cells and the cells were allowed to grow two days under the same conditions as described above. At the end of the second day, cells were put under selection media which consisted of DMEM supplemented with both 600 μg/mL G418 and 0.75 μg/mL puromycin. Cells were grown until separate colonies were formed. Five colonies were collected and transferred to a 6 well tissue culture treated dish. A total of 75 colonies were collected. Cells were allowed to grow until a confluent monolayer was obtained. Cells were then tested for the presence of Maxi-K channel alpha and betal subunits using an assay that monitors binding of 125I-iberiotoxin-D19Y/Y36F to the channel. Cells expressing 125I-iberiotoxin-D19Y/Y36F binding activity were then evaluated in a functional assay that monitors the capability of Maxi-K channels to control the membrane potential of transfected HEK-293 cells using fluorescence resonance energy transfer (FRET) ABS technology with a VIPR instrument. The colony giving the largest signal to noise ratio was subjected to limiting dilution. For this, cells were resuspended at approximately 5 cells/mL, and 200 μl were plated in individual wells in a 96 well tissue culture treated plate, to add ca., one cell per well. A total of two 96 well plates were made. When a confluent monolayer was formed, the cells were transferred to 6 well tissue culture treated plates. A total of 62 wells were transferred. When a confluent monolayer was obtained, cells were tested using the FRET-functional assay. Transfected cells giving the best signal to noise ratio were identified and used in subsequent functional assays. For functional assays: The transfected cells (2E+06 Cells/mL) are then plated on 96-well poly-D-lysine plates at a density of about 100,000 cells/well and incubated for about 16 to about 24 hours. The medium is aspirated of the cells and the cells washed one time with 100 μl of Dulbecco's phosphate buffered saline (D-PBS). One hundred microliters of about 9 μM coumarin (CC2DMPE)-0.02% pluronic-127 in D-PBS per well is added and the wells are incubated in the dark for about 30 minutes. The cells are washed two times with 100 μl of Dulbecco's phosphate-buffered saline and 100 μl of about 4.5 μM of oxanol (DiSBAC2(3)) in (raM) 140 NaCl, 0.1 KCl, 2 CaCl2, 1 MgCl2, 20 Hepes-NaOH, pH 7.4, 10 glucose is added. Three micromolar of an inhibitor of endogenous potassium conductance of HEK-293 cells is added. A Maxi-K channel blocker is added (about 0.01 micromolar to about 10 micromolar) and the cells are incubated at room temperature in the dark for about 30 minutes.
The plates are loaded into a voltage/ion probe reader (VIPR) instrument, and the fluorescence emission of both CC2DMPE and DiSBAC2(3) are recorded for 10 sec. At this point, 100 μl of high-potassium solution (mM): 140 KCl, 2 CaCl2, 1 MgCl2, 20 Hepes-KOH, pH 7.4, 10 glucose are added and the fluorescence emission of both dyes recorded for an additional 10 sec. The ratio CC2DMPE/DiSBAC2(3), before addition of high-potassium solution equals 1. In the absence of Maxi-K channel inhibitor, the ratio after addition of high-potassium solution varies between 1.65-2.0. When the Maxi-K channel has been completely inhibited by either a known standard or test compound, this ratio remains at 1. It is possible, therefore, to titrate the activity of a Maxi-K channel inhibitor by monitoring the concentration-dependent change in the fluorescence ratio.
The compounds of this invention were found to cause concentration-dependent inhibition of the fluorescence ratio with IC50 5S in the range of about InM to about 20 μM, more preferably from about 10 nM to about 500 nM. The activity for blocking Maxi-K channels by compounds of this invention is 1 μM or less. By way of example, the compounds of formulas II, CCCCXXXII, CLXIII, CCCIII, and CCCVII have IC50 values of 240 nM; 385 nM; 210 nM; 1235 nM; and 210 nM, respectively.
B. Electrophysiological assays of compound effects on high-conductance calcium- activated potassium channels Methods:
Patch clamp recordings of currents flowing through large-conductance calcium- activated potassium (Maxi-K) channels were made from membrane patches excised from CHO cells constitutively expressing the α-subunit of the Maxi-K channel or HEK293 cells constitutively expressing both α- and β-subunits using conventional techniques (Hamill et al., 1981, Pflugers Archiv. 391, 85-100) at room temperature. Glass capillary tubing (Garner #7052 or Drummond custom borosilicate glass 1-014-1320) was pulled in two stages to yield micropipettes with tip diameters of approximately 1-2 microns. Pipettes were typically filled with solutions containing (mM): 150 KCl, 10 Hepes (4-(2-hydroxyethyl)-l-piperazine methanesulfonic acid), 1 Mg, 0.01 Ca, and adjusted to pH 7.20 with KOH. After forming a high resistance (>10° ohms) seal between the plasma membrane and the pipette, the pipette was withdrawn from the cell, forming an excised inside-out membrane patch. The patch was excised into a bath solution containing (mM): 150 KCl, 10 Hepes, 5 EGTA (ethylene glycol bis(β- aminoethyl ether)-N,N,N'iV-tetraacetic acid), sufficient Ca to yield a free Ca concentration of 1-5 μM, and the pH was adjusted to 7.2 with KOH. For example, 4.193 mM Ca was added to give a free concentration of 1 μM at 22 °C. An EPC9 amplifier (HEKA Elektronic, Lambrect, Germany) was used to control the voltage and to measure the currents flowing across the membrane patch. The input to the headstage was connected to the pipette solution with a Ag/ AgCl wire, and the amplifier ground was connected to the bath solution with a Ag/ AgCl wire covered with a tube filled with agar dissolved in 0.2 M KCl. The identity of Maxi-K currents was confirmed by the sensitivity of channel open probability to membrane potential and intracellular calcium concentration.
Data acquisition was controlled by PULSE software (HEKA Elektronic) and stored on the hard drive of a Macintosh computer (Apple Computers) for later analysis using PULSEFIT (HEKA Elektronic) and Igor (Wavemetrics, Oswego, OR) software.
Results:
The effects of the compounds of the present invention on Maxi-K channels were examined in excised inside-out membrane patches with constant superfusion of bath solution. The membrane potential was held at -80 mV and brief (100-200 ms) voltage steps to positive membrane potentials (typically +50 mV) were applied once per 15 seconds to transiently open Maxi-K channels. As a positive control in each experiment, Maxi-K currents were eliminated at pulse potentials after the patch was transiently exposed to a low concentration of calcium (<10 nM) made by adding 1 mM EGTA to the standard bath solution with no added calcium. The fraction of channels blocked in each experiment was calculated from the reduction in peak current caused by application of the specified compound to the internal side of the membrane patch. Compound was applied until a steady state level of block was achieved. K1 values for channel block were calculated by fitting the fractional block obtained at each compound concentration with a Hill equation. The K1 values for channel block by the compounds described in the present invention range from 0.01 nM to greater than 10 μM. The activity for blocking Maxi-K channel currents by the compounds of the present invention is 100 nM or less.

Claims

WHAT IS CLAIMED IS:
A compound of formula I:
Figure imgf000132_0001
I or a pharmaceutically acceptable salt, ester, including phosphate, enantiomer, diastereomer or mixture thereof.
Wherein: R is H, OPO3, COR2, OCOR2, -NHR2, OR2, CH(R2)2, OCNHR2, (CHR2)nNR2C(O)O(CH2)nR2, (C(Rl )2)pNRiR2; -NCOR2, (CH2)nORl, Ci-6alkyl, (CH2)nC6-10 aryl, (CH2)nheterocyclyl, C2-6 alkenyl, (CH2)nC3-6 cycloalkyl, THF, - (CH2)nNR2(CH2)n-, -(CH2)nO)sR2-, or OCOC(R2)2N(R2)2, said alkyl, alkenyl, cycloalkyl, aryl and heterocyclyl optionally substituted with 1 to 3 groups of R3;
Rl and Ri a independently represent H, (CH2)nOCONH(CH2)nR, (CH2)nCOOR, (CH2)nOR, COR, COO-C6-10aryl, COOalkylR, OCOC(R)2N(R)2, CONR(CH2)nR, (CH2)nOCOalkylR, halogen, COalkyl, Ci-όalkyl, C2-6alkenyl, (CH2)nC3-6cycloalkyl, (CH2)nC(S)N(R)2, (CH2)nC5-10 heterocyclyl, (CH2)nC6-10 aryl, (-(CH2)nO)s, (CH2)nC(O)(CH2)nC(O)OR, (CH2)nOP(O)(OR)2, or -(CHR)nN(R2)2, said alkyl, alkenyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
R2 is H, (CH2)nC00R, (CH2)n0R, COR, NRCOR, C0NR(CH2)nR, halogen, (CH2)nCOalkyl, Ci_6alkyl, C2-6alkenyl, (CH2)nC3-6cycloalkyl, (CH2)nC5-l0 heterocyclyl, (CH2)nC6-10 aryl, (-(CH2)nO)s, or -CHRN(R)2, said alkyl, alkenyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of R3;
R3: is H, C 1-6 alkyl, -Si((R)2)R, (CH2)nC5-10 heterocyclyl, -P(O)(OR)2,or -PO3, said alkyl and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
R5: is CO2R1, CH2OR, or halo; RlOa, Ri θb: together represent =0, =CH2, =NR, provided that when RiOa and Rl Ob represent =0 then Ri, Ria, Rl3, Rl4, R21 and R23 cannot all be hydrogen, also provided that when RiOa, and RlOb represent =0 then Ri cannot be (CHR)nN(R2)2 when Ria, Rl3, R21 and R23 are hydrogen, and R14 is (CH2)nCORi ;
or Rioa, Riob independently represent H, Ci -6 alkyl, C2-6 alkenyl, OH, OCOR, =CHC(O)OR, - N(Ri)COR2, said alkyl, and alkenyl, optionally substituted with 1 to 3 groups of Ra;
or Ri oa, R 10b together with an oxygen atom form a 3 membered heterocyclic ring;
Rl 3: is H, or CON(Ri )2;
Rl4: is H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, S(O)2, C3-6cycloalkyl, (CH2)nCORi, (CH2)nCO2R, (CH2)nCN, (CH2)nheterocyclyl, (CH2)naryl, (CH2)nCON(Ri)2, (CH2)nOR3, (CH2)nC(Ri)2C(R2)20R3, (CH2)nC(R2)2θR3, (CH2)nC(Rl)=CHC(O2)R, ((-CH2)n0(CH2)n- )s, (CH2)nCR=C(R)2, (CH2)nC(S)N(R)2, -(CH2)nC(CH2)R5, (CH2)nOC(O)R, (CH2)nOCH2R, said alkyl, alkenyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
R21 and R23: independently represent hydrogen, CN, COOR, CONR]R2, CONHRi, halogen, SO2R, C5-10 heterocyclyl, NO2, H, OR, COR, Ci-6 alkyl, C2-6 alkenyl, (CH2)nC5-l0 aryl, said alkyl, alkenyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
Ra is OH, Ci-6 alkyl, C3-6 cycloalkyl, (CH2)nC6-10 aryl, -O(CH2)nC6-10 aryl, CF3, halo, -SR, -O-, NO2, (CH2)n0Ri, C2-6 alkenyl, CN, N(Ri)2, COOR3, SO2R, -OP(O)(OR)2, -OPO3, or - OSi(R2)Ri;
s is 1-5; n is 0-6; and p is 0-1.
2. The compound according to claim 1 wherein Ri a and Ri 3 are hydrogen and Rl 0a and RlO^ together represent -O.
3. The compound according to claim 1 wherein Ri 4 is Ci -6 alkyl, (CH2)nC3-6 cycloalkyl, C2-6 alkenyl, (CH2)nheterocyclyl, (CH2)naryl, (CH2)nCON(Ri)2, (CH2)n0R3, (CH2)nC(Rl)2C(R2)20R3, or (CH2)nC(R2)2θR3-
4. The compound according to claim 3 wherein Ri 4 is (CH2)nCON(Ri)2, (CH2)n0R3, (CH2)nC(Rl)2C(R2)2θR3, or (CH2)nC(R2)2θR3 •
5 The compound according to claim 1 of Formula IA:
Figure imgf000134_0001
IA or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof, wherein Rl 0a and RlO^ together is -O, =NR, =CH2, or =CHC(O)OR and all other variables are as previously described.
6. The compound according to claim 5 wherein Ri 0a and RlO^ together is — O and Ri a is hydrogen. . ..
7. The compound according to claim 5 wherein Ri a is halogen, C2-6 alkenyl, C 1 -6 alkyl, CONH(CH2)nR, (CH2)nOR, COR, (CH2)nCOOR,
8. The compound according to claim 7 wherein Ri oa and RlO^ together is - O.
9. The compound according to claim 1 which is: 14(S)-(3 ' -Hydroxypropyloxy)paspalinine (II), 14-(5)-(Allyloxy)paspalinine (III),
14-(5)-(Propyloxy)paspalinine (IV),
14-(lS)-(Ethoxycarbonylmethyloxy)paspalinine (V),
14-(5)-([(3 '-(Methoxycarbonyl)-allyl]oxy)paspalinine (VI),
14-(5)-((2'-[l",3"]-Dioxolan-2"-yl)-ethyloxy)paspalinine (VII), \4-(S)-((T -(RZS)-T, 3 '-dihydroxy)-propyloxy)paspalinine (mixture of 2 diastereomers) (VIII),
14-(5)-(Ethyloxy)paspalinine (IX),
14-(5)-([2 ' -(2"-Methoxy-ethoxy)]-ethyloxy)paspalinine (X),
14-(5)-((2'-(i?/S)-2'-hydroxy)-propyloxy)paspalinine (mixture of 2 diastereomers) (XI),
14-(5)-((2'-Methoxy)-ethyloxy)paspalinine (XII), 14-(5)-(([2',5']-Dioxo-pyrrolidin-[r]-yl-oxycarbonyl)-methyloxy)paspalinine (XITT), 14-(5)-(Cyclopropylmethyloxy)paspalinine (XTV), 14-(S>((2 ' -Diethylamino)-ethyloxy)paspalinine (XV), 14-(S)-((Pyridin-4 ' -yl)-methyloxy)paspalinine (XVI), 14-(5)-(Cyanomethyloxy)paspalinine (XVII),
14-(5)-((6 ' -Hydroxymethyl-pyridin-2 ' -yl)-methyloxy)paspalinine (XVIII),
14-(5)-(Pyridin-2'-yl methyloxy)paspalinine (XIX),
14-(S)-(Pyridin-3'-yl methyloxy)paspalinine (XX),
14-(5)-((6'-Hydroxy)-hexyloxy)paspalinine (XXI), 14-(S)-((7'-Hydroxy)-heptyloxy)pasρalinine (XXII),
14-(S)-((8 ' -Hydroxy)-octyloxy)paspalinine (XXIII),
14-(5)-((9'-Hydroxy)-nonyloxy)paspalinine (XXIV),
14-(S)-((1 l'-Hydroxy)-undecyloxy)paspalinine (XXV),
14-CS)-CC 12 ' -Hydroxy)-dodecyloxy)paspalinine (XXVI), 14-(5)-((4'-Cyano)-butyloxy)paspalinine (XXVII),
14-(S)-((5 ' -Cyano)-pentyloxy)paspalinine (XXVIII),
14-(S)-((6'-Cyano)-hexyloxy)paspalinine (XXIX),
14-(S)-(Methoxycarbonylmethyl ether)paspalinine (XXX),
14-(.?)-(]V[ethoxycarbonylpropyl ether)paspalinine ( XXXI ), 14-(S>(Methoxycarbonylbutyloxy)paspalinine ( XXXII ),
14-(5)-((3'-Cyano)-propyloxy)paspalinine ( XXXIII ),
14-(5)-(Prop-2 ' -ynyloxy)paspalinine (XXXTV),
14-(5)-(([2', 4']-Diethoxy-4'-oxo)-but-2'-enyloxy)paspalinine (XXXV),
14-(S>(Benzyloxy)paspalinine (XXXVI), 14-CS)-(Pyrimidin-4'-yl methyloxy)paspalinine (XXXVII),
14-(S)-CC2 ' -Oxo-2 ' -phenyl)-ethyloxy)paspalinine (XXXVTTI),
14-(5)-((4 ' ,4' ,4' -Trifluoro)-butyloxy)paspalinine (XXXTX),
14-(5r)-((2'-(i?/S)-2'-methyl-4',4',4'-trifluoro)-butyloxy)paspalinine (mixture of 2 diastereomers)
(XL), 14-(,S)-((lH-tetrazol-5'-yl)-methyloxy)paspalinine (XLI),
14-(5)-((l '-Methyl-imidazol-2'-yl)-methyloxy)paspalinine (XLII),
14-(S)-((2'-Methyl)-allyloxy)paspalinine (XLIII),
14-(S)-C(2 ' - Acetoxy)-ethyloxy)paspalinine (XLTV),
14-(5)-((3 '-Methyl)-but-2'-enyloxy)paspalinine (XLV), 14-(5)-((2'-Ethoxycarbonyl)-prop-l '-enyloxy)paspalinine (XLVI), 14-(5)-((2 ' -Hydroxymethyl)-allyloxy)paspalinine (XLVII), 14-(S>((2'-Chloro)-allyloxy)paspaliriine (XLVIII), 14-(5)-((4 ' -Bromo)-benzyloxy)paspalinine (XLIX), 14-(5)-((4'-Cyano)-benzyloxy)paspalinine (L), 14-(S)-((4'-Trifluoromethyl)-benzyloxy)paspalinine (LI), 14-(S)-((3 ' -Bromo)-benzyloxy)paspalinine (LII), 14-(5)-((2 ' -Bromo)-benzyloxy)paspalinine (LIII), 14-(5)-((2'-(i?)-2'-Methyl-3'-hydroxy)-propyloxy)paspalinine (LIV), 14-(S)-((2 ' -(S)-2 ' -Methyl-3 ' -hydroxy)-propyloxy)paspalinine (LV), 14-(5)-([2'-(teA-t-butyldimethylsilyloxy)]-ethyloxy)paspalinine (LVI), 14-(5)-((2 ' -Phenylcarbonyloxy)-ethyloxy)paspalinine (LVII), 14-(5)-((2 ' -Benzyloxy)-ethyloxy)paspalinine (LVIII), 14-(5)-([3 ' -(tert-butyldimethylsilyloxy)] -propyloxy)paspalinine (LEX), 14-(S)-((2 ' - [N-Q "-hydroxy-2",2"-dimethylpropylamino)] -2 ' -oxo)-ethyloxy)paspalinine (LX), 14-(S)-((2'-[N-benzylamino]-2'-oxo)-ethyloxy)paspalinine (LXI), 14-(5)-((2 ' -Oxo-2 ' -piperidin- 1 "-yl)-ethyloxy)paspalinine (LXII), 14-(S)-((2 ' - [iV-cyclopropylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXIII), 14-(5)-((2 ' - [W-pentylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXIV), 14-(5)-((2 ' - [N, N-dimethylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXV), 14-(S)-((2'-Morpholin-4"-yl-2'-oxo)-ethyl oxy)paspalinine (LXVI),
14-(5)-((2 ' - [iV-pyridin-2"-ylmethyl] -2 ' -oxo)-ethyloxy)paspalinine (LXVII), 14-(5)-((2 ' - Amino-2 ' -oxo)-ethyloxy)paspalinine (LXVIII), 14-(S)-((2 ' -Methylamino-2 ' -oxo)-ethyloxy)paspalinine (LXLX), 14-(S)-((2'-(4"-Methyl-piperazin-l"-yl)-2'-oxo)-ethyloxy)paspalinine (LXX), 14-(5)-((2'-Oxo-2'-piperazin-l"-yl)-ethyloxy)paspalinine (LXXI),
14-(iS)-((2'-[iV-isopropylamino]-2'-oxo)-ethyloxy)paspalinine (LXXII),
14-(S)-((2 ' - [N-cyclohexylamino]-2 ' -oxo)-ethyloxy)paspalinine (LXXIII),
14-(S)-((2 ' - [N-ethylamino] -2' -oxo)-ethyloxy)paspalinine (LXXIV),
14-(5)-((2 ' - [N-(2"-dimethylamino)]-ethylamino-2 ' -oxo)-ethyloxy)paspalinine (LXXV), 14-(5)-((2'-(2"-Methoxy)-ethylamino-2'-oxo)-ethyloxy)paspalinine (LXXVI), 14-(S)-((2 ' - [N-cyclopentylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXXVII), 14-(5)-((2 '- [iV-(2"-acetylamino)] -ethylamino-2 ' -oxo)-ethyloxy)paspalinine (LXXVIII), 14-(5)-((2 ' - [JV-cyclopropylmethylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXXIX), 14-(S)-((2 '- [N-cyclobutylamino] -2 ' -oxo)-ethyloxy)paspalinine (LXXX), 14-(S)-((2' - [N-(propylamino)] -2 ' -oxo)-ethyloxy)paspalinine (LXXXI), 14-(S)-((2 ' - [N-(butylamino)] -2 ' -oxo)-ethyloxy)paspalinine (LXXXII), 14-(5)-((2'-[N-(2"-diethylamino)]-ethylamino-2'-oxo)-ethyloxy)paspalinine (LXXXIII), 14-(5)-((2'-(2"-Hydroxy)-ethylamino-2'-oxo)-ethyloxy)paspalinine (LXXXTV), 14-(5)-((2'-[N-(2"-butyl-2"-(S)-amino)]-2'-oxo)-ethyloxy)paspalinine (LXXXV), 14-(5)-((2'-[N-(2"-butyl-2"-(i?)-amino)]-2'-oxo)-ethyloxy)paspalinine (LXXXVI),
14-(5)-((2'-(l"-Methoxypropyl-2"-(5)-amino)-2'-oxo)-ethyloxy)paspalinine (LXXXVII), 14-(5)-((2'-(l"-Hydroxypropyl-2"-(i?)-amino)-2'-oxo)-ethyloxy)paspalinine (LXXXViπ), 14-(S)-((2 '-( 1 "-Hydroxypropyl-2"-(5)-amino)-2 ' -oxo)-ethyloxy)paspalinine (LXXXIX), 14-(5)-((2'-(l"-Methoxypropyl-2"-(i?/S)-amino)-2'-oxo)-ethyloxy)paspalinine (XC), 14-(5)-((2'-[iV-(3"-hydroxy-propylamino)]-2'-oxo)-ethyloxy)paspalinine (XCI),
14-(5)-((2'-[N-(2"-(JR)-hydroxy-2"-phenyl-ethylamino)]-2'-oxo)-ethyloxy)paspalinine (XCII), 14-(S)-((2 '- [N-(2"-(5)-hydroxy-2"-phenyl-ethylamino)] -2 ' -oxo)-ethyloxy)paspalinine (XCIII), 14-(5)-((2'-[N-(2"-hydroxy-l"-(Λ)-phenyl-ethylamino)]-2'-oxo)-ethyloxy)paspalinine (XCIV), 14-(S)-((2 ' - [N-(2"-hydroxy- 1 "-(S)-phenyl-ethylamino)] -2 ' -oxo)-ethyloxy)paspalinine (XC V), 14-(S)-((2 ' - [_V-( 1 "-hydroxy-cyclohexylmethylamino)] -2 ' -oxo)-ethyloxy)paspalinine (XCVI), 14-(5)-((2'-Oxo-2'-[N-phenylamino])-ethyloxy)paspalinine (XCVII), 14-(S)-((1 'H-[I \2\3']-triazol-4'-yl)-methyloxy)paspalinine (XCVIII), 14-(5)-((2'H-pyrazol-3'-yl)-methyloxy)paspalinine (XCIX), 14-(S)-((3 ' -Methylisoxazol-5 ' -yl)-methyloxy)paspalinine (C), (5)-((2'-Amino-2'-thioxo)-ethyloxy)paspalinine (CI),
14-(5)-((4 ' -Cyclopropyl-thiazol-2 ' -yl)-methyloxy)paspalinine (CII),
14-(S)-((4 ' -Methyl-thiazol-2 ' -yl)-methyloxy)paspalinine (CIII),
14-(5)-((4',5'-Dimethyl-thiazol-2'-yl)-methyloxy)paspalinine (CIV),
14-(S)-C[6 ' -(2 ' -Methyl-3 'H-pyrimid-4 ' -onyl)] -methyloxy)paspalinine (CV), 14(5)-([6'-(3'H-pyrimid-4'-onyl)]-methyloxy)paspalinine (CVI), 14(S)-(Q ' -Ethoxycarbonyl-2 ' -oxo)-propyloxy)paspalinine (CVII), 14-(5)-([6'-(2'-te^-butyl-3'H-pyrimid-4'-onyl)]-methyloxy)paspalinine (CVIII), 14(iS)-(3'-Oxypropyl phosphoric acid diphenyloxo)paspalinine (CIX), 14(5)-((2'-Ηydroxy)-ethyloxy)paspalinine (CX), 14(S)-((3 ' -Hydroxy-2 ' -(i?/S)-methyl)-propyloxy)paspalinine (mixture of 2 diastereomers) (CXI), 14(5)-((2'-(Λ/S)-Hydroxy-3'-methyl)-butyloxy)paspalinine (mixture of 2 diastereomers) (CXII), 14(5)-((2'-Hydroxy-2'-methyl)-propyloxy)paspalinine (CXIII), 14(5)-((3 ' -Hydroxy-3 ' -methyl)-butyloxy)paspalinine (CXTV), 14-(5)-((3'-Oxy)-propyl ether-3 '-phosphoric acid mono-p-nitrophenyloxo)paspalinine (CXIII), 14(5)-((3'-Hydroxy)-benzyloxy)paspalinine (CXVI), 14(5)-((2'-Hydroxy)-benzyloxy)paspalinine (CXVII), 14(S)-(3'-Oxypropyl phosphoric acid dibenzyloxo)paspalinine (CXVIII), 14(S)-(3'-Oxypropyl phosphorate bis-triethylammonium)paspalinine (CXIX),
10-(E/Z)-([(4'-Methyl)-benzylimino]-14(5)-[N-(2'-cyclopropylamino)]-2'-oxo- ethyloxy)paspalinine (CXX),
10-(E/2)-([N-(propylimino)]-14(5)-[N-(2'-propylamino)]-2'-oxo-ethyloxy)paspalinine (ratio of
EIZ isomers = 1/0.4) (CXXI),
10-(E/2)-([7V-(cyclopropylmethylimino)] - 14(5)- [N-Q. ' -cyclopropylamino)] -2 ' -oxo- ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXXII), 10-(E/Z)-([iV-(cyclobutylimino)]-14(5)-[N-(2'-cyclobutylamino)]-2'-oxo-ethyloxy)paspalinine
(ratio of EIZ isomers = 1/0.4) (CXXffl),
10-(E/Z)-([N-(cyclopentylimino)] - 14(5)- [N-(2 ' -cyclopentylamino)] -2 ' -oxo-ethyloxy)paspalinine
(ratio of EIZ isomers = 1/0.4) (CXXIV),
10-(E/Z)-([N-(butylimino)]- 14(5)- [JV-(2 ' -butylamino)] -2 ' -oxo-ethyloxy)paspalinine (ratio of ElZ isomers = 1/0.4) (CXXV),
10-(£/Z)-([N-(ethylimino)] - 14(5)- [N-(2 ' -ethylamino)] -2 ' -oxo-ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXXVI),
10-(E/Z)-([N-(2-methoxyethylimino)] - 14(5)- [N-(T -(2-methoxyethyl)amino)] -2 ' -oxo- ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXXVI), 10-(E/Z)-([imino)]-14(S)-[N-(2'-(cyclopropylamino)]-2'-oxo-ethyloxy)paspalinine (ratio of EIZ isomers - 1/1) (CXXVπi),
10-(E/Z)-( [TV-(methylimino)] - 14(5}- [N-(2 ' -propylamino)]-2 ' -oxo-ethyloxy)paspalinine (ratio of
EIZ isomers = 1/0.7) (CXXIX),
10-(E/Z)-( [_V-(3 -hydroxypropylimino)]- 14(5)- [N-(2 ' -isopropylamino)] -2 ' -oxo- ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.4) (CXXX),
10-(E/Z)-([N-(4-methylbenzylimino)] - 14(5)- [_V-(2 ' -isopropylamino)] -2 ' -oxo- ethyloxy)paspalinine (ratio of EIZ isomers = 1/0.7) (CXXXI),
14(5)-(4' -Bromobenzoyloxy)paspalinine (CXXXII),
14(S)-(Morpholin-4-yl-acetoyloxy)paspalinine (CXXXV), 14(5)-Isonicotinoyloxy-paspalinine (CXXXVI),
14(5)-Nicotinoyloxy-paspalinine (CXXXVII), 14(5)-(Methoxy-acetoxy)paspalinine (CXXXIX), 14(5)-(Dimethylamino-acetoxy)paspalinine (CXL), 14(5)-Cyclopropanecarbonyloxypaspalinine (CXLI), 14(S)-Propionoyloxypaspalinine (CXLII),
14(S)-Ethoxy-acetoxypaspalinine (CXLIII), 14(5)-(3 '-Methoxypropionoyloxy)paspalinine (CXLIV), 14(5)-Cyclobutanecarbonyloxypaspalinine (CXLV), 14(S)-Cyclopentanecarbonyloxypaspalinine (CXLVI),
14(5)-(3 ' ,3 ' ,3 ' -Trifluoropropionoyloxy)paspalinine (CXLVII), 14(S)-(2 ' -Methoxy-ethoxy)-acetoxypaspalinine (CXLVIII),
14(iS)-(Furan-2'-carbonyloxy)paspalinine (CXLIX), 14(S)-(Tetrahydro-furan-2'-carbonyloxy)paspalinine (CL), 14(S)-Methylsulfanyl-acetoxypaspalinine (CLI),
14(5)-((5)-2'-Dimethylamino-3' -phenyl -propionoyloxy)paspalinine (CLII),
14(5)-Acetoxypaspalinine (CLIII), 14(<S)-Butyroyloxypaspalinine (CLV),
14(S)-(3 ' ,3 ' -Dimethyl-butyroyloxy)paspalinine (CLVI), 14(5)-(r-Methyl-cyclopropanecarbonyloxy)paspalinine (CLVII), 14(5')-(2'-Methyl-cyclopropanecarbonyloxy)paspalinine (CLVIII),
14(5)-(Benzyloxycarbonylamino-acetoxy)paspalinine (CLIX),
14(5)-(Benzyloxycarbonyl-methyl-amino)-acetoxypaspalinine (CLX),
14(5)-(3 '-Benzyloxycarbonylamino-propionoyloxy)paspalinine (CLXI), 14(S>Pentanoyloxypaspalinine (CLXII),
14(S)-((i?)-Tetrahydro-furan-2'-carbonyloxy)paspalinine (CLXIII),
14(5)-((5)-2'-Benzyloxycarbonylamino-3 '-methyl-butyroyloxy)paspalinine (CLXIV),
14(5)-(Tetrahydro-pyran-4'-carbonyloxy)paspalinine (CLXV),
14(S>((2'£,4'E)-Hexa-2',4'-dienoyloxy)paspalinine (CLXVI), 14(5)-Acryloyloxypaspalinine (CLXVII),
14(S)-Hexanoyloxypaspalinine (CLXVIII,
14(S)-Benzoyloxypaspalinine (CLXLX),
14(5)-((5)-2 ' -(9 '//-Fluoren-9 ' -ylmethoxycarbonylamino)-3 ' -methyl-butyroyloxy)paspalinine
(CLXX), 14(S)-((9 'H-Fluoren-9 ' -ylmethoxycarbonylamino)-acetoxy)paspalinine (CLXXI),
14(5)-([2-(2-Methoxy-ethoxy)-ethoxy]-acetoxy)paspalinine (CLXXII),
14(S)-Cycloheptanecarbonyloxypaspalinine (CLXXIII), 14(S)-Diphenyl-acetoxypaspalinine (CLXXIV),
14(S)-((R)-2 ' -Methoxy-3 ' -methyl-butyroyloxy)paspalinine (CLXXV),
14(5)-[(4'-(r-Methoxycarbonyl)-piperidinyl)-carbonyloxy]-paspalinine (CLXXVI),
14(5)-((5)-2 ' -Dimethylamino-propionoyloxy)paspalinine (CLXXVII), 14(S)-((S)-2' -Methoxy-3 '-phenyl-propionoyloxy)paspalinine (CLXXVIII),
14(S)-(I '-Methoxy-cyclopropanecarbonyloxy)paspalinine (CLXXLX),
14(S)-(2 ' -Methoxy-2 ' -methyl-propionoyloxy)paspalinine (CLXXX),
14(S)-(I '-Dimethylamino-cyclopropanecarbonyloxy)paspalinine (CLXXXI),
14(5)-((i?)-2'-Dimethylamino-propionoyloxy)paspalinine (CLXXXII), 14(S)-(2 ' -Methyl-5 ' -trifluoromethyl-oxazole-4 ' -carbonyloxy)paspalinine (CLXXXIII),
14(S)-(Pyrimidine-5 ' -carbonyloxy)paspalinine (CLXXXIV),
14(S)-Nonanoyloxypaspalinine (CLXXXV),
14(S)-(2 ' -Bromo-3 ' -methyl-butyroyloxy)paspalinine (CLXXXVI),
14(S)-Undecanoyloxypaspalinine (CLXXXVII), 14(5)-Decanoyloxypaspalinine (CLXVIII),
14(S)-Octanoyloxypaspalinine (CLXXXIX),
14(S)-Heptanoyloxypaspalinine (CXC),
14(5)-(5 ' -Bromo-furan-2 ' -carbonyloxy)paspalinine (CXCI),
14(S)-(2'-Methyl-imidazo[r,2'-α]pyridine-3'-carbonyloxy)paspalinine (CXCII), 14(5)-(βenzoLόJfuran-2'-carbonyloxy)paspalinine (CXCIlI),
14(5)-(Benzo[<f]imidazo[2',r-ό]thiazole-2'-carbonyloxy)paspalinine (CXCIV),
14(S)-(3 ' -Oxo-butyroyloxy)paspalinine (CXCV),
14(5)-(Thiophene-2 ' -carbonyloxy)paspalinine (CXCVI),
14(5)-(Adamantane-l '-carbonyloxy)paspalinine (CXCVII), 14(5)-((S)-2'-Dimethylamino-butyroyloxy)paspalinine (CXCVIII),
14(5)-Cyclohexanecarbonyloxypaspalinine (CXCDC),
14(5)-(Pyridine-2 ' -carbonyloxy)paspalinine (CC),
14(5)-((i?)-2 ' -Methoxy-3 ' -phenyl-propionoyloxy)paspalinine (CCI),
14(S>(Pyridin-2 ' -yl-acetoxy)paspalinine (CCII), 14(S>((4'-Oxo-3',4'-dihydro-phthalazin-l '-yl)-acetoxy)paspalinine (CCIV),
14(S)-(3 ' -Iodo-benzoyloxy)paspalinine (CCV),
14(5)-(4' -Iodo-benzoyloxy)paspalinine (CCVI),
14(5)-(Phenylacetyl)paspalinine (CCVII),
14(S>Dodecanoyloxypaspalinine (CCVIII), 14(S)-(4'-Bromo-phenyl)carbamoyloxypaspalinine (CCIX), 14(S)-(3 ' -Chloropropy^carbamoyloxypaspalinine (CCX), 14(S)-(Benzyl)carbamoyloxypaspalinine (CCXI), 14(S)-(Cyclohexyl)carbamoyloxypaspalinine (CCXII), 14(S>(Allyl)carbamoyloxypaspalinine (CCXIII), 14(5)-(Isopropyl)carbamoyloxypaspalinine (CCXIV), 14(S)-(«-Propyl)carbamoyloxypaspalinine (CCXV), 14(5)-((5)-Propionoyloxy methyl)carbamoyloxypaspalinine (CCXVI), 14(S)-((5)-(-)-2'-Butyroyloxy methyl)carbamoyloxypaspalinine (CCXVII), 14(5)-((5)-(-)-2'-Valeroyloxy methyl)carbamoyloxypaspalinine (CCXVIII), 14(S)-(2 ' -BromoethyOcarbamoyloxypaspalinine (CCXIX),
14(S)-(4'-Dimethylaminophenyl)carbamoyloxypaspalinine (CCXX), 14(5)-Cyclopentylcarbamoyloxypaspalinine (CCXXI), 14(5)-(3 ' ,4 ' -methylenedioxypheny^carbamoyloxypaspalinine (CCXXII), 14(S)-Morpholinocarbamoyloxypaspalinine (CCXXIII), 14(S)-Pyrrolindinecarbamoyloxypaspalinine (CCXXTV), 14(5)-Piperidinecarbamoyloxypaspalinine (CCXXV), 14(5)-tert-Butylcarbamoyloxypaspalinine (CCXXVI), 14(5)-(iV,J/V-Dimethyl)carbamoyloxypaspalinine (CCXXVII), 14(5)-(Ethylcarbamyl)carbaπioyloxypaspalinine (CCXXVIII) l4(5)-(4' -Methyl- r-piperazine)carbamoyloxypaspalinine (CCXXIX), 14(5)-(«-Hexyl)carbamoyloxypaspalinine (CCXXX), 14(1S)-(N,iV-Diethyl)carbamoyloxypaspalinine, (CCXXXI) 14(5)-(«-Butyl)carbamoyloxypaspalinine (CCXXXII), 14(5)-Carbanioyloxypaspalinine (CCXXXIII), 14(5)-(Cyclopropyl)carbamoyloxypaspalinine (CCXXXIV),
14(iS)-(4' -Benzyl- 1 '-piperazine)carbamoylόxypaspalinine (CCXXXV), 14(5)-(4'-Phenyl-l '-piperazine)carbamoyloxypaspalinine (CCXXXVI), 14(iS)-(2'-pyrimidyl-r-piperazine)carbamoyloxypaspalinine (CCXXXVII), 14(5)-(4' -acetyl- r-piperazine)carbamoyloxypaspalinine (CCXXXVIII), 14(5)- [(4 ' -tert-Butoxycarbonylpiperazin- 1 ' -yl)-carbonyloxy] -paspalinine (CCXXXIX), 14(5)-(4' -Ethyl- 1 ' -piperazine)carbamoyloxypaspalinine (CCXL), 14(5)-(4'-Isopropyl-l '-piperazine)carbamoyloxypaspalinine (CCXLI), 14(5)-(4 ' -Cyclopentyl- 1 ' -piperazine)carbamoyloxypaspalinine (CCXLII), 14(5)-(4' -(2 '-Pyridyl)-r-piperazine)carbamoyloxypaspalinine (CCXLIII), 14(5)-(2'-Hydroxyethyl)carbamoyloxypaspalinine (CCXLIV), 14(S)-(2 ' -Morpholinoethy^carbamoyloxypaspalinine (CCXLV), 14(S)-(2 ' - Aminobenzyl)carbamoyloxypaspalinine (CCXLVI), 14(S)-(Cyclobutyl)carbamoyloxypaspalinine (CCXLVII), 14(S)-(Methylcyclohexyl)carbamoyloxypaspalinine (CCXLVIII), 14(5)-(4'-Methoxybenzyl)carbamoyloxypaspalinine (CCXLIX), 14(S)-(TV, N-Diethylamino ethyl)carbamoyloxypaspalinine (CCL), 14(5)-(3 ' -Morpholinopropyl)carbamoyloxypaspalinine (CCLI), 14(5)-((i?)-2 ' -Hydroxy- 1' -methyl-ethyl)carbamoyloxypaspalinine (CCLII), 14(S)-(4' -Benzylpiperidine)carbamoyloxypaspalinine (CCLIII), 14(S)-[(4'-Methoxycarbonylpiperidin-l '-yl)-carbonyloxy]-paspalinine (CCLIV), 14(S)-(OS)- r-Hydroxymethyl-3 '-methyl-butyl) carbamoyloxypaspalinine (CCLV), 14(5)-((5)-r-Hydroxymethyl-3'-methylsulfanyl-propyl)carbamoyloxypaspalinine (CCLVI), 14(S)-(I '-Ethylpropyl)carbamoyloxypaspalinine (CCLVII), 14(S)-(Ethyl)carbamoyloxypaspalinine (CCLVIII), 14(S)-(2'-(N,N-Dimethylamino)ethyl)carbamoyloxypaspalinine (CCLIX), 14(S)-(2'-Methoxyethyl)carbamoyloxypaspalinine (CCLX), 14(S)-( 1 ' -Hydroxymethyl-cyclopenty^carbamoyloxypaspalinine (CCLXI), 14(S)-(3 '-MethoxypropyOcarbamoyloxypaspalinine (CCLXII), 14(S)-(Cycloproplymethyl)carbamoyloxypaspalinine (CCLXIII), 14(S)-(I '-Hydroxymethyl-3 '-methyl-butyl)carbamoyloxypaspalinine (CCLXIV),
14(S)-((i?)- 1 ' -Hydroxymethyl-2 ' -methyl-propyl)carbamoyloxypaspalinine (CCLXV), 14(S)-((S)-r-Hydroxymethyl-3'-methyl-butyl)carbamoyloxypaspalinine (CCLXVI), 14(S)-(r-Hydroxymethyl-benzyl)carbamoyloxypaspalinine (CCLXVII), 14(S)-(4 ' - Aminobenzyl)carbamoyloxypaspalinine (CCLXVIII), 14(S)-(2'-Methylpropyl)carbamoyloxypaspalinine (CCLXIX), 14(S)-(3 ' -ethoxypropyl)carbamoyloxypaspalinine (CCLXX), 14(S)-(4 ' -Hydroxypiperidine)carbamoyloxypaspalinine (CCLXXI), 14(S)-(4 ' -(2 ' -Hydroxyethyl)piperidine)carbamoyloxypaspalinine (CCLXXII), 14(S)- (2 ' -Pyridin-2 ' -yl-ethyOcarbamoyloxypaspalinine (CCLXXIII), 14(S)-(Pyridine-4'-yl-methyl)carbamoyloxypaspalinine (CCLXXIV), 14(S)-(I '-Benzyl-piperidin-4'-yl)carbamoyloxypaspalinine (CCLXXV), H(S)-(T, 2' -Dimethoxy-ethyOcarbamoyloxypaspalinine (CCLXXVI), 14(S)-((4 ' -Methoxy-phenyO-ethyOcarbamoyloxypaspalinine (CCLXXVII), 14(S)-(3'-Isopropoxy-propyl)carbamoyloxypaspalinine (CCLXXViπ), 14(S)-((i?)-l '-phenyl-ethyl)carbamoyloxypaspalinine (CCLXXDC), 14(5)-(2',2'-Dimethyl-[r,3']dioxolan-4'-ylmethyl)carbamoyloxypaspalinine (CCLXXX), 14(S)-(2 ' ,2 ' -Dimethyl-3 ' -hydroxy-propyOcarbamoyloxypaspalinine (CCLXXXI), 14(5)-(2'-Piperidin-l '-yl-ethyOcarbamoyloxypaspalinine (CCLXXXII), 14(5)-(Furan-2'-yl-methyl)carbamoyloxypaspalinine (CCLXXXIII), 14(5)-(Cycloheptyl)carbamoyloxypaspalinine (CCLXXXIV),
14(5)-(4'-Methyl-benzyl)carbamoyloxypaspalinine (CCLXXXV), 14(5)-((4'-hydroxy)phenethyl)carbamoyloxypaspalinine (CCLXXXVI), 14(S)-C(S)- 1 '-Phenyl-ethyOcarbamoyloxypaspalinine (CCLXXXVII), 14(S)-((S)-sec-Butyl)carbamoyloxypaspalinine (CCLXXXVIII), 14CS)-C(S)- 1 ' -(Tetrahydro-fϊιran-2 ' -yl)methyl)carbamoyloxypaspalinine (CCLXXXIX), 14(S)-((Λ)- 1 ' -(Tetrahydro-furan-2 ' -yl)methyl)carbamoyloxypaspalinine (CCXC), 14(S)-((S)-2 ' -Methoxymethyl-pyrrolidine)carbamoyloxypaspalinine (CCXCI), 14(S)-((i?)-2 ' -Hydroxymethyl-pyrrolidine)carbamoyloxypaspalinine (CCXCII), 14(<S)-((i?)-3'-Hydroxy-pyrrolidine)carbamoyloxypaspalinine (CCXCIII), 14(5)-((5)-2'-Hydroxymethyl-pyrrolidine)carbamoyloxypaspalinine (CCXCIV), 14(5)-(3 ',6'-Dihydro-2'H-pyridine)carbamoyloxypaspalinine (CCXCV), 14(S>(2'-(1 ',3 '-Dihydro-isoindole))carbamoyloxypaspalinine (CCXCVI), 14(S)-( 1 ' -(4 ' -Methyl-piperidine))carbamoyloxypaspalinine (CCXC VII), 14(S)-(I '-Azepane)carbamoyloxypaspalinine (CCXCVIII), 14(S)-(Toluene-4'-sulfonoyloxypaspalinine (CCXCIX), 14(S)-tert-Butoxycarbonyloxypaspalinine (CCC), 14(S)-(2'-(Pyridin-2'-yloxy)paspalinine (CCCI), Paspalin-14-one (CCCII), 14(i?)-Hydroxypaspalinine (CCCIII), 13,14-(Dioxanoyloxypaspalinine (CCCIV), Paspalin-13-ene (CCCVI), 14(S)-Hydroxy- 17-oxo-paspalinine (CCCVπ), 14(S)-Hydroxypaspalin- 10-exo-ene (CCC VIII), 10(S)-(Oxaspiro)- 14(S)-hydroxypaspalinine (CCCLX), 10-(Carbomethoxymethylene)-14-(iS)-hydroxypaspalinine (CCCX), 10(S)-Methyl- 14(S)-hydroxypaspalinine (CCCXI), 11,14-Thiophene-paspalinine (CCCXII), 14(S)-Hydroxyl-21 -bromopaspalinine (CCCXIII), (14(S)-N-(3-Hydroxy-2,2-dimethyl-propyl))-(21-bromo)-acetamide-paspalinine (CCCXV), 14(S>Hydroxy-21 -methoxycarbonylpaspalinine (CCCXVI), 14(5)-(Acetamide-N-(3'-hydroxy-2',2'-dimethyl-propyl)-3'-phosphonooxy (bis- triethylammonium))paspalinine (CCCXVIII),
14(5)-(2'-Hydroxy-ethoxy-phosphonooxy (bis-triethylammonium))-ethyloyloxy)paspalinine
(CCCXX), 14(S>(2'-Hydroxy-ethoxy)-21-bromopaspalinine (CCCXXI),
14(5)- [2 ' -(Methoxycarbonyl)-ethyloxy] -21 -bromo-paspalinine (CCCXXII),
14(5)-(Methyl-allyloxy)-21 -bromopaspalinine (CCCXXIII),
14(5)-(N-Propyl-acetamide)-paspalinine (CCCXXIV),
14(S)-(2 ' -Hydroxy-2 ' -methyl-propoxy)-21 -bromopaspalinine (CCCXXV), 14(5),21 -dihydroxypaspalinine (CCCXXVII),
14(5)-Hydroxy-21 -vinylpaspalinine (CCCXXVIH),
14(5)-Hydroxy-21 -phenylpaspalinine (CCCXXIX),
14(5)-Hydroxy-21 -methoxypaspalinine (CCCXXX),
14(S>Hydroxy-21 -nitropaspalinine (CCCXXXI), 14(5)-Hydroxy-21 -cyanopaspalinine (CCCXXXII),
14(5)-[2'-(Methoxycarbonyl)-ethyloxy]-21-cyano-paspalinine (CCCXXXiπ),
14(5)-(N-Isopropyl-acetamide)-21 -cyanopaspalinine (CCCXXXIV),
14(5)-(N-Butyl-acetamide)-21 -cyanopaspalinine (CCCXXXV),
14(5)-(N-/ert-Butyl-acetamide)-21 -cyanopaspalinine (CCCXXXVI), 14(S)-(N-Propyl-acetamide)-21 -cyanopaspalinine (CCCXXXVII),
14(S)-(N-Ethyl-acetamide)-21 -cyanopaspalinine (CCCXXXVIII),
14(5)-(3-Hydroxypropyloxy)-21-cyanopaspalinine (CCCXXXIX),
14(S)-(3 ' -Hydroxy-propoxy-phosphono-oxy(bis-triethylammonium))-propyloyloxy)-21 - cyanopaspalinine (CCCXL), 14(5)-(2'-Hydroxyethyloxy)-21 -cyanopaspalinine (CCCXLI),
14(SΗ2'-Hydroxy-ethoxy-phosphono-oxy (bis-triethylammonium))-ethyloyloxy)-21 - cyanopaspalinine (CCCXLIII),
14(S)-((Isobutryoyloxy 2 '-ethoxy)-21 -cyanopaspalinine (CCCXLIV),
14(S)-(Methyl-allyloxy)-21 -cyanopaspalinine (CCCXLV), l-«-Butylcarbamoyl-14(S)-(«-butyl)carbamoyloxypaspalinine (CCCXLVI),
1 -Carboxoyloxy pentylamide- 14(5)-(n-pentyl)carbamoyloxypaspalinine (CCCXLVII),
1 -Bromo- 14(5)-hydroxypaspalinine (CCCXLVIII),
1 - Allyl- 14(5)-allyloxypaspalinine (CCCXLIX),
1 -Allyl- 14(5)-propyloxypaspalinine (CCCL), 1 -Propyl- 14(S>allyloxypaspalinine (CCCLI), 1 -Methoxymethyl- 14(5)-propyloxypaspalinine (CCCLII),
1 -Acetyl- 14(S)-propyloxypaspalinine (CCCLIII),
1 -(2 ' ,2 ' -Dimethyl-methylpropionoyloxy)- 14(5)-propyloxypaspalinine (CCCLIV),
1 -(2-Hydroxyethyloxycarbonyl)- 14(5)-propyloxypaspalinine (CCCLV), 1 -Carbonyloxy propylamide- 14(S)-propyloxypaspalinine (CCCLVI),
1 -(3 -Hydroxypropyloxycarbonyl)- 14(iS)-propyloxypaspalinine (CCCLVII),
1 -[(3 '-(N,N-Dimethylaminoacetoxy)-propyloxy)-carbonyl]- 14(S)-propyloxypaspalinine
(CCCLViπ),
14-(5)-((4'-cyano)-butyloxy)-21 -bromopaspalinine (CCCXCI), 14(S)-Isopropylcarbamoyloxy-21 -bromopaspalinine (CCCXCIII), l-(Hydroxymethyl)-14-(S)-propyloxy paspalinine (CCCXCVII),
1 -(fl-Propylcarbamoyloxymethyl)- 14-(5)-propyloxypaspalinine (CCCXCVIII), or a pharmaceutically acceptable salt, ester, including phosphate, enantiomer, diastereomer or mixture thereof.
10. A compound according to claim 9 which is:
14(S)-(3 ' -hydroxypropyloxy)paspalinine (II),
14-(S)-((2'-(i?/S)-2'-hydroxy)-propyloxy)paspalinine (mixture of 2 diastereomers) (XI),
14-(5)-((2'-(i?)-2'-methyl-3'-hydroxy)-propyloxy)paspalinine (LiV), 14-(S')-((2'-(5')-2'-methyl-3'-hydroxy)-propyloxy)paspalinine (LV),
14-(5)-((2'-[N-(3"-hydroxy-2",2"-dimethylpropylamino)]-2'-oxo)-ethyloxy)paspalinine (LX),
14(<S)-(3'-oxypropyl phosphorate bis-triethylamrnonium)paspalinine (CXTX), 14(5)-
(isopropyl)carbamoyloxypaspalinine (CCXIV),
(14(S)-N-(3-Hydroxy-2,2-dimethyl-propyl))-(21-bromo)-acetamide-paspalinine (CCCXV), 14(5)-(Acetamide-N-(3'-hydroxy-2 ',2' -dimethyl -propyl)-3'-phosphonooxy (bis- triethylammonium))paspalinine (CCCXVIII),
14(5)-(2 ' -Hydroxy-ethoxy-phosphonooxy (bis-triethylammonium))-ethyloyloxy)paspalinine (CCCXX),
14(5)-Hydroxy-21 -cyanopaspalinine (CCCXXXII), l-(3-Hydroxypropyloxycarbonyl)-14(5)-propyloxypaspalinine (CCCLVII), 14(5)-((2 ' -hydroxy)-ethyloxy)paspalinine (CX), 14(5)-(2 '-Hydroxy-ethoxy)-(21 -bromo)-paspalinine (CCCXXI), 14(S)-(Methyl acetate)-21-(bromo)-paspalinine (CCCXXII), 14(5)-(3-Hydroxypropyloxy)-21 -(cyano)-paspalinine (CCCXXXIX), 14(5)-(3 ' -Hydroxy-propoxy-phosphono-oxy(bis-triethylammonium))-propyloyloxy)-21 -(cyano)- paspalinine (CCCXL),
14(5)-(2'-Hydroxyethyloxy)-21-(cyano)-paspalinine (CCCXLI),
14(5)-(2 ' -Hydroxy-ethoxy-phosphono-oxy (bis-triethylammonium))-ethyloyloxy)-21 -(cyano)- paspalinine (CCCXLIII), l-(Hydroxymethyl)-14-(5)-propyloxy paspalinine (CCCXCVII) or a pharmaceutically acceptable salt, ester, including phosphate, enantiomer, diastereomer or mixture thereof.
1 1. A method for treating ocular hypertension or glaucoma comprising administration to a patient in need of such treatment a therapeutically effective amount of a compound of structural formula I of claim 1.
12. A method for treating macular edema, macular degeneration, increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension, and/or a neuroprotective effect comprising administration to a patient^in need of such treatment a pharmaceutically effective amount of a compound of claim 1 ; or a pharmaceutically acceptable salt, ester including phosphate, enantiomer, diastereomer or mixture thereof.
13. A composition comprising a compound of formula I of claim 1 and a pharmaceutically acceptable carrier.
14. A composition according to claim 9 wherein one or more of an active ingredient belonging to the group consisting of: β -adrenergic blocking agent, parasympatho- mimetic agent, sympathomimetic agent, carbonic anhydrase inhibitor, EP4 agonist, a prostaglandin or derivative thereof, hypotensive lipid, neuroprotectant, and/or 5-HT2 receptor agonist is optionally added.
PCT/US2008/011557 2007-10-11 2008-10-07 Maxi-k channel blockers and methods of use WO2009048559A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102070427A (en) * 2011-01-10 2011-05-25 南通功成精细化工有限公司 Synthesis methods of flocumafen and flocumafen intermediate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050239863A1 (en) * 2002-06-17 2005-10-27 Garcia Maria L Novel maxi-k channel blockers, methods of use and process for making the same

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050239863A1 (en) * 2002-06-17 2005-10-27 Garcia Maria L Novel maxi-k channel blockers, methods of use and process for making the same

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102070427A (en) * 2011-01-10 2011-05-25 南通功成精细化工有限公司 Synthesis methods of flocumafen and flocumafen intermediate

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