EP1144415A2 - Functionalized heterocycles as chemokine receptor modulators - Google Patents

Functionalized heterocycles as chemokine receptor modulators

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Publication number
EP1144415A2
EP1144415A2 EP99963110A EP99963110A EP1144415A2 EP 1144415 A2 EP1144415 A2 EP 1144415A2 EP 99963110 A EP99963110 A EP 99963110A EP 99963110 A EP99963110 A EP 99963110A EP 1144415 A2 EP1144415 A2 EP 1144415A2
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EP
European Patent Office
Prior art keywords
methyl
carboxylic acid
benzopyrano
decahydro
quinolizine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99963110A
Other languages
German (de)
French (fr)
Inventor
Geraldine C. Harriman
Christine Nylund Kolz
Jay R. Luly
Bruce David Roth
Yuntao Song
Bharat Kalidas Trivedi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Millennium Pharmaceuticals Inc
Original Assignee
Warner Lambert Co LLC
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Filing date
Publication date
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of EP1144415A2 publication Critical patent/EP1144415A2/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D491/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems

Definitions

  • the present invention relates to functionalized heterocycles useful as modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A,
  • Chemokines mediate a range of proinflammatory effects on leukocytes, such as chemotaxis, degranulation, and intigran activation (Baggiolini et al., Adv.
  • Chemokine receptors also serve as coreceptors for HIV-1 entry into cells. This came from observations that RANTES, MlP-l ⁇ , and MlP-l ⁇ suppressed infection of susceptible cells in vitro by macrophage-tropic primary HIV-1 isolates
  • CXCR-4 was found to support infection and cell fusion of CD4 + cells by laboratory-adapted, T-tropic HIV-1 strains (Feng et al., Science (Wash. DC), 1996;272:872-7).
  • CCR-5 a RANTES, MlP-l ⁇ , and MlP-l ⁇ receptor, was subsequently identified as the principle coreceptor for primary macrophage-tropic strains (Choe et al., Cell, 1996;85:1135-48; Alkhatib et al., Science (Wash.
  • CCR-5 ⁇ 32 a defective CCR-5 allele that contains an internal 32-base pair deletion
  • the truncated protein encoded by this gene is apparently not expressed at the cell surface.
  • CCR-5 ⁇ 32 homozygous individuals comprise ⁇ 1% of the Caucasian population and heterozygous individuals comprise -20%. In studies of about 2700 HIV-1 infected individuals, no ⁇ 32 homozygotes were found. Individuals who are heterozygous for ⁇ 32 CCR-5 allele have been shown to progress more slowly to
  • CCR-5 as the principle coreceptor for primary HIV isolates provides an opportunity to understand disease pathogenesis, and more importantly to identify a new avenue for the treatment of HIV-1 infection.
  • the instant invention is a series of functionalized heterocycles that block the CD-4/GP-120 interaction with CCR-5 receptor, and thus can be useful in the treatment of HIV infection manifested in AIDS.
  • the compounds of the invention are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation comprising the administration of an effective amount of the compound.
  • the present invention is directed to the use of the foregoing substituted heterocycles as modulators of chemokine receptor activity.
  • these compounds are useful as modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR1, CXCR2, and/or CXCR-4.
  • the compounds of the present invention are preferred as modulators of the chemokine receptor CCR-5.
  • the compounds of the instant invention are those of Formula I which may exist in both closed and open form.
  • A is O, S, and additionally A is NRj when X is C-R9;
  • X is N when A is NRj or
  • X is C-R9 wherein R9 is halogen, hydrogen, alkyl, -CF3, CH2F, CHF2,
  • each occurrence of m is independently an integer of from 0 to 2, q is an integer of from 0 to 1, and r is an integer of from 0 to 3;
  • Y is hydrogen, alkyl, arylalkyl, aryl, (CH 2 ) m - NR 7 R 8' -N(R])-(CH 2 ) V - C(RyRg)-aryl, or ORJ Q wherein RJ Q is hydrogen, alkyl, cycloalkyl, cycloalkyl fused to an aryl ring, aryl, (CH2) s aryl, -CH 2 CF3, (CH2)tC(R7R 8 )-(CH2)uaryl,
  • s is an integer of from 1 to 3
  • t is an integer of from 0 to 3
  • u is an integer of from 0 to 3
  • v is an integer of from 1 to 3
  • w is an integer of from 0 to 2;
  • Z is CR or N
  • R ⁇ is hydrogen or alkyl and each occurrence of R1 is independently hydrogen or alkyl; R and R2 are each independently selected from: hydrogen, alkyl, halogen,
  • R 7 and R 8 are each independently hydrogen, alkyl, aryl, arylalkyl, -CF3, or R and R 8 may be taken together to form a cyclic ring of from
  • R3 is hydrogen or alkyl
  • R4 is hydrogen, alkyl, aryl, or aralkyl
  • R5 is alkyl, aryl, arylalkyl, acyl
  • R4 and R5 are taken together with the atoms to which they are attached to form a cyclic ring of from 5 to 7 atoms;
  • Rg is hydrogen or alkyl
  • R5 when not taken together with R4 can be taken together with R5 with the atoms to which they are attached to form a ring of from 5 to 7 atoms; N-R5 is also the corresponding N-oxide;
  • R ⁇ 1 is hydrogen or alkyl; n is an integer of from 1 to 3; j is an integer of from 1 to 2, and j is the integer 0 when Y is hydrogen, alkyl, arylalkyl, or aryl; with the proviso that pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l- carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ethyl ester is not included.
  • Preferred compounds are those of Formula 1 above wherein Ri is hydrogen.
  • X is C-R9.
  • Still other preferred compounds are those wherein R ] is hydrogen and
  • X is C-R9, wherein R9 is alkyl.
  • Still other preferred compounds are those wherein R] is hydrogen
  • X is C-R9, wherein R9 is alkyl; R4 and R5 are taken together with the atoms to which they are attached to form a ring of from 5-7 atoms; and Y is OR 10 . Still other preferred compounds are those wherein Rj is hydrogen, X is C-R9, wherein R9 is alkyl;
  • R4 and R5 are taken together to form a 6-membered ring
  • Y is ORJ O wherein RJ Q is alkyl, aryl or -(CH2) s aryl,
  • Still other preferred compounds are those wherein R] is hydrogen
  • X is C-R9, wherein R9 is Me
  • R4 and R5 are taken together to form a 6-membered ring
  • Rg is hydrogen; n is 2; and Y is ORjo wherein Ri Q is alkyl, aryl or RJQ is -(CH2)t-C(R 7 R 8 )-
  • R 7 and R can each independently be H, alkyl,
  • More preferred compounds are those of Formula 1 and selected from: Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, methyl ester;
  • 1,3-Benzenedicarboxylic acid 5-[[[[(3,7,8,9,10,12,13,14,14a,15- decahydro-2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin- l-yl)carbonyl]oxy]methyl]-, diethyl ester; 1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15- decahydro-2-methylpy ⁇ olo[3 ⁇ 2':5,6][l]benzopyrano[3,2-i]quinolizin- 1 -yl)carbonyl]oxy]methyl]-;
  • the instant invention includes pharmaceutical compositions of compounds of Formula 1 and methods of using the compounds for modulating chemokine receptor activity, for preventing or treating infection by HIV, delaying the onset of AIDS, treating AIDS, and treating inflammatory disease.
  • alkyl means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, /z-propyl, isopropyl, ??-butyl, sec-butyl, isobutyl, tert-butyl, «-pentyl, /.-hexyl, 72-heptyl, /.-octyl, and the like.
  • the alkyl can be substituted with fluorine, for example, additionally the alkyls can be substituted with from 1 to 3 substituents selected from alkoxy, carboxy, hydroxy, nitro, halogen, amino, and substituted amino to provide other active compounds.
  • Alkyl includes cycloalkyl of from 3 to 7 carbons which can be substituted with, for example, 1 to 3 substituents selected from alkyl, alkoxy, carboxy, hydroxy, nitro, halogen, and amino and substituted amino. Cycloalkyl can be fused to an aryl ring such as phenyl, pyridyl, and the like.
  • Alkoxy is O-alkyl of from 1 to 6 carbon atoms as defined above for alkyl.
  • Acyl is -C-alkyl, wherein alkyl is as defined above.
  • aryl means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as defined for alkyl, nitro, cyano, carboxy, O O O O
  • alkyl II defined above for alkyl, -C-N(alkyl)2 as defined above for alkyl, -(CH2) n 2-NH2 wherein n ⁇ is an integer of 1 to 5, -(CH2)n2-NH-alkyl as defined above for alkyl and n ⁇ , -(CH2) n 2-N(alkyl)2 as defined above for alkyl and x?-.
  • the term further includes heteroaryl which is a mono or bicyclic heteroaromatic radical having 5 to
  • heteroatom such as N, O, S, including, for example, 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl.
  • heteroaryls can be unsubstituted or substituted as above for aryl.
  • aralkyl or arylalkyl means an aryl radical attached to an alkyl radical wherein aryl and alkyl are as defined above, for example, benzyl, fluorenylmethyl, and the like.
  • Halogen is fluorine, chlorine, bromine, or iodine.
  • Some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with the ring nitrogen atom at N-l 1. Further, some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with nitrogen atoms optionally present in RJO- These structural forms are within the scope of the present invention.
  • Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids,
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M. et al., "Phannaceutical Salts,” J. ofPharma. Sci, 1977;66:1).
  • the acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge supra., 1977).
  • the base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner.
  • the free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration.
  • the present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Additionally, the compounds of the present invention may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of the present invention can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • Such liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds utilized in the pharmaceutical method of this invention can be administered at the initial dosage of about 1 mg to about 100 mg per kilogram daily.
  • a daily dose range of about 25 mg to about 75 mg per kilogram is preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • the compounds of Formula I are valuable antagonists of the CCR-5 chemokine receptor. Compounds which are antagonists of the CCR-5 chemokine receptor are expected to have efficacy in inhibiting HIV infection and are thus useful in the treatment of AIDS. The compounds of the present invention were evaluated in a CCR-5 receptor binding assay.
  • the 125 ⁇ _gpi20/sCD4/CCR-5 binding assay was carried out similarly as described in Wu et al., N ⁇ twre, 1996;384:179-183. Briefly, the envelope g ⁇ l20 protein derived from HIV-1 JR-FL (Trkola et al., Nature, 1996;384:184-186), a M-tropic strain, was iodinated using solid phase lactoperoxidase to a specific activity of 20 ⁇ Ci/ ⁇ g.
  • binding reaction in a final volume of 100 ⁇ L binding buffer [50 mM HEPES, pH 7.5, 1 mM CaCl 2 , 5 mM MgCl 2 , and 0.5% BSA]
  • 25 ⁇ L (2.5 ⁇ g) of membranes prepared from CCR-5/L 1.2 cells were mixed with 25 ⁇ L (3 nM) sCD4, followed by 25 ⁇ L (0.1 nM) radio-labeled gpl20 in the presence or absence of 25 ⁇ L compound dissolved in DMSO (final concentration of DMSO 0.5%).
  • the reactions were incubated at room temperature for 45 to 60 minutes and stopped by transferring the mixture to GFB filter plates, which were then washed 3 to 4 times with binding buffer containing 0.5 M ⁇ aCl. The plates were dried and MicroScint scintillation fluid was added before counting.
  • the compounds of present invention block the sCD-4/GP-120 binding to CCR-5 receptor with affinity less than or equal to 200 ⁇ M.
  • indole intermediates The preparation of indole intermediates is shown in Scheme II. Reaction of bromoacetate with nitriles in an aprotic solvent, preferably THF, in the presence of activated Zn at reflux under nitrogen atmosphere gives amino crotonates V. Alternatively, amino crotonates V can be obtained by reacting the corresponding ⁇ -ketoester with ammonia in EtOH.
  • the ⁇ -ketoesters can be derived from 2,2,6- trimethyl-4H-l,3-dioxin-4-one and the corresponding alcohols.
  • Esters or amides IX can be made from acid VIII following several standard esterification procedures or a standard procedure for amide synthesis using HBTU as the coupling reagent.
  • ester synthesis Mitsunobu procedure is preferred where appropriate alcohols, DEAD, and PI13P are used, and the reaction is carried out at ambient temperature.
  • Another preferred procedure to make esters is treating the acid with a base, preferably DBU, and alkylhalides or arylalkylhalides in a polar solvent, preferably DMF or acetonitrile at ambient temperature.
  • a base preferably DBU
  • alkylhalides or arylalkylhalides in a polar solvent, preferably DMF or acetonitrile at ambient temperature.
  • R' H or CH 3 CO
  • the substituted 5-hydroxybenzofurans (C) were prepared by condensing the appropriate 1,4-benzoquinone (A) with the appropriate 3-aminocrotonate (B) in acetic acid. The solvent was removed in vacuo, and the product was purified by recrystalhzation or flash chromatography on silica gel.
  • the mannich base (E) was added to a dioxane solution of enamine (F), which was freshly prepared by treating its perchlorate salt with aqueous sodium hydroxide, extracting the enamine into ether, drying and concentrating the extracts in vacuo.
  • the resulting solution was heated between 80-100°C until the reaction was complete.
  • the mixture was concentrated in vacuo and the product purified by recrystalhzation or flash chromatography on silica gel.
  • the iodopyridine 3 is then converted to the azaindole 4 via palladium catalyzed cyclization with the appropriately substituted alkyne (Tetrahedron Lett., 1998;39:5355; Tetrahedron Lett., 1993;34:2823). Conversion of 3 to 4 is followed by oxidation of the hydroxymethylene to the corresponding acid 5 using
  • Compound I in an aprotic solvent preferably E-2O, CH2CI2, or THF
  • a solution of oxalyl chloride in the same aprotic solvent at temperatures ranged from -10°C to 30°C, preferably at 0°C to 25°C, followed by treatment of an amine of choice in an aprotic solvent to give the desired product II.
  • the desired product III can be obtained by reacting compound I with oxalyl chloride in an aprotic solvent, preferably Et2 ⁇ , CH2CI2, or THF, at temperatures ranged from
  • the desired product III can be made by reacting compound I with compound IV in an aprotic solvent such as Et2 ⁇ , CH 2 C1 2 , or THF.
  • the benzylester I is subjected to hydrogenolysis reaction conditions in aprotic polar solvents, preferably THF, at ambient temperature to give acid II.
  • aprotic polar solvents preferably THF
  • the acid II is treated subsequently with benzoyl chloride in presence of an organic base, such as Et3N, to afford the mixed anhydride III.
  • the mixed anhydride I is mixed with the desired alcohol, the resultant reaction mixture was heated to 100°C to 180°C until the mixed anhydride is consumed affording the corresponding ester.
  • the present invention is further directed to combinations of the present compounds with one or more agents useful in the prevention or treatment of AIDS.
  • the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the anti-HIV compounds, immunomodulators, anti-infectives, or prophactic or therapeutic vaccines known to those of ordinary skill in the art.
  • HIVID Hoffman-La Roche HIV infection, AIDS, ARC Dideoxycytidine ddl Dideoxyinosine Bristol-Myers Squibb HIV infection, AIDS, ARC; combination with AZT/d4T
  • Efavirenz DMP 266
  • ARC non-nucleoside RT inhibitor
  • Famciclovir Smith Kline Herpes zoster, herpes simplex Foscavir/Foscarnet Astra CMV, HSV l-2 ANTIVIRALS (cont'd)
  • Roussel non-nucleoside reverse transcriptase inhibitor
  • Lamivudine 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT
  • PNU- 140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor)
  • Enkephalin (Chicago, IL) MTP-PE Muramyl- Ciba-Geigy Corp. Kaposi's sarcoma
  • Tripeptide Granulocyte Colony Amgen AIDS in combination w/AZT
  • Tumor Necrosis Genentech ARC in combination w/gamma Factor; TNF Interferon
  • Isethionate (IM & (Rosemont, IL)
  • Erythropoietin AZT therapy Recombinant Human Serono AIDS-related wasting, cachexia
  • the solution was concentrated in vacuo to give an oily mixture; a solution of 1 : 1 hexane/ethyl acetate was used to redissolve the oil.
  • the desired product was purified by flash chromatography. Residual diethylhydrazinedicarboxylate remaining in the product was removed by trituration with hot water; the resulting solid was dried under vacuum at 40°C.
  • the 5-acetyl group was removed in the following manner: the protected ester (1 eq) was dissolved in a small amount of MeOH. NaOMe (4 eq) was added and the mixture stirred until no starting material remained (-45 minutes).
  • the pH of the solution was adjusted to 1 with the addition of aqueous HCI, and a copious white precipitate occurred.
  • the solid was filtered, washed with water (2 x 20 mL), and dried under vacuum at 40°C.
  • the pH of the solution was adjusted to 1 with the addition of aqueous HCI, and the solution was extracted with ethyl acetate (2 x 25 mL).
  • the organic layer was dried over Na2SO4 and evaporated to give a solid.
  • the solid may be further purified by recrystalhzation from appropriate solvents. According to the Procedure A,
  • Intermediate C can be synthesized from Intermediate B according to the procedure described in Example 9, Step A.
  • Procedure C A General Procedure for the Synthesis of ethyl 3-alkyl- 3-aminocrotonates (K-O)
  • Activation of Zn To a stirred 3N HCI solution (50 mL) was added Zn (20 g) and stirred at room temperature for 15 minutes. The HCI solution was decanted, and this was repeated two times. The activated Zn was washed with distilled H 2 O (2 ⁇ , 100 mL), ethanol (2 ⁇ , 50 mL), and ether (2 ⁇ , 50 mL). The activated Zn was then placed under reduced pressure for 12 hours at 40°C.
  • Procedure D General procedure for the synthesis of ethyl 2-alkyl-5-hydroxy-
  • Procedure F General procedure for deacylation of the amides The amide of interest (1 eq) was dissolved in a small amount of MeOH.
  • Step A 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-fluoro-benzyl ester
  • DMF dimethyl methyl-N-(2-aminoethyl)-2-methyl-lH-indole-3-carboxylic acid
  • Step B 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-fluoro-benzyl ester
  • Step C Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 8,9, 11 , 12, 13 , 13a, 14, 14a-octahydro-2-methyl-, (4-fluorophenyl)methyl ester
  • Step A 4-Dimethylaminomethyl-lH-indol-5-ol
  • Step B 1,2,3,4,6,7,8,9-Octahydro-quinolizinylium perchlorate
  • Step C Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12,13,14,14a,15-decahydro-
  • a mixture of perchlorate salt (406 mg, 1.71 mmol, Example 3, Step B) and 20 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL). The combined ether layer was dried over Na 2 SO4 and concentrated in vacuo.
  • Step B 4-Dimethylaminomethyl-2-methyl-lH-indol-5-ol
  • Step C Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-
  • a mixture of perchlorate salt 973 mg, 4.10 mmol, Example 3, Step B
  • 30 mL of ether was added 40 mL of aqueous NaOH (2N).
  • the resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 40 mL). Combined ether layer was dried over Na 2 SO4 and concentrated in vacuo.
  • the residual oil was dissolved in 7 mL of dioxane, then 4-dimethylaminomethyl-
  • Step A 6-Bromo-4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3- carboxylic acid ethyl ester 6-Bromo-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester, prepared according to the literature procedure [Bell M.R.; Oesterlin R.; Beyler A.L.; Harding H.R.; Potts G.O., J. Med. Chem., 1967;10:264-266], (3.01 g, 10.1 mmol) and aqueous Me2NH (40%>, 2.79 mL, 22.2 mmol) were mixed with
  • Step B 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid propyl ester 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid propyl ester (1.27 g, 5.43 mmol) and aqueous Me2NH (40%, 1.50 mL, 12.0 mmol) were mixed with 10 mL of EtOH, the mixture was heated with a heat gun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%, 0.528 g, 6.52 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was then concentrated in vacuo to reduce the volume by half. Precipitate formed. Filtration and drying under vacuum gave 0.86 g (54%) of pure titled compound as a white solid: mp 135-137°C (dec);
  • Step B To a mixture of perchlorate salt (0.458 g, 1.93 mmol, Example 3, Step B) and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL). Combined ether layer was dried over Na 2 SO4 and concentrated in vacuo. The residual oil was dissolved in 5.0 mL of dioxane, then indole mannich base
  • Step B To a mixture of perchlorate salt (0.710 g, 2.23 mmol, Example 3, Step B) and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 5.0 mL of dioxane, then indole Mannich base
  • Step A 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester was synthesized from intermediate C according to Procedure G
  • Step B By a procedure similar to that described in Example 7, Step C.
  • Step C Yield: 0.269 g (50.7%); mp 199-200°C; IR: 3376, 3337, 2932, 2857, 1698, 1669, 1433,
  • Procedure I General Procedure for the Synthesis of Ethyl 2-alkyl- [(pyrano[2,3-b]quinolizidine)[5,6-e]]indole-3-carboxylate. To a stirred solution of NaOH (50% w/w, 100 mL) and ether (20 mL) was added iminium perchlorate salt
  • Step B Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid
  • Step A tert-Butyl 3-amino-3-methylcrotonate Activation of Zn: To a stirred 3N HCI solution (50 mL) was added Zn (20 g) and stirred at room temperature for 15 minutes. The HCI solution was decanted, and this was repeated two times. The activated Zn was washed with distilled H2O (2x, 100 mL), ethanol (2 ⁇ , 50 mL), and ether (2x, 50 mL). The activated Zn was then placed under reduced pressure for 12 hours at room temperature.
  • Step B tert-Butyl 5-hydroxy-2-methyl-3-indolecarboxylate.
  • 1 ,4-Benzoquinone (3.30 g, 30 mmol) in ethanol (15 mL) was heated up until all solid was dissolved.
  • tert-Butyl 3 -amino-3 -methyl crotonate (5.50 g, 35 mmol) in ethanol (15 mL) was added to the hot solution, and the reaction mixture was refluxed for 6 hours, cooled, and concentrated under reduced pressure. The residue was subjected to flash column chromatography (AI2O3, ethyl acetate) to afford 3.57 g of title compound (14.4 mmol, 48%) as a brown crystal, mp 114.0-116.0°C.
  • Step C tert-Butyl 4-(dimethylamino)methylene-5-hydroxy-2-methyl- 3-indolecarboxylate.
  • tert-butyl 5-hydroxy-2-methyl- 3-indolecarboxylate (1.48 g, 6.0 mmol) in ethanol (4.5 mL) was added formaldehyde (0.55 mL, 7.2 mmol) and dimethylamine (1.66 mL, 13.2 mmol). The solution was stirred at 60°C for 10 hours, cooled and concentrated under reduced pressure.
  • Step A l,6-Dimethyl-l,2,3,4-tetrahydro-pyridine l,6-Dimethyl-l,2,3,4-tetrahydro-pyridine was synthesized according to the procedure published in Lipp A., Liebigs Ann. Chem., 1898;289:216.
  • Step B 2,6a,7-Trimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-3,7-diaza- cyclopenta[a]anthracene-l -carboxylic acid ethyl ester
  • Step A l-Ethyl-6-methyl-2,3,4,5-tetrahydropyridinium perchlorate l-Ethyl-6-methyl-2,3,4,5-tetrahydropyridinium perchlorate was synthesized according to the procedure published in Ladenburg A., Liebigs Ann. Chem., 1899;304:54.
  • Step B 7-Ethyl-2,6a-dimethyl-7,8,9,l 0,10a, 11 -hexahydro-3H,6aH-6-oxa-
  • Step A 6-Ethyl-l-methyl-2,3,4,5-tetrahydropyridinium perchlorate
  • 6-Ethyl-l-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate was synthesized according to the procedure published in Leonard N.J.; Hauck, Jr., F.P., J. Am. Chem. Soc, 1957;79:5279.
  • Step B 6a-Ethyl-2,7-dimethyl-7,8,9,l 0,10a, 11 -hexahydro-3H,6aH-6-oxa-
  • 6-Ethyl-l-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate (0.712 g, 3.16 mmol, Example 21, Step A) was dissolved in a minimum amount of water and treated with 50%> aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et 2 O, and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated into the reaction flask to give 6-ethyl-l -methyl- 1,2,3, 4-tetrahydro- pyridine.
  • Step A l,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate 1 ,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate was synthesized according to the procedure published in Leonard N.J., Hauck, Jr., F.P., J. Am. Chem. Soc, 1957;79:5279.
  • Step B 6a,7-Diethyl-2-methyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester l,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate (0.485 g,
  • Example 23 Step A was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et 2 O, and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated into the reaction flask to give 207 mg (1.49 mmol) of 1,6-diethyl- 1,2,3,4-tetrahydro-pyridine. The residue was dissolved in dioxane (1.3 mL) and
  • Step A l-Benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate l-Benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate was synthesized according to the procedure published in M ⁇ hrle H.; Dwuletzki H.Z., Naturforsch., B: Anorg. Chem., Org. Chem., 1986;41b:1323.
  • Step B 7-Benzyl-2,6a-dimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-
  • Step A l-Methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate
  • Step B 2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-
  • Step A 2,3,5,6,7,8-Hexahydro-lH-indolizinylium perchlorate 2,3,5,6,7,8-Hexahydro-lH-indolizinylium perchlorate was synthesized according to the procedure published in Reinecke M.G.; Kray L.R., J. Org. Chem., 1964;29:1736.
  • Step B lH,7H-Indolizino[8',8a':5,6]pyrano[3,2-e]indole-l-carboxylic acid, 8,9,1 l,12,13,13a,14,14a-octahydro-2-methyl-, ethyl ester 2,3,5,6,7,8-Hexahydro-lH-indolizinylium perchlorate (0.330 g,
  • Example 27 Example 27, Step A was dissolved in a minimum amount of water and treated with 50%> aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et O, and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated into the reaction flask to give 143 mg (1.16 mmol) of enamine. 1 ,2,3,5,6,7-Hexahydro-indolizine was dissolved in dioxane (1.5 mL) and
  • Step A 1, 2,3, 5, 6,7-Hexahydro-pyrrolizinylium perchlorate
  • Step B 3H,7H-Pyrrolizino[r,8':5,6]pyrano[3,2-e]indole-l-acetic acid, 8,9,1 1 ,12,12a, 13-hexahydro-2-methyl-, ethyl ester 1,2,3,5,6,7-Hexahydro-pyrrolizinylium perchlorate (0.904 g, 4.31 mmol,
  • Example 28 was dissolved in a minimum amount of water and treated with 50%) aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et2 ⁇ , and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated into the reaction flask to give 325 mg (2.98 mmol) of enamine, 2,3,5,6-tetrahydro-lH- pyrrolizine.
  • Step A 1 ,3,4,8, 9, 9a-Hexahydro-2H-quinolizine l,3,4,8,9,9a-Hexahydro-2H-quinolizine was synthesized according to the procedure published in Bohlmann F. et al., Chem. Ber., 1973;106:3026.
  • Step B 2-Methyl-8,9,10,10a,l l,12,12a,13-octahydro-3H,6aH,7H-6-oxa-3,6b- diaza-benzo[a]cyclopenta[h]anthracene-l -carboxylic acid ethyl ester 1, 3,4,8, 9,9a-Hexahydro-2H-quinolizine (0.372 g, 2.71 mmol, Example 29, Step A) was dissolved in dioxane (2.7 mL) and 4-dimethylaminomethyl-5- hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.374 g, 1.36 mmol) was added.
  • Example 30 3H-pyrido[l",2":r2']azepino[3'2':5,6]pyrano[3,2-e]indole-l -acetic acid, 7,8,9,10,12,13, 14,15, 15a,16-decahydro-2-methyl-, ethyl ester, or 7H-Azepino[l",2":l"2']pyrido[3',2':5,6] ⁇ yrano[3,2-e]indole-l-acetic acid, 3,8,9,10,11, 13, 14,15,15a,16-decahydro-2-methyl-, ethyl ester
  • Step A 2,3,4,6,7,8,9,10-Octahydro-pyrido[l,2-a]azepine perchlorate
  • Procedure K General procedure for the condensation reaction: 1,2,3,4,6,7,8,9- octahydro-quinolizinylium perchlorate (17.8 mmol, 1.2 eq) was converted to the enamine in the following manner: the imine was dissolved in IN NaOH (10 mL) and the solution extracted with 2 x 20 mL of diethyl ether. The extracts were combined dried, and evaporated under vacuum to yield a white solid. The solid was dissolved in dioxane (10 mL).
  • Step A 4-Dimethylaminomethyl-5-hydroxy-2-methyl- 1 H-indole-3-carboxylic acid benzyl amide was synthesized from Intermediate X according to Procedure J. Yield: 0.582 g (69.2%); mp: 208-210 °C; IR: 3312, 1610, 1510, 1437, 1207, 747,
  • Example 32 was synthesized according to Procedure K. Yield: 0.228 g (35.9%); mp: 235-237°C; IR: 3177, 2929, 1627, 1429, 1089 cm " 1 . 1H NMR
  • Step A 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid ethylamide
  • 5-Hydroxy-2-methyl-l-H-indole carboxylic acid (3.28 g, 17.2 mmol) was dissolved in dry DMF (20 mL) under nitrogen atmosphere and cooled to 0°C in an ice-water bath.
  • To this solution were added in succession triethylamine (2.39 mL, 17.2 mmol) and solid O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.51 g, 17.2 mmol).
  • reaction mixture was stirred at that temperature for 15 minutes, gaseous ethylamine was bubbled in for 10 minutes. After sequentially 15 minutes stirring at 0°C and 15 minutes at ambient temperature, reaction mixture was mixed with 60 mL of EtOAc, the resulting mixture was successively washed with IN HCI aqueous solution (2 x 60 mL), brine (2 x 60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a solid. The crude product was further purified by flash chromatography (100%> EtOAc) followed by recrystalhzation from EtOAc to provide 0.81 g (18%) of pure titled compound as a white solid: mp 199-201°C
  • Step B 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethylamide 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid ethylamide (0.708 g, 3.24 mmol) was mixed with 7 mL of EtOH, aqueous Me2NH (40%, 0.895 mL,
  • Step C Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxamide, N- ethyl-8,9,l l,12,13,13a,14,14a-octahydro-2-methyl-
  • perchlorate salt 263 mg, 1.11 mmol, Example 3, Step B
  • 30 mL of ether was added 40 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved.

Abstract

The present invention is a novel series of functionalized heterocycles as chemokine receptor modulators of Formula (I) useful as modulators of chemokine receptor activity. The compounds are useful in the treatment and prevention of the AIDS virus. Intermediates useful in the prepartion of the final products, pharmaceutical compositions containing the final products are also taught.

Description

FUNCTIONALIZED HETEROCYCLES AS CHEMOKINE
RECEPTOR MODULATORS
BACKGROUND OF THE INVENTION
The present invention relates to functionalized heterocycles useful as modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A,
CCR-2B, CCR-3, CCR-4, CCR-5, CXCR1, CXCR2, CXCR-3, and/or CXCR4 and to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier. More particularly, the present invention is directed to methods for inhibiting HIV infectivity. Chemokines mediate a range of proinflammatory effects on leukocytes, such as chemotaxis, degranulation, and intigran activation (Baggiolini et al., Adv.
Immunol, 1994;55:97-179; Oppenheim et a\., Annu. Rev. Immunol., 1991;
9:617-48; Miller et al., Crit. Rev. Immunol, 1992;12: 17-46). These effects are mediated by binding to the seven-transmembrane-spanning G-protein coupled receptors (Baggiolini et al., Adv. Immunol, 1994;55:97-179; Murphy, Annu. Rev.
Immunol, 1994;12:593-633; Schall et al., Curr. Opin. Immunol, 1994;6:865-73;
Gerard et al., Curr. Opin. Immunol, 1994;6; 140-5; Mackay, Curr. Bio., In press).
Chemokine receptors also serve as coreceptors for HIV-1 entry into cells. This came from observations that RANTES, MlP-lα, and MlP-l β suppressed infection of susceptible cells in vitro by macrophage-tropic primary HIV-1 isolates
(Cocchi et al., Science (Wash. DC), 1995 ;270:1811-5). The chemokine receptor
CXCR-4 was found to support infection and cell fusion of CD4+ cells by laboratory-adapted, T-tropic HIV-1 strains (Feng et al., Science (Wash. DC), 1996;272:872-7). CCR-5, a RANTES, MlP-lα, and MlP-lβ receptor, was subsequently identified as the principle coreceptor for primary macrophage-tropic strains (Choe et al., Cell, 1996;85:1135-48; Alkhatib et al., Science (Wash. DC), 1996;272:1955-8; Doranz et al., Cell, 1996;85:1149-58; Deng et al, Nature (Lond.) 1996;381 :661-6; Dragic et al., Nature (Loud.), 1996;381 :667-3). The importance of CCR-5 for HIV-1 transmission was underscored by the observation that certain individuals who had been repeatedly exposed to HIV-1 but remained uninfected had a defect in CCR-5 expression (Liu et al., Cell, 1996; 86:367-77; Samson et al., Nature (Lond.), 1996;382:722-5; Dean et al., Science (Wash. DC), 1996;273:1856-62; Huang et al., Nature Med., 1996;2:1240-3). These noninfectable individuals were found to be homozygous for a defective CCR-5 allele that contains an internal 32-base pair deletion (CCR-5 Δ32). The truncated protein encoded by this gene is apparently not expressed at the cell surface. CCR-5 Δ32 homozygous individuals comprise ~1% of the Caucasian population and heterozygous individuals comprise -20%. In studies of about 2700 HIV-1 infected individuals, no Δ32 homozygotes were found. Individuals who are heterozygous for Δ32 CCR-5 allele have been shown to progress more slowly to
AIDS than wild-type homozygous individuals (Samson et al., Nature (Loncl), 1996;382:722-5; Dean et al., Science (Wash. DC), 1996;273:1856-62; Huang et al., Nature Med., 1996;2:1240-3). Thus, the identity of CCR-5 as the principle coreceptor for primary HIV isolates provides an opportunity to understand disease pathogenesis, and more importantly to identify a new avenue for the treatment of HIV-1 infection.
The instant invention is a series of functionalized heterocycles that block the CD-4/GP-120 interaction with CCR-5 receptor, and thus can be useful in the treatment of HIV infection manifested in AIDS.
SUMMARY OF THE INVENTION
The compounds of the invention are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation comprising the administration of an effective amount of the compound.
The present invention is directed to the use of the foregoing substituted heterocycles as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR1, CXCR2, and/or CXCR-4. In particular, the compounds of the present invention are preferred as modulators of the chemokine receptor CCR-5. The compounds of the instant invention are those of Formula I which may exist in both closed and open form.
ring close ring open
or a pharmaceutically acceptable salt thereof wherein: A is O, S, and additionally A is NRj when X is C-R9;
X is N when A is NRj or
X is C-R9 wherein R9 is halogen, hydrogen, alkyl, -CF3, CH2F, CHF2,
-(CH2)m-OR1, aryl, arylalkyl, -(CH2)m-NR7R8, or
(CH2)n wherein m is an integer of from 0 to 2 and
each occurrence of m is independently an integer of from 0 to 2, q is an integer of from 0 to 1, and r is an integer of from 0 to 3; Y is hydrogen, alkyl, arylalkyl, aryl, (CH2)m-NR7R8' -N(R])-(CH2)V- C(RyRg)-aryl, or ORJ Q wherein RJ Q is hydrogen, alkyl, cycloalkyl, cycloalkyl fused to an aryl ring, aryl, (CH2)saryl, -CH2CF3, (CH2)tC(R7R8)-(CH2)uaryl,
cyc oalkyl
wherein s is an integer of from 1 to 3, t is an integer of from 0 to 3, u is an integer of from 0 to 3, v is an integer of from 1 to 3, and w is an integer of from 0 to 2;
Z is CR or N;
R\ is hydrogen or alkyl and each occurrence of R1 is independently hydrogen or alkyl; R and R2 are each independently selected from: hydrogen, alkyl, halogen,
-CN,
-NO2,
-(CH2)m-NR7R8, -(CH2)m-COOR7, -(CH2)m-CONR7R8,
O I
-(CH2)mN-S-R7 ,
O
-(CH2)m-OR7, -(CH2)m-SO NR7R8, and
-(CH2)m-S(O)pR7 wherein each occurrence of R7 and R8 are each independently hydrogen, alkyl, aryl, arylalkyl, -CF3, or R and R8 may be taken together to form a cyclic ring of from
3 to 7 atoms which ring may have O, S, or NRj and p is an integer of from 0 to 2 ;
R3 is hydrogen or alkyl;
R4 is hydrogen, alkyl, aryl, or aralkyl;
R5 is alkyl, aryl, arylalkyl, acyl; or
R4 and R5 are taken together with the atoms to which they are attached to form a cyclic ring of from 5 to 7 atoms;
Rg is hydrogen or alkyl;
R5 when not taken together with R4 can be taken together with R5 with the atoms to which they are attached to form a ring of from 5 to 7 atoms; N-R5 is also the corresponding N-oxide;
R} 1 is hydrogen or alkyl; n is an integer of from 1 to 3; j is an integer of from 1 to 2, and j is the integer 0 when Y is hydrogen, alkyl, arylalkyl, or aryl; with the proviso that pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l- carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ethyl ester is not included. Preferred compounds are those of Formula 1 above wherein Ri is hydrogen.
Other preferred compounds are those of Formula 1 above wherein Ri is hydrogen and
X is C-R9.
Still other preferred compounds are those wherein R] is hydrogen and
X is C-R9, wherein R9 is alkyl.
Still other preferred compounds are those wherein R] is hydrogen,
X is C-R9, wherein R9 is alkyl; R4 and R5 are taken together with the atoms to which they are attached to form a ring of from 5-7 atoms; and Y is OR10. Still other preferred compounds are those wherein Rj is hydrogen, X is C-R9, wherein R9 is alkyl;
R4 and R5 are taken together to form a 6-membered ring; and
Y is ORJ O wherein RJ Q is alkyl, aryl or -(CH2)saryl,
-(CH2)rC(R7R8)-(CH2)u-aryl.
Still other preferred compounds are those wherein R] is hydrogen,
X is C-R9, wherein R9 is Me;
R4 and R5 are taken together to form a 6-membered ring;
Rg is hydrogen; n is 2; and Y is ORjo wherein Ri Q is alkyl, aryl or RJQ is -(CH2)t-C(R7R8)-
(CH2)u-aryl wherein t is 0, R7 and R can each independently be H, alkyl,
-(CH2)vOH or (CH2)uCOOR7, and -(CH2)vNRιR2 where u and v are as defined above. More preferred compounds are those of Formula 1 and selected from: Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, methyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-bromo-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ethyl ester;
Pyrrolo[3', 2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, propyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-methylpropyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2,2-dimethylpropyl ester; Pyrrolo[3',2 ':5, 6] [l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7, 8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, phenylmethyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 1 -methylethyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, cyclopropylmethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 2-( 1 -piperidinyl)ethyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-(phenylmethyl)-, ethyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 2- ethyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 2- cyclopropyl-3, 7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-, ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-propyl-, ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-(2-methylpropyl)-, ethyl ester; Pyrrolo[3 ' ,2 ' :5 ,6] [ 1 ]benzopyrano[3 ,2-i]quinolizine- 1 -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 , 1 -dimethylethyl ester;
2,6a,7-Trimethyl-7, 8,9,10,10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-di aza- cyclopenta[a]anthracene-l -carboxylic acid ethyl ester;
7-Ethyl-2,6a-dimethyl-7,8,9, 10, 10a, 11 -hexahydro-3H,6aH-6-oxa- 3, 7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester;
6a-Ethyl-2,7-dimethyl-7,8,9, 10, 1 Oa, 1 1 -hexahydro-3H,6aH-6-oxa- 3, 7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester;
6a,7-Diethyl-2-methyl-7,8,9, 10, 1 Oa, 1 1 -hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester; 7-Benzyl-2,6a-dimethyl-7,8,9, 10, 1 Oa, 11 -hexahydro-3H,6aH-6-oxa-
3,7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester;
2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 3, 7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-e]indole-l -carboxylic acid, 8,9,11,12,13, 13a,14,14a-octahydro-2-methyl-, ethyl ester;
3H,7H-Pyrrolizino[l ',8':5,6]pyrano[3,2-e]indole-l -acetic acid, 8,9,1 1,12,12a, 13-hexahydro-2-methyl-, ethyl ester;
2-Methyl-8,9, 10, 1 Oa, 11 , 12, 12a, 13-octahydro-3H,6aH,7H-6-oxa-3 ,6b- diaza-benzo[a]cyclopenta[h]anthracene-l -carboxylic acid ethyl ester; 3H-Pyrido[l",2":l'2']azepino[3'2':5,6]pyrano[3,2-e]indole-l-acetic acid,
7, 8, 9,10,12, 13, 14,15, 15a,16-decahydro-2-methyl-, ethyl ester or 7H-Azepino[l",2": 2']pyrido[3',2':5,6]pyrano[3,2-e]indole-l -acetic acid, 3,8,9,10,11, 13,14,15, 15a,16-decahydro-2-methyl-, ethyl ester;
Pyrrolo[3 ' ,2 ' : 5,6] [ 1 Jbenzopyrano [3 ,2-i]quinolizine- 1 -carboxamide, 8,9,1 1, 12,13, 13a,14,14a-octahydro-2-methyl-N-(phenylmethyl)-;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxamide, N- ethyl-8,9,11, 12,13, 13a,14,14a-octahydro-2-methyl-; Pyrrolo[3\2\'5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxaldehyde, 8,9, 11, 12, 13, 13a, 14, 14a-octahydro-2-methyl-;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l- carboxamide,8,9,l 1,12,13,13a, 14, 14a-octahydro-N,2-dimethyl-; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
8,9,1 l,12,13,13a,14,14a-octahydro-2-methyl-, (4-fluorophenyl)-methyl ester;
Indazolo[4',5':5,6]pyrano[3,2-/]quinolizine-l-carboxylic acid, 3,7,8,9,10,12, 13,14,14a,15-decahydro-2-methyl-, ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,12,12-trimethyl-, phenylmethyl ester,
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 , 7, 8, 9, 10, 12, 13 , 14, 14a, 15-decahydro-2, 10, 10-trimethyl-, phenyl methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5 -fluoro-3 , 7, 8, 9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
5-fluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester; 12H-Furo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-fluoro-7,8,9,10,13,14,14a,15-octahydro-2-methyl-, ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 4,5-difluoro-3,7,8,9, 10, 12,13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 4,5-dichloro-3,7,8,9,10, 12, 13, 14,14a, 15-decahydro-2-methyl-, phenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 , 7, 8, 9, 10, 12, 13 , 14, 14a, 15 -decahydro-4, 5 -dimethoxy-2-methy 1-, phenyl methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10,12,13,14, 14a,15-decahydro-2,5-dimethyl-, phenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,4-dimethyl-, phenylmethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2,4-dimethyl-, 1 -(4-fluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, l-[3-
(methoxycarbonyl)phenyljethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -(3-carboxyphenyl)ethyl ester; 1 -Propanaminium, N,N,N-trimethyl-, salt with l-(3-carboxyphenyl)ethyl 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-pyrrolo[3',2':5,6][l]- benzopyrano[3,2-i]quinolizine-l -carboxylate (1 :1);
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (3-nitrophenyl)methyl ester; Pyrrolo[3',2':5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13, 14,14a, 15-decahydro-2-m ethyl-, l-(3-cyanophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 1 -[3-[(dimethylamino)carbonyl]phenyl]ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -[3-[(dimethylamino)methyl]- phenyl] ethyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 1 , 13, 14, 14a, 15-decahydro-2-methyl-,2-phenylethyl ester;
Pyrrolo[3 ',2 ' :5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [4-(methoxycarbonyl)phenyl]- methyl ester;
Pyrrolo[3 ',2 ' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2, -methyl-, (4-carboxyphenyl)methyl ester; 1 -[3-(4-Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl- 1 H-indol- 4-ylmethyl]-l,2,3,4,6,7,8,9-octahydro-quinolizinylium; chloride;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, [4-(hydrox ymethyl)phenyl]- methyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3 ,78,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-naphthalenylmethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl)phenyl]- methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]- methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (3-carboxyphenyl)methyl ester);
Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (3-carboxypheny)- methyl 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][l]- benzopyrano[3,2-i]quinolizine-l -carboxylate (1 :1);
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, [3-[(dimethylamino)methyl]- phenyljmethyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [3-[(dimethylamino)carbonyl]- phenyljmethyl ester; Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [2-(4-morpholinyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-[l ,l '-biphenyl]-4-yl ethyl ester; Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (2,6-difluorophenyl)methyl ester;
Pyrrolo[3', 2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (l-phenyl-2,2,2-trifluoro)ethy] ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -[3-(trifluoromethyl)phenyl]- ethyl ester; Pyrrolo[3',2':5,6 ][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(dimethylamino)ethyl ester;
Pyrrolo[3',2':5,6 ][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 2-(l-pyrrolidinyl)ethyl ester;
Pyrrolo[3',2':5,6 ] [ 1 ]benzopyrano[3 ,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-(l-naphthalenyl)ethyl ester;
Pyrrolo[3',2':5,6 ][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -phenylcyclobutyl ester;
Pyrrolo[3',2':5,6 ] [ 1 ]benzopyrano[3 ,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-phenylcylopropyl ester;
Pyrrolo[3',2':5,6 ] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1-pyrazinylethyl ester;
Pyrrolo[3',2':5,6 ][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-(4-quinolinyl)ethyl ester;
Pyrrolo[3',2':5,6 ][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-(2-pyrimidinyl)ethyl ester;
Pyrrolo[3',2':5,6 ] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid,
5-chloro-3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester; Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
5-chloro-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl, 1 -(4-fluorophenyl)ethyl ester;
Quinolizinium, l-[[(4-fluorophenyl)methoxy]carbonyl]-5-hydroxy-
2-methyl-lH-indol-4-yl]methyl]- 1,2, 3,4,6, 7,8, 9-octahydro-, chloride;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro- 1 ,2-dimethyl-, (4-fluorophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -phenylpropyl ester;
Quinolizinium, 1, 2,3,4,6, 7, 8, 9-octahydro- l-[[5-hydroxy-2-methyl-
3-[(phenylmethoxy)carbonyl]- 1 H-indol-4-yl]methyl]-, chloride;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (4-nitrophenyl)methyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lR)-l-phenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro- 1 -phenyl- 1 -(trifluoromethyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, bicyclo[2.2.1]hept-2-yl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)- 1 -methylethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -phenylcyclopentyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -phenylcyclohexyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 3-(hydroxymethyl)phenyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (3-hydroxyphenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, (1S)-1 -(4-pyridinyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [6-(methoxycarbonyl)- 2-pyridinyl]methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 2-pyridinylmethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (6-carboxy-2-pyridinyl)methyl ester; Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (6-carboxy- 2-pyridinyl)methyl 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2- methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylate (l .T); Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)-
3-pyridinyl]methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (5-carboxy-3-pyridinyl)methyl ester; Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (5-carboxy-
3-pyridinyl)methyl 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2- methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylate (1 :1); Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(4'-methyl[ 1 , 1 '-biphenyl]- 3-yl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(2,6-dimethylphenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ( 1 S,2R)-2-(dimethylamino)-
1 -phenylpropyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (lR,2S)-2-(dimethylamino)- 1 -phenylpropyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -naphthalenyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, diphenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3, 7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (lR)-2,3-dihydro-lH-inden-l-yl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 ,2-dihydro- 1 -acenaphthylenyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, cyclohexyl(phenyl)methyl ester;
Pyrrolo[3'.2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 9H-fluoren-9-yl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1,2,3,4-tetrahydro- 1 -naphthalenyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, [(2R,3R)- 3-phenyloxiranyl]methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-oxo-l,2-diphenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 10,l l-dihydro-5H- dibenzo[a,d]cyclohepten-5-yl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (2-methylphenyl)phenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, cyclopropyl(4-fluorophenyl)methyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3,4-dihydro-2H- 1 -benzothiopyran-4-yl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (lS)-l-(2-bromoρhenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2,2,2-trifluoroethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [(2S,3S)- 3-phenyloxiranyl]methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro- 1 -methyl-
1 -(trifluoromethyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro- 1 -(4-fluorophenyl)- 1 -(trifluoromethyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1-cyclopentyl-l-phenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -[ 1 , 1 '-biphenylj-4-yl- 1 -methylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 1 -methyl- l-phenyl-2-propynyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1,1 -diphenyl ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1 -methyl- 1,2-diphenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)cyclohexyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1 ,2-diphenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3, 7,8, 9,10,12, 13, 14,14a, 15-decahydro-2-methyl-, 1 -phenyl-2-propynyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, [1,1 '-biphenyl] -4-ylmethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizme-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 4-pyridinylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 1,2,3,4-tetrahydro- 7,8-dimethoxy-2-methyl-4-isoquinolinyl ester;
PyπOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizme-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-[3-(dimethylamino)ρhenyl]- ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 , 1 -dimethyl-2-pyrazinyl ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 4-(diρropylamino)- 1 , 1 -dimethyl-2-butynyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (lS)-2,3-dihydro-lH-inden-l-yl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lS,2S)-2-(dimethylamino)- 1 -phenylpropyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, [4-(trifluoromethyl)phenyl]- methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (4-chlorophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-, phenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-, ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-hydroxyethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (3-methylphenyl)methyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (1S)-1 -phenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -phenylethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carbothioic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, S-(phenylmethyl) ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-m ethyl-, 3-pyridinylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-[4-(trifluoromethyl)phenyl]- ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(pentafluorophenyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(2,6-difluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ( 1 S)- 1 -(2-furanyl)ethyl este; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-(4-morpholinyl)- 1 -phenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lR)-l-(2-furanyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-methoxy-2-oxo- 1 -phenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(3-ρyridinyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (S)-carboxy(phenyl)methyl ester; Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (S)- carboxy(phenyl)methyl, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2- methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylate (1 :1); Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lR)-2-methoxy-2-oxo-
1 -phenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, (R)-carboxy(phenyl)methyl ester; Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (R)- carboxy(phenyl)methyl, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro- 2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylate (1 :1);
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 4-pyridinylmethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-(4-pyridinyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(2-pyridinyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-thienylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ( 1 S)- 1 -(4-fluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, ( 1 R)- 1 -(4-fluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 3-pyridinylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 2-ethoxy-2-oxoethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 3-furanylmethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, (2-nitrophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-furanylmethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(2-chlorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, carboxymethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(2,6-dichlorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(2-methoxyphenyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(5-carboxy-3-ρyridinyl)ethyl ester;
1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15- decahydro-2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin- l-yl)carbonyl]oxy]methyl]-, diethyl ester; 1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15- decahydro-2-methylpyιτolo[3^2':5,6][l]benzopyrano[3,2-i]quinolizin- 1 -yl)carbonyl]oxy]methyl]-;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl)methyl ester;
PynOlo[3^2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (5-amino-
2-chlorophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -acetic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-.alpha.-oxo-, ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2,4,5-trimethyl-, phenylmethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizme-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 , 1 -dimethyl-2-propynyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid,
3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2,2,2-trichloro- 1,1 -dimethylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid,
3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, tricyclo[3.3.1.13'7]dec-l-yl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 1 -methyl- 1 -phenylethyl ester;
PyπOlo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -methylcyclohexyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid,
3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 , 1 ,2-trimethylpropyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -methylcyclopentyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-.']quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -cyclohexyl- 1 -methylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 ,4-dimethyl-4-piperidinyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 4-fluorophenyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 3-methylphenyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, phenyl ester; PynOlo[3',2':5,6][l]benzopyrano[3,2-.']quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 3-(methoxycarbonyl)phenyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-pyridinyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-(trifluoromethyl)-, ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid,
3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [5-[(dimethylamino)methyl]- 2-furanyl]methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 2-carboxy-2-methylpropyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 3-(dimethylamino)- 2,2-dimethylpropyl ester;
Propanedioic acid, monoanhydride with 3,7,8,9,10,12,13,14,14a,15- decahydro-2-methylpyrrolo[3',2':5,6][l]-benzopyrano[3,2-/]quinolizine- 1 -carboxylic acid, 1,1 -dimethylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2- ]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-(dimethylamino)- 2-methylpropyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-(lH-imidazol-l-yl)ethyl ester;
P.yrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-m ethyl-, 2-benzofuranylmethyl ester;
Pyrrolo[3,,2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ( 1 R,2S)-2-(dimethylamino)- 1 - phenylpropyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ( 1 S,2R)-2-(dimethylamino)- 1 - phenylpropyl ester;
Pyrrolo[3 ' ,2 ' : 5,6] [ 1 ]benzopyrano[3 ,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)cyclopropyl ester; Pyridinium, 3-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro-2- methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin-l- yl)carbonyl]oxy]methyl]-l -methyl-, methanesulfonate;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizinium, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,l l-dimethyl-l-[(S)-(l- phenylethoxy)carbonyl]-, methanesulfonate; and
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (lS)-l -phenylethyl ester, 1 1 -oxide.
The instant invention includes pharmaceutical compositions of compounds of Formula 1 and methods of using the compounds for modulating chemokine receptor activity, for preventing or treating infection by HIV, delaying the onset of AIDS, treating AIDS, and treating inflammatory disease.
DETAILED DESCRIPTION OF THE INVENTION
In this present invention, compounds of Formula I can exist in two forms
(close and open form) at the bicyclic aminal moiety. The equilibrium between these two forms is pH dependent. At a neutral or basic pH (pH >7.0), these compounds predominantly exist in the closed form. However, at an acidic pH range (pH <7.0), these molecules may exist as a mixture of both close and open form. The ratio of closed and open form may depend on pH and solvent, as well as the nature of substituents R, R -R6- an 1 n-
In the compounds of Formula I, the term alkyl means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, /z-propyl, isopropyl, ??-butyl, sec-butyl, isobutyl, tert-butyl, «-pentyl, /.-hexyl, 72-heptyl, /.-octyl, and the like. The alkyl can be substituted with fluorine, for example, additionally the alkyls can be substituted with from 1 to 3 substituents selected from alkoxy, carboxy, hydroxy, nitro, halogen, amino, and substituted amino to provide other active compounds. Alkyl includes cycloalkyl of from 3 to 7 carbons which can be substituted with, for example, 1 to 3 substituents selected from alkyl, alkoxy, carboxy, hydroxy, nitro, halogen, and amino and substituted amino. Cycloalkyl can be fused to an aryl ring such as phenyl, pyridyl, and the like.
Alkoxy is O-alkyl of from 1 to 6 carbon atoms as defined above for alkyl. O
II
Acyl is -C-alkyl, wherein alkyl is as defined above. The term aryl means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as defined for alkyl, nitro, cyano, carboxy, O O O
II II II
SO3H, CHO, -C-alkyl as defined above for alkyl, -C-NH2, -C-NH-alkyl as O
II defined above for alkyl, -C-N(alkyl)2 as defined above for alkyl, -(CH2)n2-NH2 wherein n^ is an integer of 1 to 5, -(CH2)n2-NH-alkyl as defined above for alkyl and n^, -(CH2)n2-N(alkyl)2 as defined above for alkyl and x?-. The term further includes heteroaryl which is a mono or bicyclic heteroaromatic radical having 5 to
10 atoms which may contain one or more of heteroatom such as N, O, S, including, for example, 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl. The heteroaryls can be unsubstituted or substituted as above for aryl.
The term aralkyl or arylalkyl means an aryl radical attached to an alkyl radical wherein aryl and alkyl are as defined above, for example, benzyl, fluorenylmethyl, and the like.
Halogen is fluorine, chlorine, bromine, or iodine. Some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with the ring nitrogen atom at N-l 1. Further, some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with nitrogen atoms optionally present in RJO- These structural forms are within the scope of the present invention.
Some of the compounds of Formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M. et al., "Phannaceutical Salts," J. ofPharma. Sci, 1977;66:1).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge supra., 1977). The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.
The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use as agents for the treatment of HIV infection, the compounds utilized in the pharmaceutical method of this invention can be administered at the initial dosage of about 1 mg to about 100 mg per kilogram daily. A daily dose range of about 25 mg to about 75 mg per kilogram is preferred.
The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. The compounds of Formula I are valuable antagonists of the CCR-5 chemokine receptor. Compounds which are antagonists of the CCR-5 chemokine receptor are expected to have efficacy in inhibiting HIV infection and are thus useful in the treatment of AIDS. The compounds of the present invention were evaluated in a CCR-5 receptor binding assay.
CCR-5 Receptor Binding Assay
The 125ι_gpi20/sCD4/CCR-5 binding assay was carried out similarly as described in Wu et al., Nαtwre, 1996;384:179-183. Briefly, the envelope gρl20 protein derived from HIV-1 JR-FL (Trkola et al., Nature, 1996;384:184-186), a M-tropic strain, was iodinated using solid phase lactoperoxidase to a specific activity of 20 μCi/μg. For each binding reaction (in a final volume of 100 μL binding buffer [50 mM HEPES, pH 7.5, 1 mM CaCl2, 5 mM MgCl2, and 0.5% BSA]), 25 μL (2.5 μg) of membranes prepared from CCR-5/L 1.2 cells were mixed with 25 μL (3 nM) sCD4, followed by 25 μL (0.1 nM) radio-labeled gpl20 in the presence or absence of 25 μL compound dissolved in DMSO (final concentration of DMSO 0.5%). The reactions were incubated at room temperature for 45 to 60 minutes and stopped by transferring the mixture to GFB filter plates, which were then washed 3 to 4 times with binding buffer containing 0.5 M ΝaCl. The plates were dried and MicroScint scintillation fluid was added before counting.
The compounds of present invention, represented by Formula I, block the sCD-4/GP-120 binding to CCR-5 receptor with affinity less than or equal to 200 μM.
Synthesis of CCR-5 Analogs Synthesis of the final target compounds is shown in Scheme 1.
Compound II in a protic solvent, preferably ethanol, was treated with aqueous formaldehyde and dimethylamine at temperatures which ranged from 0-90°C, preferably at 25-60°C, to give the Mannich base III. Condensation of III with a enamine at temperatures which ranged from 50-1 10°C, preferably at 80-100°C, under nitrogen atmosphere in an aprotic solvent, preferably dioxane, gives compound IV. Alkylation of IV with NaH and alkylhalides in an aprotic solvent, preferably DMF, under nitrogen atmosphere at temperatures which ranged from -10 to 25°C, preferably at 0-25°C, provides compound I (where Rj ≠ H).
The preparation of indole intermediates is shown in Scheme II. Reaction of bromoacetate with nitriles in an aprotic solvent, preferably THF, in the presence of activated Zn at reflux under nitrogen atmosphere gives amino crotonates V. Alternatively, amino crotonates V can be obtained by reacting the corresponding β-ketoester with ammonia in EtOH. The β-ketoesters can be derived from 2,2,6- trimethyl-4H-l,3-dioxin-4-one and the corresponding alcohols. Condensation of amino crotonates V with substituted benzoquinone in a solvent, preferably acetic acid, ethanol, or nitromethane at temperatures which ranged from 25°C to reflux affords substituted 5-hydroxyindoles VI. The indole ester VI is hydrolyzed to the corresponding acid VII using aqueous NaOH at temperatures which ranged from 50-100°C, preferably at reflux, under nitrogen. To suppress the decarboxylation reaction, it is important that after the reaction is done the reaction mixture was cooled to 0°C in an ice-water bath and acidified with a concentrated acid, preferably HCI, at 0°C to generate the acid. Esters or amides IX can be made from acid VIII following several standard esterification procedures or a standard procedure for amide synthesis using HBTU as the coupling reagent. For the ester synthesis, Mitsunobu procedure is preferred where appropriate alcohols, DEAD, and PI13P are used, and the reaction is carried out at ambient temperature. Another preferred procedure to make esters is treating the acid with a base, preferably DBU, and alkylhalides or arylalkylhalides in a polar solvent, preferably DMF or acetonitrile at ambient temperature. The following schemes are illustrative of the procedures useful in the preparation of final compounds. Variations known to skilled chemists are considered part of the invention. Scheme 1
Preparation of Final Target Compounds
III
Scheme 2 Preparation of Substituted Indole Derivatives
VI VII
ester or amide formation
R' = H or CH3CO
VIII IX
Scheme 3
Substituted 5-hydroxybenzofurans (C).
The substituted 5-hydroxybenzofurans (C) were prepared by condensing the appropriate 1,4-benzoquinone (A) with the appropriate 3-aminocrotonate (B) in acetic acid. The solvent was removed in vacuo, and the product was purified by recrystalhzation or flash chromatography on silica gel.
Mannich Bases (E). The 5-hydroxybenzofuran (C, D) was treated with aqueous dimethylamine and aqueous formaldehyde in ethanol at 50°C or, alternatively, with N,N,N',N'- tetrame hyldiaminomethane in refluxing dioxane until the reaction was complete. The solution was concentrated under reduced pressure, and the product was purified by recrystalhzation.
Benzofurans (G).
The mannich base (E) was added to a dioxane solution of enamine (F), which was freshly prepared by treating its perchlorate salt with aqueous sodium hydroxide, extracting the enamine into ether, drying and concentrating the extracts in vacuo. The resulting solution was heated between 80-100°C until the reaction was complete. The mixture was concentrated in vacuo and the product purified by recrystalhzation or flash chromatography on silica gel.
Scheme 4
Synthesis of 7-Azaindoles Analogs
Procedures:
Starting with commercially available 3-hydroxy-2-phenylazopyridine (1) the corresponding aminopyridine is synthesized by reducing 1 in the presence of H2 (57 bar) and Pd/C in acetic acid at 65°C (Synthesis, 1990: 681) to afford amine 2. Amine 2 is then transformed into 2-amino-5-hydroxy-3-iodopyridine through reaction with iodine and acetic acid (Synthesis, 1990:681) at room temperature. The iodopyridine 3 is then converted to the azaindole 4 via palladium catalyzed cyclization with the appropriately substituted alkyne (Tetrahedron Lett., 1998;39:5355; Tetrahedron Lett., 1993;34:2823). Conversion of 3 to 4 is followed by oxidation of the hydroxymethylene to the corresponding acid 5 using
KMnO4 in the presence of K2CO3 (Gazz. Chim. Ita , 1932;62:844).
Alternatively, direct conversion of 3 to 5 is accomplished by using the carboxy substituted alkyne. Esterification of 5 to the desired ester is effected using diimide coupling reagents and the desired alcohol (J. Org. Chem., 1995;60:5214). Substitution of the pyridine ring using formaldehyde and dimethyl amine
(Tetrahedron Lett., 1966:4459) afforded 7. Intermediate 7 is then converted to the final azaindole analog 8 by reacting 7 and the quinolizidine imine shown in refluxing ethanol (J Het. Chem., 1970;7:131).
Scheme 5 Preparation of Final Target Compounds From Novel Intermediate
Compound I in an aprotic solvent, preferably E-2O, CH2CI2, or THF, was treated with a solution of oxalyl chloride in the same aprotic solvent at temperatures ranged from -10°C to 30°C, preferably at 0°C to 25°C, followed by treatment of an amine of choice in an aprotic solvent to give the desired product II. The desired product III can be obtained by reacting compound I with oxalyl chloride in an aprotic solvent, preferably Et2θ, CH2CI2, or THF, at temperatures ranged from
-10°C to 30°C, preferably at 0°C to 25°C, followed by treatment of an alcohol of choice in an aprotic solvent. Alternatively, the desired product III can be made by reacting compound I with compound IV in an aprotic solvent such as Et2θ, CH2C12, or THF.
Scheme 6
Preparation of the Mixed Anhydride
III
General Description
The benzylester I is subjected to hydrogenolysis reaction conditions in aprotic polar solvents, preferably THF, at ambient temperature to give acid II. The acid II is treated subsequently with benzoyl chloride in presence of an organic base, such as Et3N, to afford the mixed anhydride III. Scheme 7
Synthesis of Esters From the Mixed Anhydride
II
General Description
The mixed anhydride I is mixed with the desired alcohol, the resultant reaction mixture was heated to 100°C to 180°C until the mixed anhydride is consumed affording the corresponding ester.
The present invention is further directed to combinations of the present compounds with one or more agents useful in the prevention or treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the anti-HIV compounds, immunomodulators, anti-infectives, or prophactic or therapeutic vaccines known to those of ordinary skill in the art.
ANTIVIRALS
Drug Name Manufacturer Indication
097 Hoechst/Bayer HIV infection, AIDS, ARC (non- nucleoside reverse transcriptase (RT) inhibitor)
GW141 W94/ Glaxo Wellcome HIV infection, AIDS, ARC
VX478 (protease inhibitor)
Amprenavir
GW1592U89 Glaxo Wellcome HIV infection, AIDS, ARC
Abacavir (RT inhibitor)
Acemannan Carrington Labs ARC (Irving, TX)
Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, in Combination with AZT
AD-439 Tanox Biosystems HIV infection, AIDS, ARC
AD-519 Tanox Biosystems HIV infection, AIDS, ARC
Adefovir dipivoxil Gilead Sciences HIV infection
AL-721 Ethigen ARC, PGL HIV positive, AIDS
(Los Angeles, CA)
Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIV in combination
Alferon Interferon Interferon Sciences Kaposi's sarcoma, HIV in combination
Ansamycin Adria Laboratories ARC
LM 427 (Dublin, OH) Erbamont (Stamford, CT)
Antibody which Advanced Biotherapy AIDS, ARC neutralizes pH Concepts labile alpha (Rockville, MD) aberrant
Interferon
AR177 Aronex Pharm HIV infections, AIDS, ARC beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated diseases ANTIVIRALS (cont'd)
Drug Name Manufacturer Indication
BMS-232623 Bristol-Myers HIV infection, AIDS, ARC
(CGP-73547) Squibb/Novartis (protease inhibitor) BMS-234475 Bristol-Myers HIV infection, AIDS, ARC
(CGP-61755) Squibb/Novartis (protease inhibitor) (-)6-Chloro-4(S)- Merck HIV infection, AIDS, ARC cyclopropylethynyl- (non-nucleoside reverse
4(S)-trifluoro- transcriptase inhibitor) methyl- 1 ,4-dihydro-
2H-3 , 1 -benzoxazin-
2-one CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes, papillomavirus
Combivir AZT+3TC Glaxo Wellcome HIV infection, AIDS, ARC Curdlan sulfate AJI Pharma USA HIV infection Cytomegalovirus Medlmmune CMV retinitis immune globin Cytovene Ganciclovir Syntex/Roche Sight threatening CMV, peripheral CMV, retinitis
Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC
(RT inhibitor)
Dextran Sulfate Ueno Fine Chem. Ind. AIDS, ARC, HIV positive Ltd. (Osaka, Japan) asymptomatic
HIVID (ddc) Hoffman-La Roche HIV infection, AIDS, ARC Dideoxycytidine ddl Dideoxyinosine Bristol-Myers Squibb HIV infection, AIDS, ARC; combination with AZT/d4T
DMP-450 Triangle HIV infection, AIDS, ARC Pharmaceutical (protease inhibitor)
Efavirenz (DMP 266) DuPont Merck HIV infection, AIDS, ARC (non-nucleoside RT inhibitor)
EL10 Elan Corp, PLC HIV infection (Gainesville, GA)
Famciclovir Smith Kline Herpes zoster, herpes simplex Foscavir/Foscarnet Astra CMV, HSV l-2 ANTIVIRALS (cont'd)
Drug Name Manufacturer Indication
FTC Triangle HIV infection, AIDS, ARC
Pharmaceutical (reverse transcriptase inhibitor)
GS 840 Gilead HIV infection, AIDS, ARC (reverse transcriptase inhibitor)
HBY097 Hoechst Marion HIV infection, AIDS, ARC
Roussel (non-nucleoside reverse transcriptase inhibitor)
Hypericin VIMRx Pharm. HIV infection, AIDS, ARC
Recombinant Human Triton Biosciences AIDS, Kaposi's sarcoma, ARC
Interferon Beta (Almeda, CA)
Interferon alpha-n3 Interferon Sciences ARC, AIDS
Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddl/ddC
ISIS 2922 ISIS Pharmaceuticals CMV retinitis
JE 2147 (KNI-764) Japan Energy/ HIV infection, AIDS, ARC
Protease inhibitor Agouron PI (reverse transcriptase inhibitor); also with AZT
KNI-272 Nat'l Cancer Institute HIV-associated diseases
Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT
Lobucavir Bristol-Myers Squibb CMV infection - HBV infection
Nelfinavir Agouron HIV infection, AIDS, ARC
Pharmaceuticals (protease inhibitor)
Nevirapine Boeheringer HIV infection, AIDS, ARC
Ingleheim (RT inhibitor)
Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH)
Peptide T Peninsula Labs AIDS
Octapeptide (Belmont, CA)
Sequence ANTIVIRALS (cont'd)
Drug Name Manufacturer Indication
PNU- 140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor)
Probucol Vyrex HIV infection, AIDS
RBD-CD4 Sheffield Med. Tech HIV infection, AIDS, ARC (Houston, TX)
Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor)
S-1153 Agouron/Shionogi NnRTI
Saquinavir Hoffmann-La Roche HIV infection, AIDS, ARC (protease inhibitor)
Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, ARC
Didehydrodeoxy- thymidine
Valaciclovir Glaxo Wellcome Genital HSV & CMV infections
Virazole Ribavirin Viratek/ICN Asymptomatic HIV positive,
(Costa Mesa, CA) LAS, ARC
Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapies
IMMUNO-MODULATORS
Drug Name Manufacturer Indication
AS-101 Wyeth-Ayerst AIDS
Bropirimine Pharmacia Upjohn Advanced AIDS
Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX)
CL246,738 American Cyanamid AIDS, Kaposi's sarcoma Lederle Labs
EL10 Elan Corp, PLC HIV infection (Gainesville, GA)
FP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells
Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor) IMMUNO-MODULATORS (cont'd)
Drug Name Manufacturer Indication
Granulocyte Genetics Institute AIDS
Macrophage Sandoz
Colony Stimulating
Factor Granulocyte Hoeschst-Roussel AIDS
Macrophage Immunex
Colony Stimulating
Factor Granulocyte Schering-Plough AIDS, combination w/AZT
Macrophage
Colony Stimulating
Factor HIV core Particle Rorer Seropositive HIV
Immunostimulant IL-2 Interleukin-2 Cetus AIDS, in combination w/AZT IL-2 Interleukin-2 Hoffman-La roche AIDS, ARC, HIV, in Immunex combination w/AZT
IL-2 Interleukin-2 Chiron AIDS, increase in CD4 cell
(aldeslukin) counts Immune Globulin Cutter Biological Pediatric AIDS, in combination
Intravenous (Berkeley, CA) w/AZT
(human) IMREG-1 Imreg AIDS, Kaposi's sarcoma, ARC,
(New Orleans, LA) PGL
IMREG-2 Imreg AIDS, Kaposi's sarcoma, ARC,
(New Orleans, LA) PGL
Imuthiol Diethyl Merieux Institute AIDS, ARC
Dithio Carbamate Alpha-2 Interferon Schering Plough Kaposi's sarcoma w/AZT,
AIDS
Methionine- TNI Pharmaceutical AIDS, ARC
Enkephalin (Chicago, IL) MTP-PE Muramyl- Ciba-Geigy Corp. Kaposi's sarcoma
Tripeptide Granulocyte Colony Amgen AIDS, in combination w/AZT
Stimulating Factor IMMUNO-MODULATORS (cont'd)
Drug Name Manufacturer Indication
Remune Immune Response Immunotherapeutic
Corp. rCD4 Recombinant Genentech AIDS, ARC Soluble Human CD4 rCD4-IgG hybrids AIDS, ARC
Recombinant Soluble Biogen AIDS, ARC Human CD4
Interferon Alfa 2a Hoffman-La Roche Kaposi's sarcoma AIDS, ARC, in combination w/AZT
SK&F 106528 Smith Kline HIV infection
Soluble T4
Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ)
Tumor Necrosis Genentech ARC, in combination w/gamma Factor; TNF Interferon
ANTI-INFECTIVES
Drug Name Manufacturer Indication
Clindamycen with Pharmacia Upjohn PCP
Primaquine Fluconazole Pfizer Cryptococcal meningitis, candidiasis
Pastille Nystatin Squibb Corp. Prevention of oral candidiasis
Pastille Ornidyl Eflomithine Merrell Dow PCP Pentamidine LyphoMed PCP treatment
Isethionate (IM & (Rosemont, IL)
IV) Trimethoprim Antibacterial Trimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxis isethionate for inhalation ANTI-INFECTIVES (cont'd)
Drug Name Manufacturer Indication
Spiramycin Rhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen Pharm. Histoplasmosis; cryptococcal
R51211 meningitis Trimetrexate Warner-Lambert PCP
OTHER
Drug Name Manufacturer Indication
Daunorubicin NeXstar, Sequus Karposi's sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemia associated with
Erythropoietin AZT therapy Recombinant Human Serono AIDS-related wasting, cachexia
Growth Hormone Megestrol Acetate Bristol-Myers Squibb Treatment of anorexia associated w/AIDS
Testosterone Alza, Smith Kline AIDS-related wasting
Total Enteral Norwich Eaton Diarrhea and malabsorption
Nutrition Pharmaceuticals related to AIDS
It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.
The following examples are illustrative of the intermediate and final compounds and methods for their preparation. They are not intended to limit the scope of the invention. EXPERIMENTALS
Synthesis of Intermediate Indole derivatives
5-Acetoxy-2-methyl-lH-indole-3-carboxylic acid (A)
5-Hydroxy-2-methyl-l-H-indole-carboxylic acid (8.54 g, 44.7 mmol) was dissolved in aqueous sodium hydroxide (2N, 45 mL). 1 -acetyl- lH-2,3- triazolo(4,5-b-)-pyridine (7.24 g, 44.7 mmol) was dissolved in THF (30 mL), and the solution was added to the solution of 5-hydroxy-2-methyl-l-H-indole- carboxylic acid. The mixture was stirred until little or no starting material remained, -30 minutes; a white precipitate formed. The mixture was cooled to 0°C and concentrated HCI was added dropwise until the pH was ~1. The resulting white solid was filtered, washed with water (2 x 50 mL), recrystallized from ethanol, and dried under vacuum, yield 6.95 g (67%); mp 233-235°C (dec); IR: 3331, 1740, 1642, 1234, 1207 cm" 1. lH NMR (DMSO-d6) δ: 2.21 (s, 3H CH3CO2), 2.59 (s, IH, ArCH3), 6.79 (d, J= 6.84 Hz, IH, ArH), 7.27 (d, J= 8.55 Hz, IH, ArH), 7.53 (s, IH, ArH), 1 1.77 (s, IH, NH) 1 1.93 (s, IH,
COOH). MS(APCI+): m/z 234.1 (MH+). Analysis calculated for C^H! 1N1O4: C, 61.80; H, 4.75; N, 6.01. Found: C, 61.48; H, 4.66; N, 5.86.
Procedure A. General procedure for the preparation of esters
5-Hydroxy-2-methyl-l-H-indole-carboxylic acid or 5-acetoxy-2-methyl- lH-indole-3-carboxylic acid (4-28 g) was combined with enough THF to effect dissolution. Triphenylphosphine (1 eq) and the alcohol of interest (2.5-4.0 eq, depending on solubility) were added to the THF solution. Diethylazodicarboxylate (DEAD, 1 eq) was added dropwise to the mixture over the course of 1-1.5 hour. The mixture was stirred overnight at ambient temperature. The solution was concentrated in vacuo to give an oily mixture; a solution of 1 : 1 hexane/ethyl acetate was used to redissolve the oil. The desired product was purified by flash chromatography. Residual diethylhydrazinedicarboxylate remaining in the product was removed by trituration with hot water; the resulting solid was dried under vacuum at 40°C. For compounds made with 5-acetoxy-2-methyl-lH-indole- 3-carboxylic acid, the 5-acetyl group was removed in the following manner: the protected ester (1 eq) was dissolved in a small amount of MeOH. NaOMe (4 eq) was added and the mixture stirred until no starting material remained (-45 minutes). The pH of the solution was adjusted to 1 with the addition of aqueous HCI, and a copious white precipitate occurred. The solid was filtered, washed with water (2 x 20 mL), and dried under vacuum at 40°C. Alternatively, the pH of the solution was adjusted to 1 with the addition of aqueous HCI, and the solution was extracted with ethyl acetate (2 x 25 mL). The organic layer was dried over Na2SO4 and evaporated to give a solid. The solid may be further purified by recrystalhzation from appropriate solvents. According to the Procedure A,
Intermediates B-G were synthesized.
5-Acetoxy-2-methylindole-3-carboxylic acid benzyl ester (B) Yield: 8.32 g (21.6%); mp 152-154°C; IR: 3310, 1752, 1662, 1226, 1094 cm"1 ; lH NMR (DMSO-d6) δ 2.21 (s, 3H, CH3CO2), 2.60 (s, 3H, ArCH3), 5.28 (s, 2H, CH2Ph), 6.82 (dd, J= 8.55, 2.44 Hz, IH, ArH), 7.26-7.41 (m, 6H, ArH), 7.53 (d,
J= 2.44 Hz, IH, ArH), 11.9 (s, IH, NH). MS(APCI+): 324.1 (MH+). Analysis calculated for C19H17N1O4: C, 70.58; H, 5.30; N, 4.33. Found: C, 70.47; H,
5.43; N, 4.24.
5-Hydroxy-2-methylindole-3-carboxylic acid benzyl ester (C) Yield: 5.03 g (76%); mp 191-193°C; IR: 3227, 1654, 1472, 1429, 1094 cm"1. JH NMR
(DMSO-d6) δ 2.54 (s, 3H, alkyl CH3 ), 5.26 (s, 2H, PhCH2), 6.55 (d, J= 6.10 Hz, IH, ArH), 7.08 (d, J= 8.8 Hz, IH, ArH), 7.24-7.42 (m, 6H, ArH), 8.82 (s, IH, aromatic OH), 11.55 (s, IH, NH). MS(APCI+): m/z 282.0 (MH+). Analysis calculated for Cι7H15NιO3: C, 71.71; H, 5.44; N, 4.92. Found: C, 71.72; H, 5.49; N, 4.85.
Alternatively, Intermediate C can be synthesized from Intermediate B according to the procedure described in Example 9, Step A. 5-Acetoxy-2-methylindole-3-carboxylic acid propyl ester (D) Yield: 2.16 g
(37%); mp 134-136°C; IR: 3263, 2966, 1758, 1677, 1657, 1215 cm"1. 1H NMR (DMSO-d6) δ 0.99 (t, J= 7.51 Hz, 3H, CH2CH2CH3), 1.71 (sextet, J= 7.33 Ηz, 3Η, CH2CH2CH3), 2.26 (s, 3H, CH3CO), 2.63 (s, 3H, ArCH3), 4.17 (t, J= 6.41 Hz, 2H, CH2CH2CH3), 6.86 (dd, J= 8.61, 2.20 Hz, IH, ArH), 7.34 (d,
J= 8.61 Hz, IH, ArH), 7.55 (d, J= 2.20 Hz, IH, ArH), 1 1.9 (s, IH, NH). MS(APCI+): m/z 276.0 (MH+). Analysis calculated for Cι5H17N1O4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.13; H, 6.28; N, 5.10.
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 2-isopropyl ester (E) Yield: 0.720 g (12%); mp 188-189°C; IR: 3409, 3391, 1663, 1467, 1181, 1095 (cm" 1).
*H NMR (DMSO-d6) δ 1.27 (d, J= 6.35 Hz, 6H, CH(CH3)2), 2.52 (s, 3Η, CH3),
5.04 (septet, J= 6.35 Hz, IH, CH(CH3)2), 6.53 (dd, J= 8.55, 2.44 Hz, IH, ArH),
7.06 (d, J= 8.55 Hz, IH, ArH), 7.25 (d, J= 2.44 Hz, IH, ArH), 8.77 (s, IH, OH)
11.4 (s, IH, NH). MS(APCI+): m/z 234 A (MH+). Analysis calculated for Ci3H15NιO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.79; H, 6.53; N, 5.88.
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid cyclopropylmethyl ester (F) Yield: 0.532 g (8.3%); mp 187-188°C; IR: 3388, 3297, 1663, 1466, 1 179,
1094 cm'1. !H NMR (DMSO-d6) δ 0.00-0.04 (m, 2H, cyclopropyl CH2CH2),
0.22-0.26 (m, 2H, cyclopropyl CH CH2), 0.86-0.93 (m, IH, CH2CH), 2.27 (s, 3Η, ArCH3), 3.72 (d, J= 7.32 Hz, 2H, CH2CH), 6.27 (dd, J= 8.55, 2.44 Hz, IH,
ArH), 6.79 (d, J= 8.55, IH, ArH), 6.99 (d, J= 2.20, IH, ArH), 8.51 (s, IH, OH),
11.2 (s, IH, NH). MS(APCI+): m/z 246 A (MH+). Analysis calculated for C14H15N1O3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.50; H, 6.19; N, 5.67.
5-Acetoxy-2-methylindole-3-carboxylic acid 1-phenyl-propyl ester (G) Yield: 1.36 g (23%); mp 144-145.5°C; IR: 3289, 1755, 1661, 1459, 1216, 1204,
1089 cm"1. lH NMR (DMSO-d6) δ 0.863 (t, J= 7.32 Hz, 3H, CH2CH3),
1.82-1.98 (m, 2Η, CHCH2CH3), 2.22 (s, 3H, CH3CO), 2.63 (s, 3H, ArCH3), 5.80 (t, J= 6.84 Hz, IH, benzylic CH), 6.83 (dd, J= 8.79, 2.20 Hz, IH, ArH), 7.21-7.36 (m, 6H, ArH), 7.60 (d, J= 2.20 Hz, IH, ArH), 11.9 (s, IH, NH). MS(APCI-): m/z 350.1 (M-l). Analysis calculated for C21^1^04: C, 71.78;
H, 6.02; N, 3.99. Found: C, 71.53; H, 6.02; N, 3.81.
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid isobutyl ester (H) 5-Hydroxy-
2-methyl-lH-indole-3-carboxylic acid isobutyl ester was synthesized according to the general procedure A and was recrystallized from hexane/CH2Cl2 to give
1.39 g (26.2%) of white solid: mp 188-190°C; IR (KBr) 3385, 3272, 2963, 1655,
1630, 1464, 1174, 1094 cm"1; lH NMR (400 MHz, DMSO-d6) δ 0.95 (d, J= 6.84 Hz, 6H, CH(CH3) ), 1.94 (n, J= 6.84 Ηz, 1Η, CΗ(CH3)2), 2.54 (s, 3Η,
CCH3), 3.95 (d, J= 1.95 Ηz, 2Η, OCH2), 6.54 (dd, J= 8.55, 2.44 Ηz, 1Η, ArH),
7.07 (d, J= 8, 1 Η, ArΗ), 7.25 (s, 1Η, ArH), 8.81 (s, 1Η, OH), 11.49 (s, 1Η, NH);
MS(APCI+): m/z 248.1(MΗ+). Analysis calculated for C14H17NO3: C, 68.00; H,
6.93; N, 5.66. Found: C, 67.92; H, 6.87; N, 5.54.
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 2,2-dimethyl-propyl ester (I)
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 2,2-dimethyl-propyl ester was synthesized according to the general procedure A and was recrystallized from CH2C12 to give 2.31 g (33.8%) of white solid: mp 195-196°C; IR (KBr) 3262,
2960, 1652, 1464, 1170, 1094 cm"1 ; !H NMR (400 MHz, DMSO-d6) δ 0.97 (s, 9H, C(CH3)3), 2.55 (s, 3H, ArCH3), 3.87 (s, 2H, OCH2), 6.55 (dd, J= 8.55,
2.44 Hz, IH, ArCH), 7.07 (d, J= 8.55 Hz, IH, ArCH), 7.29 (s, IH, ArH), 8.82 (s,
IH, OH), 11.50 (s, IH, NH); MS(APCI+): m/z 262.1(MH+). Analysis calculated for Cι5H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C, 68.55; H, 7.23; N, 5.41.
Procedure B: An Alternative General Procedure for the Preparation of Esters A solution of 5-acetoxy-2-methyl-lH-indole-3-carboxylic acid (Aldrich,
5.00 g, 21.4 mmol) and diethyl azodicarboxylate (Aldrich, 3.73 g, 21.4 mmol) in 7 mL of THF was added dropwise to a mixture of triphenyl phosphine (Aldrich, 5.62 g, 21.4 mmol) and an alcohol of choice (Aldrich, 2.00-4.00 g, 32.2 mmol) in 32 mL of THF over an hour. After stirring at room temperature for 24 hours, the mixture was concentrated. The product was purified by flash column chromatography on silica gel (10%o MeOH,CHCl3) to give the corresponding ester.
5-Hydroxy-2-mefhyl-lH-indole-3-carboxylic acid 2-piperdin-l-yl-ethyl ester (J)
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 2-piperdin-lyl-ethyl ester was synthesized according to the procedure B and was recrystallized from hexane/ethyl acetate to give 0.350 g (26.9%) of white solid: mp 210-212°C; IR
(KBr) 3203, 2934, 1690, 1455, 1175, 1067 cm"1 ; lH NMR (400 MHz, DMSO-d6) δ 1.31 (m, 2H, NCH2CH2CH2), 1.42 (m, 4Η, NCH2CH2), 2.38 (m,
4Η, NCH2CH2CH2), 2.53 (s, 3H, ArCH3), 2.59 (t, J= 6.10 Hz, 2H, OCH2CH2), 4.22 (t, J= 6.10 Ηz, 2Η, OCH2CH2N), 6.54 (dd, J= 8.66, 2.32 Hz, IH, ArH), 7.06 (d, J= 8.55 Hz, IH, ArH), 7.27 (s, IH, ArH), 8.77 (s, IH, OH), 11.48 (s, IH, NH); MS(APCI+): m/z 303.1(MH+). Analysis calculated for C1 H22N2O3: C, 67.05; H, 7.28; N, 9.20. Found: C, 66.93; H, 7.28; N, 9.00.
Procedure C: A General Procedure for the Synthesis of ethyl 3-alkyl- 3-aminocrotonates (K-O)
Activation of Zn: To a stirred 3N HCI solution (50 mL) was added Zn (20 g) and stirred at room temperature for 15 minutes. The HCI solution was decanted, and this was repeated two times. The activated Zn was washed with distilled H2O (2χ, 100 mL), ethanol (2χ, 50 mL), and ether (2χ, 50 mL). The activated Zn was then placed under reduced pressure for 12 hours at 40°C. To a stirred solution of dry THF (30 mL) and activated Zn (3.27 g, 50 mmol) in a flame dried 100 mL round bottom flask under an inert atmosphere was added 0.2 mL of ethylbromoacetate (1) at room temperature. The reaction was then heated to reflux. After the solution turned green (15-30 min), the alkyl cyanide (10 mmol) was added at once, and ethylbromoacetate (4.44 mL, 40 mmol) was added dropwise over 30 minutes and refluxed for an additional 30 minutes and then allowed to cool to room temperature. To the stirred solution was added THF (30 mL) and K2CO3 (13 mL, 50% w/w) and stirred vigorously for 30 minutes.
The solution was then placed in a centrifuge tube and centrifuged. The supernatant was decanted, and the pellet was resuspended in THF (30 mL), shaken vigorously and centrifuged (procedure repeated twice). The combined supernatant were dried over MgSO4, filtered, and concentrated under reduced pressure to yield of ethyl
3-alkyl-3-aminocrotonate as a crude product which was used directly in the next step.
Ethyl 3-amino-3-benzylcrotonate (K) !H NMR (250 MHz, CDCI3) δ 1.26 (t,
J= 7.1 Hz, 3H), 3.46 (s, 2H), 4.12 (q, J= 7.15 Hz, 2H), 4.64 (s, IH), 7.27 (m, 5H).
Ethyl 3-amino-3-ethylcrotonate (L) 1H NMR (250 MHz, CDCI3) δ 1.47 (t, J= 7.5 Hz, 3H), 1.26 (t, J= 7.1 Hz, 3H), 2.16 (q, 5.7 Hz, 2H), 4.1 1 (q, J= 5.4 Hz, 2H), 4.55 (s, IH). 13C NMR (62.5 MHz, CDCI3) δ 12.0, 14.5, 29.3, 30.3, 58.5, 82.6, 164.9, 170.5.
Ethyl 3-amino-3-cyclopropylcrotonate (M) !H NMR (250 MHz, CDCI3) δ
0.74 (m, 2H), 0.86 (m, 2H), 1.25 (t, J= 1 Hz, 3H), 2.27 (s, IH), 4.10 (q, J= 1 Hz, 2H), 4.45 (s, IH). 13C NMR (62.5 MHz, CDCI3) δ 7.1, 14.6, 15.8, 58.5, 80.7, 165.1, 170.4. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH OAc/ CH3CN, APCI+) / = 7.24 min, m/z = 156 (M+l).
Ethyl 3-amino-3-propylcrotonate (N) 1H NMR (250 MHz, CDCI3) δ 0.95 (t,
J- 7.3 Hz, 3H), 1.26 (t, J= 7.1 Hz, 3H), 1.56 (s, J= 7.3 Hz, 2H), 2.10 (d,
J= 7.3 Hz, 2H), 4.1 (q, J= 7.2 Hz, 2H), 4.53 (s, IH). 13C NMR (62.5 MHz, CDCI3) δ 13.5, 14.5, 21.1, 38.4, 58.30, 84 LC/MS (150 mm x 4.6 mm, C-18,
5 micron, 10 mM NH4OAc/CH3CN, APCI+) t = 8.02 min, m/z = 158.4 (M+l). Ethyl 3-amino-3-isobutylcrotonate (O) !H NMR (250 MHz, CDCI3) δ 0.95 (d,
J- 6.4 Hz, 6H), 1.26 (t, J= 7.1 Hz, 3H), 1.9 (m, IH), 1.96 (d, J= 7.0 Hz, 2H),
4.11 (q, J= 7.1 Hz, 2H), 4.51 (s, IH). LC/MS (150 mm x 4.6 mm, C-18,
5 micron, 10 mM NH4OAc/CH3CN, APCI+) / = 8.69 min, m/z = 172.4 (M+l).
Procedure D: General procedure for the synthesis of ethyl 2-alkyl-5-hydroxy-
3-indolecarboxylates (P-T)
To a stirred solution of ethyl 3-alkyl-3-aminocrotonate (15.3 mmol) in acetic acid (50 mL) was added 1,4-benzoquinone (3.3 g, 30.5 mmol). The solution was stirred overnight at room temperature and then filtered through a frit. The solid was washed with cold distilled water and dried in an Abderhalden over
P2O5 to afford the ethyl 2-alkyl-5-hydroxy-3-indolecarboxylate.
Ethyl 2-benzyl-5-hydroxy-3-indolecarboxylate (P) 70% yield (from starting nitrile) of a white powder. ]H NMR (250 MHz, DMSO) δ 1.32 (t, J= 7.08 Hz, 3H), 4.26 (q, J= 7.05 Hz, 2H), 4.41 (s, 2H), 6.63 (dd, J= 8.5, 2.2 Hz, IH), 7.25 (m, 7H), 8.88 (s, IH), 1 1.64 (s, IH). 13C NMR (62.5 MHz, DMSO) δ 14.5,
17.3, 32.8, 58.7, 102.1, 105.4, 111.8, 126.2, 127.8, 128.4, 129.3, 139.0, 146.1, 152.3, 165.1. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 M NH4OAC/CH3CN, APCI+) t = 7.83, m/z = 296.3 (M+l).
Ethyl 2-ethyl-5-hydroxy-3-indolecarboxylate (Q) 54% yield (from starting nitrile) as a white powder. lH NMR (250 MHz, DMSO) δ 1.23 (t, J= 7.6 Hz, 3H),
1.33 (t, J= 7.1 Hz, 3H), 3.04 (q, J= 7.5 Hz, 2H), 4.24 (q, J= 7.1 Hz, 2H), 6.5 (dd, J= 8.7, 2.4 Hz, IH), 7.14 (d, J= 8.5 Hz, IH), 7.33 (d, J= 2.4 Hz, IH), 8.82, (s,
IH), 11.48 (s, IH). 13C NMR (62.5 MHz, DMSO) δ 13.6, 14.4, 20.7, 58.4, 105.3, 111.3, 111.6, 127.9, 128.9, 150.0, 152.2, 165.0. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAc/CH3CN, APCI+) t = 7.60 min, m/z = 234.3 (M+l).
Ethyl 2-cyclopropyl-5-hydroxy-3-indolecarboxylate (R) 83% yield (from starting nitrile) as a white powder. 1H NMR (250 MHz, DMSO) δ 0.97 (m, 2H), 1.10 (m, 2H), 1.35 (t, J= 7.1 Hz, 3H), 3.00 (m IH), 4.26 (q, J= 7.0 Hz, 2H), 6.59 (dd, 8.7, 2.4 Hz, IH), 7.8 (d, J= 8.7 Hz, IH), 7.30 (d, J= 2.4 Hz, IH), 8.81 (s, IH),
10.93 (s, IH). 13C NMR (62.5 MHz, DMSO) δ 8.8, 9.2, 14.5, 17.2, 21.0, 58.5, 102.9, 105.1, 111.1, 111.4, 127.9, 128.8, 150.1, 152.1, 165.4, 171.9. LC/MS (150 mm x 4.6mm, C-18, 5 micron, 10 mM NH4OAc/CH3CN, APCI+) t = 7.03 min, m/z = 246.3 (M+l).
Ethyl 5-hydroxy-2-propyl-3-indolecarboxylate (S) 62%> yield (from starting nitrile) as a white powder. ]H NMR (250 MHz, DMSO) δ 0.93 (t, J= 7.3 Hz, 3H), 1.35 (t, J= 7.1 Hz, 3H), 1.67 (m, 2H) 3.01 (t, J= 9.0 Hz, 2H), 4.26 (q, J= 7.1 Hz, 2H), 6.77 (dd, J= 8.7, 2.2 Hz, IH), 7.16 (d, J= 8.6 Hz, IH), 7.35 (d, J= 2.2 Hz, IH), 8.86 (s, IH), 1 1.51 (s, IH). 13C NMR (62.5 MHz, DMSO) δ
13.7, 14.4, 17.2, 22.3, 29.2, 58.4, 105.2, 111.3, 115.5, 127.9, 128.9, 148.4, 149.6, 152.1, LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAc/CH3CN,
APCI+) / = 7.21 min, m/z = 248.4 (M+l).
Ethyl 2-isobutyl-5-hydroxy-3-indolecarboxylate (T) 68% yield (from starting nitrile) the as a white powder. lH NMR (250 MHz, DMSO) δ 0.91 (d, J= 6.6 Hz,
6H), 1.35 (t, J= 7.1 Hz, 3H), 2.06 (m, 1H), 2.91 (d, J= 7.2 Hz, 2H), 4.25 (q, J= 7.1 Hz, 2H), 6.62 (dd, J= 8.6, 2.4 Hz, IH), 7.16 (d, J= 8.5 Hz, IH), 7.35 (d,
J= 2.4 Hz, IH), 8.85 (s, IH), 11.5 (s, IH). 1 3C NMR (62.5 MHz, DMSO) δ 14.4, 17.2, 22.3, 28.6, 36.2, 58.4, 102.0, 105.2, 1 1 1.2, 11 1.4, 127.9, 128.8, 147.6, 152.1, 165.0. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 M NH4OAc/CH3CN,
APCI+) t = 7.69 min, m/z = 262.4 (M+l).
Procedure E: General procedure for the preparation of indole amides
5-Acetoxy-2-methyl-lH-indole-3-carboxylic acid (1.0 g, 4.3 mmol) was dissolved in 10 mL of DMF, and E-3N (0.6 mL, 1 eq) was added. The solution was stirred for 5 minutes. The solution was cooled to 0°C and HBTU (1.63 g,
4.3 mmol) was added, then stirred for 15 minutes. The amine (2 N in THF, 4 eq) was added, and the solution stirred until the starting material was consumed, ~1 hour water was added. The pH of the resulting mixture was adjusted to 5 with HCI (IN), and extracted with ethyl acetate. The organic layer was dried and evaporated to give the crude product which can be further purified by flash chromatography or recrystalhzation.
Intermediates U-V were synthesized according to Procedure E. Acetic acid 2-methyl-3-methylcarbamoyl-lH-indol-5-yl ester (U) Yield: 0.093 g (18%); mp 201-203°C; IR: 3402, 1748, 1609, 1218, 1170 cm"1. ]H NMR (DMSO-d6) δ
2.21 (s, 3H, CH3CO), 2.45 (s, 3H, ArCH3), 2.72 (d, J= 4.39 Hz, 3H, NHCH3),
6.76 (dd, J= 8.79, 1.46 Ηz, 1Η, ArΗ), 7.24 (d, J= 8.79 Ηz, 1Η, ArΗ), 7.25 (bs, 1Η, CONHCΗ3), 7.41 (s, IH, ArH), 1 1.5 (s, IH, indole NH). MS(APCI+): m/z
241 A (MH+); Analysis calculated for C13Hi4N2O3-0.9 H O; C, 59.49; H, 6.07; N, 10.67. Found: C, 59.51 ; H, 6.12; N, 10.55.
Acetic acid 3-benzylcarbamoyl-2-methyl-lH-indol-5-yl ester (V) Yield: 0.454 g (33%); mp 182-184°C; IR: 3413, 3319, 3222, 3191, 1750, 1609, 1228, 1216,
1 170 cm" 1. I-H NMR (DMSO-d^) δ 2.20 (s, 3H, CH3CO), 2.54 (s, 3H, ArCH3),
4.42 (d, J= 6.1 Hz, 2H, NHCH2Ph), 6.77 (dd, J= 8.55, 1.95 Ηz, 1Η, ArΗ), 7.15-7.19 (m, 1Η, ArΗ), 7.25-7.34 (m, 5Η, ArH), 7.45 (d, J= 1.71 Hz, IH, ArH),
7.89 (t, J= 6.10 Hz, IH, CONHCH2Ph), 1 1.5 (s, IH, indole NH). MS(APCI+): m/z 323.2 (MH+); Analysis calculated for Ci9H1 8N203: C, 70.79, H, 5.63, N, 8.69. Found: C, 70.62, H, 5.78, N, 8.60.
Procedure F: General procedure for deacylation of the amides The amide of interest (1 eq) was dissolved in a small amount of MeOH.
MeONa (4 eq) was added and the mixture stirred until no starting material remained, ~45 minutes. The pH of the solution was adjusted to 1 with the addition of aqueous HCI, and the solution extracted with 2 x 25 L of ethyl acetate. The organic layer was dried and evaporated to give a solid. Recrystalhzation from ethyl acetate yields a white solid.
Intermediates W-X were synthesized according to Procedure F. 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid methyl amide (W) Yield:
0.201 g (70%); mp 226-227°C; IR: 3366, 1602, 1558, 1552, 1215, 1 198 cm" 1. H NMR (DMSO-d6) δ 2.45 (s, 3H, AiCH^ obscured by DMSO peak), 2.70 (d,
J= 4.40 Hz, 3H, CONHCH3), 6.51 (d, J= 8.55 Ηz, 1Η, ArΗ), 7.02 (d,
J= 8.55 Ηz, 1Η, ArΗ), 7.07 (s, 1Η, ArΗ), 7.13-7.14 (m, 1Η, CONHCΗ3), 8.65 (s,
IH, OH), 11.0 (s, IH, indole NH). MS(APCI+): m/z 205.1 (MH+); Analysis calculated for Ci !H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.53;
H, 5.91; N, 13.44.
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl amide (X) Yield: 0.228 g (65.7%); mp: 194-196°C; IR: 3392, 3246, 1610, 1528, 1465, 1214,
1 188 cm"1. ]H NMR (DMSO-d6) δ: 2.48 (s, 3H, ArCH3), 4.41 (d, J= 5.86 Hz, 2H, NHCH2Ph), 6.52 (d, J= 8.06, 1Η, ArΗ), 7.04 (d, J= 8.55, 1Η, ArΗ), 7.12 (s,
1Η, ArΗ) 7.17-7.31 (m, 5Η, ArH), 7.71-7.78 (m, IH, CONHCH2Ph), 8.68 (s, IH,
OH), 11.1 (s, IH, indole NH). MS(APCI+): m/z 281.1 (MH+); Analysis calculated for Cι 7H16N O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.78; H, 5.70; N, 9.87.
Example 1 Pyrrolo[3 ',2 ' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid,
3, 7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, ethyl ester
Synthesized according to procedures published in J Het. Chem., 1970;7:1311-1319.
Example 2
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 8,9,11,12,13, 13a,14,14a-octahydro-2-methyl-, (4-fluorophenyl)methyl ester
Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-fluoro-benzyl ester To a solution of 5-hydroxy-2-mefhyl-l-H-indole-carboxylic acid (4.6 g, 24.1 mmol) in DMF (100 mL) was added DBU (3.67 g, 24.1 mmol) followed by 4-fluorobenzyl bromide (5.0 g, 26.5 mmol). The resulting mixture was stirred at room temperature under nitrogen for 3 days and then partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was separated, washed with water (2 x 100 mL) and then dried over Na2SO4 and concentrated in vacuo to give a white solid. Recrystalhzation from ethyl acetate gave 3.4 g (47%) of pure titled compound as a white solid: mp 209-210°C; IR 3412, 3377, 3305, 1667,
1512, 1466, 1221, 1 176, 1094 cm"1 ; !H NMR (DMSO-d6) δ 2.53 (s, 3H, CH3),
5.23 (s, 2H, CH2), 6.55 (dd, J = 8.79, 2.20 Hz, IH, ArH), 7.08 (d, J= 8.79 Hz,
IH, ArH), 7.14-7.17 (m, 2H, ArH), 7.19 (d, J= 2.20 Hz, IH, ArH), 7.44-7.48 (m,
2H, ArH), 8.81 (s, IH, OH), 1 1.55 (s, IH, NH); MS(APCI+): m/z 300.1 (MH+). Analysis calculated for Cι7H14F N O3: C, 68.22; H, 4.71 ; N, 4.68. Found:
C, 67.91 ; H, 4.65; N, 4.59.
Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-fluoro-benzyl ester
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-fluoro-benzyl ester (2.90 g, 9.69 mmol) and aqueous Me2NH (40%, 2.67 mL, 21.3 mmol) were mixed with 22 mL of EtOH, aqueous HCHO (37%, 0.940 g, 11.6 mmol) was then added. The resulting reaction mixture was heated with a heatgun until a clear solution was obtained. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was allowed to stand at 4°C for 15 hours, white precipitate formed. Filtration and drying under vacuum gave 1.56 g (45%) of pure titled compound as a white solid: mp 131-133°C (dec); IR 3376, 3214, 1693, 1686, 1513, 1424, 1259, 1227, 1085, 806 cm"1; !H NMR (DMSO-d6) δ 2.12 (s, 6H,
N(CH3)2), 2.45 (s, 3Η, ArCH3), 3.97 (s, 2H, ArCH2NMe2), 5.23 (s, 2H,
CO2CH2Ar), 6.56 (d, J= 8.61 Hz, IH, ArH), 7.06 (d, J= 8.61 Hz, IH, ArH),
7.18-7.24 (m, 2H, ArH), 7.49-7.54 (m, 2H, ArH), 11.5 (bs, IH, exchangeable proton); MS(APCI+): m/z 357.2 (MH+). Analysis Calculated for
C20H21N2θ3Fr0.1H2O: C, 67.06; H, 5.97; N, 7.82; F, 5.30; H2O, 0.50. Found:
C, 66.90; H, 5.81; N, 7.53; F, 5.33; H2O, 0.20.
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 8,9, 11 , 12, 13 , 13a, 14, 14a-octahydro-2-methyl-, (4-fluorophenyl)methyl ester
To a mixture of perchlorate salt (1.27 g, 5.36 mmol, Example 3, Step B) and 50 mL of ether was added 50 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 50 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 15 mL of dioxane, then indole mannich base (1.47 g, 4.12 mmol) was added; the resulting reaction mixture was refluxed under nitrogen for 5.5 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a brown solid. Recrystalhzation from CH3CN gave 1.63 g (88%>) of pure titled compound as a brown solid: mp 209-214°C
(decomposed); IR 2934, 1704, 1152, 1431, 1235, 1 148, 1078, 827 cm"1; lH NMR (DMSO-d6) δ 1.06-1.67 (m, 10H, aliphatic CH2 and CH), 1.81-1.86 (m, IH, aliphatic CH), 2.30-2.46 (m, 2H, obscured by DMSO peak, aliphatic CH), 2.46 (s, 3H, ArCH3), 2.60-2.70 (m, 2H, aliphatic CH), 2.84-2.91 (m, IH, aliphatic CH), 3.17 (dd, J= 18.3, 6.78 Hz, IH, aliphatic CH), 5.21 (ABq, Jab = 1 1.9 Hz,
^ab = 19.0 Hz, 2H, CO2CH2Ar), 6.59 (d, J= 8.61 Ηz, 1Η, ArΗ), 7.03 (d,
J= 8.61 Ηz, 1Η, ArΗ), 7.17-7.25 (m, 2Η, ArH), 7.48-7.52 (m, 2H, ArH), 11.5 (bs,
IH, NH); MS(APCI+): m/z 449.3 (MH+). Analysis calculated for C27H29N2O3Fr0.08CH3CN: C, 72.20; H, 6.52; N, 6.45; F, 4.20. Found:
C, 71.88; H, 6.35; N, 6.42; F, 4.15.
Example 3 (Intermediate) Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12,13,14,14a,15- decahydro-
Step A: 4-Dimethylaminomethyl-lH-indol-5-ol
5-Hydroxyindole (Aldrich, Milwaukee, WI, 5.09 g, 38.2 mmol) was dissolved in 25 mL of EtOH, aqueous Me2NH (40%, 5.28 mL, 42.1 mmol) was added followed by aqueous HCHO (37%, 3.65 g, 45.9 mmol). The resulting reaction mixture was stirred at ambient temperature for 1.5 hours during which time a precipitate formed. Filtration and drying under vacuum gave 4.13 g (57%) of pure titled compound as a beige solid: mp 137-139°C; IR 3316, 1625, 1592,
1523, 1450, 1239, 1 198, 724 cm" 1 ; H NMR (DMSO-d6) δ 2.25 (s, 6H,
CH N(CH3)2, 3.76 (s, 2H, CH2N(CH3)2), 6.29-6.30 (m, IH, ArH), 6.54 (d,
J= 8.61 Hz, lH, ArH), 7.10 (d, J= 8.60 Hz, IH, ArH), 7.18-7.20 (m, IH, ArH),
10.8 (bs, IH, exchangeable proton); MS(APCI+): m/z 191.1 (MH+). Analysis calculated for C\ ιH14N2O: C, 69.45; H, 7.42; N, 14.72. Found: C, 69.36; H,
7.38; N, 14.71.
Step B: 1,2,3,4,6,7,8,9-Octahydro-quinolizinylium perchlorate
The synthesis is found in David A. Evans, A new endocyclic enamine synthesis. JACS, 1970;92:7593-7595 and Leonard N.J., Hay A.S., Fulmer R.W., Gash V.W., Unsaturated amines. III. Introduction of α,β-unsaturation by means of mercuric acetate: ΔK^Xdehydroquinolizidine, J. Am. Chem. Sue, 1955;77:439- 444.
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12,13,14,14a,15-decahydro- To a mixture of perchlorate salt (406 mg, 1.71 mmol, Example 3, Step B) and 20 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL). The combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 5 mL of dioxane, then 4-dimethylaminomethyl-lH- indol-5-ol (250 mg, 1.31 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 4 hours. The reaction mixture was cooled to ambient temperature and a precipitate formed. Filtration and recrystalhzation from EtOAc gave 0.17 g (46%>) of pure titled compound as a beige solid: mp >250°C; IR 3414,
3148, 1454, 1242, 1 148, 888 cm-1 ; ]H NMR (DMSO-dg) δ 1.13-1.65 (m, 9H, aliphatic CH2 and CH), 1.76-1.91 (m, 2H, aliphatic CH), 2.36-2.52 (m, obscured by DMSO peak, 3H, aliphatic CH), 2.68-2.77 (m, IH, aliphatic CH),
2.88-2.96 ( , IH, aliphatic CH), 3.06 (dd, J= 17.6, 6.78 Hz, IH, aliphatic CH), 6.22-6.23 (m, IH, ArH), 6.56 (d, J= 8.61 Hz, IH, ArH), 7.07 (d, J= 8.61 Hz, IH,
ArH), 7.19-7.21 (m, IH, ArH), 10.8 (bs, IH, NH); MS(APCI+): m/z 383.1 (MH+). Analysis calculated for Cι8H22N2θ-0.1H2O: C, 76.08; H, 7.87; N, 9.86; H2O, 0.63. Found: C, 76.09; H, 7.81; N, 9.83; H2O, 0.74.
Example 4 (Intermediate) Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12,13, 14,14a,15- decahydro-2-methyl-
Step A: 2-Methyl-lH-indol-5-ol
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester (Aldrich, Milwaukee, WI, 20.0 g, 91.2 mmol) was mixed with aqueous NaOH (2N, 365 mL, 730 mmol), the resulting reaction mixture was refluxed under nitrogen for 1 hour. After cooling to 70°C, the reaction solution was treated with concentrated aqueous HCI until pH = 1. The resulting dark brown solution was extracted with ether (3 x 300 mL). Combined ether solution was dried over Na2SO4 and concentrated in vacuo affording a brown solid. Recrystalhzation from EtOAc/CH2Cl2 gave 1 1.7 g (81%) of pure titled compound as a light brown solid: mp 129-130°C; IR 3387, 3333, 1588, 1453, 1368, 1173, 783 cm"1 ; ]H NMR (DMSO-d6) δ 2.29 (s, 3H, ArCH3), 5.88-5.89 (m, IH, ArH), 6.45 (dd, J= 8.42, 2.38 Hz, IH, ArH), 6.68 (d, J= 2.38 Hz, IH, ArH), 7.00 (d, J= 8.42 Hz, IH, ArH), 8.44 (s, IH, NH),
10.5 (bs, IH, OH); MS(APCI+): m/z 148.1 (MH+). Analysis calculated for C9H9NO: C, 73.45; H, 6.16; N, 9.52. Found: C, 7.13; H, 6.18; N, 9.41.
Step B: 4-Dimethylaminomethyl-2-methyl-lH-indol-5-ol
2-Methyl-lH-indol-5-ol (5.00 g, 34.0 mmol) was dissolved in 20 mL of EtOH, aqueous Me2NH (40%, 9.40 mL, 74.7 mmol) was added followed by aqueous HCHO (37%, 3.30 g, 40.8 mmol). The resulting reaction mixture was stirred at ambient temperature for 2 hours, then mixed with 50 mL of water, precipitate formed. Filtration and recrystalhzation from ethanol (<50°C) gave 3.0 g (43%>) of pure titled compound as a white solid: mp 133-135°C; IR 3404, 3385, 1598, 1515, 1428, 1271, 1204, 798, 778 cm"1; ]H NMR (DMSO-dg) δ 2.23 (s, 6H, N(CH3)2), 2.30 (s, 3H, ArCH3), 3.68 (s, 2H, CH N), 5.98 (s, IH, ArH), 6.42 (d, J= 8.42 Hz, IH, ArH), 6.95 (d, J= 8.79 Hz, IH, ArH), 10.6 (bs, 1H, exchangeable proton); MS(APCI+): m/z 205.2 (MH+). Analysis calculated for Cι2H16N2O: C, 70.56; H, 7.90; N, 13.71. Found: C, 70.39; H, 7.87; N, 13.75.
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl- To a mixture of perchlorate salt (973 mg, 4.10 mmol, Example 3, Step B) and 30 mL of ether was added 40 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 40 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 7 mL of dioxane, then 4-dimethylaminomethyl-
2-methyl-lH-indol-5-ol (697 mg, 3.41 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a brown solid. Trituration with EtOAc gave 1.01 g (59%) of pure titled compound as a beige solid: mp 267-270°C (dec); IR 3407, 3189, 2926, 1435, 1212, 1 197, 774 cm"1 ;
!H NMR (DMSO-d6) δ 1.13-1.64 (m, 9H, aliphatic CH2 and CH), 1.74-1.89 (m,
2H, aliphatic CH), 2.31 (s, 3H, CH3), 2.35-2.50 ( , obscured by DMSO peak, 3H, aliphatic CH), 2.67-2.75 (m, IH, aliphatic CH), 2.87-3.31 (m, 2H, aliphatic CH), 5.92 (m, IH, ArH), 6.45 (d, J= 8.61 Hz, IH, ArH), 6.94 (d, J= 8.79 Hz, IH, ArH), 10.6 (bs, IH, exchangeable proton); MS(APCI+): m/z 297.1 (MH+).
Analysis calculated for Ci9H2 N2O: C, 76.99; H, 8.16; N, 9.45. Found: C, 76.79;
H, 8.19; N, 9.35.
Example 5 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-bromo- 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, ethyl ester
Step A: 6-Bromo-4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3- carboxylic acid ethyl ester 6-Bromo-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester, prepared according to the literature procedure [Bell M.R.; Oesterlin R.; Beyler A.L.; Harding H.R.; Potts G.O., J. Med. Chem., 1967;10:264-266], (3.01 g, 10.1 mmol) and aqueous Me2NH (40%>, 2.79 mL, 22.2 mmol) were mixed with
30 mL of EtOH, the mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%, 0.982 g, 12.1 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 48 hours during which time white precipitate formed. Filtration and drying under vacuum gave 1.91 g (53%) of pure titled compound as a white solid: mp 179-180°C (dec); IR 3339, 1700, 1688, 1426, 1092, 833 cm"1; *H NMR (DMSO-d6) δ 1.30 (t, J= 7.14 Hz, 3H, CH2CH3), 2.26 (s, 6Η, N(CH3)2), 2.49 (s, 3Η, obscured by DMSO peak, ArCH3), 4.16 (s, 2H, ArCH2NMe2), 4.23 (q, J= 6.96 Hz, 2H, CH2CH3), 7.38 (s, IH, ArH), 11.6 (bs, IH, exchangeable proton); MS(APCI+): m/z 355.0 (MH+). Analysis calculated for c15Hi9N2O3Br: C, 50.72; H, 5.39; N, 7.89; Br, 22.49. Found: C, 50.71 ; H, 5.31 ;
N, 7.75; Br, 22.67.
Step B:
To a mixture of perchlorate salt (1.40 g, 5.90 mmol, Example 3, Step B) and 50 mL of ether was added 50 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 50 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 20 mL of dioxane, then bromoindole mannich base (1.61 g, 4.54 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 4 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a thick oil. The crude product was further purified by chromatography (50% EtOAc in hexanes) to give a white foam, trituration with EtOAc/hexanes gave 1.42 g (54%) of pure titled compound as a white solid: mp
184-185°C; IR 3295, 2930, 1662, 1426, 1185, 1110, 1081, 869 cm"1; ]H NMR (CDCl3) δ 1.15-2.08 (m, 1 1H, aliphatic CH2 and CH), 1.39 (t, J= 7.14 Hz, 3H,
CH2CH3), 2.45-2.65 (m, 2Η, aliphatic CH), 2.60 (s, 3H, ArCH3), 2.85-3.00 (m,
2H, aliphatic CH), 3.17-3.30 (m, IH, aliphatic CH), 3.50 (dd, J= 18.0, 6.96 Hz, IH, aliphatic CH), 4.34 (q, J= 7.14 Hz, CH2CH3), 7.35 (s, IH, ArH), 8.10 (bs,
IH, NH); MS(APCI+): m/z 441 Λ (MH+). Analysis calculated for C22H2 N3O3Br: C, 59.06; H, 6.08; N, 6.26; Br, 17.86. Found: C, 59.1 1 ; H, 6.07;
N, 6.07; Br, 17.97.
Example 6 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, propyl ester
Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid propyl ester
5-Acetoxy-2-methyl-lH-indole-3-carboxylic acid propyl ester (intermediate D, 2.04 g, 7.42 mmol) was mixed with 20 mL of methanol, NaOCH3 (1.60 g, 29.6 mmol) was then added. The resulting reaction mixture was stirred at ambient temperature for 1.5 hour. The reaction mixture was then mixed with 20 mL of water, the resulting reaction mixture was treated with 5% HCI until pH = 1 affording a white precipitate. The solid was isolated by filtration and recrystallized from EtOAc/hexanes to give 1.39 g (80%>) pure titled compound as a beige solid, mp 188-189°C (dec); IR 3381, 3297, 1661, 1457, 1 178, 1090, 794,
783 cm'1; ]H NMR (DMSO-d6) δ 0.989 (t, J= 7.51 Hz, 3H, CH2CH2CH3), 1.72 (sextet, J= 7.14 Ηz, 2Η, CH2CH2CH3), 2.57 (s, 3H, ArCH3), 4.14 (t,
J= 6.41 Hz, 2H, CH2CH2CH3), 6.58 (dd, J= 8.42, 2.20 Hz, IH, ArH), 7.1 1 (d,
J= 8.61 Hz, IH, ArH), 7.29 (d, J= 2.20 Hz, IH, ArH), 8.83 (s, IH, OH), 1 1.5 (bs,
IH, NH); MS(APCI+): m/z 234 A (MH+). Analysis calculated for C13H15NO3O.O6H2O: C, 66.63; H, 6.50; N, 5.98. Found: C, 66.27; H, 6.38; N, 5.84.
Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid propyl ester 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid propyl ester (1.27 g, 5.43 mmol) and aqueous Me2NH (40%, 1.50 mL, 12.0 mmol) were mixed with 10 mL of EtOH, the mixture was heated with a heat gun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%, 0.528 g, 6.52 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was then concentrated in vacuo to reduce the volume by half. Precipitate formed. Filtration and drying under vacuum gave 0.86 g (54%) of pure titled compound as a white solid: mp 135-137°C (dec);
IR 3217, 2969, 1684, 1420, 1141, 1075 cm" 1; JH NMR (DMSO-d6) δ 0.953 (t, 7= 7.32 Hz, 3H, CH2CH2CH3), 1.70 (sextet, J= 7.33 Ηz, 2Η, CH2CH2CH3), 2.19 (s, 6H, N(CH3)2), 2.49 (s, 3Η, obscured by DMSO peak, ArCH3), 4.06 (s, 2H, ArCH2NMe2), 4.13 (t, J= 6.78 Hz, 2H, CH2CH2CH3), 6.56 (d, J= 8.61 Hz, IH, ArH), 7.07 (d, J= 8.42 Hz, IH, ArH), 11.5 (bs, IH, exchangeable proton);
MS(APCI+): m/z 291.1 (MH+). Analysis calculated for Cι6H22N203: C, 66.19; H, 7.64; N, 9.65. Found: C, 65.94; H, 7.67; N, 9.31. Step C:
To a mixture of perchlorate salt (0.763 g, 3.21 mmol, Example 3, Step B) and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL).
Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 5.0 mL of dioxane, then indole Mannich base (0.717 g, 2.47 mmol) was added; the resulting reaction mixture was refluxed under nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a thick oil. The crude product was further purified by chromatography (50% EtOAc in hexanes) to give a white solid. Recrystalhzation from CH3CN gave 0.67 g (70%) of pure titled compound as a white solid: mp 162-164°C; IR 3329, 2931, 1702, 1665, 1434, 1235, 1200,
1149, 1079, 948, 781 cnr1 ; lH NMR (CDCI3) δ 0.992 (t, J= 7.32 Hz, 3H, CH2CH2CH3), 1.76 (sextet, J= 7.08 Ηz, 2Η, CH2CH2CH3), 1.29-1.86 (m, 10H, aliphatic CH2 and CH), 2.1 1 (d, J= 13.43 Hz, IH, aliphatic CH), 2.27-2.58 (m,
2H, aliphatic CH), 2.58 (s, 3H, ArCH3), 2.82-2.86 (m, 2H, aliphatic CH),
3.00-3.10 (m, IH, aliphatic CH), 3.46 (dd, J= 18.1, 6.84 Hz, IH, aliphatic CH), 4.21 (t, J= 6.84 Hz, CH2CH2CH3), 6.73 (d, J= 8.79 Hz, IH, ArH), 7.01 (d, J= 8.79 Hz, IH, ArH), 8.06 (bs, IH, NH); MS(APCI+): m/z 383.1 (MH+).
Analysis calculated for C23H30N2O3: C, 72.22; H, 7.91; N, 7.32. Found:
C, 72.19; H, 7.88; N, 7.36.
Example 7 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 2-methylpropyl ester
Step A:
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid isobutyl ester (intermediate H, 1.03 g, 4.17 mmol) and aqueous Me2NH (40%, 1.15 mL, 9.17 mmol) were mixed with 4 mL of EtOH, aqueous HCHO (37%, 0.406 g,
5.01 mmol) was then added. The resulting reaction mixture was heated with a heat gun until a clear solution was obtained. The reaction mixture was stirred at 50°C for 4.5 hours. The reaction mixture was then allowed to stand for 16 hours at 4°C. Cotton-like white crystals formed. Filtration and drying under vacuum gave 0.62 g (49%>) of pure titled compound as a white solid: mp 122-124°C (dec); IR 3229,
2957, 1686, 1424, 1242, 1085, 1000 cm"1; JH NMR (DMSO-d6) δ 0.951 (d,
J= 6.59 Hz, 6H, CH2CH(CH3)2), 1.98 (m, J= 6.59 Ηz, 1Η, CΗ2CH(CΗ3)2),
2.18 (s, 6H, N(CH3)2), 2.50 (s, 3Η, obscured by DMSO peak, ArCH3), 3.97 (d,
J= 6.59 Hz, 2H, CH2CH(CH3)2), 4.07 (s, 2H, ArCH2NMe2), 6.56 (d, J= 8.61 Hz, IH, ArH), 7.06 (d, J= 8.42 Hz, IH, ArH), 11.5 (bs, IH, exchangeable proton); MS(APCI+): m/z 305.2 (MH+). Analysis calculated for Ci7H 4N2O3-1.03H2O: C, 63.23; H, 8.13; N, 8.67. Found: C, 62.84; H, 7.30; N,
8.44.
Step B: To a mixture of perchlorate salt (0.458 g, 1.93 mmol, Example 3, Step B) and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 5.0 mL of dioxane, then indole mannich base
(0.451 g, 1.48 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 3 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a thick oil. The crude product was further purified by chromatography (50%> EtOAc in hexanes) to give 0.40 g (52%) of pure titled compound as a white solid: mp 203-204.5°C; IR 3341, 2933, 1700, 1673, 1434, 1236, 1082, 886, 781 cm"1 ; lH NMR (CDCI3) δ 0.984 (d,
J= 6.84 Hz, 6H, CH2CH(CH3)2), 1.32-1.90 (m, 10Η, aliphatic CΗ2 and CH),
2.04 (m, J= 6.59 Hz, IH, CH2CH(CH3)2), 2.08-2.18 (m, IH, aliphatic CH),
2.40-2.60 (m, 2H, aliphatic CH), 2.59 (s, 3H, ArCH ), 2.84-2.88 (m, 2H, aliphatic
CH), 2.97-3.10 (m, IH, aliphatic CH), 3.46 (dd, J= 18.1, 6.84 Hz, IH, aliphatic CH), 4.00-4.09 (m, 2H, CH2CH(CH3)2), 6.73 (d, J= 8.79 Hz, IH, ArH), 7.02 (d,
J= 8.79 Hz, IH, ArH), 8.05 (bs, IH, NH); MS(APCI+): m/z 397.2 (MH+). Analysis calculated for C24H32N2O3: C, 72.70; H, 8.13; N, 7.06. Found:
C, 72.85; H, 8.19; N, 7.00.
Example 8 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2,2-dimethylpropyl ester
Step A:
5-Hydroxy-2-methyl-lH-indole-3 -carboxylic acid 2,2-dimethyl propyl ester (intermediate I, 1.55 g, 5.93 mmol) and aqueous Me2NH (40%, 1.64 mL,
13.1 mmol) were mixed with 4 mL of EtOH, aqueous HCHO (37%, 0.406 g, 5.01 mmol) was then added. The resulting reaction mixture was heated with a heat gun until a clear solution was obtained. The reaction mixture was stirred at 50°C for 4.5 hours. The reaction mixture was mixed with 50 mL of EtOAc, the mixture was washed with water (2 x 50 mL), the organic phase was dried over
Na2SO4 and concentrated in vacuo affording a thick oil. The crude product was further purified by flash chromatography (10%>-20% methanol in CHCI3 to give
0.90 g (48%>) of pure titled compound as a white solid: mp 150-151 °C (dec); IR
3251, 2953, 1690, 1424, 1238, 1081, 801 cm"1; lK NMR (DMSO-d6) δ 0.970 (s,
9H, CH2C(CH3)3), 2.18 (s, 6Η, N(CH3)2), 2.52 (s, 3H, ArCH3), 3.91 (s, 2H, CH2C(CH3)3), 4.08 (s, 2H, ArCH2NMe2), 6.57 (d, J= 8.42 Hz, IH, ArH),
7.07 (d, J= 8.61 Hz, IH, ArH), 11.5 (bs, IH, exchangeable proton); MS(APCI+): m/z 319.2 (MH+). Analysis calculated for Cι8H26N2O3: C, 67.90; H, 8.23; N, 8.80. Found: C, 67.53; H, 8.04; N, 8.57.
Step B: To a mixture of perchlorate salt (0.710 g, 2.23 mmol, Example 3, Step B) and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 5.0 mL of dioxane, then indole Mannich base
(0.690 g, 2.90 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 4 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a thick oil. The crude product was further purified by chromatography (50% EtOAc in hexanes) to afford a white solid. Recrystalhzation from CH3CN gave 0.92 g (44%) of pure titled compound as a white solid: mp 240-243 °C; IR 3187, 2934, 1700, 1433, 1235,
1077, 883, 780 cm' 1; ^ NMR (DMSO-d6) δ 0.96 (d, 9H, CH2C(CH3)3),
1.19-1.57 (m, 9Η, aliphatic CH2 and CH), 1.70-1.80 (m, IH, aliphatic CH),
1.76-1.85 (m, IH, aliphatic CH), 2.34-2.45 (m, 2H, obscured by DMSO peak aliphatic CH), 2.53 (s, 3H, ArCH3), 2.63-2.79 (m, 2H, aliphatic CH),
2.85-2.95 (m, IH, aliphatic CH), 3.25-3.35 (m, IH, obscured by water peak aliphatic CH), 3.94 (ABq, Jab = 10.62 Hz, j/ab = 24.1 Hz, 2H, CH2C(CH3)3),
6.61 (d, J= 8.42 Hz, IH, ArH), 7.04 (d, J= 8.61 Hz, IH, ArH), 11.51 (bs, IH, NH); MS(APCI+): m/z 411.3 (MH+). Analysis calculated for C24H32N2O3: C, 73.14; H, 8.35; N, 6.82. Found: C, 73.16; H, 8.52; N, 6.77.
Procedure G: General procedure for the Mannich reaction
The 5-hydroxy indole ester of choice, (2.2-17.9 mmol, 1 eq) was dissolved in EtOH by stirring while warming the solution; the solution was cooled. Aqueous
HCHO (37%, 1.2 eq) and Me2NH (40%, 2.2 eq) were added, and the reaction was stirred at 50°C until the ratio of starting material to product was constant. The ethanol was removed in vacuo, the brown oil was purified by flash chromatography (using MeOH/CHCl3 as the eluent) to afford the desired product.
Example 9
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester
Step A: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester was synthesized from intermediate C according to Procedure G
Yield: 3.36 g (55%); H NMR (DMSO-d6) δ 2.10 (s, 6H, CH2N(CH3)2), 2.45 (s,
3Η, ArCH3), 3.97 (s, 2H, CH2NMe ), 5.21 (s, 2H, CO2CH2Ph), 6.53 (d,
J= 8.30 Ηz, 1Η, ArΗ), 7.04 (d, J- 8.55 Ηz, 1Η, ArΗ), 7.29-7.43 (m, 5Η, ArH), 1 1.5 (s, IH, NH). MS(APCI+): m/z 339.1 (MH+).
Step B:
By a procedure similar to that described in Example 7, Step C
Yield: 3.30 g (77%); mp 162-164°C; IR: 2930, 2855, 1700, 1432, 1077 cm"1.
]H NMR (DMSO-d6) δ 1.11-1.67 (m, 10H, aliphatic CH2 and CH), 1.82-1.86 (m, 1H, aliphatic CH), 2.30-2.48 (m, 2H, obscured by DMSO peak, aliphatic CH), 2.48 (s, 3H, ArCH3), 2.62-2.70 (m, 2H, aliphatic CH), 2.86-2.92 (m, IH, aliphatic
CH), 3.19 (dd, J= 18.3, 6.78 Hz, IH, aliphatic CH), 5.23 (ABq, Jab = 12.1 Hz,
*>ab = 16.4 Hz, 2H, CO2CH Ph), 6.59 (d, J= 8.61 Ηz, 1Η, ArΗ), 7.03 (d, J= 8.61 Ηz, 1Η, ArΗ), 7.30-7.46 (m, 5Η, ArH), 1 1.5 (bs, IH, NH); MS(APCI+):
431.2 (MH+). Analysis calculated for C2 H30N2O3: C, 75.35; H, 7.02; N, 6.51.
Found: C, 75.16; H, 6.97; N, 6.47.
Example 10 Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1-methylethyl ester
Step A:
4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid isopropyl ester was synthesized from intermediate E according to Procedure G. Yield: 0.490 g (61 %); ]H NMR δ 1.26 (d, J= 6.35 Hz, 6H, CH(CH3)2), 2.17 (s,
6Η, CH2N(CH3)2), 2.45 (s, 3Η, ArCH3), 4.03 (s, 2H, CH2NMe2), 5.04 (sextet, J= 6.35, IH, CO2CH(CH3)2), 6.52 (d, J= 8.55 Hz, IH, ArH), 7.02 (d, J= 8.55 Hz, IH, ArH), 1 1.4 (s, IH, NH). MS(APCI+): m/z 291.1 (MH+).
Step B: By a procedure similar to that described in Example 7, Step C.
Yield: 0.390 g (60.4%); mp 186-188°C; IR: 2976, 2930, 2856, 1703, 1433,
1079 cm" 1. !H NMR (DMSO-d6) δ 1.10-1.57 (m, 9H, aliphatic CH2 and CH), 1.23 (d, J= 5.62 Hz, 3H, CH3), 1.25 (d, J= 5.86 Hz, 3H, CH3), 1.71-1.74 (m, IH, aliphatic CH), 1.85-1.88 (m, IH, aliphatic CH), 2.32-2.44 (m, 2H, obscured by DMSO peak, aliphatic CH), 2.44 (s, 3H, ArCH3), 2.63-2.74 ( , 2H, aliphatic
CH), 2.83-2.89 (m, IH, aliphatic CH), 3.21-3.28 (m, IH, aliphatic CH, obscured by water peak), 5.01 (septet, IH, CO2CH(CH3)2), 6.56 (d, J= 8.79 Hz, IH, ArH),
6.99 (d, J= 8.80 Hz, IH, ArH), 11.4 (bs, IH, NH); MS(APCI+): 383.1 (MH+). Analysis calculated for C23H30N O3: C, 72.22; H, 7.91; N, 7.32. Found: C, 71.98; H, 7.85; N, 7.29.
Example 11 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3, 7,8,9, 10,12, 13,14,14a, 15-decahydro-2-methyl-, cyclopropylmethyl ester
Step A:
4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid cyclopropyl methyl ester was synthesized from intermediate F according to
Procedure G. Yield: 0.406 g (62.1%); ]H NMR (DMSO-d6) δ 0.309-0.346 (m, 2H, cyclopropyl CH2CH ), 0.538-0.584 (m, 2H, cyclopropyl CH2CH2),
1.16-1.24 (m, IH, cyclopropyl CH), 2.23 (s, 6Η, CH2N(CH3)2), 2.52 (s, 3Η,
ArCH3), 4.02 (d, J= 7.32, 2H, CO2CH2CH), 4.10 (s, 2H, CH2NMe2), 6.58 (d,
J= 8.55 Hz, IH, ArH), 7.09 (d, J= 8.55 Hz, IH, ArH), 11.5 (s, 1H, NH).
MS(APCI+): m/z 303.1 (MH+).
Step B:
By a procedure similar to that described in Example 7, Step C. Yield: 0.269 g (50.7%); mp 199-200°C; IR: 3376, 3337, 2932, 2857, 1698, 1669, 1433,
1081 cm"1. !H NMR (CDC13) δ 0.337-0.373 (m, 2H, cyclopropyl CH2CH2), 0.596-0.641 (m, 2H, cyclopropyl CH2CH2), 1.21-1.89 (m, 10H, aliphatic CH2 and CH), 2.15-2.18 (m, IH, aliphatic CH), 2.48-2.64 (m, 2H, obscured by ArCH3 peak, aliphatic CH), 2.64 (s, 3H, ArCH3), 2.86-2.96 (m, 2H, aliphatic
CH), 3.00-3.10 (m, IH, aliphatic CH), 3.52 (dd, J- 18.1, 6.84 Hz, IH, aliphatic CH), 4.07-4.17 (m, IH, CO2CH2), 6.77 (d, J= 8.55 Hz, IH, ArH), 7.06 (d,
J= 8.79 Hz, IH, ArH), 8.10 (bs, IH, NH); MS(APCI+): 395.1 (MH+). Analysis calculated for C24H30N2O3 : C, 73.07; H, 7.66; N, 7.10. Found: C, 72.96; H,
7.70; N, 6.97.
Example 12 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 2-( 1 -piρeridinyl)ethyl ester
Step A:
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 2-piperdin-l-yl-ethyl ester (intermediate J, 0.770 g, 2.55 mmol) and aqueous Me2NFI (40%, 0.704 mL,
5.60 mmol) were mixed with 2 mL of EtOH, aqueous HCHO (37%, 0.248 g, 3.06 mmol) was then added. The resulting reaction mixture was heated with a heatgun until a clear solution was obtained. The reaction mixture was stirred at 50°C for 2 days. The reaction mixture was then diluted with EtOAc, then washed with water and dried over Na2SO4- The solution was concentrated in vacuo affording an oil. The crude product was further purified by flash chromatography (10%-20% MeOH in CHCI3) to give an oil (402 mg, 44% crude yield) which was the desired product with minor impurities: H NMR (DMSO-d5) δ 1.31-1.33 (m, 2H, piperidine CH2), 1.40-1.45 (m, 4H, 2 x piperidine CH2), 2.16 (s, 6H, CH2N(CH2N(CH3)2), 2.30-2.40 (m, 4Η, 2 x piperidine CH2), 2.47 (s, 3H, ArCH3), 2.52-2.55 (m, 2H, OCH2CH2N), 4.01 (s, 2Η, CH2N(CH3)2), 4.22 (t, J = 5.86 Hz, 2H, OCH2CH N), 6.52 (d, J= 8.55 Hz, IH, ArH), 7.02 (d, J= 8.55 Hz,
IH, ArH), 11.4 (bs, IH, exchangeable proton); MS (APCI+): m/z 360.2 (MH+).
Step B:
By a procedure similar to that described in Example 7, Step C. Yield: 0.137 g (37%); mp 169-171°C; IR: 2928, 1696, 1434, 1094, 1081 cm"1. }H NMR
(DMSO-d6) δ 1.11-1.54 (m, 15H, aliphatic CH2 and CH), 1.71-1.74 (m, IH, aliphatic CH), 1.86-1.90 (m, IH, aliphatic CH), 2.34-2.47 (m, 6H, obscured by DMSO peak, aliphatic CH), 2.47 (s, 3H, ArCH3), 2.52 (t, J= 5.62 Hz, 2H,
OCH2CH2N), 2.62-2.71 (m, 2Η, aliphatic CH), 2.84-2.89 (m, IH, aliphatic CH), 3.24-3.33 (m, IH, aliphatic CH, obscured by water peak), 4.14-4.26 (m, 2H,
OCH2CH N), 6.56 (d, J= 8.79 Hz, IH, ArH), 7.00 (d, J= 8.55 Hz, IH, ArH),
1 1.5 (bs, IH, NH); MS(APCI+): m/z 452.3 (MH+). Analysis calculated for c27H37N303-°-15H20: c> 71-38; H> 8-28; N> 9.25; H2O, 0.59. Found: C, 71.08; H, 8.25; N, 9.02; H2O, 0.21.
Procedure H: General Procedure for the Synthesis of Ethyl 2-alkyl-4-
(dimethylamino)methylene-5-hydroxy-3-indolecarboxylate. To a stirred solution of ethyl 2-alkyl-5-hydroxy-3-indolecarboxylate (2.63 mmol) in ethanol (8 mL) was added formaldehyde (0.24 mL, 3.16 mmol) and dimethylamine (0.73 mL, 5.80 mmol). The solution was stirred at 45°C for 3 hours, cooled and concentrated under reduced pressure. The residue was subjected to flash column chromatography (SiO2, 1 : 1 ethyl acetate/hexane then 10:1 ethyl acetate/ethanol) to afford the desired product.
Procedure I: General Procedure for the Synthesis of Ethyl 2-alkyl- [(pyrano[2,3-b]quinolizidine)[5,6-e]]indole-3-carboxylate. To a stirred solution of NaOH (50% w/w, 100 mL) and ether (20 mL) was added iminium perchlorate salt
(0.42 g, 1.78 mmol, Example 3, Step B). The solution was extracted with ether (10 x 100 mL), dried over MgSO4 and concentrated under reduced pressure to afford the enamine as a white solid. To a stirred solution of dioxane (2.5 mL/mmol) was added the enamine (0.197 g, 1.43 mmol) and indole (1.43 mmol). The solution was refluxed overnight, cooled to room temperature, concentrated under reduced pressure and subjected to flash column chromatography (Siθ2, 99:1 dichloromethane/methanol) to afford the desired product.
Example 13 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-(phenylmethyl)-, ethyl ester
Step A:
Ethyl 2-benzyl-4-(dimethylamino)methylene-5-hydroxy- 3-indolecarboxylate 84% yield as a white solid was synthesized from intermediate P according to Procedure H. lH NMR (250 MHz, CD3OD) δ 1.38 (t,
J- 7.2 Hz, 3H), 4.32 (q, J= 8.5 Hz, 2H), 4.46 (s, 2H), 6.68 (dd, J= 6.8, 2.5 Hz, IH), 7.17 (m, 5H) 7.47 (d, j = 2.25 Hz, IH). LC/MS (150 mm x 4.6 mm, C-18,
5 micron, 10 mM NH4OAc/CH3CN, APCI+) t = 7.86 min, m/z = 353.2 (M+l).
Step B:
Pyrrolo[3 ',2 ' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-(phenylmethyl)-, ethyl ester was synthesized according to Procedure I. 68% yield as a white solid. ^H NMR
(250 MHz, CDCI3) δ 1.36 (t, J= 7.2 Hz, 3H), 1.42 (m, 3H), 1.68 (m, 5H),
1.92 (m, 2H), 2.15 (d, J= 13.3 Hz, IH), 2.53 (m, 2H), 2.85 (m, 2H), 3.09 (m, IH), 3.48 (dd, J= 20.0, 7.5 Hz, IH), 4.35 (q, J= 7.1 Hz, 2H), 4.40 (s, 2H), 6.75 (d,
J= 8.6 Hz, IH), 6.96 (d, J= 8.7 Hz, IH), 7.29 (m, 5H), 7.90 (s, IH). 13C NMR (62.5 MHz, CDCI3) δ 14.5, 19.7, 25.0, 25.5, 27.0, 30.2, 31.2, 34.5, 36.7, 49.6, 59.9, 67, 87.2, 107, 109.6, 111.4, 114.1, 126, 127.0, 128.9, 129.1, 138, 144, 149, 167. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN,
APCI+) t = 10.73, m/z = 445.6 (M+l) Elemental Analysis Calculated: C, 75.64; H, 7.25; N, 6.30. Found: C, 75.71; H, 7.34; N, 6.23.
Example 14 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 2-ethyl- 3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester
Step A:
Ethyl 4-(dimethylamino)methylene-2-ethyl-5-hydroxy- 3-indolecarboxylate was synthesized from intermediate Q according to
Procedure H 55% yield as a white solid. *H NMR (250 MHz, DMSO) δ 1.23 (t, J= 7.4 Hz, 3H), 1.32 (t, J= 7.0 Hz, 3H), 2.46 (s, 6H), 2.91 (q, J= 7.6 Hz, 2H), 4.30 (q, J= 7.1 Hz, 2H), 4.44 (s, 2H), 6.61 (d, J= 8.6 Hz, IH), 7.1 1 (d, J
= 8.4 Hz, IH), 9.70 (bs, IH). 13C NMR (62.5 MHz, DMSO) δ 14.1 , 14.3, 17.3, 21.1, 58.2, 59.1, 103.2, 110.8, 111.6, 112.1, 125.3, 129.4, 148.1, 153.0, 165.6. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAc/CH3CN, APCI+) t = 6.25 min, m/z = 291.3 (M+l).
Step B:
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 2-ethyl-3, 7,8,9,10,12, 13, 14,14a,15-decahydro-, ethyl ester was synthesized according to Procedure I 43% yield as a white solid. *H NMR (250 MHz, CDCI3) δ l .34 (t, J= 7.6 Hz, 3H), 1.36 (t, J= 7.2 Hz, 3H), 1.63 (m, 5H), 1.88 (m, 3H), 2.15 (d, J= 13.3 Hz, IH), 2.47 (m, 2H), 2.82 (m, 2H), 3.02 (q, J= 7.5 Hz, 2H), 3.48 (dd, J= 17.9, 6.8 Hz, IH), 4.35 (q, J= 7.2 Hz, 2H), 6.77 (d, J= 8.7 Hz, IH),
7.06 (d, J = 8.7 Hz, IH), 7.26 (s, IH), 8.19 (s, IH). 13C NMR (62.5 MHz, CDC13) δ 13.7, 14.4, 19.7, 21.8, 25.0, 25.5, 27.0, 30.1, 31.1, 36.7, 49.6, 59.8, 67.0, 87.1, 106, 109.4, 113.8, 126, 130, 148, 149, 167. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAc/CH3CN, APCI+) t = 10.75, m/z = 383.5 (M+l)
Elemental Analysis: Calculated C, 72.22; H, 7.90; N 7.32. Found C, 72.03; H, 7.96; N, 7.19.
Example 15 Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 2-cyclopropyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester
Step A:
Ethyl 2-cyclopropyl-4-(dimethylamino)methylene-5-hydroxy- 3-indolecarboxylate was synthesized from intermediate R according to Procedure H. 64% yield as a white solid. ]H NMR (250 MHz, DMSO) δ 0.92 (m,
2H), 1.04 (m, 2H), 1.33 (t, J= 7.1 Hz, 3H), 2.22 (s, 6H), 3.98 (s, 2H), 4.27 (q, J =
7.1 Hz, 2H), 6.58 (d, J= 8.4 Hz, IH), 7.14 (d, J= 8.8 Hz, IH), 10.88 (s, IH). 13C NMR (62.5 MHz, DMSO) δ 8.4, 8.9, 14.3, 1703, 43.9, 58.3, 59.2, 1 10.6, 11 1.3, 112.0, 129.1, 147.3, 152.8, 165.9.
Step B:
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 2-cyclopropyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester was synthesized according to Procedure I. 60% yield as a white solid. ΪH NMR (250 MHz, CDCI3) δ 0.79 (m, 2H), 1.07 (d, J= 8.54, 2H), 1.37 (m, 3H), 1.40 (t, J= 7.2 Hz, 3H), 1.61 (m, 9H), 1.92 (m, IH), 2.17 (d, J= 15.0 Hz, 2H), 2.60 (m, 3H), 2.83 (m, 2H), 3.48 (dd, J= 17.9, 6.8 Hz, IH), 4.37 (q, J= 7.1 Hz, 2H), 6.75 (d, J= 8.6 Hz,
IH), 7.03 (d, J= 8.7 Hz, IH), 7.84 (s, IH). 13C NMR (62.5 MHz, CDC13) δ 4.8,
6.0, 7.5, 7.7, 9.5, 14.5, 19.7, 25.0, 25.5, 27.0, 30.0 ,36.7, 49.6, 59.8, 71.1, 74.8, 75.3, 75.8, 76.0, 77.5, 87.1, 109.4, 111.1, 113.8. LC/MS (150 mm x 4.6 mm, C- 18, 5 micron, 10 mM NH4OAc/CH3CN, APCI+) t = 10.70 min, m/z = 395.5 (M+l). Elemental Analysis: Calculated (as hydrate) C, 69.88; H, 7.82; N, 6.79. Found C, 69.92; H, 7.87; N, 6.67.
Example 16 Pyrrolo[3 ',2' :5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-propyl-, ethyl ester
Step A:
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3, 7,8,9, 10,12, 13, 14,14a,15-decahydro-2-propyl-, ethyl ester was synthesized from intermediate S according to Procedure H. 24% yield as a white solid. LC/MS (150 mm x 4.6mm, C-18, 5 micron, 10 mM NH4OAc/CH3CN, APCI+)
/ = 7.45 min, m/z = 305.3 (M+l).
Step B:
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-propyl-, ethyl ester was synthesized according to Procedure I. 28% yield as a white solid. H NMR (250 MHz, CDCl3) δ 0.99 (t, J= 7.3 Hz, 3H), 1.40 (m, 4H), 1.44 (t, J= 7.1 Hz, 3H), 1.68 (m,
7H), 1.92 (m, IH), 2.12 (d, J= 12.0 Hz, IH), 2.55 (m, 2H), 2.92 (m, 5H),
3.47 (dd, J= 16.7, 6.6 Hz, IH), 4.35 (q, J= 7.1 Hz, 2H), 6.77 (d, J= 8.7 Hz, IH),
7.05 (d, J= 8.7 Hz, IH), 8.12 (s, IH). 13C NMR (62.5 MHz, CDCI3) δ 13.9, 14.4, 19.8, 23.0, 25, 26, 27.0, 30.1, 30.5, 36.7, 49.6, 59.7, 87.1, 1 10, 1 1 1, 1 13.8, 127, 129, 146, 149, 167. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAc/CH3CN, APCI+) t = 11.56 min, m/z = 397.5 (M+l). Elemental
Analysis: Calculated C, 72.69; H, 8.13; N, 7.06. Found C, 72.30; H, 8.18; N, 6.79.
Example 17 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-(2-methylpropyl)-, ethyl ester
Step A:
Ethyl 2-isobutyl-4-(dimethylamino)methylene-5-hydroxy- 3-indolecarboxylate was synthesized from intermediate T according to Procedure H. 39% yield as a white solid. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAc/CH3CN, APCI+) t = 7.86 min, m/z = 319.3 (M+l).
Step B: Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-(2-methylpropyl)-, ethyl ester was synthesized according to Procedure I. 27% yield as a white solid. *H NMR (250 MHz, CDCI3) δ 0.95 (d, J= 4.3 Hz, 3H), 0.98 (d, J= 4.3 Hz, 3H) 1.23 (m,
IH), 1.39 (t, J= 7.1 Hz, 3H), 1.42 (m, 6H), 1.63 (m, 6H), 1.88 (m, lH), 2.00 (m, IH), 2.16 (d, J= 13.3 Hz, IH), 2.53 (m, 2H), 2.86 (m, 4H), 3.01 (m, IH),
3.47 (dd, J= 17.4, 7.2 Hz, IH), 4.34 (q, 7= 7.1, 2H), 6.77 (d, J= 8.6 Hz, IH),
7.06 (d, J= 8.7 Hz, IH), 8.04 (s, IH). 13C NMR (62.5 MHz, CDCI3) δ 14.5, 19.8,
22.5, 22.6, 25.0, 25.5, 27.0, 29.4, 30.1, 31.2, 36.7, 37.5, 49.5, 59.7, 87.1 , 109.3, 111.4, 113.8, 166.1. LC/MS ( 150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAc/CH3CN, APCI+) t = 6.43 min, m/z = 411.4 (M+l). Elemental Analysis:
Calculated C, 73.14; H, 8.35; N, 6.82. Found C, 73.04; H, 8.55; N, 6.60.
Example 18 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1 -dimethylethyl ester
Step A: tert-Butyl 3-amino-3-methylcrotonate Activation of Zn: To a stirred 3N HCI solution (50 mL) was added Zn (20 g) and stirred at room temperature for 15 minutes. The HCI solution was decanted, and this was repeated two times. The activated Zn was washed with distilled H2O (2x, 100 mL), ethanol (2χ, 50 mL), and ether (2x, 50 mL). The activated Zn was then placed under reduced pressure for 12 hours at room temperature. To a stirred suspension of anhydrous THF (10 mL) and activated Zn (0.83 g, 13 mmol) in a flame dried 100 L round bottom flask was added 5 drops of tert-butyl bromoacetate at room temperature.
The mixture was then heated to reflux for 15 minutes. 0.60 mL (6 mmol) Acetonitrile was added at once and tert-butyl bromoacetate (1.50 L, 10 mmol) was added dropwise over 30 minutes. The reaction mixture turned to green when about 2/3 of tert-butyl bromoacetate was added. The mixture was refluxed for an additional 30 minutes and then allowed to cool to room temperature. To the stirred solution was added THF (30 mL) and K2CO3 (2 g dissolved in 3 mL water) and stirred vigorously for 30 minutes. The solution was then placed in a centrifuge tube and centrifuged. The supernatant was decanted and the pellet was resuspended in THF (30 mL), shaken vigorously and centrifuged (2χ). The combined supernatant was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 0.78 g (83%) of tert-butyl 3-amino-3-methylcrotonate as light yellow liquid which solidifies at 0°C to a light yellow solid. ^H NMR (250 MHz, CDC13) δ 1.45 (s, 9H), 1.84 (s, 3H), 4.43 (s, 2H). 13C NMR (62.5 MHz, CDCI3) δ 22.3, 28.6, 78.1, 86.0, 158.9, 171.1.
Step B: tert-Butyl 5-hydroxy-2-methyl-3-indolecarboxylate. 1 ,4-Benzoquinone (3.30 g, 30 mmol) in ethanol (15 mL) was heated up until all solid was dissolved. tert-Butyl 3 -amino-3 -methyl crotonate (5.50 g, 35 mmol) in ethanol (15 mL) was added to the hot solution, and the reaction mixture was refluxed for 6 hours, cooled, and concentrated under reduced pressure. The residue was subjected to flash column chromatography (AI2O3, ethyl acetate) to afford 3.57 g of title compound (14.4 mmol, 48%) as a brown crystal, mp 114.0-116.0°C. lH NMR
(250 MHz, DMSO) δ 1.57 (s, 9H ), 2.55 (s, 3H), 6.57 (dd, J= 8.6, 2.3 Hz, IH), 7.09 (d, J= 8.6 Hz, IH,), 7.28 (d, J= 2.3 Hz, IH), 8.78 (s, IH), 1 1.41 (s, IH). 13C NMR (62.5 MHz, d6-MeOH) δ 14.4, 29.1, 80.6, 105.3, 106.8, 1 12.2, 129.9, 131.1, 145.9, 153.1, 161.7, 167.9.
Step C: tert-Butyl 4-(dimethylamino)methylene-5-hydroxy-2-methyl- 3-indolecarboxylate. To a stirred solution of tert-butyl 5-hydroxy-2-methyl- 3-indolecarboxylate (1.48 g, 6.0 mmol) in ethanol (4.5 mL) was added formaldehyde (0.55 mL, 7.2 mmol) and dimethylamine (1.66 mL, 13.2 mmol). The solution was stirred at 60°C for 10 hours, cooled and concentrated under reduced pressure. The residue was extracted with ether (30 mL), filter, evaporated solvent under reduced pressure again to afford 1.54 g of title compound (5.05 mmol, 84%) as a brown crystal, mp 151.0°C (decompose). lH NMR (250 MHz, d6-MeOH) δ 1.63 (s, 9H), 1.88 (s, 3H), 2.61 (s, 3H), 2.90 (s, 6H), 4.76 (s, 2H), 6.81 (d, J= 8.7 Hz, IH), 7.27 (d, J= 8.6 Hz, IH). 13C NMR
(62.5 MHz, d6-MeOH) δ 16.1, 24.2, 29.0, 43.1, 55.4, 82.0, 107.7, 1 12.4, 115.4,
131.6, 146.5, 154.1 , 161.7. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAC/CH3CN, APCI+) t = 7.75 min, m/z = 305.4 (M+l). Step D:
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1 -dimethyl ethyl ester To a stirred solution of NaOH (50%> w/w, 100 mL) and ether (20 mL) was added 0.082 g (0.20 mmol) of iminium salt (Example 3, Step B). The solution was extracted with ether (3 x 30 mL), dried over MgSO4 and concentrated under reduced pressure to afford the enamine as a white solid. 1.0 mL dioxane was added to the enamine and then tert-butyl 4-(dimethylamino)methylene-5-hydroxy- 2-methyl-3 -indole carboxylate (0.061 g, 0.20 mmol) followed by 0.5 mL dioxane. The solution was refluxed overnight, cooled to room temperature, concentrated under reduced pressure and subjected to flash column chromatography (Siθ2,
1 :1 hexane/ethyl acetate) to afford 0.031 g desired product (0.08 mmol, 40%) as a white solid; mp 214.0°C (decompose). lH NMR (250 MHz, CDC13) δ 1.45 (m,
4H), 1.61 (s, 9H), 1.69 (m, 5H), 1.89 (m, IH), 2.14 (d, J= 15 Hz, lH), 2.49 (m, 2H), 2.56 (s, 3H), 2.84 (d, J= 6 Hz, 2H), 3.06 (m, IH), 3.48 (dd, J= 18, 7 Hz,
IH), 6.74 (d, J= 8.6 Hz, IH), 7.01(d, J= 8.6 Hz, IH), 8.07 (s, IH). 13C NMR (62.5 MHz, CDCI3) δ 14.8, 19.8, 25.0, 25.5, 27.1, 28.6, 30.2, 31.2, 36.7, 49.6,
66.4, 80.0, 87.2, 108.0, 109.2, 1 1 1.3, 1 13.6, 126.0, 129.2, 140.6, 148.7, 165.6. LC/MS (150 mm x 4.6 mm, C-18, 5 micron, 10 mM NH4OAc/CH3CN, APCI+) / =7.98 min, m/z = 397.4 (M+l). Elemental Analysis: Calculated C, 72.70; H, 8.13;
N, 7.06. Found C, 72.28; H, 8.23; N, 6.72.
Example 19 2,6a,7-Trimethyl-7,8,9, 10, 10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza- cyclopenta[a]anthracene-l -carboxylic acid ethyl ester
Step A: l,6-Dimethyl-l,2,3,4-tetrahydro-pyridine l,6-Dimethyl-l,2,3,4-tetrahydro-pyridine was synthesized according to the procedure published in Lipp A., Liebigs Ann. Chem., 1898;289:216.
Step B: 2,6a,7-Trimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-3,7-diaza- cyclopenta[a]anthracene-l -carboxylic acid ethyl ester
A solution of l,6-dimethyl-l,2,3,4-tetrahydropyridine (0.100 g, 0.899 mmol, Example 19, Step A) and 4-dimefhylaminomethyl-5-hydroxy- 2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.200 g, 0.724 mmol) in dioxane (0.800 mL) under N2 was heated at 100°C for 4 hours. An additional 1.0 mL of dioxane was added, and heating was continued for 24 hours. The solution was cooled to room temperature, concentrated, and the residue was purified by flash column chromatography on silica gel using 50%-75% ethyl acetate:hexane and recrystallized with ethyl acetate to give 12 mg (4.8%) of 2,6a,7-trimefhyl-7,8,9, 10, 10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza- cyclopenta[a]anthracene-l -carboxylic acid ethyl ester as a white powder: mp
169-173°C; lU NMR (400 MHz, CDCI3) δ 1.34 (m, 2H), 1.36 (t, J= 7.08 Hz, 3H, CH2CH3), 1.45 (s, 3Η, CH3C(O)N), 1.56 (m, 2Η), 1.66 (m, IH), 1.93 (m, IH), 2.56 (s, 3H, CH3), 2.58 (s, 3Η, CH3), 2.87 (bd, J= 17.58 Ηz, 2Η), 3.50 (dd, J= 18.19, 6.72 Hz, IH,), 4.31 (q, J= 7.08 Hz, 2H, CH2CH3), 6.68 (d, J= 8.79 Hz, IH, ArH), 7.01 (d, J= 8.30 Ηz, 1 Η, ArH), 8.03 (bs, 1Η, NH); MS
(APCI+) m/z 343.2 (MΗ+). Analysis calculated for C2θH26N2θ3-0.17 H2O: C, 69.53; H, 7.68; N, 8.11. Found: C, 69.52; H, 7.33; N, 7.84.
Example 20 7-Ethyl-2,6a-dimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-3,7-diaza- cyclopenta[a]anthracene-l -carboxylic acid ethyl ester
Step A: l-Ethyl-6-methyl-2,3,4,5-tetrahydropyridinium perchlorate l-Ethyl-6-methyl-2,3,4,5-tetrahydropyridinium perchlorate was synthesized according to the procedure published in Ladenburg A., Liebigs Ann. Chem., 1899;304:54.
Step B: 7-Ethyl-2,6a-dimethyl-7,8,9,l 0,10a, 11 -hexahydro-3H,6aH-6-oxa-
3,7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester l-Ethyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate (0.245 g, 1.08 mmol, Example 20, Step A) was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic The aqueous solution was extracted with 4 x10 L of Et2θ, and the combined extracts were washed with 1 x10 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated into the reaction flask to give 90 mg (0.724 mmol) of 1-ethyl- 6-methyl-l,2,3,4-tetrahydro-pyridine. The residue was dissolved in dioxane (0.750 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid ethyl ester (0.200 g, 0.724 mmol) was added. The resulting solution was heated at reflux under N2 for 4 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 100% ethyl acetate and recrystallized with ethyl acetate to give 98 mg (38%) of 7-ethyl-2,6a-dimethyl-7,8,9,10,10a,l l- hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester as a white powder: mp 173-174°C; IR (KBr) 3298, 2930, 2856, 1669,
1433, 1238, 1094 cm"1; H NMR (300 MHz, CDC13) δ 1.16 (m, 3H, CH3CH2N),
1.37 (m, IH), 1.40 (m, IH), 1.48 (s, 2H), 1.56 (s, 2H), 1.64 (m, 2H), 1.97 ( , IH), 2.61 (s, 3H, CH3), 2.72 (m, 1Η), 2.84 (m, 1Η), 2.90 (bd, J= 19.04 Ηz, 2Η), 3.16 (m, IH), 3.54 (dd, J= 18.31, 6.78 Hz, IH), 4.35 (qd, J= 7.14, 1.65 Hz, 2H,
OCH2CH3), 6.70 (d, J= 8.61 Hz, IH, ArH), 7.03 (d, J= 8.61 Ηz, ArH), 8.06 (bs,
1Η, NH); MS (APCI+) m/z 357.1 (MΗ+). Analysis calculated for C21H28N2O3: C, 70.76; H, 7.92; N, 7.86. Found: C, 70.49; H, 7.80; N, 7.66. Example 21
Isomer A:
6a-Ethyl-2,7-dimethyl-7,8,9, 10, 1 Oa, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza- cyclopentafa] anthracene- 1 -carboxylic acid ethyl ester
Step A: 6-Ethyl-l-methyl-2,3,4,5-tetrahydropyridinium perchlorate
6-Ethyl-l-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate was synthesized according to the procedure published in Leonard N.J.; Hauck, Jr., F.P., J. Am. Chem. Soc, 1957;79:5279.
Step B: 6a-Ethyl-2,7-dimethyl-7,8,9,l 0,10a, 11 -hexahydro-3H,6aH-6-oxa-
3,7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester 6-Ethyl-l-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate (0.712 g, 3.16 mmol, Example 21, Step A) was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic The aqueous solution was extracted with 4 x 15 mL of Et2O, and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated into the reaction flask to 6-ethyl-l-methyl-l,2,3,4-tetrahydro- pyridine. The residue was dissolved in dioxane (2.1 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.581 g, 2.10 mmol) was added. The resulting solution was monitored by tic and MS as it was stirred at room temperature under N2 for 2 hours, heated at 50°C for 24 hours, at 60°C for 3 hours, at 70°C for 17 hours, and between 89-90°C for 4.5 hours. The darkening solution was cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 20-60% ethyl acetate:hexanes to give 56 mg (7.5 %) of a single isomer A of 6a-ethyl-2,7-dimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 3, 7-diaza-cyclopenta[a] anthracene- 1 -carboxylic acid ethyl ester with a larger Rf value as a white powder: mp 144-147°C; IR (KBr) 3375, 2975, 2937, 2858, 1671, 1470, 1432, 1245, 1202 cm"1; ]H NMR (400 MHz, CDC13) δ 0.91 (m, 3H, CH3CH2C(O)N), 1.34 (m, 2H), 1.36 (m, 3H, OCH2CH3), 1.54 (bs, 1Η), 1.63 (m, 1Η), 1.76 (m, 1Η), 1.84 (m, 1Η), 2.06 (m, 1Η), 2.46 (s, 3Η, CH3), 2.52 (m, 1Η),
2.57 (2, 3Η, CH3), 2.79 (d, J= 18.07 Ηz, 1Η), 2.88 (m, 1Η), 3.37 (dd, J= 18.07, 6.59 Ηz, 1Η), 4.31 (m, 2Η, OCH2CH3), 6.67 (d, J= 8.79 Hz, IH, ArH), 6.99 (d,
J= 8.55 Ηz, 1Η, ArH), 8.03 (bs, 1Η, NH); MS (APCI+) m/z 357.2 (MΗ+). Analysis calculated for C2ιH28N O3-0.04 H2O: C, 70.61; H, 7.92; N, 7.84; water, 0.22. Found: C, 70.27; H, 7.92; N, 7.58; water, 0.22.
Example 22
Isomer B:
6a-Ethyl-2,7-dimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-3,7-diaza- cyclopenta[a]anthracene-l -carboxylic acid ethyl ester
6-Ethyl-l-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate (0.712 g, 3.16 mmol, Example 21, Step A) was dissolved in a minimum amount of water and treated with 50%> aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et2O, and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated into the reaction flask to give 6-ethyl-l -methyl- 1,2,3, 4-tetrahydro- pyridine. The residue was dissolved in dioxane (2.1 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.581 g, 2.10 mmol) was added. The resulting solution was monitored by tic and MS as it was stirred at room temperature under N2 for 2 hours, heated at 50°C for 24 hours, at 60°C for 3 hours, at 70°C for 17 hours, and between 89-90°C for 4.5 hours. The darkening solution was cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 20-60% ethyl acetate:hexanes to give 37 mg (4.9 %) of a single isomer B of 6a-ethyl-2,7-dimethyl-7,8,9,l 0,10a, 1 l-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester with a smaller Rf value as a fine off-white powder: mp 158-161°C; IR (KBr) 3310, 2957, 2928,
2862, 1654, 1436, 1419, 1204 cm-1 ; l H NMR (400 MHz) δ 1.08 (m, 3H, CH3CH2C(O)N), 1.20 (m, IH), 1.37 (m, 3H, OCH2CH3), 1.41 (m, 1Η), 1.52 (s,
3Η, CH3), 1.59 (m, 2Η), 1.85 (bd, J= 13.18 Hz, IH), 2.30 (m, IH), 2.35 (m, 2H), 2.58 (s, 3H, CH3), 2.91 (m, 1Η), 3.11 (m, 2Η), 4.32 (m, 2H, OCH2CH3), 6.72 (d,
J= 8.55 Hz, IH, ArH), 7.00 (d, J= 8.79 Ηz, 1Η, ArH), 8.03 (bs, 1Η, NH); MS
(APCI+) m/z 357.2 (MΗ+). Analysis calculated for C21H28N2O3: C, 70.76; H,
7.92; N, 7.86. Found: C, 71.45; H, 8.44; N, 6.65. HPLC (ALLTECH/ALLTIMA C-18 1 :1 H2O/CH3CN + 0.05% TFA): retention time = 4.940 min, 99.40% purity.
Example 23
6a,7-Diethyl-2-methyl-7,8,9, 10, 10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza- cyclopenta[a]anthracene-l -carboxylic acid ethyl ester
Step A: l,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate 1 ,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate was synthesized according to the procedure published in Leonard N.J., Hauck, Jr., F.P., J. Am. Chem. Soc, 1957;79:5279.
Step B: 6a,7-Diethyl-2-methyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester l,6-Diethyl-2,3,4,5-tetrahydro-pyridinium perchlorate (0.485 g,
2.02 mmol, Example 23, Step A) was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et2O, and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated into the reaction flask to give 207 mg (1.49 mmol) of 1,6-diethyl- 1,2,3,4-tetrahydro-pyridine. The residue was dissolved in dioxane (1.3 mL) and
4-dimethylaminomethyl-5 -hydroxy-2 -methyl- lH-indole-3 -carboxylic acid ethyl ester (0.373 g, 1.35 mmol) was added. The resulting solution was heated at 100°C under N2 for 7 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 20-100% ethyl acetate:hexanes and recrystallized with ethyl acetate to give 123 mg (25%>) of 6a,7-diethyl-2-methyl-7,8,9, 10, 10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza- cyclopenta[a]anthracene-l -carboxylic acid ethyl ester as a white crystalline solid: mp 162-163°C; IR (KBr) 3390, 2972, 2929, 2859, 1654, 1432, 1201 , 1097 cm"1 ;
!H NMR (400 MHz, CDC1 ) δ 0.900 (m, 2H, CH3CH2C(O)N), 1.11 (m, 2H, CH3CH2N), 1.34 (m, 2H), 1.36 (m, 3H, CH3CH2O), 1.57 (m, 2H), 1.85 (m, 2H),
2.06 (m, IH), 2.57 (s, 3H, CH3), 2.70 (m, 2Η), 2.79 (bd, J= 18.31 Hz, IH), 2.84 (m, IH), 3.00 (m, IH), 3.37 (m, IH), 4.31 (m, 2H, CH3CH2O), 6.64 (d, J= 8.55 Ηz, 1Η, ArH), 6.98 (d, J= 8.55 FIz, 1Η, ArH), 8.00 (bs, 1Η, NH); MS (APCI+) m/z 371.1 (MΗ+). Analysis calculated for C 2H30N2O3: C, 71.32; H, 8.16; N, 7.56. Found: C, 71.28; H, 7.77; N, 7.32.
Example 24 7-Benzyl-2,6a-dimethyl-7,8,9, 10, 10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza- cyclopenta[a]anthracene-l -carboxylic acid ethyl ester
Step A: l-Benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate l-Benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate was synthesized according to the procedure published in Mδhrle H.; Dwuletzki H.Z., Naturforsch., B: Anorg. Chem., Org. Chem., 1986;41b:1323.
Step B: 7-Benzyl-2,6a-dimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-
3,7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester An excess of l-benzyl-6-methyl-2,3,4,5-tetrahydro-pyridinium perchlorate (Example 24, Step A) was dissolved in a minimum amount of water and treated with 50%) aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 20 mL of Et2O, and the combined extracts were washed with 1 x 20 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated to give the enamine. l-Benzyl-2-methyl-l,2,3,4-tetrahydro-pyridine (0.447 g, 2.39 mmol) was dissolved in dioxane (2.4 mL) and 4-dimethylaminomethyl-5-hydroxy-2- methyl-lH-indole-3-carboxylic acid ethyl ester (0.330 g, 1.20 mmol) was added. The resulting solution was heated at 80-90°C under N2 for 20 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 10-20% ethyl acetate:hexanes and recrystallized with ethyl acetate to give 208 mg (42%) of 7-benzyl-2,6a-dimethyl- 7,8,9, 10, 10a, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene- 1 -carboxylic acid ethyl ester of an off-white powder: mp 196-198°C; IR (KBr)
3397, 2983, 2923, 2897, 2854, 1668, 1432, 1200, 1097 cm"1; !H NMR (400 MHz, CDCI3) δ 1.36 (m, IH), 1.37 (m, 3H, OCH2CH3), 1.50 (s, 3Η,
CH3C(O)N), 1.53 (m, 3Η), 2.03 (m, IH), 2.56 (m, IH), 2.58 (s, 3H, CH3), 2.71 (m, 1Η), 2.94 (d, J= 18.07 Ηz, 1Η), 3.53 (dd, J= 18.07, 6.84 Ηz, 1Η), 3.58 (d, J = 15.14 Ηz, 1Η, NCH(Η)Ph), 4.32 (m, 2H, OCH2CH3), 4.47 (d,
J= 14.89 Hz, IH, NCH(H)Ph), 6.71 (d, J= 8.55 Ηz, 1Η, ArH), 7.01 (d, J= 8.55 Ηz, 1Η, ArH), 7.18 (t, J= 7.08 Ηz, 1Η, PhH), 7.28 (m, 2Η, PhH),
7.35 (d, J= 7.33 Ηz, 2Η, PhH), 8.06 (bs, 1Η, NH); MS (APCI+) m/z
419.2 (MΗ+). Analysis calculated for C26H30N2O3Η2O: C, 74.39; H, 7.24; N, 6.67; water, 0.30. Found: C, 74.27; H, 7.25; N, 6.54; water, 0.31.
Isomer A:
2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-3,7-diaza- cyclopenta[a] anthracene- 1 -carboxylic acid ethyl ester
Step A: l-Methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate
A procedure for the synthesis of l-methyl-6-phenyl-2,3,4,5-tetrahydro- pyridinium perchlorate is published in Leonard N.J.; Hauck Jr. F.P., J. Am. Chem. Soc, 1957;79:5279.
Step B: 2,7-Dimethyl-6a-phenyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa-
3, 7-diaza-cyclopenta[a] anthracene- 1 -carboxylic acid ethyl ester An excess of l-methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate (Example 25, Step A) was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic The aqueous solution was extracted with 4 x 20 mL of E-2O, and the combined extracts were washed with 1 x 20 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated to give the enamine. l-Methyl-6-phenyl-l,2,3,4,-tetrahydro-pyridine(0.428 g, 2.47 mmol) was dissolved in dioxane (1.8 mL) and 4-dimethylaminomethyl-5-hydroxy- 2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.342 g, 1.24 mmol) was added. The reaction mixture was heated at 75-80°C under N2 for 16 hours, 1.0 mL of dioxane was added and heating was continued at 90°C for 5 hours. Dried toluene (1.0 mL) was added to the mixture and it was heated at 100°C for 26 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 10-50%) ethyl acetate:hexanes to give a single isomer A with a smaller Rf value, which was recrystallized with e heπhexanes to give 73 mg (15%) of 2,7-dimethyl-6a-phenyl- 7,8,9, 10, 1 Oa, 11 -hexahydro-3H,6aH-6-oxa-3,7-diaza-cycloρenta[a]anthracene- 1-carboxylic acid ethyl ester as an off-white powder; mp 176-177°C; IR (KBr)
3400, 2942, 2930, 2859, 1647, 1434, 1206, 1099, 1079 cm"1; *H NMR (400 MHz, CDC13) δ 1.20 (m, 3H, OCH2CH3), 1.48 (m, 2Η), 1.67 (d, J= 13.18 Hz, IH), 1.84 (m, IH), 2.13 (s, 3H, CH3), 2.35 (m, 1Η), 2.52 (s, 3Η,
CH3), 2.58 (m, 1Η), 2.68 (m, 1Η), 2.81 (d, J= 17.33 Ηz, 1Η), 2.90 (m, 1Η), 4.17 (q, J= 7.08 Ηz, 2Η, OCH2CH3), 6.89 (d, J= 8.79 Hz, IH, ArH), 7.06 (d, J= 8.79 Ηz, 1Η, ArH), 7.15 (m, 3Η, PhH), 7.35 (m, 2Η, PhH), 8.07 (bs, 1Η, NH); MS (APCI+) m/z 405.2 (MΗ+). Analysis calculated for C25H 8N2O3: C, 74.23; H, 6.98; N, 6.93. Found: C, 73.93; H, 7.1 1; N, 6.66.
Example 26
Isomer B:
2,7-Dimethyl-6a-phenyl-7,8,9, 10, 10a, 1 1 -hexahydro-3H,6aH-6-oxa-3 ,7-diaza- cyclopenta[a]anthracene-l -carboxylic acid ethyl ester
An excess of l-methyl-6-phenyl-2,3,4,5-tetrahydro-pyridinium perchlorate (Example 25, Step A) was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic The aqueous solution was extracted with 4 x 20 mL of Et2O, and the combined extracts were washed with 1 x 20 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated to give the enamine. l-Methyl-6-phenyl-l,2,3,4,-tetrahydro-pyridine(0.428 g, 2.47 mmol) was dissolved in dioxane (1.8 mL) and 4-dimethylaminomethyl-5-hydroxy- 2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.342 g, 1.24 mmol) was added. The reaction mixture was heated at 75-80°C under N2 for 16 hours, 1.0 mL of dioxane was added and heating was continued at 90°C for 5 hours. Dried toluene (1.0 mL) was added to the mixture and it was heated at 100°C for 26 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 10-50% ethyl acetate rhexanes, recrystallized with etheπhexanes and the filtrate further purified by silica gel chromatography using 1-10% ethyl acetate :hexanes to give 70 mg (14%) of a single isomer B of 2,7-dimethyl-6a-phenyl-7,8,9,l 0,10a, 11-hexahydro-
3H,6aH-6-oxa-3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester with a larger Rf value as a course peach powder: mp 184-186°C; IR (KBr) 3380,
2926, 1698, 1684, 1436, 1073 cm"1; *H NMR (400 MHz, CDC13) δ 1.37 (t, J= 7.08 Hz, 3H, OCH2CH3), 1.49 (m, 2Η), 1.64 (m, IH), 1.76 (m, IH), 2.29 (m, IH), 2.31 (s, 3H, CH3), 2.59 (s, 3Η, CH3), 2.97 (d, J= 17.58 Ηz, 1Η), 3.52 (m,
1Η), 3.77 (m, 1Η), 4.32 (m, 2Η, OCH2CH3), 4.89 (bs, IH), 6.74 (d, J= 8.55 Hz, IH, ArH), 7.02 (d, J= 8.55 Ηz, 1Η, ArH), 7.33 (m, 5Η, PhH), 8.06 (bs, IH, NH); MS (APCI+) m/z 405.2 (MΗ+). Analysis calculated for C25H28N2O3: C, 74.23; H, 6.98; N, 6.93. Found: C, 74.18; H, 6.90; N, 6.72
Example 27 lH,7H-Indolizino[8',8a':5,6]pyrano[3,2-e]indole-l -carboxylic acid, 8,9,11,12,13, 13a, 14, 14a-octahydro-2 -methyl-, ethyl ester
Step A: 2,3,5,6,7,8-Hexahydro-lH-indolizinylium perchlorate 2,3,5,6,7,8-Hexahydro-lH-indolizinylium perchlorate was synthesized according to the procedure published in Reinecke M.G.; Kray L.R., J. Org. Chem., 1964;29:1736.
Step B: lH,7H-Indolizino[8',8a':5,6]pyrano[3,2-e]indole-l-carboxylic acid, 8,9,1 l,12,13,13a,14,14a-octahydro-2-methyl-, ethyl ester 2,3,5,6,7,8-Hexahydro-lH-indolizinylium perchlorate (0.330 g,
1.48 mmol, Example 27, Step A) was dissolved in a minimum amount of water and treated with 50%> aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et O, and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated into the reaction flask to give 143 mg (1.16 mmol) of enamine. 1 ,2,3,5,6,7-Hexahydro-indolizine was dissolved in dioxane (1.5 mL) and
4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.321 g, 1.16 mmol) was added. The resulting solution was heated at reflux under N2 for 5 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 100% acetone and recrystallized with ethyl acetate to give 129 mg (31 >) of 1H,7H-
Indolizino[8',8a':5,6]pyrano[3,2-e]indole-l -carboxylic acid, 8,9,11,12, 13, 13a,14,14a-octahydro-2-methyl-, ethyl ester as an off-white powder: mp 170-172°C; IR (KBr) 3396, 3353, 2929, 2853, 1668, 1434, 1 156, 1096,
1075 cm"1; !H NMR (300 MHz, CDC13) δ 1.38 (m, 2H), 1.40 (t, J= 7.14 Hz, 3H, OCH2CH3), 1.68 (m, 3Η), 1.90 (m, 3H), 2.05 (m, IH), 2.61 (s, 3H, CH3),
2.74 (m, 1Η), 2.84 (m, 1Η), 2.97 (d, J= 17.40 Ηz, 1Η), 3.09 (m, 2Η), 3.47 (dd, J= 17.76, 6.78 Hz, IH), 4.36 (m, 2H, OCH2CH3), 6.67 (d, J= 8.61 Hz, IH,
ArH), 7.03 (d, J= 8.61 Ηz, 1Η, ArH), 8.06 (bs, 1Η, NH); MS (APCI+) m/z 355.2 (MΗ+). Analysis calculated for C2iH26N2O3-0.23H2O: C, 70.34; H, 7.44; N, 7.81. Found: C, 70.35; H, 7.48; N, 7.61.
Example 28 3H,7H-Pyrrolizino[r,8':5,6]pyrano[3,2-e]indole-l-acetic acid, 8,9,1 l,12,12a,13- hexahydro-2-methyl-, ethyl ester
Step A: 1, 2,3, 5, 6,7-Hexahydro-pyrrolizinylium perchlorate
1,2,3, 5,6, 7-Hexahydro-pyrrolizinylium perchlorate was synthesized according to the procedure published in Miyano S. et al., Synthesis, 1978;9:701.
Step B: 3H,7H-Pyrrolizino[r,8':5,6]pyrano[3,2-e]indole-l-acetic acid, 8,9,1 1 ,12,12a, 13-hexahydro-2-methyl-, ethyl ester 1,2,3,5,6,7-Hexahydro-pyrrolizinylium perchlorate (0.904 g, 4.31 mmol,
Example 28, Step A) was dissolved in a minimum amount of water and treated with 50%) aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 15 mL of Et2θ, and the combined extracts were washed with 1 x 15 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated into the reaction flask to give 325 mg (2.98 mmol) of enamine, 2,3,5,6-tetrahydro-lH- pyrrolizine. The residue was dissolved in dioxane (2.8 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.794 g, 2.88 mmol) was added. The resulting solution was heated at 80°C under N2 for 17 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 15%
MeOH:CH2Cl2 and recrystallized with ether to give 105 mg (1 1%) of 3H,7H- pyrrolizinof l',8' :5,6]pyrano[3,2-e]indole- 1 -acetic acid, 8,9, 11 , 12, 12a, 13- hexahydro-2-methyl-, ethyl ester as a white powder; mp 206-207°C; IR (KBr)
2972, 2901, 2864, 2828, 1694, 1429, 1 196, 1087 cm"1; ^ NMR (400 MHz, CDC-3) δ 1.37 (t, J= 7.08 Hz, 3H, OCH2CH3), 1.60 (m, 2Η), 1.91 (m, IH),
1.99 (m, 2H), 2.10 (m, IH), 2.27 (m, 2H), 2.46 (m, IH), 2.55 (m, IH), 2.60 (s, 3H, CH3), 3.22 (m, 1Η), 3.35 (m, 1Η), 3.36 (d, J= 4.88 Ηz, 1Η), 4.34 (m, 2Η, OCH2CH3), 6.76 (d, J= 8.55 Hz, IH, ArH), 7.00 (d, J= 8.55 Ηz, 1Η, ArH),
8.26 (m, 1Η, NH); MS (APCI+) m/z 341.1 (MΗ+). Analysis calculated for C20H24N2°3: c> 70-57; H> 7.11; N, 8.23. Found: C, 70.40; H, 7.27; N, 7.94.
Example 29 2-Methyl-8,9, 10, 1 Oa, 11 , 12, 12a, 13-octahydro-3H,6aH,7H-6-oxa-3,6b-diaza- benzo[a]cyclopenta[h]anthracene-l -carboxylic acid ethyl ester
Step A: 1 ,3,4,8, 9, 9a-Hexahydro-2H-quinolizine l,3,4,8,9,9a-Hexahydro-2H-quinolizine was synthesized according to the procedure published in Bohlmann F. et al., Chem. Ber., 1973;106:3026.
Step B: 2-Methyl-8,9,10,10a,l l,12,12a,13-octahydro-3H,6aH,7H-6-oxa-3,6b- diaza-benzo[a]cyclopenta[h]anthracene-l -carboxylic acid ethyl ester 1, 3,4,8, 9,9a-Hexahydro-2H-quinolizine (0.372 g, 2.71 mmol, Example 29, Step A) was dissolved in dioxane (2.7 mL) and 4-dimethylaminomethyl-5- hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester (0.374 g, 1.36 mmol) was added. The resulting solution was heated at 80°C under N2 for 17 hours, at reflux for 24 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 10-20% ethyl acetate:CH2Cl2 and recrystallized with cyclohexane to give 71 mg (14%) of 2-methyl-8,9, 10, 10a, 1 1 , 12, 12a, 13-octahydro-3H,6aH,7H-6-oxa-3 ,6b-diaza- benzo[a]cyclopenta[h]anthracene-l -carboxylic acid ethyl ester as an off-white powder: mp 178-180°C; IR (KBr) 3372, 2929, 2859, 1669, 1654, 1435, 1 198,
1095, 1079 cm" 1 ; JH NMR (400 MHz, CDCI3) δ 1.15 (m, IH), 1.35 (t, J= 7.08 Hz, 3H, OCH2CH3), 1.36 (m, 4Η), 1.49 (m, 2H), 1.65 (m, 3H), 2.20 (m, IH), 2.58 (s, 3H, CH3), 2.68 (m, 1Η), 2.82 (m, 1Η), 2.89 (d, J= 17.58 Ηz, 1Η), 3.05 (m, IH), 3.45 (m, IH), 4.31 (m, 2H, OCH2CH3), 4.68 (s, IH, CH(O)N),
6.68 (d, J= 8.79 Ηz, 1Η, ArH), 6.99 (d, J= 8.55 Ηz, 1Η, ArH), 8.03 (bs, 1Η,
NH); minor diastereomer diagnostic peaks ^Η NMR (400 MHz, CDCI3) δ
6.75 (d, J= 8.55 Hz, IH, ArH); MS (APCI+) m/z 369.1 (MΗ+). Analysis calculated for C22H28N2O3: C, 71.71; H, 7.66; N, 7.60. Found: C, 71.96; H,
7.92; N, 7.09. HPLC (ALLTECH/ALLTIMA C-18 150 mm x 4.6 mm column, 1 : 1 H2O/CH3CN + 0.5% TFA): retention time = 3.526 min (11.26%), 3.882 min (85.82 %) (diastereomers), 97.08 % purity. HPLC (Alltima Silica 5 micron, 150 mm x 4.5 mm column, 95:5 hexane + 0.05 % Et2NH,ethanol + 0.05%
Et2NH): retention time = 5.19 min (84.08 %), 5.87 min (8.63 %) (diastereomers), 92.71 % purity.
Example 30 3H-pyrido[l",2":r2']azepino[3'2':5,6]pyrano[3,2-e]indole-l -acetic acid, 7,8,9,10,12,13, 14,15, 15a,16-decahydro-2-methyl-, ethyl ester, or 7H-Azepino[l",2":l"2']pyrido[3',2':5,6]ρyrano[3,2-e]indole-l-acetic acid, 3,8,9,10,11, 13, 14,15,15a,16-decahydro-2-methyl-, ethyl ester
Step A: 2,3,4,6,7,8,9,10-Octahydro-pyrido[l,2-a]azepine perchlorate
A synthesis of 2,3,4,6, 7,8,9, 10-octahydro-pyrido[l,2-a]azepine perchlorate is published in Mclntosh J.M. et al., Can. J. Chem., 1983;61 :2016.
Step B:
An excess of 2,3,4,6,7,8,9,10-octahydro-pyrido[l,2-a]azepine perchlorate (Example 30, Step A) was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 20 mL of Et2θ, and the combined extracts were washed with 1 x 20 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated to give
582 mg (3.85 mmol) of the crude enamine. The residue was dissolved in dioxane (3.8 mL) and 4-dimefh ylaminomethyl-5-hydroxy-2-m ethyl- lH-indole- 3-carboxylic acid ethyl ester (0.797 g, 2.88 mmol) was added. The reaction mixture was heated at 80°C under N2 for 6 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 10% ethyl acetate:CH2Cl2-100% ethyl acetate and recrystalhzation with iso-octane to give 18 mg (2%) of a single compound, either 3H-pyrido[l",2":l'2']azepino[3'2':5,6]pyrano[3,2-e]indole-l -acetic acid, 7,8,9,10,12,13,14,15, 15a,16-decahydro-2-methyl-, ethyl ester or 7H- azepino[l",2":l '2']pyrido[3',2':5,6]pyrano[3,2-e]indole-l -acetic acid, 3,8,9,10,1 1,13, 14, 15, 15a, 16-decahydro-2-methyl-, ethyl ester as a fine white powder: mp 1 18-121°C; IR (KBr) 3379, 3306, 2926, 2853, 1671, 1435, 1151,
1094, 1073 cm"1 ; JH NMR (400 MHz, CDCI3) δ 0.86 (m, IH), 1.35 (m, 3H), 1.36 (m, 3H, OCH2CH3), 1.45 (m, 3Η), 1.60 ( , 3H), 1.69 (dd, J= 14.65,
10.01 Hz, IH), 1.95 (m, IH), 2.19 (m, IH), 2.41 (m, IH), 2.54 (m, IH), 2.57 (s, 3H, CH3), 2.80 (d, J= 18.56 Ηz, 1Η), 3.1 1 (m, 1Η), 3.34 (m, 1Η), 3.48 (m, 1Η),
4.31 (m, 2Η, OCH CH3), 6.70 (d, J= 8.55 Hz, IH, ArH), 6.98 (d, J= 8.55 Ηz,
1Η, ArH), 8.01 (bs, 1Η, NH); MS (APCI+) m/z 383.1 (MΗ+). Analysis calculated for C23H30N2O3: C, 72.22; H, 7.91 ; N, 7.32. Found: C, 72.14; H, 7.95; N, 6.97.
Procedure J: General procedure for the Mannich reaction: The amide (1.1 mmol), 1 eq) was dissolved in EtOH by stirring while warming the solution: the solution was cooled. Aqueous HCHO (37%, 1.32 mmol, 1.2 eq) and Me2NH (40%,
2.42 mmol, 2.2 eq) were added, and the reaction was allowed to stir. After several hours, a white precipitate begins to form in the solution; the reaction may be heated to 5°C to speed the reaction. Upon completion, there is little or no starting material present. Water was added to the solution, and the mixture was then cooled in an ice bath. The resulting white solid was collected by filtration and dried under vacuum. Procedure K: General procedure for the condensation reaction: 1,2,3,4,6,7,8,9- octahydro-quinolizinylium perchlorate (17.8 mmol, 1.2 eq) was converted to the enamine in the following manner: the imine was dissolved in IN NaOH (10 mL) and the solution extracted with 2 x 20 mL of diethyl ether. The extracts were combined dried, and evaporated under vacuum to yield a white solid. The solid was dissolved in dioxane (10 mL). A solution of the 4-dimethylaminomethyl-5- hydroxy-2-methyl-lH-indole-3-carboxylic acid methyl or benzyl amide (14.8 mmol, 1 eq) was dissolved in dioxane (10 mL) and added to the enamine. The solution was refluxed for 19 hours, resulting in the formation of a white precipitate. The mixture was cooled in an ice bath, and the resulting solid was collected by filtration. The solid was washed sparingly with CH3CN and dried under vacuum at 50 degrees for 24 hours.
Example 31 8,9,1 1, 12,13,13a,14,14a-Octahydro-N,2-dimethyl-pyrrolo[3',2':5,6][l]- benzopyrano[3,2-i]quinolizine-l -carboxamide
Step A:
4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3 -carboxylic acid methyl amide was synthesized from Intermediate W according to Procedure J. Yield: 0.186 g (63.2%); mp: decomposition at >210°C; IR: 3319, 1615, 1515,
1433, 1218, 801 cm"1. !H NMR (DMSO-d6) δ: 2.14 (s, 6H, CH2N(CH3)2),
2.28 (s, 3Η, ArCH3), 2.70 (d, J= 3.91 Hz, 3H, CONHCH3), 3.69 (s, 2Η,
CH2N(CH )2), 6.48 (d, J= 8.55 Hz, IH, ArH), 6.97 (d, J= 8.55 Hz, IH, ArH),
8.06 (s, IH, CONHCH3), 10.88 (s, IH, indole NH). MS(APCI+): m/z 262.1 (MH+); Analysis calculated for Ci4H19N3O2: C, 64.35, H, 7.33, N, 16.08.
Found: C, 64.26, H, 7.44, N, 15.87. Step B:
8,9, 11 , 12, 13, 13a, 14, 14a-Octahydro-N,2-dimethyl- pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxamide was synthesized according to Procedure K. Yield: 0.057 g (9.8%); mp: decomposition at >210°C; IR: 3392, 3057, 2935, 2857, 1625, 1429, 1215 cm"1 ; 2H NMR
(DMSO-d6) δ 1.08-1.54 (m, 9H, aliphatic CH2 and CH), 1.63-1.69 (m, IH, aliphatic CH), 1.81-1.93 (m, IH, aliphatic CH), 2.27 (s, 3H, ArCH3),
2.31-2.45 (m, 3H, obscured by DMSO peak, aliphatic CH), 2.63-2.69 (m, IH, aliphatic CH), 2.68 (d, J= 3.91 Hz, 3H, CONHCH3), 2.87-2.95 (m, 1Η, aliphatic CΗ), 3.05 (dd, J= 18.3, 5.37 Ηz, 1Η, aliphatic CΗ), 6.49 (d, J= 8.79 Ηz, 1Η,
ArΗ), 6.94 (d, J= 8.79 Ηz, 1Η, ArΗ), 7.70-7.75 (m, 1Η, CONHCΗ3), 10.9 (s, IH,
NH); MS(APCI+): m/z 354.2 (MH+); Analysis calculated for 21H27N3o2-0.5C4H8θ2(CH3Cθ2Et): C, 69.49, H, 7.86, N, 10.57. Found:
C, 69.64, H, 7.75, N, 10.54.
Example 32
8,9,l l,12,13,13a,14,14a-octahydro-2-methyl-N-(phenylmethyl)- pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxamide
Step A: 4-Dimethylaminomethyl-5-hydroxy-2-methyl- 1 H-indole-3-carboxylic acid benzyl amide was synthesized from Intermediate X according to Procedure J. Yield: 0.582 g (69.2%); mp: 208-210 °C; IR: 3312, 1610, 1510, 1437, 1207, 747,
697 (cm" 1). ]H NMR (DMSO-d6) δ: 2.05 (s, 6H, CH2N(CH3)2), 2.31 (s, 3Η,
ArCH3), 3.67 (s, 2H, CH2N(CH3)2), 4.40 (d, J= 5.86 Hz, 2H, CONHCH2), 6.46 (d, J= 8.55, 1Η, ArΗ), 6.98 (d, J= 8.55, 1Η, ArΗ), 7.18-7.34 (m, 5Η, ArH),
8.63 (t, J= 5.86, IH, CONHCH2), 10.76 (s, IH, aromatic OH), 10.91 (s, IH, indole NH). MS(APCI+): m/z 338.2 (MH+); Analysis calculated for C20H23N3O2; C, 71.19, H, 6.87, N, 12.45. Found: C, 70.82, H, 6.86, N, 12.24.
Step B:
Example 32 was synthesized according to Procedure K. Yield: 0.228 g (35.9%); mp: 235-237°C; IR: 3177, 2929, 1627, 1429, 1089 cm" 1. 1H NMR
(DMSO-d6) δ 1.08-1.17 (m, 3H, aliphatic CH2 and CH), 1.35-1.61 (m, 7H, aliphatic CH2 and CH), 1.85-1.88 (m, IH, aliphatic CH), 2.26-2.45 (m, 3H, obscured by DMSO peak, aliphatic CH), 2.29 (s, 3H, ArCH3), 2.61-2.67 (m, IH, aliphatic CH), 2.82-2.88 (m, IH, aliphatic CH), 2.97 (dd, J= 17.6, 6.59 Hz, IH, aliphatic CH), 4.33-4.43 (m, 2H, CONHCH2Ph), 6.49 (d, J= 8.55 Ηz, 1Η, ArΗ),
6.94 (d, J= 8.55 Ηz, 1Η, ArΗ), 7.17-7.31 (m, 5Η, ArH), 8.36 (t, J= 6.10 Hz, IH,
CONHCH2PI1), 10.9 (s, IH, indole NH); MS(APCI+): m/z 430.2 (MH+); Analysis calculated for C2 H31N3O2-0.1C4H802: C, 75.07, H, 7.31, N, 9.59. Found:
C, 74.99, H, 7.33, N, 9.54.
Example 33
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxamide, N-ethyl- 8,9, 11 , 12, 13, 13a, 14,14a-octahydro-2 -methyl-
Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid ethylamide 5-Hydroxy-2-methyl-l-H-indole carboxylic acid (3.28 g, 17.2 mmol) was dissolved in dry DMF (20 mL) under nitrogen atmosphere and cooled to 0°C in an ice-water bath. To this solution were added in succession triethylamine (2.39 mL, 17.2 mmol) and solid O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.51 g, 17.2 mmol). The resulting reaction mixture was stirred at that temperature for 15 minutes, gaseous ethylamine was bubbled in for 10 minutes. After sequentially 15 minutes stirring at 0°C and 15 minutes at ambient temperature, reaction mixture was mixed with 60 mL of EtOAc, the resulting mixture was successively washed with IN HCI aqueous solution (2 x 60 mL), brine (2 x 60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a solid. The crude product was further purified by flash chromatography (100%> EtOAc) followed by recrystalhzation from EtOAc to provide 0.81 g (18%) of pure titled compound as a white solid: mp 199-201°C
(dec); IR 3372, 1609, 1523, 1464, 1246, 1216, 1193 cm"1 ; H NMR (DMSO-dg) δ 1.11 (t, J= 7.14 Hz, 3H, CH2CH3), 2.48 (s, 3Η, ArCH3), 3.25 (quintet, J= 6.96 Hz, 2H, NHCH2CH3), 6.54 (dd, J= 8.61, 2.20 Hz, IH, ArH), 7.06 (d,
J= 8.42 Hz, IH, ArH), 7.09 (d, J= 2.01 Hz, IH, ArH), 7.23 (t, J= 5.68 Hz, IH,
NHEt), 8.70 (s, IH, NH), 11.1 (bs, IH, OH); MS(APCI+): m/z 219.1 (MH+). Analysis calculated for Ci2H14N2θ2-0.13H2O: C, 65.34; H, 6.52; N, 12.70.
Found: C, 65.00; H, 6.38; N, 12.64.
Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethylamide 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid ethylamide (0.708 g, 3.24 mmol) was mixed with 7 mL of EtOH, aqueous Me2NH (40%, 0.895 mL,
7.13 mmol) was added followed by aqueous HCHO (37%, 0.315 g, 3.89 mmol). A clear reaction solution was obtained. The resulting reaction mixture was stirred at ambient temperature for 2 hours during which time precipitate formed. Filtration and drying under vacuum gave 0.298 g (33%) of pure titled compound as a white solid: mp 198-200°C (dec); IR 3346, 3189, 2986, 1615, 1436, 1215, 801 cm"1 ;
!H NMR (DMSO-d6) δ 1.11 (t, J= 7.14 Hz, 3H, CH2CH3), 2.18 (s, 6Η, N(CH3)2), 2.32 (s, 3Η, ArCH3), 3.24 (quintet, J= 6.78 Hz, 2H, CH2CH3), 3.78
(s, 2H, ArCH2NMe2), 6.50 (d, J= 8.42 Hz, IH, ArH), 7.01 (d, J= 8.61 Hz, IH,
ArH), 10.6 (bs, IH, exchangeable proton), 10.9 (bs, IH, exchangeable proton);
MS(APCI+): m/z 276.1 (MH+). Analysis calculated for C15H21N3O2: C, 65.43;
H, 7.69; N, 15.26. Found: C, 65.24; H, 7.73; N, 14.92. Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxamide, N- ethyl-8,9,l l,12,13,13a,14,14a-octahydro-2-methyl- To a mixture of perchlorate salt (263 mg, 1.11 mmol, Example 3, Step B) and 30 mL of ether was added 40 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 40 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 20 mL of dioxane, then 4-dimethylaminomethyl- 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethylamide (234 mg, 0.851 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a brown solid. The crude product was recrystallized from CH3CN, and then further purified by chromatography (10%>
MeOH in HCCI3) to give 0.070 g (17%) of pure titled compound as a yellow solid: mp 264-266°C (dec); IR 3313, 2930, 1623, 1604, 1435, 1216, 872 cm"1;
! H NMR (DMSO-d6) δ 1.08 (t, J= 7.14 Hz, 3H, CH2CH3), 1.18-1.58 (m, 9Η, aliphatic CH2 and CH), 1.71-1.75 (m, IH, aliphatic CH), 1.92-1.96 (m, IH, aliphatic CH) 2.32 (s, 3H, ArCH3), 2.38-2.49 (m, obscured by DMSO peak, 3H, aliphatic CH), 2.66-2.73 (m, IH, aliphatic CH and CH2), 2.90-2.94 (m, IH, aliphatic CH), 3.10 (dd, J= 18.3, 6.78 Hz, IH, aliphatic CH), 3.23 (quintet,
J= 6.78 Hz, NHCH2CH3), 6.53 (d, J= 8.79 Hz, IH, ArH), 6.98 (d, J= 8.61 Hz,
IH, ArH), 7.87 (t, J= 5.68 Hz, IH, NHEt), 10.9 (bs, IH, exchangeable proton);
MS(APCI+): m/z 368.2 (MH+). Analysis calculated for C22H29N3O2: C, 71.90;
H, 7.95; N, 11.43. Found: C, 71.52; H, 7.97; N, 11.25.
Example 34
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxaldehyde, 8,9,l l,12,13,13a,14,14a-octahydro-2-methyl-
To a solution of DMF (642 μL, 8.29 mmol) in CH2CI2 was added POCI3
(736 μL, 7.89 mmol) dropwise under nitrogen atmosphere. After stirring at ambient temperature for 10 minutes, pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]- quinolizine, 3, 7,8, 9,10,12, 13, 14,14a,15-decahydro-2-methyl- (Example 4, 1.17 g,
3.95 mmol) was added. When reaction was done as shown by TLC, the reaction mixture was poured into 300 mL of saturated aqueous NaHCO3 solution and stirred vigorously for 10 minutes. The resulting mixture was extracted with CHCI3 (4 x 100 mL), the combined organic phase was washed with water (1 x 200 mL) and brine (1 x 200 mL), dried over Na2SO4, and concentrated in vacuo affording a golden solid. The crude product was further purified by flash chromatography (25% acetone in EtOAc). Recrystalhzation from EtOH/Et2O gave 0.63 g (49%) of pure titled compound as a white solid: mp 262°C (dec); IR
3178, 2931, 1633, 1617, 1484, 1474, 1436, 1391 , 1 130, 1085, 868, 772 cm" 1 ; IH NMR (DMSO-d6) δ 1.14-1.59 (m, 9H, aliphatic CH2 and CH), 1.75-1.87 (m, 2H, aliphatic CH), 2.34-2.54 (m, obscured by DMSO peak, 2H, aliphatic CH), 2.56 (s, 3H, ArCH3), 2.63-2.70 (m, IH, aliphatic CH), 2.83-2.90 (m, 2H, aliphatic CH),
3.22-3.29 (m, IH, obscured by water peak, aliphatic CH), 6.60 (d, J= 8.55 Hz, IH, ArH), 7.04 (d, J= 8.55 Hz, IH, ArH), 10.0 (s, lH, ArCHO), 11.9 (bs, IH, exchangeable proton); MS(APCI+): m/z 325.2 (MH+). Analysis calculated for
C20H24N2O2: C, 74.05; H, 7.46; N, 8.63. Found: C, 73.97; H, 7.48; N, 8.58. Example 35 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, methyl ester
Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid methyl ester
Synthetic procedure is available in: Studies on the Nenitzescu synthesis of 5-hydroxyindoles. Patrick, James B.; Saunders, Elizabeth K., Tetrahedron Lett., 1979;42:4009-4012.
Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid methyl ester
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid methyl ester (10.0 g, 49.0 mmol) and aqueous Me2NH (40%, 12.0 mL, 107 mmol) were mixed with
32 mL of EtOH, aqueous HCHO (37%, 4.75 mL, 58 mmol) was then added. After stirring at ambient temperature for 16 hours, the reaction mixture was mixed with 100 mL of water. The resulting mixture was extracted with EtOAc (3 x 100), the combined organic phase was washed with water (1 x 100 mL) and brine (1 x 100 mL), dried over Na2SO4 and filtered. The filtrate was treated with HCI gas, precipitate formed and was isolated by filtration. Trituration in hot acetone (150 mL) gave 3.88 g of white solid. The white solid was suspended in 150 mL of EtOAc and mixed with 100 mL of 10% aqueous K2CO3 solution, the mixture was stirred until a clear solution is obtained, two layers were separated, the aqueous layer was extracted with EtOAc (50 mL). The combined organic phase was over Na2SO4 and concentrated in vacuo to give 3.22 g (25%) of light tan crystals.
Recrystalhzation of small portion of the crude product from acetone/water gave pure titled compound as white crystals: mp 145-146°C; H NMR (CDCI3) δ
2.33 (s, 6H, N(CH3)2), 2.55 (s, 3Η, ArCH3), 3.84 (s, 3H, C02CH3), 4.19 (s, 2H,
ArCH2NMe2), 6.72 (d, J= 8.55 Hz, IH, ArH), 7.04 (d, J= 8.55 Hz, IH, ArH); MS(APCI+): m/z 263,1 (MH+). Analysis calculated for C14Hi8N2O3: C, 64.11; H, 6.92; N, 10.68. Found: C, 63.77; H, 6.85; N, 10.54.
Step C:
To a mixture of perchlorate salt (2.17 g, 9.10 mmol, Example 3, Step B) and 50 mL of ether was added 50 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 50 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 8 mL of dioxane, then indole mannich base (2.00 g, 7.60 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 2.5 hours followed by stirring at ambient temperature for 16 hours. The reaction mixture was concentrated in vacuo affording a thick oil. Crystallization from CH3CN gave 1.75 g (63%) of pure titled compound as a white solid: mp
205-205.5°C; IR 3242, 2938, 1696, 1441, 1236, 1079, 884 cm"1 ; !H NMR (CDCI3) δ 1.21-1.80 (m, 9H, aliphatic CH2 and CH), 1.82-1.95 (m, IH, aliphatic
CH), 2.09-2.13 (m, IH, aliphatic CH), 2.41-2.77 (m, 2H, obscured by ArCH3 peak, aliphatic CH), 2.77 (s, 3H, ArCH3), 2.82-2.86 (m, 2H, aliphatic CH),
3.00-3.07 (m, IH, aliphatic CH), 3.44 (dd, J= 18.1 , 6.59 Hz, IH, aliphatic CH), 3.83 (s, 3H, CO2CH3), 6.73 (d, J= 8.55 Hz, IH, ArH), 7.01 (d, J= 8.79 Hz, IH, ArH), 8.12 (bs, IH, NH); MS(APCI+): m/z 355.2 (MH+). Analysis calculated for
C21H26N2°3: C, 71.16; H, 7.39; N, 7.90. Found: C, 71.17; H, 7.32; N, 8.00.
Example 36 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2, 12, 12-trimethyl-, phenylmethyl ester and/or
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2,10,10-trimethyl-, phenylmethyl ester
Step A: 4,4-Dimethyl-l ,2,3,4,6,7,8,9-octahydro-quinolizinylium perchlorate
The synthesis of 4,4-dimefhyl- 1,2, 3,4,6, 7,8, 9-octahydro-quinolizinylium perchlorate from l-chloro-3-iodopropane and 2,3,4,5-tetrahydro-2,2,6- trimethylpyridine was adapted from the procedure described in Evans, D.A.;
Domeier, L.A. Org Synth Coll Vol VI, p 819. ]H NMR (400 MHz, CDCI3) δ 1.52 (s, 6H, C(CH3)2), 1.75-1.86 (m, 4Η, aliphatic CH), 1.88-2.00 (m, 4Η, aliphatic CH), 2.80-2.87 (m, 4Η, aliphatic CH), 2.65-2.75 (m, 2Η, NCH2); MS
(APCI+) m/z 166.0 (parent MΗ+).
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2, 12,12-trimethyl-, phenylmethyl ester and/or Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2,10,10-trimethyl-, phenylmethyl ester One equivalent of 4,4-dimefhyl- 1, 2, 3,4,6, 7,8, 9-octahydro-quinolizinylium perchlorate (1.45 mmol, 0.385 g) was dissolved in a minimum amount of water and treated with 50% aqueous NaOH until strongly basic. The aqueous solution was extracted with 4 x 20 mL of Et2θ and the combined extracts were washed with 1 x 20 mL of saturated aqueous NaCl, dried with MgSO4, filtered, and concentrated to give the enamine. The residue was dissolved in dioxane (14 mL) and 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (1.45 mmol, 0.490 g) was added. The reaction mixture was heated at 90°C under N2 for 18 hours, cooled to room temperature, and concentrated. The crude residue was purified by flash column chromatography on silica gel using
100%) ethyl acetate and trituration with ether to give 90 mg (14%) of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2,l 2, 12-trimethyl-, phenylmethyl ester and/or pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2,10,10-trimethyl-, phenylmethyl ester as a yellow foam: IR (KBr) 3383, 2932, 2857, 1675, 1432, 1090, 1072 cm"1; Η NMR (400 MHz, DMSO-d6) δ 1.07 (s, 3H, CH3), 1.23 (s, 3Η, CH3), 1.09-1.26 (m, 5Η, aliphatic CH), 1.42-1.61 (m, 6Η, aliphatic CH), 1.90 (d, J=12.70 Ηz, 1Η, aliphatic CH), 2.58 (d, .7=18.56 Ηz, 1Η, aliphatic CH), 2.64-2.75 (m, 3Η, aliphatic CH), 3.1 1-3.19 (m, 2Η, aliphatic CH), 3.24-3.30 (m, 1Η, aliphatic CH), 5.15-5.25 (m,
2Η, OCH2Ar), 6.52 (d, J=8.79 Ηz, 1Η, ArH), 6.99 (d, J=8.55 Ηz, 1Η, ArH),
7.30-7.42 (m, 5Η, ArH), 1 1.50 (s, 1Η, NH); MS (APCI+) m/z 459.3 (MΗ+). Anal. Calcd for C29H34N2O3-0.19 H2O: C, 75.39; H, 7.50; N, 6.06; H2O, 0.74. Found:
C, 75.00; H, 7.73; N, 5.79; H2O, 0.36.
Example 37
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, ethyl ester
Step A: 6-Fluoro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester
6-Fluoro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester was synthesized according to the procedure published in Littell, R.; Allen, G.R., Jr. J. Org. Chem. 1968;33:2064.
Step B: 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid ethyl ester
4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid ethyl ester was prepared according to Procedure G from
6-fluoro-5-hydroxy-2-mefhyl-lH-indole-3-carboxylic acid ethyl ester (4.51 mmol, 1.07 g). The product precipitated out of the reaction solution upon reducing the volume by one-third and was recrystallized from acetonitrile to give a yellow- orange solid (0.510 g, 38%): mp 174-176°C (dec); IR (KBr) 3278, 2975, 1692, 1443, 1124, 1078 cm"1 ; !Η NMR (400 MHz, DMSO-dg) δ 1.32 (t, J=7.08 Hz,
3H, OCH2CH3), 2.26 (s, 6Η, N(CH3)2), 2.50 (s, 3Η, ArCi/3), 4.17 (s, 2H, NCH2Ar), 4.24 (q, J=7.08 Ηz, 2Η, OCH2CH3), 7.05 (d, J=10.50 Hz, IH, ArH),
1 1.56 (bs, 1Η, NH); 19F NMR (DMSO-d6) δ -141.69 (d, J=10.68 Ηz); MS
(APCI+) m/z 295.1 (MΗ+). Anal. Calcd for C15H19F1N2O3: C, 61.21; H, 6.51 ; N, 9.52; F, 6.45. Found: C, 61.32; H, 6.55; N, 9.51 ; F, 6.61. Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-fluoro-3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ethyl ester Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-fluoro-3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, ethyl ester was synthesized according to Procedure I from 4-dimethylaminomethyl-6-fluoro-
5 -hydroxy-2-methyl-lH-indole-3 -carboxylic acid ethyl ester (1.66 mmol, 0.488 g). The compound was purified by silica gel flash column chromatography (50:50 ethyl acetate: hexanes) and recrystallized from ethyl acetate to give a white solid (32%): mp 184-186°C; IR (KBr) 3367, 2932, 2858, 1670, 1456, 1437, 1135 cm"1; lΗ NMR (400 MHz, CDCI3) δ 1.37 (t, J=7.08 Hz, 3H, OCH2CH3),
1.25-1.47 (m, 4Η, aliphatic CH), 1.60-1.78 (m, 5Η, aliphatic CH), 1.85-1.95 (m, 1Η, aliphatic CH), 2.09 (bd, J=13.43 Ηz, 1Η, aliphatic CH), 2.43-2.49 (m, 2Η, aliphatic CH), 2.57 (s, 3Η, ArCH3), 2.87-2.92 (m, 2Η, aliphatic CH),
3.05-3.18 (m, 1Η, aliphatic CH), 3.43-3.50 (m, 1Η, aliphatic CH), 4.32 (q, J=7.08 Ηz, 2Η, OCH2CH3), 6.86 (d, J=10.01 Hz, IH, ArH), 8.09 (bs, 1Η, NH);
19F NMR (CDCI3) δ -140.62 (d, J=10.68 Ηz); MS (APCI+) m/z 387.1 (MΗ+). Anal. Calcd for C22H2 FιN2O3: C, 68.37; H, 7.04; N, 7.25; F, 4.92. Found: C, 68.30; H, 7.11; N, 7.09; F, 4.97.
Example 38 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-fluoro-
3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester
Step A: 6-Fluoro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid
6-Fluoro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester (Example 37, Step A, 9.02 mmol, 2.14g) was dissolved in 40 mL of 2N sodium hydroxide and heated at reflux for 1 hour. The solution was cooled to 0°C and carefully acidified to pΗ 9 with concentrated ΗC1. The solution was extracted with CΗ2C12, the extracts were discarded and the aqueous layer was further acidified at 0°C to pH 4 with concentrated HCI. The precipitate was filtered off and dried in vacuo for 18 hours to afford a tannish pink solid (1.16 g, 62%>): mp 202-204°C (dec); IR (KBr) 3584, 3358, 1649, 1471, 1109 cm"1; lU NMR
(400 MHz, DMSO-d6) δ 2.53 (s, 3H, ArCH3), 7.04 (d, J=1 1.23 Ηz, 1Η, ArH), 7.46 (d, J=9.03 Ηz, 1 Η, ArH), 9.17 (s, 1 Η, ArOH), 11.46 (s, 1 Η, NH or COOH), 11.76(s, 1Η, COOH or NH); 19F NMR (DMSO-d6) δ -141.60 (t, J=l 0.68 Ηz); MS (APCI-) m/z 208.0 (M-l).
Step B: 6-Fluoro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester
To a suspension of 6-fluoro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (4.92 mmol, 1.03 g) in 10.0 mL of DMF at room temperature under N2 was added dropwise via syringe l,8-diazabicyclo[5.4.0]undec-7-ene (4.92 mmol, 0.736 mL) followed by benzyl bromide (5.42 mmol, 0.644 mL). After 48 hours, water (10 mL) was added, and the precipitate was filtered off, dried, and recrystallized from chloroform to give a white, cottony solid (0.677 g, 46%): mp
191-193°C; IR (KBr) 3384, 3254, 1662, 1475, 1327, 1129, 1098 cm'1; !Η NMR (400 MHz, DMSO-d6) δ 2.59 (s, 3H, ArCH3), 5.32 (s, 2Η, OCH2C6H5), 7.12 (d,
J=10.99 Hz, IH, ArH), 7.31-7.49 (m, 6Η, ArH), 9.29 (s, 1Η, ArOH), 11.67 (s, 1Η,
NH); 19F NMR (DMSO-d6) δ -140.96-141.01 (m); MS (APCI-) m/z 298.1 (M-1).
Anal. Calcd for Cι7Η14F1N1O3-0.04 H2O: C, 68.06; H, 4.73; N, 4.67; F, 6.33;
H2O, 0.24. Found: C, 67.69; H, 4.63; N, 4.57; F, 6.61; H2O, 0.10.
Step C: 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester
A solution of 6-fluoro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (2.26 mmol, 0.677 g) and NNN',N'-tetramethyldiaminomethane
(2.49 mmol, 0.34 mL) in 5 mL of dioxane under Ν2 was heated at reflux for
21 hours. An additional aliquot of N,NN',N'-tetramethyldiaminomethane (2.49 mmol, 0.34 mL) was added, and the reaction was continued at reflux for 24 hours, cooled to room temperature, and concentrated. The residue was recrystallized from ethyl acetate to afford a light yellow solid (0.260 g, 32%): mp
167-169°C; IR (KBr) 3280, 2951, 1692, 1443, 1123, 1081 cm"1; ΪΗ ΝMR (400 MHz, DMSO-d6) δ 2.12 (s, 6H, Ν(CH3)2), 2.44 (s, 3Η, ArCH3), 4.04 (s, 2Η, NCH2Nr), 5.23 (s, 2Η, OCH2C6H5), 7.01 (d, J=10.50 Hz, IH, ArH),
7.31-7.44 (m, 5Η, ArH), 11.57 (s, 1Η, NH); 19F NMR (DMSO-d6) δ -141.55 (d, J=10.68 Ηz); MS (APCI+) m/z 357.1 (MΗ+). Anal. Calcd for 20H21FlN2θ3-0-07 C4H8O2: C, 67.18; H, 5.99; N, 7.73; F, 5.24. Found: C, 66.81; H, 6.20; N, 7.74; F, 5.49. Step D: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
5-fluoro-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-fluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester was synthesized according to Procedure I from 4-dimethylaminomethyl-6-fluoro- 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (0.601 mmol, 0.214 g), heating at 80°C for 40 hours. The product was purified by silica gel flash column chromatography (30-50%> ethyl acetate/hexanes) and recrystallized from ether to give a white solid (0.169 g, 63%): mp 179-181°C; ER (KBr) 2932, 2857,
1699, 1453, 1131, 1075 cm"1; !Η NMR (400 MHz, CDCI3) δ 1.17-1.38 (m, 3H, aliphatic CH), 1.41-1.48 (m, 1Η, aliphatic CH), 1.55-1.85 (m, 6Η, aliphatic CH), 2.03 (bd, J=12.94 Ηz, 1Η, aliphatic CH), 2.42-2.48 (m, 2Η, aliphatic CH), 2.55 (s, 3Η, ArCH3), 2.79 (d, J=17.58 Ηz, 1Η, aliphatic CH), 2.85-2.92 (m, 1Η, aliphatic CH), 3.04-3.17 (m, 1Η, aliphatic CH), 3.35 (dd, J=18.31, 6.51 Ηz, 1Η, aliphatic
CH), 5.25-5.37 (m, 2Η, OCH2C6H5), 6.86 (d, J=10.25 Hz, IH, ArH),
7.28-7.38 (m, 3Η, ArH), 7.40-7.44 (m,2Η, ArH), 8.07 (bs, 1Η, NH); 19F NMR (CDCI3) δ -142.0 (m); MS (APCI+) m/z 449.1 (MΗ+). Anal. Calcd for C2 Η29F1N2O3: C, 72.30; H, 6.52; N, 6.25; F, 4.24. Found: C, 72.28; H, 6.45; N, 6.09; F, 4.50.
Example 39 12H-Furo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-fluoro- 7,8,9,10,13, 14,14a, 15-octahydro-2-m ethyl-, ethyl ester
Step A: 6-Fluoro-5-hydroxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester
To a solution of 2-fluoro-[l,4]benzoquinone (38.3 mmol, 4.82 g) in 300 mL of glacial acetic acid was added 3-amino-but-2-enoic acid ethyl ester (31.9 mmol, 4.12 g). The solution was heated at reflux for 1.5 hours, cooled to room temperature, and concentrated. The product was isolated by silica gel flash column chromatography (30-50% ethyl acetate/hexanes) to afford a yellow solid (0.456 g, 6%): mp 138-139°C; IR (KBr) 3284, 2991, 1680, 1469, 1422, 1326,
1110 cm" 1; H NMR (400 MHz, DMSO-dg) δ 1.36 (t, J=7.08 Hz, 3H, OCH2CH3), 2.68 (s, 3Η, ArCH3), 4.32 (q, J=7.08 Ηz, 2Η, OCH2CH3), 7.43 (d,
J=8.79 Hz, IH, ArH), 7.55 (d, J=l 0.74 Hz, IH, ArH), 9.82 (s, 1Η, ArOH); 19F NMR (DMSO-dό) δ -137.42 (t, J=9.16 Ηz); MS (APCI-) m/z 231 A (M-1). Anal.
Calcd for Cι2Ηj 1F1O4: C, 60.50; H, 4.65; F, 7.98. Found: C, 60.50; H, 4.46; F, 8.20.
Step B: 4-Dimethylaminomethyl-6-fluoro-5-hydroxy-2-methyl-benzofuran-
3-carboxylic acid ethyl ester
A solution of 6-fluoro-5-hydroxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester (1.90 mmol, 0.452 g) and NN,N',N'-tetramethyldiaminomethane (2.09 mmol, 0.285 mL) in 4 mL of dioxane under Ν2 was heated at reflux for
4.5 hours, cooled to room temperature, and concentrated. Water (10 mL) was added to the residue, and the resultant precipitate was filtered off, dried, and recrystallized from t-butyl methyl ether to give a light yellow solid (0.225 g,
40%): mp 120-122°C; IR (KBr) 2989, 1706, 1446, 1384, 1322, 1 120 cm"1 ; 1H NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=7.08 Hz, 3H, OCH2CH3), 2.21 (s, 6Η, N(CH3)2), 2.57 (s, 3Η, ArCH3), 4.03 (s, 2Η, NCH2Ar), 4.32 (q, J=7.08 Ηz, 2Η, OCH2CH3), 7.48 (d, J=10.25 Hz, IH, ArH); 19F NMR (DMSO-d6) δ -137.69 (d,
J-10.68 Ηz); MS (APCI+) m/z 296.1 (MΗ+). Anal. Calcd for Cι5H18F1NιO : C, 61.01; H, 6.14; N, 4.74; F, 6.43. Found: C, 61.06; H, 6.07; N, 4.61; F, 6.47.
Step C: 12H-Furo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-fluoro-7,8,9,10,13,14,14a,15-octahydro-2-methyl-, ethyl ester 12H-Furo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-fluoro-7, 8,9,10,13, 14,14a,15-octahydro-2-methyl-, ethyl ester was synthesized according to Procedure I (90°C, 21 hours) from 4-dimethylaminomethyl-6-fluoro-
5-hydroxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester (0.603 mmol, 0.178 g). The product was purified by silica gel flash column chromatography (30%) ethyl acetate/hexanes) and recrystallized from ether to afford a white solid (0.210 g, 90%): mp 147-149°C; IR (KBr) 2936, 2848, 1717, 1453, 1242, 1125 cm-1; !H NMR (400 MHz, CDCI3) δ 1.25-1.37 (m, 2H, aliphatic CH),
1.38 (t, J=7.08 Ηz, 3Η, OCH2CH3), 1.40-1.52 (m, 2Η, aliphatic CH),
1.57-1.80 (m, 5Η, aliphatic CH), 1.84-1.96 (m, 1Η, aliphatic CH), 2.02 (d, J=13.43 Ηz, 1Η, aliphatic CH), 2.42-2.58 (m, 2Η, aliphatic CH), 2.61 (s, 3Η, ArCH3), 2.83-2.91 (m, 1Η, aliphatic CH), 2.90 (d, J=17.82 Ηz, 1Η, aliphatic CH), 3.06-3.16 (m, 1Η, aliphatic CH), 3.34-3.40 (m, 1Η, aliphatic CH), 4.34 (q,
J=7.08 Ηz, 2Η, OCH2CH3), 7.03 (d, J=9.77 Hz, IH, ArH); 19F NMR (CDCI3) δ
-137.90 (d, J=9.16 Ηz); MS (APCI+) m/z 388.2 (MΗ+). Anal. Calcd for C22H26F1N1°4: , 68.20; H, 6.76; N, 3.62; F, 4.90. Found: C, 68.12; H, 6.84; N, 3.56; F, 4.96.
Example 40
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 4,5-difluoro- 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester
Step A: 2,3-Difluoro-benzene-l,4-diol
2,3-Difluorophenol (Aldrich, 183.2 mmol, 24.32 g) was oxidized using potassium persulfate nitrate following the procedure of Feiring, A.E.; Sheppard, W.A. J. Org. Chem. 1975;40:2543. The crude material was purified by silica gel flash column chromatography (10% acetonitrile/chloroform) and recrystallized from chloroform to give a light yellow solid (7.32 g, 27%): mp 156-158°C; IR
(KBr) 3343 (br), 1514, 1505, 1259, 1 199, 1041 cm"1; ]H NMR (400 MHz,
DMSO-d6) δ 6.52 (d, J=5.37 Hz, 2H, ArH), 9.45 (s, 2Η, ArOH); 19F NMR
(DMSO-d6) δ -159.78 (d, J=4.58 Ηz); MS (APCI-) m/z 145.0 (M-1). Anal. Calcd for C6Η4F2O2: C, 49.33; H, 2.76; F, 26.01. Found: C, 49.09; H, 2.73; F, 26.37.
Step B: 2,3-Difluoπ [l,4]benzoquinone
2,3-Difluoro-benzene-l,4-diol (49.1 mmol, 7.17 g) was oxidized using ammonium cerium(IV) nitrate following the procedure of Feiring, A.E.; Sheppard, W.A. J. Org. Chem. 1975;40:2543 to afford a bright yellow solid (6.63 g, 94%): mp 97.0-98.5°C; IR (KBr) 3352, 1684, 1333 cm"1; *H NMR (400 MHz, DMSO- dβ) δ 6.98 (s, 2H, ArH); 19F NMR (DMSO-d6) δ -144.85 (s); MS (APCI-) m/z 144.0 (M-). Anal. Calcd for C6H2F2O2: C, 50.02; H, 1.40; F, 26.37. Found: C, 49.89; H, 1.31; F, 26.19.
Step C: 6,7-Difluoro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester
To a solution of 2,3-difluoro-[l,4]benzoquinone (1.26 mmol, 0.180 g) in 3.4 mL of glacial acetic acid was added 3-amino-but-2-enoic acid benzyl ester (1.05 mmol, 0.200 g). The mixture was heated at 50°C for 18 hours, cooled to room temperature, and the precipitate was filtered off. The beige solid was washed with glacial acetic acid and dried in vacuo to give clean product. The filtrate was neutralized, water (20 mL) was added, and the solution was extracted with ethyl acetate (4 x 20 mL). The extracts were dried over MgSO4, filtered, concentrated and the residue purified by silica gel flash column chromatography (20%> ethyl acetate/hexanes). The pure portions were combined to give 0.174 mg (52%) of off-white solid, which was recrystallized from acetonitrile: mp 215-217°C; IR
(KBr) 3457, 3243, 1658, 1480, 1338, 1150 cm"1; ]Η NMR (400 MHz, DMSO- d6) δ 2.58 (s, 3H, ArCH3), 5.31 (s, 2Η, OCH2C6H5), 7.29-7.45 (m, 6H, ArH),
9.75 (s, 1Η, ArOH), 12.13 (s, 1Η, NH); MS (APCI+) m/z 318.0 (MΗ+). Anal. Calcd for Cι7H13F2N1O3-0.04 C2H4O2: C, 64.17; H, 4.15; N, 4.38; F, 1 1.89. Found: C, 63.80; H, 4.15; N, 4.05; F, 12.18. Step D: 4-Dimethylaminomethyl-6,7-difluoro-5-hydroxy-2-methyl-lH-indole- 3 -carboxylic acid benzyl ester
4-Dimethylaminomethyl-6,7-difluoro-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester was prepared according to Procedure G from
6,7-difluoro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester
(8.08 mmol, 2.56 g). The reaction was heated at 50°C for 21 hours, the precipitate was filtered off, washed with ethanol, and dried to give a light yellow solid
(1.49 g, 49%): mp 159-160°C (dec); IR (KBr) 3235, 1688, 1438, 1365, 1301, 1123, 1083 cm"1 ; !Η NMR (400 MHz, DMSO-d6) δ 2.13 (s, 6H, N(CH3) ),
2.46 (s, 3Η, ArCH3), 4.00 (s, 2Η, ArCH2N), 5.24 (s, 2Η, OCH2C6H5),
7.27-7.38 (m, 3H, ArH), 7.41-7.44 (m, 2Η, ArH), 12.08 (s, 1Η, NH); 1 9F NMR (DMSO-d6) δ -168.26 (d, 7=21.4 Ηz), -159.68 (d, 7=21.4 Hz); MS (APCI+) m/z
375.0 (MH+). Anal. Calcd for C2oH20F2N2O3: C, 64.16; H, 5.38; N, 7.48; F, 10.15. Found: C, 64.00; H, 5.44; N, 7.36; F, 10.15.
Step E: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 4,5-difluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester Pyιrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 4,5-difluoro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-mefhyl-, phenylmethyl ester was synthesized according to Procedure I (90°C, 18 hours) from 4-dimethylaminomethyl-6,7-difluoro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (3.82 mmol, 1.43 g). The product was purified by silica gel flash column chromatography (5-10% ethyl acetate/dichloromethane) to give 1.37 g (77%) of cream colored solid. A portion was recrystallized from t-butyl methyl ether/hexanes to afford a white solid: mp 159-160°C; IR (KBr) 3297, 2933, 2857, 1704, 1455, 1141, 1124 cm"1; H NMR (400 MHz, CDC13) δ 1.17-1.36 (m, 3H, aliphatic CH), 1.43-1.49 (m, 1Η, aliphatic CH), 1.57-1.78 (m, 6Η, aliphatic CH), 2.00 (d, 7=13.7 Ηz, 1Η, aliphatic CH), 2.46 (d, 7=9.77 Ηz, 1Η, aliphatic CH), 2.53-2.57 (m, 1Η, aliphatic CH), 2.57 (s, 3Η, ArCH3), 2.71 (d, 7=18.31 Ηz, 1Η, aliphatic CH), 2.83-2.88 (m, 1Η, aliphatic CH), 3.06-3.16 (m, 1Η, aliphatic CH),
3.24-3.30 (m, 1Η, aliphatic CH), 5.24-5.36 (m, 2Η, OCH2C6H5), 7.32-7.38 (m,
3H, ArH), 7.42 (d, 7=6.84 Ηz, 2Η, ArH), 8.21 (s, 1Η, NH); 19F NMR (CDCI3) δ
-166.80 (d, 7=19.84 Ηz), -162.52 (d, 7=21.36 Ηz); MS (APCI+) m/z 461 Λ (MΗ+). Anal. Calcd for C27H28F2N2O3: C, 69.51 ; H, 6.05; N, 6.00; F, 8.14. Found: C, 69.36; H, 5.99; N, 5.88; F, 8.37.
Example 41 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 4,5-dichloro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester
Step A: 6,7-Dichloro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester
6,7-Dichloro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester was prepared from 2,3-dichloro-[l,4]benzoquinone (16.8 mmol, 2.98 g) and 3-amino-but-2-enoic acid benzyl ester (25.3 mmol, 4.83 g) following the procedure for the corresponding ethyl ester reported by Grinev, A.N.; Zaitsev, I.A.; Shvedov, N.I.; Terent'ev, A.P.7 Org. Chem. USSR (English) ;28:439. Yield
0.649 g (11%): mp 235-236°C; IR (KBr) 3421, 3281, 1651, 1098 cm"1; lH ΝMR (400 MHz, DMSO-d6) δ 2.59 (s, 3H, ArCH3), 5.29 (s, 2Η, OCH2C6H5), 7.30 (t,
7=7.08 Hz, IH, ArH), 7.34-7.38 (m, 2Η, ArH), 7.42 (d, 7=7.32 Ηz, 2Η, ArH), 7.51 (s, IH, ArH); MS (APCI-) m/z 348.0 (M-1). ΗPLC (ALLTECΗ/ALLTIMA C-18, 1 :1-2:98 Η2O/CΗ3CΝ + 0.05% TFA): retention time=6.573 min, 98.41% purity.
Step B: 4-Dimethylaminomethyl-6,7-dichloro-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester
4-Dimethylaminomethyl-6,7-dichloro-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester was prepared according to Procedure G from 6,7-dichloro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (3.06 mmol, 1.07 g). The reaction was heated at 50°C for 22.5 hours, concentrated and purified by silica gel flash column chromatography (30-50% acetone/hexanes) to afford a golden yellow solid (0.830 g, 67%): mp 167-170°C; IR (KBr) 3328,
1695, 1438, 1409, 1330, 1281, 1107 cm-1 ; ]Η NMR (400 MHz, DMSO-d6) δ 2.18 (s, 6H, N(CH3)2), 2.52 (s, 3Η, ArCH3), 4.06 (s, 2Η, ArCH2N), 5.27 (s, 2Η, OCH2C6H5), 7.30-7.39 (m, 3H, ArH), 7.41-7.47 (m, 2Η, ArH), 11.84 (s, 1Η, NH); MS (APCI+) m/z 407.1 (M+). Anal. Calcd for C2oΗ 0Cl2N2O3: C, 58.98;
H, 4.95; N, 6.88; Cl, 17.41. Found: C, 58.87; H, 4.96; N, 6.68; Cl, 17.23. Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 4,5-dichloro-3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 4,5-dichloro-3,7,8, 9,10,12, 13, 14,14a,15-decahydro-2-methyl-, phenylmethyl ester was synthesized according to Procedure I (80°C, 18 hours) from 4-dimethylaminomethyl-6,7-dichloro-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester (1.82 mmol, 0.742 g). The product was purified by silica gel flash column chromatography (10%> acetone/hexanes) to give 0.684 g (75%) peach colored foam: mp 100-105°C; IR (KBr) 3424, 2932, 2853, 1685,
1430, 1125, 1076 cm"1; lΗ NMR (400 MHz, DMSO-d6) δ 1.00-1.30 (m, 3H, aliphatic CH), 1.37-1.76 (m, 8Η, aliphatic CH), 2.37-2.40 (m, 1Η, aliphatic CH), 2.46-2.49 (m, 1Η, aliphatic CH), 2.50 (s, 3Η, ArCH3), 2.63-2.69 (m, 2Η, aliphatic
CH), 2.95-2.99 (m, 1Η, aliphatic CH), 3.17 (dd, 7=18.31, 6.74 Ηz, 1Η, aliphatic CH), 5.23 (dd, 7=28.08, 12.21 Ηz, 2Η, OCH2C6H5), 7.31-7.39 (m, 3H, ArH), .42-7.44 (m, 2Η, ArH), 11.85 (s, 1Η, NH); MS (APCI+) m/z 499.1 (MΗ+). Anal. Calcd for C27H28C12N2O3-0.07 H2O: C, 64.77; H, 5.66; N, 5.59; Cl, 14.16;
H2O, 0.25. Found: C, 64.37; H, 5.64; N, 5.51 ; Cl, 13.96; H2O, 0.32.
Example 42 Pyιrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-4,5-dimethoxy-2-methyl-, phenylmethyl ester
Step A: 6,7-Dimethoxy-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester
2,3-Dimethoxy-[l,4]benzoquinone (10.4 mmol, 1.74 g) was added to a solution of 3-amino-but-2-enoic acid benzyl ester (8.62 mmol, 1.65 g) in ethanol
(25 mL) at 0°C. The reaction was warmed to room temperature and then heated at reflux for 18 hours. The solvent was removed and the product was purified by silica gel flash column chromatography (30-50%> ethyl acetate/hexanes) and recrystallized from toluene to give a peach colored solid (0.621 g, 21 >): mp 154-156°C; IR (KBr) 3336, 3267, 1660, 1468, 1327, 1 146, 1081 cm"1 ; Η NMR
(400 MHz, DMSO-d6) δ 2.56 (s, 3H, ArCH3), 3.73 (s, 3Η, OCH3), 3.89 (s, 3Η, OCH3), 5.29 (s, 2Η, OCH2C6H5), 7.11 (s, IH, ArH), 7.29-7.43 (m, 5Η, ArH),
8.79 (s, 1Η, ArOH), 1 1.59 (s, 1Η, NH); MS (APCI-) m/z 340.0 (M-1). Anal. Calcd for C19Η19N1O5: C, 66.85; H, 5.61 ; N, 4.10. Found: C, 66.69; H, 5.55; N, 3.79.
Step B: 4-Dimethylaminomethyl-6,7-dimethoxy-5-hydroxy-2-methyl-lH-indole-
3-carboxylic acid benzyl ester
4-Dimethylaminomethyl-6,7-methoxy-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester was prepared according to procedure G from 6,7-dimethoxy-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester
(1.69 mmol, 0.577 g). The reaction was heated at 50°C for 18 hours, concentrated and purified by silica gel flash column chromatography (0-3% triethylamine/ethyl acetate) and recrystallized from cyclohexane to afford a lemon yellow solid (0.274 g, 41%): mp 132-134°C; IR (KBr) 3312, 1698, 1440, 1415, 1290,
1129 cm"1; !H NMR (400 MHz, DMSO-d6) δ 2.10 (s, 6H, N(CH3)2), 2.44 (s, 3Η, ArCH3), 3.73 (s, 3Η, ArOCH3), 3.86 (s, 3Η, ArOCH3), 3.94 (s, 2Η, ArCH N), 5.21 (s, 2Η, OCH2C6H5), 7.29-7.38 (m, 3H, ArH), 7.41-7.43 (m, 2Η,
ArH), 11.48 (s, 1Η, NH); MS (APCI+) m/z 399.0 (MΗ+). Anal. Calcd for C22H26 2O5: C, 66.32; H, 6.58; N, 7.03. Found: C, 66.47; H, 6.58; N, 6.73.
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-4,5-dimethoxy-2-methyl-, phenylmethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-4,5-dimethoxy-2-methyl-, phenylmethyl ester was synthesized according to Procedure I (90°C, 21 hours) from 4-dimethylaminomethyl-6,7-dimethoxy-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester (0.595 mmol, 0.237 g). The product was purified by silica gel flash column chromatography (50%> ethyl acetate/hexanes) and recrystallized from 2,2,4-trimethylpentane to give 0.089 g (30%) white solid: mp 130-136°C; IR (KBr) 3307, 2931, 2856, 1833, 1700, 1684, 1448, 1418, 1282,
1 137, 1123 cm"1 ; Η NMR (400 MHz, CDCI3) δ 1.24-1.38 (m, 4H, aliphatic CH), 1.44-1.55 (m, 1Η, aliphatic CH), 1.59-1.80 (m, 6Η, aliphatic CH), 2.09 (d,
7=13.98 Ηz, 1Η, aliphatic CH), 2.51 (d, 7=10.37 Ηz, 1Η, aliphatic CH), 2.58 (s, 3Η, ArCH3), 2.78 (d, 7=18.08 Ηz, 1Η, aliphatic CH), 2.85-2.91 (m, 1Η, aliphatic
CH), 3.08-3.14 (m, 1Η, aliphatic CH), 3.29-3.36 (m, 1Η, aliphatic CH), 3.96 (s, 3Η, OCH3), 4.05 (s, 3Η, OCH3), 5.26-5.37 (m, 2Η, OCH2C6H5), 7.31-7.40 (m, 3H, ArH), 7.44 (d, 7=6.99 Ηz, 2Η, ArH), 8.29 (s, 1Η, NH); MS (APCI+) m/z
491.1 (MΗ+). HPLC (ALLTECH/ALLTIMA C-18, 1 :1-2:98 H2O/CH3CN + 0.05 % TFA): retention time=4.527 min, 100.00% purity. Example 43 PyπOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2,5-dimethyl-, phenylmethyl ester
Step A: 6-Methyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester
6-Methyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (2.42 g, 10%)) was obtained from methyl-[l,4]benzoquinone (Aldrich, 81.9 mmol, 10.0 g) and 3-amino-but-2-enoic acid benzyl ester (79.5 mmol, 15.2 g) following the procedure for the corresponding ethyl ester reported by Allen, G.R., Jr.;
Pidacks, C; Weiss, M.J. 7 Am. Chem. Soc 1966;88:2536. The crude reaction product consisted of a mixture of the desired 6-methyl-5-hydroxy-2-methyl-lH- indole-3-carboxylic acid benzyl ester and the regioisomer, 7-methyl-5-hydroxy- 2-methyl-lH-indole-3-carboxylic acid benzyl ester. The regioisomers were separated following the procedure for the corresponding ethyl esters reported by
Poletto, J.F.; Allen, G.R., Jr.; Sloboda, A.E.; Weiss, M.J. 7 Med. Chem. 1973;16:757. Each isomer was separately recrystallized from acetone to give X-ray quality crystals. Single crystal X-ray analysis indicated that the higher Rf isomer (silica gel, 50%> ethyl acetate/hexanes) was 6-methyl-5-hydroxy-2-methyl- lH-indole-3-carboxylic acid benzyl ester: mp 196-197°C; IR (KBr) 3399, 3314,
1655, 1469, 1438, 1086 cm"1 ; }Η NMR (400 MHz, DMSO-d6) δ 2.14 (s, 3H,
ArCH3), 2.53 (s, 3Η, ArCH3), 5.28 (s, 2Η, OCH2C6H5), 6.99 (s, IH, ArH),
7.28-7.42 (m, 6Η, ArH), 8.81 (s, 1Η, ArOH), 11.42 (s, 1Η, NH); MS (APCI+) m/z 296.0 (MH+). Anal. Calcd for Cι8H17N1O3-0.25 H2O: C, 72.10; H, 5.88; N, 4.67. Found: C, 71.72; H, 5.54; N, 4.74.
Step B: 4-Dimethylaminomethyl-6-methyl-5-hydroxy-2-methyl- lH-indole- 3 -carboxylic acid benzyl ester
4-Dimethylaminomethyl-6-methyl-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester was prepared according to Procedure G from 6-methyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (7.48 mmol, 2.21 g) with the addition of 49.4 mmol of dimethylamine and 26.9 mmol of formaldehyde. The reaction was heated at 50°C for 70 hours, concentrated and purified by silica gel flash column chromatography (0-5% triethylamine/ethyl acetate) to afford a tan solid (1.67 g, 63%>). A portion was recrystallized from ethyl acetate to give a light yellow solid: mp 162-164°C; IR
(KBr) 3313, 1688, 1432, 1227, 1119, 1075 cm"1 ; ]Η NMR (400 MHz, DMSO- d6) δ 2.13 (s, 9H, N(CH3)2 and ArCH3), 2.44 (s, 3Η, ArCH3), 4.01 (s, 2Η,
ArCH N), 5.22 (s, 2Η, OCH2C6H5), 6.95 (s, IH, ArH), 7.29-7.44 (m, 5Η, ArH),
1 1.40 (s, 1Η, NH); MS (APCI+) m/z 353.1 (MΗ+). Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.30; H, 6.92; N, 7.87.
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2,5-dimethyl-, phenylmethyl ester
Pyrrolo[3',2':5,6][l]benzoρyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2,5-dimethyl-, phenylmethyl ester was synthesized according to Procedure I (90°C, 24 hours) from 4-dimethylaminomethyl-6-methyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (4.45 mmol, 1.57 g). The product was purified by silica gel flash column chromatography (20-50% acetone/hexanes then 20-40%> ethyl acetate/dichloromethane) to give 0.953 g (48%) yellow solid: mp 1 10-115°C; IR
(KBr) 3379, 2931, 2857, 1673, 1425, 1123, 1071 cm"1 ; !H NMR (400 MHz, DMSO-d6) δ 1.05-1.16 (m, 2H, aliphatic CH), 1.21-1.25 (m, 1Η, aliphatic CH),
1.33-1.42 (m, 2Η, aliphatic CH), 1.45-1.66 (m, 5Η, aliphatic CH), 1.78 (d, 7=13.67 Ηz, 1Η, aliphatic CH), 2.18 (s, 3Η, ArCH3), 2.34 (d, 7=9.28 Ηz, 1Η, aliphatic CH), 2.44 (s, 3Η, ArCH3), 2.41-2.46 (m, 1Η, aliphatic CH),
2.62-2.70 (m, 2Η, aliphatic CH), 2.87-2.95 (m, 1Η, aliphatic CH), 3.16 (dd, 7=18.07, 6.59 Hz, IH, aliphatic CH), 5.19 (dd, 7=25.15, 12.21 Ηz, 2Η, OCH C6H5), 6.90 (s, IH, ArH), 7.28-7.37 (m, 3Η, ArH), 7.41 (d, 7=6.84 Ηz, 2Η, ArH), 11.37 (s, 1Η, NH); MS (APCI+) m/z 445.3 (MΗ+). Anal. Calcd for
C28H32N2°3-°-16 H2θ: C, 75.16; H, 7.28; N, 6.26; H2O, 0.64. Found: C, 74.76; H, 7.35; N, 6.07; H2O, 0.34.
Example 44 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2,4-dimethyl-, phenylmethyl ester
Step A: 7-Methyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester
7-Methyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (2.04 g, 8.7%) yield) was obtained as an off-white powder from methyl-
[l,4]benzoquinone (81.9 mmol, 10.0 g) and 3-amino-but-2-enoic acid benzyl ester (79.5 mmol, 15.2 g) as in Example 43, Step A. Single crystal X-ray analysis indicated that the lower Rf isomer (silica gel, 50% ethyl acetate/hexanes) was
7-methyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester: mp 188-189°C; IR (KBr) 3430, 3286, 1641, 1446, 1294, 1 153, 1098 cm"1; ]Η NMR (400 MHz, DMSO-d6) δ 2.32 (s, 3H, ArCH3), 2.58 (s, 3Η, ArCH3), 5.27 (s, 2Η,
OCH C6H5), 6.39 (d, 7=1.22 Hz, IH, ArH), 7.10 (d, 7=1.71 Ηz, 1Η, ArH), 7.26-7.31 (m, 1Η, ArH), 7.34-7.38 (m, 2Η, ArH), 7.42 (d, 7=7.81 Ηz, 1Η, ArH),
8.71 (s, 1Η, ArOH), 11.42 (s, 1Η, NH); MS (APCI+) m/z 296.0 (MΗ+). Anal. Calcd for C^H^N^: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.02; H, 5.70; N, 4.40.
Step B: 4-Dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester
4-Dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl- 1 H-indole- 3-carboxylic acid benzyl ester was prepared according to procedure G from
7-methyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (6.62 mmol, 1.85 g), 41.3 mmol of dimethylamine, and 22.5 mmol of formaldehyde. The reaction was heated at 50°C for 46 hours, concentrated, purified by silica gel flash column chromatography (0-5% triethylamine/ethyl acetate) and recrystallized from ethyl acetate to give a light tan solid (0.900 g,
41%): mp 161-164°C; IR (KBr) 3307, 1684, 1292, 1220, 1070 cm"1 ; Η NMR (400 MHz, DMSO-d6) δ 2.08 (s, 6H, N(CH3)2), 2.30 (s, 3Η, ArCH3), 2.47 (s, 3Η, ArCH3), 3.89 (s, 2Η, ArCH2N), 5.22 (s, 2Η, OCH2C6H5), 6.37 (s, IH, ArH), 7.28-7.38 (m, 3Η, ArH), 7.43 (d, 7=7.08 Ηz, 2Η, ArH), 1 1.28 (s, 1Η, NH); MS (APCI+) m/z 353.2 (MH+). Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.20; H, 6.82; N, 7.79.
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2,4-dimethyl-, phenylmethyl ester Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2,4-dimethyl-, phenylmethyl ester was synthesized according to Procedure I (80°C, 39 hours) from 4-dimethylaminomethyl-7-methyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (2.55 mmol, 0.900 g). The product was purified by silica gel flash column chromatography (30%> ethyl acetate/hexanes then 20-50% ethyl acetate/dichloromethane) to give 0.569 g (50%>) off-white solid: mp 183-187°C;
IR (KBr) 3325, 2929, 1664, 1431, 1279, 1221, 1 107, 1075 cm'1 ; ]Η NMR (400 MHz, DMSO-d6) δ 1.06-1.15 (m, 2H, aliphatic CH), 1.19-1.22 (m, 1Η, aliphatic CH), 1.31-1.62 (m, 8Η, aliphatic CH), 1.81 (d, 7=12.94 Ηz, 1Η, aliphatic CH), 2.30 (s, 3Η, ArCH3), 2.33-2.42 (m, 1Η, aliphatic CH), 2.45 (s, 3Η, ArCH3),
2.55 (d, 7=17.82 Ηz, 1Η, aliphatic CH), 2.61-2.66 (m, 1Η, aliphatic CH), 2.82-2.88 (m, 1Η, aliphatic CH), 3.09-3.15 (m, 1Η, aliphatic CH), 5.20 (dd, 7=24.90, 12.21 Ηz, 2Η, OCH2C6H5), 6.41 (s, IH, ArH), 7.28-7.43 ( , 5Η, ArH),
11.31 (s, 1Η, NH); MS (APCI+) m/z 445.3 (MΗ+). Anal. Calcd for C28H32N2O3: C, 75.65; H, 7.26; N, 6.30. Found: C, 75.62; H, 7.34; N, 6.31.
Example 45 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2,5-dimethyl-, 1 -(4-fluorophenyl)ethyl ester
Step A: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2,5-dimethyl-, anhydride with benzoic acid
To a solution of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-
1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,5-dimethyl-, phenylmethyl ester (1.88 mmol, 0.837 g) and triethylamine (1.88 mmol, 0.262 mL) in 18 mL of tetrahydrofuran was added 20% Pd(OH) /C (0.200 g,
24 wt%>). The mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 20 minutes and filtered through celite, rinsing with tetrahydrofuran, to give the carboxylic acid: MS (APCI+) m/z 355.2 (MH+). To the filtrate under N2 at room temperature was added benzoyl chloride (1.88 mmol,
0.218 mL) dropwise. After 60 hours at room temperature, the precipitate was filtered off, the filtrate was concentrated, and the residue was triturated with ether to afford a light peach solid (0.517 g, 60%): H NMR (400 MHz, DMSO-d6) selected diagnostic peaks δ 2.23 (s, 3H, ArCH3), 2.48 (s, 3Η, ArCH3), 7.00 (s,
1Η, ArH), 7.57 (t, 7=7.81 Ηz, 2Η, ArH), 7.73 (t, 7=7.57 Ηz, 1Η, ArH), 8.06 (d,
7=7.32 Ηz, 2Η, ArH), 11.94 (s, 1Η, NH); MS (APCI+) m/z 459.2 (MΗ+).
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2,5-dimethyl-, l-(4- fluorophenyl)ethyl ester Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12, 13, 14,14a,15-decahydro-2,5-dimethyl-, anhydride with benzoic acid (1.13 mmol, 0.517 g) was added to 4-fluoro-α-methylbenzyl alcohol (3.38 mmol, 0.427 mL) and heated with stirring at 150°C for 2 minutes. A homogeneous solution formed, was cooled to room temperature, dissolved with ethyl acetate (10 mL), and stirred with a saturated aqueous solution of NaHCO3- The layers were separated, and the aqueous phase was extracted with 3 portions (10 mL) of ethyl acetate. The combined extracts were concentrated, and the product was purified by silica gel flash column chromatography (10-15% acetone/hexanes) to give a shiny beige powder (0.256 g, 48%): mp 124-128°C; IR (KBr) 3378, 2933,
1675, 1425, 1228, 1127, 1059 cm" 1; NMR (400 MHz, DMSO-dg) δ
1.07-1.28 (m, 3H, aliphatic CH), 1.42-1.65 (m, 6Η, aliphatic CH), 1.57 (d, 7=6.75 Ηz, 3Η, OCH(CH3)Ar), 1.71-1.74 (m, 1Η, aliphatic CH), 1.79-1.87 (m, 1Η, aliphatic CH), 2.21 & 2.22 (s, 3Η, ArCH3, diastereomers), 2.38 (d, 7=11.09 Ηz, 1Η, aliphatic CH), 2.46-2.49 (m, 1Η, aliphatic CH), 2.50 & 2.52 (s,
3Η, ArCH3, diastereomers), 2.64-2.72 (m, 2Η, aliphatic CH), 2.92-2.98 (m, 1Η, aliphatic CH), 3.10-3.29 (m, 1Η, aliphatic CH), 5.94-6.00 (m, 1Η, OCH(CΗ3)Ar),
6.92 & 6.93 (s, IH, ArH, diastereomers), 7.16-7.22 (m, 2Η, ArH), 7.45-7.51 (m,
2Η, ArH), 11.40 (s, 1Η, NH); 19F NMR (DMSO-d6) -115.13 & -114.94 (s, diastereomers); MS (APCI+) m/z 477.3 (MΗ+). Anal. Calcd for C29H33F1N2O3:
C, 73.09; H, 6.98; N, 5.88; F, 3.99. Found: C, 72.84; H, 7.02; N, 5.78; F, 3.89.
Example 46 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2,4-dimethyl-, 1 -(4-fluorophenyl)ethyl ester
Step A: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2,4-dimethyl-, anhydride with benzoic acid
Following the procedure in Example 45, Step A, pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2,4-dimethyl-, phenylmethyl ester
(1.10 mmol, 0.491 g) was converted to the mixed anhydride intermediate (cream colored solid, 0.512 g, 100%): MS (APCI+) m/z 459.3 (MH+).
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2,4-dimethyl-, l-(4- fluorophenyl)ethyl ester Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2,4-dimethyl-, 1 -(4-fluorophenyl)ethyl ester was synthesized following the procedure in Example 45, Step B from pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3, 7,8, 9,10,12,13, 14,14a,15-decahydro-2,4-dimethyl-, anhydride with benzoic acid (1.12 mmol, 0.512 g). The product was purified by silica gel flash column chromatography (10-20%> acetone/hexanes) to give a fluffy off-white powder (0.227 g, 43%): mp 105-108°C; IR (KBr) 3325, 2931 , 1674, 1512, 1433, 1222,
1109, 1059 cm" ; ] H NMR (400 MHz, DMSO-dg) δ 1.12- 1.26 (m, 3H, aliphatic
CH), 1.39-1.72 (m, 7Η, aliphatic CH), 1.57 (d, 7=6.51 Ηz, 3Η, OCH(CH3)Ar),
1.82-1.91 (m, 1Η, aliphatic CH), 2.31-2.36 (m, 1Η, aliphatic CH), 2.33 & 2.34 (s, 3Η, ArCH3, diastereomers), 2.43-2.47 (m, 1Η, aliphatic CH), 2.54 & 2.56 (s, 3Η, ArCH3, diastereomers), 2.58-2.70 (m, 2Η, aliphatic CH), 2.86-2.91 (m, 1Η, aliphatic CH), 3.06-3.25 (m, 1Η, aliphatic CH), 5.94-6.01 (m, 1Η, OCH(CΗ3)Ar), 6.43 & 6.45 (s, IH, ArH, diastereomers), 7.16-7.22 (m, 2Η, ArH), 7.45-7.51 (m,
2Η, ArH), 11.31 & 11.32 (s, 1Η, NH, diastereomers); 19F NMR (DMSO-d6)
-(115.13-115.08) & -(114.92-114.91) (m, diastereomers); MS (APCI+) m/z 477.3 (MΗ+). Anal. Calcd for C29H33F2N2O3-0.12 H2O: C, 72.75; H, 7.00; N, 5.85; F, 3.97; H2O, 0.45. Found: C, 72.38; H, 7.13; N, 5.73; F, 3.61; H2O, 0.31.
Example 47 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, l-[3- (methoxycarbonyl)phenyl] ethyl ester
Step A: 3-(l-Hydroxyethyl)benzoic acid methyl ester
A 500 mL stainless steel reactor was purged with N and charged successively with 1 -(3-bromophenyl)ethanol (0.126 mol, 25.4 g), DMSO (150 mL), methanol (3.70 mol, 150 mL), triethylamine (0.143 mol, 20.0 mL), Pd(OAc) (2.78 mmol, 0.625 g), and l,3-bis(diphenylphosphino)propane
(2.62 mmol, 1.08 g). The reactor was sealed, purged with N2 and then with CO, pressurized to 663 psi with CO, rocked and heated to 80°C for 12 hours. The reactor was re-pressurized to 724 psi with CO, rocked and heated to 100°C for 70 hours. The reaction was cooled to room temperature, filtered through celite, concentrated, and partitioned between H2O and CH2CI2. The aqueous phase was extracted with CH2CI2 (3 x 100 mL), and the extracts were washed with water
(3 x 100 mL), dried over MgSO4, and concentrated to an oil. The product was purified by silica gel flash column chromatography (10-25% ethyl acetate/hexanes) to give 3-(l-hydroxyethyl)benzoic acid methyl ester (15.1 g,
66%): JH NMR (400 MHz, CDC13) δ 1.50 (d, 7=6.59 Hz, 3H, CH(CH3)OH),
1.86 (d, 7=3.66 Hz, IH, CH(CH3)OH), 3.90 (s, 3Η, CO2CH3), 4.92-4.97 (m, 1Η, CH(CΗ3)OΗ), 7.39-7.43 (m, IH, ArH), 7.57 (d, 7=7.57 Ηz, 1Η, ArH), 7.92 (d,
7=7.57 Ηz, 1Η, ArH), 8.02 (s, 1Η, ArH).
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1 -[3-(methoxycarbonyl)phenyl]ethyl ester A 100 mL flask was charged with 3-(l-hydroxyethyl)benzoic acid methyl ester (18.0 mmol, 3.24 g) followed by pyrrolo[3',2':5,6][l]benzopyrano[3,2- i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride with benzoic acid (Example 86, 4.50 mmol, 2.00 g) and heated with stirring at 150°C until a homogeneous solution was obtained (4.5 min). The solution was cooled to room temperature, dissolved in ethyl acetate and stirred with a saturated aqueous solution of NaΗCθ3- A white solid precipitated out and was filtered away. The layers of the filtrate were separated, the aqueous phase was extracted with ethyl acetate (3 x 25 mL), and the combined extracts were dried and concentrated to give a thick oil. The product was purified by silica gel flash column chromatography (20%> acetone/hexanes) to give a white solid (0.776 g,
34%): mp 100-103, 155-156°C (diastereomers); IR (KBr) 3375, 2931, 2855, 1725,
1704, 1432, 1200, 1078, 1065 cm"1 ; !H NMR (400 MHz, CDCI3) δ 1.20-1.29 (m,
IH, aliphatic CH), 1.32-1.34 (m, 2Η, aliphatic CH), 1.38-1.47 (m, 1Η, aliphatic CH), 1.53-1.58 (m, 2Η, aliphatic CH), 1.62-1.82 (m, 4Η, aliphatic CH), 1.68 (d, 7=6.59 Ηz, 3Η, OCH(CH3)Ar), 2.01-2.12 (m, 1Η, aliphatic CH), 2.41-2.45 (m,
1Η, aliphatic CH), 2.50-2.53 (m, 1Η, aliphatic CH), 2.60 & 2.62 (s, 3Η, ArCH3, diastereomers), 2.69-2.85 (m, 2Η, aliphatic CH), 2.98-3.04 (m, 1Η, aliphatic CH), 3.29-3.43 (m, 1Η, aliphatic CH), 3.89 (s, 3Η, CO2CH3), 6.09-6.17 (m, 1Η,
OCH(CΗ3)Ar), 6.73 & 6.74 (d, 7=8.55 Hz, IH, ArH, diastereomers), 7.01 & 7.02 (d, 7=8.79 & 8.55 Ηz, 1Η, ArH, diastereomers), 7.41 & 7.42 (t, 7=7.81 & 7.57 Hz, IH, ArH, diastereomers), 7.61 & 7.63 (d, 7=7.57 Ηz, 1Η, ArH, diastereomers), 7.93-7.95 & 7.95-7.97 (m, 1Η, ArH, diastereomers), 8.06 (bs, 1Η,
NH), 8.10 & 8.13 (s, 1Η, ArH, diastereomers); MS (APCI+) m/z 503.1 (MΗ+). Anal. Calcd for C30H34N2O5: C, 71.69; H, 6.82; N, 5.57. Found: C, 71.58; H,
6.95; N, 5.42.
Example 48 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(3-carboxyphenyl)ethyl ester 2H
A solution of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-
1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-[3- (methoxycarbonyl)phenyl] ethyl ester (1.43 mmol, 0.717 g) in methanol (18 mL) and IN NaOH (5.71 mmol, 5.71 mL) was heated at 55-60°C for 1 hour. The solution was cooled to room temperature, the methanol was removed by rotary evaporation, and the aqueous phase was neutralized with IN HCI. A precipitate formed and was filtered off and purified by silica gel flash column chromatography (10-15% MeOH/CHCl3) to afford a cream colored powder
(0.522 g, 75%): mp 244-250°C (dec); IR (KBr) 3413-3229 (b), 2931, 1685, 1432,
1 195, 1 150, 1078, 1063 cm"1 ; lH NMR (400 MHz, DMSO-d6) δ 1.03-1.22 (m, 3H, aliphatic CH), 1.38-1.72 (m, 7Η, aliphatic CH), 1.57 (d, 7=6.35 Ηz, 3Η,
OCH(CH3)Ar), 1.78-1.88 (m, 1Η, aliphatic CH), 2.28-2.38 (m, 1Η, aliphatic CH),
2.40-2.47 (m, 1Η, aliphatic CH), 2.51 & 2.55 (s, 3Η, ArCH3, diastereomers),
2.56-2.69 (m, 2Η, aliphatic CH), 2.81-2.92 (m, 1Η, aliphatic CH), 3.06-3.23 (m, 1Η, aliphatic CH), 5.96-6.04 (m, 1Η, OCH(CΗ3)Ar), 6.57 & 6.58 (d, 7=8.55 & 8.30 Hz, IH, ArH, diastereomers), 7.01 & 7.02 (d, 7=8.30 Ηz, 1Η, ArH, diastereomers), 7.45-7.50 (m, IH, ArH, diastereomers), 7.64 & 7.67 (d, 7=10.25 & 8.55 Ηz, 1Η, ArH, diastereomers), 7.83 & 7.85 (d, 7=6.10 & 7.32 Ηz, 1Η, ArH, diastereomers), 7.96 & 7.98 (s, 1Η, ArH, diastereomers), 1 1.54 (s, 1Η, NH),
13.00 (s, 1Η, CO2H); MS (APCI+) m/z 489.1 (MΗ+). Anal. Calcd for C29H32N2O5-O.5OH2O-O.2O SiO2: C, 68.35; H, 6.53; N, 5.50; H2O, 1.77. Found:
C, 67.96; H, 6.81; N, 5.22; H2O, 1.81. HPLC (ALLTECH/ALLTIMA C-18,
60:40-20:80 H2O/CH3CN + 0.05% TFA): retention time=4.843 & 4.970 min
(diastereomers), 95.53%> purity.
Example 49 1-Propanaminium, N,N,N-trimethyl-, salt with 1 -(3-carboxyphenyl)ethyl
3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][l]- benzopyrano[3,2-i]quinolizine-l -carboxylate (1 :1)
An aqueous solution of choline bicarbonate (0.935 mmol, 0.165 mL, 5.66 M) was added to a suspension of pyrrolo[3',2':5,6][l]benzopyrano[3,2- ijquinolizine- 1 -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, l-(3-carboxyphenyl)ethyl ester (0.935 mmol, 0.457 g) in ethanol (23 mL), and the mixture was heated at 75-80°C for 30 minutes, cooled to room temperature, and filtered. The filtrate was concentrated. The residue was stirred vigorously with ether and filtered to give a light yellow solid. The solid was dissolved in hot
CHCI3, filtered, concentrated, and dried at 60°C in vacuo to give a yellow powder
(0.233 g, 42%): mp 210-216°C; IR (KBr) 3428-3211 (b), 2930, 1684, 1566, 1432,
1878, 1870, 1079, 1063 cm"1; }H NMR (400 MHz, DMSO-d6) δ 1.03-1.26 (m,
3H, aliphatic CH), 1.36-1.72 (m, 6H, aliphatic CH), 1.55 (d, 7=6.35 Ηz, 3Η, OCH(CH3)Ar), 1.80-1.88 (m, 1Η, aliphatic CH), 2.30-2.42 (m, 2Η, aliphatic CH), 2.51 & 2.52 (s, 3H, ArCH3, diastereomers), 2.61-2.70 (m, 2Η, aliphatic CH),
2.81-2.92 (m, 1Η, aliphatic CH), 3.07 (s, 9Η, N(CH3)3), 3.1 1-3.23 (m, 1Η, aliphatic CH), 3.26-3.35 (m, 2Η, CH2OH & aliphatic CH), 3.36 (t, 7=4.88 Ηz, 2Η,
OCH2CH2N(CH3)3), 3.77-3.83 (m, 2H, OCH2CH2N(CH3)3), 5.91-5.99 (m, IH, OCH(CH3)Ar), 6.54-6.58 (m, IH, ArH), 7.01-7.04 (m, 1Η, ArH), 7.21-7.28 (m,
1Η, ArH), 7.32-7.38 (m, 1Η, ArH), 7.71-7.79 (m, 1Η, ArH), 7.91 & 7.93 (s, 1Η, ArH, diastereomers), 11.70 (s, 1Η, NH); MS (APCI-) m/z 487.1 (parent M-1). Anal. Calcd for C29Η31N2O5O.88 C5H14NO-0.50 H2O-0.50 CHCI3: C, 62.84;
H, 6.97; N, 6.23; H2O, 1.39. Found: C, 62.92; H, 6.17; N, 6.93; H2O, 1.72.
Example 50
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (3-nitrophenyl)methyl ester
Following the procedure from Example 47, Step B, 3-nitrobenzyl alcohol (18.0 mmol, 2.81 g) and pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-
1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, anhydride with benzoic acid (Example 86, 4.50 mmol, 2.00 g) were converted to pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-mefhyl-, (3-nitrophenyl)methyl ester. The product was purified by silica gel flash column chromatography (25-50% ethyl acetate/hexanes) and recrystallized from ethyl acetate to afford a light yellow powder (1.10 g, 51%): mp 203-205°C; IR (KBr) 3383, 3181, 2929, 2855, 1709,
1532, 1430, 1351, 1236, 1075, 886 cm"1; ^H NMR (400 MHz, DMSO-d6) δ
1.02-1.16 (m, 2H, aliphatic CH), 1.19-1.24 (m, 1Η, aliphatic CH), 1.32-1.62 (m, 7Η, aliphatic CH), 1.82 (d, 7=13.18 Ηz, 1Η, aliphatic CH), 2.33 (d, 7=9.76 Ηz, 1H, aliphatic CH), 2.41 (d, 7=11.23 Hz, IH, aliphatic CH), 2.48 (s, 3Η, ArCH3),
2.60-2.67 (m, 2Η, aliphatic CH), 2.84-2.89 (m, 1Η, aliphatic CH), 3.15-3.21 (m, 1Η, aliphatic CH), 5.32-5.40 (m, 2Η, OCH Ar), 6.59 (d, 7=8.79 Ηz, 1Η, ArH),
7.03 (d, 7=8.55 Ηz, 1Η, ArH), 7.65-7.69 (m, 1Η, ArH), 7.89 (d, 7=7.57 Ηz, 1Η, ArH), 8.18 (d, 7=8.06 Ηz, 1Η, ArH), 8.29 (s, 1Η, ArH), 1 1.58 (s, 1Η, NH); MS
(APCI+) m/z 476.1 (MΗ+). Anal. Calcd for C2 H29N3O5: C, 68.20; H, 6.15; N,
8.84. Found: C, 67.89; H, 6.20; N, 8.74.
Example 51 Pyιτolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, l-(3-cyanophenyl)ethyl ester
Step A: 3-(l-Hydroxyethyl)benzonitrile
To a solution of 3-acetylbenzonitrile (68.9 mmol, 10.0 g) in MeOH (230 mL) at 0°C under N2 was added NaBH4 (68.9 mmol, 2.61 g) in portions.
After 2 hours of gradual warming to room temperature, IN HCI was added and the solvent removed under reduced pressure. Dichloromethane (50 mL) was added, the layers were separated, and the aqueous phase was extracted with 3 portions of CH2C12 (50 mL). The combined extracts were washed with NaHCO3 (1 x 50 mL), saturated NaCl (1 x 50 mL), dried over MgSO , and concentrated under vacuum to give pure product as a yellow oil (10.0 g, 98%>): lU NMR (400 MHz, CDC13) δ 1.47 (d, 7=6.35 Hz, 3H, ArCH(CH3)OH),
1.99 (bs, IH, OH), 4.92 (q, 7=6.35 Ηz, 1Η, ArCH(CΗ3)OΗ), 7.43 (t, 7=7.81 Hz, 1H, ArH), 7.53 (d, 7=7.57 Ηz, 1Η, ArH), 7.59 (d, 7=7.81 Ηz, 1Η, ArH), 7.66 (s, 1Η, ArH).
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, l-(3-cyanophenyl)ethyl ester
Following the procedure from Example 47, Step B, 3-(l-hydroxyethyl)- benzonitrile (13.5 mmol, 1.98 g) and pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]- quinolizine-1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, anhydride with benzoic acid (Example 86, 3.37 mmol, 1.50 g) were converted pyrrolo[3',2':5,6][ 1 ]-benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(3-cyanophenyl)ethyl ester. The product was purified by silica gel flash column chromatography (20-30% acetone/hexanes) to afford a cream colored powder (0.614 g, 39%>): mp 131-134 and 171-173°C (diastereomers); IR (KBr) 3377, 2931, 2856, 2230, 1702, 1432, 1148, 1077, 1066 cm" 1; ]Η NMR (400 MHz, DMSO-d6) δ 1.02-1.25 (m,
3H, aliphatic CH), 1.31-1.72 (m, 7Η, aliphatic CH), 1.57 (d, 7=6.35 Ηz, 3Η, OCH(CH3)Ar), 1.79-1.88 (m, 1Η, aliphatic CH), 2.32-2.44 (m, 2Η, aliphatic CH),
2.46 (s, 3Η, ArCH3), 2.56-2.69 (m, 2Η, aliphatic CH), 2.80-2.91 (m, 1Η, aliphatic
CH), 3.02-3.28 (m, 1Η, aliphatic CH), 5.93-6.01 (m, 1Η, OCH(CΗ3)Ar), 6.56-6.60 (m, IH, ArH), 7.00-7.04 (m, 1Η, ArH), 7.51-7.59 (m, 1Η, ArH),
7.71-7.80 (m, 2Η, ArH), 7.86 & 7.90 (s, 1Η, ArH, diastereomers), 11.56 (s, 1Η,
NH); MS (APCI+) m/z 470.1 (MΗ+). Anal. Calcd for C29H31N3O3O.25 H2O:
C, 73.47; H, 6.70; N, 8.86; H2O, 0.95. Found: C, 73.18; H, 6.73; N, 8.56, H2O,
0.58.
Example 52
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1 -[3-[(dimethylamino)carbonyl]phenyl]ethyl ester
Step A: 3-(l-Hydroxyethyl)benzoic acid
A mixture of 3-(l-hydroxyethyl)benzonitrile (Example 51, Step A, 6.79 mmol, 1.00 g) in 10% aqueous NaOH (68 mL) was heated at reflux for
4.5 hours, cooled to room temperature, and extracted with ether (2 x 50 mL). The extracts were discarded. The aqueous phase was acidified with concentrated HCI, extracted with ether (3 x 50 mL), and the combined extracts were washed with brine, dried over MgSU4, and concentrated to give a white solid (0.98 g, 87%>): mp 107-1 10°C; !H NMR (400 MHz, DMSO-d6) δ 1.29 (d, 7=6.35 Hz, 3H,
ArCH(CH3)OH), 4.71-4.78 (m, IH, ArCH(CH3)OH), 5.25 (d, 7=4.40 Hz, IH,
OH), 7.39 (t, 7=7.57 Hz, IH, ArH), 7.53 (d, 7=7.57 Ηz, 1Η, ArH), 7.76 (d, 7=7.57 Ηz, 1Η, ArH), 7.91 (s, 1Η, ArH), 12.87 (s, 1Η, COOH); MS (APCI-) m/z 165.1 (M-1).
Step B: 3-(l-Ηydroxyethyl)-NN-dimethylbenzamide
To a solution of 3-(l-hydroxyethyl)benzoic acid (54.8 mmol, 9.10 g), dimethylamine (54.8 mmol, 27.4 mL of 2.0 M THF solution), and
(109 mmol, 19.1 mL) in 55 mL of DMF at 0°C under N2 was added HBTU (54.8 mmol, 20.8 g) in two portions. After 45 minutes, IN HCI (50 mL) and ether
(50 mL) were added, and the layers were separated. The aqueous phase was further acidified with IN HCI and extracted with ether (4 x 50 mL). The extracts were combined and concentrated. The aqueous phase was concentrated also. The concentrates were combined, dissolved in CH2C12, washed with 10%> HCI (1 x
20 mL), saturated NaHCO3 (1 x 20 mL), brine (1 x 20 mL), dried over MgSO4 and concentrated. The residue was purified by silica gel flash column chromatography (50-100%) ethyl acetate/hexanes) to give a mixture of 3-(l-hydroxyethyl)-NN-dimethylbenzamide, z'Pr ΝEt, and N,N,N',N'- tetramethylurea. The yield based on ^H NMR was 6.56 g (62%>). A small portion was rechromatographed to give pure product as a clear, colorless oil: !H NMR (400 MHz, DMSO-d6) δ 1.28 (d, 7=6.59 Hz, 3H, ArCH(CH3)OH), 2.86 (s, 3H,
NCH3), 2.93 (s, 3Η, NCH3), 4.67-4.73 (m, 1Η, ArCH(CΗ3)OΗ), 5.20 (d, 7=4.15 Hz, IH, OH), 7.18-7.20 (m, 1Η, ArH), 7.31-7.37 (m, 3Η, ArH); MS (APCI+) m/z 194.0 (MΗ+).
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-[3-[(dimethylamino)carbonyl]phenyl]ethyl ester Following the procedure from Example 47, Step B, 3-(l-hydroxyethyl)- N-dimethylbenzamide (14.9 mmol, 2.88 g) and pyrrolo[3',2':5,6][l]- benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15- decahydro-2-methyl-, anhydride with benzoic acid (Example 86, 3.73 mmol,
1.66 g) were combined with xylenes (10 mL) and heated at 150°C for 5 minutes to form pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -[3-[(dimethylamino)- carbonyljphenyl] ethyl ester. The product was purified by silica gel flash column chromatography (0-5% Et3Ν/ethyl acetate), dissolved in ether/ethyl acetate and washed with water (15 x 20 mL) to remove unreacted 3-(l-hydroxyethyl)-NN- dimethylbenzamide. The organic phase was concentrated and the residue was recrystallized from acetonitrile to give a white powder (1.65 g, 86%>): mp 199-202°C; IR (KBr) 3416 (br), 3219 (br), 2930, 2855, 1684, 1622, 1432, 1188, 1 146, 1091, 1062 cm" 1 ; ]H ΝMR (400 MHz, DMSO-d6) δ 1.02-1.28 (m, 3H, aliphatic CH), 1.32-1.70 (m, 7Η, aliphatic CH), 1.57 (d, 7=6.84 Ηz, 3Η, OCH(CH3)Ar), 1.76-1.88 (m, 1Η, aliphatic CH), 2.32-2.43 (m, 2Η, aliphatic CH),
2.50 & 2.51 (s, 3Η, ArCH3, diastereomers), 2.52-2.689 (m, 2Η, aliphatic CH),
2.84 (s, 3Η, NCH3), 2.84-2.89 (m, 1Η, aliphatic CH), 2.92 (s, 3Η, NCH3),
3.06-3.30 (m, 1Η, aliphatic CH), 5.94-6.01 (m, 1Η, OCH(CΗ3)Ar), 6.57 &
6.58 (d, 7=8.55 Hz, IH, ArH, diastereomers), 7.01 & 7.02 (d, 7=8.55 Ηz, 1Η, ArH, diastereomers), 7.29 (t, 7=7.33 Ηz, 1Η, ArH), 7.37-7.50 (m, 3Η, ArH),
11.53 (s, 1Η, NH); MS (APCI+) m/z 516.3 (MΗ+). Anal. Calcd for C3lH37N3O4: C, 72.21; H, 7.23; N, 8.15. Found: C, 71.96; H, 7.25; N, 8.22.
Example 53 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -[3-[(dimethylamino)methyl]phenyl]ethyl ester
Step A: l-(3-Dimethylaminomethylphenyl)ethanol
To a suspension of LiAlH4 (23.3 mmol, 0.931 g/95 %) in THF (40 mL) at
0°C under N was added a solution of 3-(l-hydroxyethyl)-NN- dimethylbenzamide (Example 52, Step B, 15.5 mmol, 3.00 g) in 10 mL of THF. After the evolution of H2 had ceased, the reaction was warmed to room temperature. After 4 hours at room temperature, the mixture was cooled to 0°C and ethyl acetate (0.74 mL) and 10% aqueous ΝaOH were sequentially added. The mixture was warmed to room temperature for 30 minutes, MgSO4 and celite were added with stirring, and the mixture was filtered through celite, washing with 20 mL of THF. The filtrate was concentrated to afford 2.73 g (99%>) of pure l-(3-dimethylaminomethylphenyl)ethanol: !H NMR (400 MHz, DMSO-dg) δ
1.26 (d, 7=6.59 Hz, 3H, ArCH(CH3)OH), 2.09 (s, 6H, N(CH3)2), 3.31 (s, 2Η, ArCH2N), 4.64-4.67 (m, 1Η, ArCH(CΗ3)OΗ), 5.08 (d, 7=4.15 Hz, IH, OH),
7.07 (d, 7=7.08 Ηz, 1Η, ArH), 7.15-7.25 (m, 3Η, ArH); MS (APCI+) m/z 180.0 (MΗ+).
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, l-[3-[(dimethylamino)methyl]phenyl]ethyl ester
Following the procedure from Example 47, Step B l-(3- dimethylaminomethylphenyl)ethanol (15.2 mmol, 2.73 g) and pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7, 8, 9,10,12, 13, 14,14a,15-decahydro-2-methyl-, anhydride with benzoic acid (Example 86, 3.81 mmol, 1.69 g) were combined with xylenes (10 mL) and heated at 150°C for 5 minutes to form pyrrolo[3',2':5,6][l]benzopyrano[3,2- ijquinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, l-[3-[(dimethylamino)methyl]phenyl]ethyl ester. The usual extractive work-up (ethyl acetate) was followed. The aqueous phase was diluted with 100 mL of acetone and the inorganic salts filtered off. The filtrate was concentrated. The organic and aqueous residues were combined, mixed with 15 mL of CH2CI2 at room temperature under N2 and treated with pyridine (68.5 mmol, 5.54 mL) and acetic anhydride (34.3 mmol, 3.23 mL) sequentially. After 48 hours, the white precipitate was filtered off, and the filtrate was washed with water (3 x 20 mL). The aqueous washes were concentrated and the product was purified by silica gel flash column chromatography (0-5% Et3N/ethyl acetate) to give a yellow solid
(0.160 g, 8.4%): mp 95-100°C; IR (KBr) 2931, 2857, 1678, 1430, 1237, 1 195, 1147, 1062 cm"1. ]H NMR (400 MHz, DMSO-dg) δ 1.09-1.27 (m, 3H, aliphatic CH), 1.32-1.68 (m, 7Η, aliphatic CH), 1.54 (d, 7=6.35 Ηz, 3Η, OCH(CH3)Ar), 1.79-1.84 (m, 1Η, aliphatic CH), 2.07 & 2.08 (s, 6Η, N(CH3) , diastereomers), 2.29-2.43 (m, 2H, aliphatic CH), 2.49 & 2.50 (s, 3Η, ArCH3, diastereomers),
2.59-2.69 (m, 2Η, aliphatic CH), 2.81-2.92 (m, 1Η, aliphatic CH), 3.02-3.17 (m, 1Η, aliphatic CH), 3.33 & 3.34 (s, 2Η, ArCH2N, diastereomers), 5.90-5.98 (m,
1Η, OCH(CΗ3)Ar), 6.56-6.59 (m, IH, ArH), 7.00-7.03 (m, 1Η, ArH), 7.12-7.21 (m, 1Η, ArH), 7.26-7.33 (m, 3Η, ArH), 11.50 & 11.51 (s, 1Η, NH, diastereomers); MS (APCI+) m/z 502.2 (MΗ+). Anal. Calcd for 3lH39N3O3-0.27 C4H8O2: C, 73.33; H, 7.90; N, 8.00. Found: C, 72.94; H,
7.90; N, 8.10.
General Procedure J. Diethyl azodicarboxylate (Aldrich, 1 eq.) was added dropwise to a mixture of
5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (1 eq.), triphenylphosphine (1 eq.), and an alcohol of choice (1.5 eq.) in THF over an hour period. After stirring at room temperature for 24 hours, the mixture was concentrated. The product was purified by recrystalhzation or flash column chromatography on silica gel (45% ethyl acetate:hexanes) to give the corresponding ester.
General Procedure K.
Under a nitrogen atmosphere, DBU (Aldrich, 1 eq.) was added to a solution of 5-acetoxy-2-methyl-lH-indole-3-carboxylic acid (1 eq.) in DMF by the syringe technique. To this reaction mixture, a solution of an alkyl halide of choice (Aldrich, 1.1 eq.) in DMF was added. After stirring at room temperature for
24 hours, the reaction mixture was diluted with CH2CI2 which induced precipitation of the desired product. The solid product was filtered off and washed with H2O.
General Procedure L. Dimethylamine (2.2 eq.) and formaldehyde (1.2 eq.) were added to a solution of the ester of choice (1.0 eq.) in 10 mL of denatured ethanol. The mixture was stirred under a nitrogen atmosphere at reflux for 24 hours. After the reaction was complete according to MS and TLC, the mixture was concentrated. The product was purified by flash column chromatography on silica gel (30%> MeOH:CH2Cl2).
General Procedure M.
1,2,3,4,6,7,8,9-Octahydroquinolizinylium perchlorate (1.7 eq.) was dissolved in 2N NaOH (excess). The solution was extracted with diethyl ether. The combined organic layers were concentrated to give a clear oil. This oil was dissolved in dioxane and added to a solution of the desired Mannich base (1 eq.) dioxane. After heating at 1 10°C for 24 hours, the reaction was cooled to room temperature and dioxane was removed to afford a brown oil. The product was purified by flash column chromatography on silica gel (40% hexanes:ethyl acetate).
General Procedure N.
A mixture of the mixed anhydride (4 eq.) and an alcohol of choice (4 eq.) was heated at 150°C for 5 minutes or until the reaction was homogeneous. After being cooled to room temperature, the oil was diluted with ethyl acetate and washed with saturated NaHCO3- The organic layer was separated and concentrated to afford a brown oil. The product was purified by flash column chromatography on silica gel.
General Procedure O.
To a solution of a ester (1 eq.) in methanol was added 2N NaOH (4 eq.). After heating at 55°C for 1 hour, the reaction became clear. The reaction mixture was cooled to 0°C and neutralized with concentrated HCI. The product precipitated out of solution as a white solid and was filtered off. The mother liquor was extracted with ethyl acetate and the solvent removed to afford additional product.
General Procedure P. To a suspension of Mannich base of choice (1 eq.) in anhydrous THF was added slowly solid LiBH4 (5 eq.). MeOH (5 eq.) was immediately added dropwise via syringe. The resulting mixture was heated at reflux for 1 hour. After cooling to 0°C, IN HCI was added to neutralize the reaction. The product precipitated out of solution as a white solid. The mother liquor was extracted with CH2C1 . The combined organic layers were dried with MgSO4, and solvent was removed to yield more product.
Example 54 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3 ,7,8,9, 10, 1 , 13, 14, 14a, 15-decahydro-2-methyl-,2-ρhenylethyl ester
Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid phenylethyl ester
5-Hydroxy-2-mefhyl-lH-indole-3-carboxylic acid phenylethyl ester was synthesized according to Procedure J from 2-phenyl-ethanol (6.39 g, 52.3 mmol) and recrystallized from hexane/ethyl acetate to give 2.40 g (31.1%) of fine white powder: mp 186- 188°C; IR (KBr) 3231, 2978, 1644, 1463, 1173, 1101 cm"1;
]H NMR (400 MHz, DMSO-d6) δ 2.49 (s, 3H, CCH3), 3.03 (t, 7=6.99 Ηz, 2Η,
OCH2CH2), 4.40 (t, 7=6.75 Ηz, 2Η, OCH2CH2), 6.57 (dd, 7=8.60, 2.29 Hz, IH,
ArH), 7.09 (d, 7=8.68 Ηz, 1Η, ArH), 7.20 (d, 7=6.99 Ηz, 1Η, ArH), 7.26-7.33 (m,
5Η, ArH), 8.81 (s, 1Η, OH), 11 -49 (s, 1Η, NH); MS(APCI+): m/z 326.1 (MΗ+). Anal. Calcd for C^H^N^: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.23; H,
5.74; N, 4.67. Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid phenylethyl ester
4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid phenethyl ester was synthesized according to Procedure L from 5-hydroxy- 2-methyl-lH-indole-3-carboxylic acid phenylethyl ester (2.89 g, 9.78 mmol) and recrystallized from ethyl acetate to give 0.250 g (15.0%) of a white solid: mp
200-201 °C; IR (KBr) 3138, 2971, 1673, 1585, 1437, 1279, 1099 cm"1 ; 1 H NMR (400 MHz, DMSO-d6) δ 2.34 (s, 3H, CCH3) 2.68 (s, 6Η, N(CH3)2), 3.00 (t, 7=6.59 Ηz, 2Η, OCH2CH2), 4.43 (t, 7=6.59 Ηz, 2Η, OCH2CH2), 4.67 (s, 2H, NCH2Ar), 6.81 (d, 7=8.79 Ηz, 1Η, ArH), 7.17-7.20 (m, 1Η, ArH), 7.23-7.28 (m,
5Η, ArH), 1 1.93 (s, 1Η, NH); MS(APCI+): m/z 353.2 (MΗ+). Anal. Calcd for C21H24N2O3: C, 61.35; H, 7.48; N, 6.81. Found: C, 60.96; H, 6.66; N, 6.42.
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,1, 13, 14,14a,15-decahydro-2-methyl-,2-phenylethyl ester
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 1 , 13 , 14, 14a, 15-decahydro-2-methyl-,2-phenylethyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy- 2-methyl-lH-indole-3-carboxylic acid phenethyl ester (0.250 g, 0.709 mmol) and recrystallized from ethyl acetate/hexanes to give 0.170 g (54.0%>) of a white solid: mp l85-186°C; IR (KBr) 3297, 2931, 2856, 1673, 1432, 1199, 1080 cm"1 ; ^H NMR (400 MHz, CDCI3) δ 1.20-1.81 (m, 10H, aliphatic CH), 2.07 (d, 7=13.92 Hz, IH, aliphatic CH), 2.41 (s, 3H, CCH3), 2.44-2.53 (m, 2Η, aliphatic CH), 2.73-2.84 (m, 2H, aliphatic CH), 2.98-3.04 (m, IH, aliphatic CH), 3.05-3.08 (m, 2H, OCH2CH ), 3.38 (dd, 7=17.95, 6.71 Ηz, 1Η, aliphatic CΗ),
4.50-4.53 (m, 2Η, OCH2CH2), 6.72 (d, 7=8.79 Hz, IH, ArH), 6.99 (d, 7=8.79 Ηz,
1Η, ArH), 7.17-7.29 (m, 5Η, ArH), 7.99 (s, 1Η, NH); MS(APCI+): m/z
445.3 (MΗ+). Anal. Calcd for C28H32N2O3: C, 75.56; H, 7.26; N, 6.30. Found:
C, 75.36; H, 7.28; N, 6.13.
Example 55 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, [4-(methoxycarbonyl)phenyl]methyl ester
Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-methoxycarbonyl- benzyl ester
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-methoxycarbonyl- benzyl ester was synthesized according to Procedure K from 4-bromomethyl- benzoic acid methyl ester (6.64 g, 29.0 mmol) and precipitated out of diethyl ether to give 4.88 g (55.0%) of light lavender powder: mp 232-234°C; IR (KBr) 3322,
2950, 1696, 1654, 1465, 1288, 1093 cm" 1 ; !H NMR (400 MHz, DMSO-dό) δ
2.57 (s, 3H, CCH3), 3.80 (s, 3Η, OCH3), 5.34 (s, 2Η, OCH2Ar), 6.55 (dd, 7=8.67,
2.32 Ηz, 1Η, ArH), 7.09 (d, 7=8.55 Ηz, 1Η, ArH), 7.24 (d, 7=2.20 Ηz, 1 Η, ArH), 7.54 (d, 7=8.06 Ηz, 2Η, ArH), 7.94 (d, 7=8.30 Ηz, 2Η, ArH), 8.83 (s, 1Η, OH), 11.59 (s, IH, NH); MS(APCI+): m/z 340.1 (MΗ+). Anal. Calcd for C19H17NιO5: C, 67.25; H, 5.05; N, 4.13. Found: C, 66.88; H, 5.06; N, 4.05.
Step B : 4-Dimethylaminomethyl-5-hydroxy-2-methyl- 1 H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester
4-Dimethylaminomethyl-5-hydroxy-2-methyl- 1 H-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester was synthesized according to Procedure L from 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (17.2 g, 50.7 mmol) and triturated with ethyl acetate to give 8.50 g (43.0%) of white solids: mp 125-126°C; IR (KBr) 3142, 2959, 1672, 1585, 1434, 1285,
1095 cm"1 ; !H NMR (400 MHz, DMSO-d6) δ 2.12 (s, 6H, N(CH3)2), 2.49 (s,
3Η, CCH3), 3.84 (s, 3Η, OCH3), 4.02 (s, 2Η, NCH2Ar), 5.34 (s, 2Η, OCH2Ar),
6.58 (d, 7=8.44 Ηz, 1Η, ArH), 7.09 (d, 7=8.44 Ηz, 1Η, ArH), 7.60 (d, 7=8.20 Ηz, 2Η, ArH), 7.98 (d, 7=8.20 Ηz, 2Η, ArH), 1 1.56 (s, 1Η, NH); MS(APCI+): m/z 397.2 (MΗ+). Anal. Calcd for C22H24N2O5: C, 66.41 ; H, 6.12; N, 7.04. Found:
C, 66.41; H, 6.01 ; N, 6.97.
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2 -methyl-, [4-(methoxycarbonyl)phenyl]methyl ester Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10, 12, 13, 14, 14a, 15-decahydro-2-methyl-,[4-(methoxycarbonyl) phenyljmethyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (0.200 g, 0.505 mmol) and recrystallized from t-butyl methyl ether to give 0.090 g (23.0%) of granular off-white solids: mp 179-180°C; IR (KBr) 3173, 2930, 2856, 1725, 1615, 1433, 1275, 1079 cm"1;
!H NMR (400 MHz, CDCI3) δ 1.21-1.81 (m, 10H, aliphatic CH), 2.06 (d,
7=8.79 Hz, IH, aliphatic CH), 2.43 (d, 7=12.70 Hz, IH, aliphatic CH), 2.50-2.53 (m, IH, aliphatic CH), 2.55 (s, 3H, CCH3), 2.73-2.84 (m, 2Η, aliphatic CH), 2.96-3.05 (m, IH, aliphatic CH), 3.38 (dd, 7=17.70, 7.20 Hz, IH, aliphatic CH),
3.89 (s, 3H, OCH3), 5.34 (dd, 7=16.36, 12.70 Ηz, 2Η, OCH2Ar), 6.73 (d,
7=8.79 Ηz, 1Η, ArH), 7.01 (d, 7= 8.79 Ηz, 1Η, ArH), 7.47 (d, 7=8.06 Ηz, 2Η, ArH), 8.01 (d, 7=8.30 Ηz, 2Η, ArH), 8.06 (s, 1Η, NH); MS(APCI+): m/z
489.3 (MΗ+). Anal. Calcd for C29H32N2O : C, 71.29; H, 6.60; N, 5.73. Found: C, 70.94; H, 6.26; N, 5.57.
Example 56 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2, -methyl-, (4-carboxyphenyl)methyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (4-carboxyphenyl)methyl ester was synthesized according to Procedure O and triturated with methanol to give 0.030 g (11.0%) of fine off-white powder : mp 243-244°C; IR (KBr) 2932, 2863,
1698, 1592, 1432, 1077 cm"1; IH NMR (400 MHz, DMSO-d6) δ 1.05-1.26 (m, 3H, aliphatic CH) 1.39-1.66 (m, 6H, aliphatic CH), 1.85 (d, 7=13.67 Hz, IH, aliphatic CH), 2.44 (d, 7=11.23 Hz, IH, aliphatic CH), 2.47-2.48 (m, IH, aliphatic CH), 2.48 (s, 3H, CCH3), 2.63-2.69 (m, 2Η, aliphatic CH), 2.85-2.91 (m, IH, aliphatic CH), 3.19 (dd, 7=18.07, 6.84 Hz, IH, aliphatic CH), 3.41-3.43 (m, IH, aliphatic CH), 5.31 (dd, 7=20.02, 12.94 Hz, 2H, OCH2Ar), 6.60 (d, 7=8.55 Ηz, 1Η, ArH), 7.04 (d, 7=8.55 Ηz, 1Η, ArH), 7.54 (d, 7=8.30 Ηz, 2Η, ArH), 7.94 (d, 7= 8.30 Hz, 2H, ArH), 11.57 (s, 1Η, NH), 12.98 (s, 1Η, CO2H); MS(APCI+): m/z
475.3 (MΗ+). Anal. Calcd for C28H3oN2O5: C, 70.17; H, 6.42; N, 5.85. Found: C, 69.78; H, 6.50; N, 5.62.
Example 57 l-[3-(4-Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl-lH-indol-4-ylmethyl]-
1 ,2,3,4,6,7,8,9-octahydro-quinolizinylium; chloride
To a solution of pyirolofS'^^SjδJflJbenzopyrano ^-iJquinolizine-l- carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [4-(methoxycarbonyl) phenyljmethyl ester (Example 56, Step C, 1.00 g,
2.05 mmol) in 25.6 mL of methanol was added 2N NaOH (4.09 mL, 8.19 mmol). After heating at 55°C for 1 hour, the mixture turned to a clear solution. The reaction mixture was cooled to 0°C and concentrated HCI was added slowly until pH 3. The aqueous layer was extracted with ethyl acetate (5 x 50 mL), and the combined organic layers were dried with MgSU4, and solvent was removed. The residue was triturated with dichloromethane to give 0.967 g (92.0%) of fine white powder: mp 230-23TC; IR (KBr) 3361, 2941, 2360, 1709, 1589, 1428, 1227,
1083 cm" 1 ; !H NMR (400 MHz, DMSO-dό) δ 1.20-1.30 (m, IH, aliphatic CH)
1.43-1.51 (m, 4H, aliphatic CH), 1.69-2.30 (m, 5H, aliphatic CH), 2.48 & 2.49 (s, 3H, CCH3, opened and closed forms) , 2.48-2.55 (m, 2Η, aliphatic CH), 2.85-3.30
(m, 2H, aliphatic CH), 3.40-3.80 (m, 3H, aliphatic CH), 5.33-5.36 (m, 2H, OCH2Ar), 6.79 & 6.82 (d, 7=8.55 & 8.06 Ηz, 1Η, ArH, opened & closed forms),
7.11 & 7.20 (d, 7=8.55 & 8.55 Ηz, 1Η, ArH, opened & closed forms), 7.54-7.56 (m, 2Η, ArH), 7.94-7.96 (m, 2Η, ArH), 9.19 (s, 1Η, OH, opened), 11.79 & 11.85 (s, 1Η, NH, opened & closed forms), 13.00 (s, 1Η, CO H); MS(APCI+): m/z 475.3 (MH+). Anal. Calcd for C28H31N2θ5Clι : C, 65.35; H, 6.12; N, 5.44. Found: C, 65.06; H, 6.17; N, 5.15.
Example 58 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, [4-(hydroxymethyl)phenyl]methyl ester
Step A: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-hydroxymethyl-benzyl ester
4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-hydroxymethyl-benzyl ester was synthesized according to Procedure P from 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-methoxycarbonyl-benzyl ester (Example 56, Step B, 2.32 g, 5.84 mmol) and triturated with acetone to give 0.993 g (47.0%>) of a white solid: mp 140-143°C;
IR (KBr) 3140, 2777, 1686, 1583, 1435, 1092 cm"1; ]H NMR (400 MHz, DMSO- d6) δ 2.51 (s, 3H, CH3), 2.71 (s, 6Η, N(CH3)2), 4.47 (d, 7=5.13 Ηz, 2Η,
ArCH2OH), 4.73 (s, 2H, NCH2Ar), 5.18 (t, 7=5.62 Ηz, 1Η, ArCΗ2OH), 5.25 (s, 2Η, OCH2Ar), 6.84 (d, 7=8.55 Ηz, 1Η, ArH), 7.28 (d, 7=8.55 Ηz, 1Η, ArH), 7.31 (d, 7=7.81 Ηz, 2Η, ArH ), 7.40 (d, 7=7.81 Ηz, 2Η, ArH), 8.60 (s, 1Η, OH), 11.97 (s, 1Η, NH); MS(APCI+): m/z 369.2 (MΗ+). HPLC (ALLTCH/ALLTIMA C-18 1 :1-2:98 H2O/CH3CN + 0.05% TFA): rentention time=4.57 min, 95.23% purity.
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl)phenyl]methyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl)- phenyljmethyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-hydroxymethyl-benzyl ester (0.969 g, 2.63 mmol) and triturated with acetone to give 0.890 g (49.0%) of a white solid: mp 198-200°C; IR (KBr) 3405, 3237, 2931, 1660, 1424, 1237, 1081 cm" 1 ; }H NMR (400 MHz, DMSO-d6) δ 1.11-1.27 (m,
3H, aliphatic CH),1.39-1.70 (m, 7H, aliphatic CH), 1.85 (d, 7=13.50 Hz, IH, aliphatic CH), 2.36 (d, 7=10.37 Hz, IH, aliphatic CH), 2.41-2.43 (m, IH, aliphatic CH), 2.47 (s, 3H, CCH3), 2.65-2.69 (m, 2Η, aliphatic CH), 2.86-2.92 (m, IH, aliphatic CH), 3.23 (dd, 7=16.64, 9.64 Hz, IH, aliphatic CH), 4.48 (d, 7=5.78 Hz, 2H, ArCH2OH), 5.17 (t, 7=5.55 Hz, IH, ArCH2OH), 5.21 (dd, 7=22.42, 12.06,
Ηz, 2Η, OCH2Ar), 6.59 (d, 7=8.44 Ηz, 1Η, ArH), 7.03 (d, 7=8.68 Ηz, 1Η, ArH),
7.31 (d, 7= 7.72 Ηz, 2Η, ArH), 7.39 (d, 7=7.96 Ηz, 2Η, ArH), 1 1.52 (s, 1Η, NH); MS(APCI+): m/z 461.2 (MΗ+). Anal. Calcd for C28H32N2O4: C, 73.02; H, 7.00;
N, 6.08. Found: C, 72.62; H, 6.84; N, 5.83.
Example 59 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3,78,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 2-naphthalenylmethyl ester
Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid naphthalen- 2-ylmethyl ester
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid naphthalen-2-ylmethyl ester was synthesized according to Procedure K from 2-bromomethyl-naphthalene (7.63 g, 34.5 mmol) and precipitated out of CH2CI2 to give 5.01 g (48.1%) of pale lavender powder: mp 243-245°C; IR (KBr) 3408, 3306, 3058, 1665, 1596, 1465,
1172, 1093 cm"1; ]H NMR (400 MHz, DMSO-d6) δ 2.59 (s, 3H, CCH3), 5.46 (s,
2Η, OCH2Ar), 6.59 (dd, 7=8.44, 2.41 Ηz, 1Η, ArH), 7.12 (d, 7=8.44 Ηz, 1Η,
ArH), 7.30 (d, 7=2.41 Ηz, 1Η, ArH), 7.51 (dd, 7=6.03, 3.38 Ηz, 1Η, ArH), 7.59 (d, 7=1.69 Ηz, 1Η, ArH), 7.61 (d, 7=1.69 Ηz, 1Η, ArH), 7.90-7.96 (m, 4Η,
ArH), 8.83 (s, 1Η, OH), 11.58 (s, 1Η, NH); MS(APCI+): m/z 332.2 (MΗ+). HPLC (ALLTCH/ALLTIMA C-18 35:65-2:98 H2O/CH3CN + 0.05% TFA): rentention time=3.70 min, 95.81% purity.
Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid naphthalen-2-ylmethyl ester
4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid naphthalen-2-ylmethyl ester synthesized according to the Procedure L from 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid naphthalen-2-ylmethyl ester (Example 57, Step A, 3.38 g, 10.2 mmol) and recrystallized from CH2CI2 to give 0.750 g (19.0%) of a white solid: mp 170-171 °C; IR (KBr) 3120, 2964, 2853,
1675, 1592, 1431, 1257, 1088 cm"1 ; IH NMR (400 MHz, DMSO-d6) δ 2.11 (s,
6H, N(CH3)2), 2.49 (s, 3Η, CCH3), 4.03 (s, 2Η, NCH2Ar), 5.43 (s, 2Η,
OCH2Ar), 6.57 (d, 7=8.68 Ηz, 1Η, ArH), 7.08 (d, 7=8.44 Ηz, 1Η, ArH), 7.51-7.53 (m, 2Η, ArH), 7.60 (d, 7=8.44 Ηz, 1Η, ArH), 7.91-7.99 (m, 4Η, ArH),
1 1.55 (s, 1Η, NH); MS(APCI+): m/z 389.2 (MΗ+). HPLC (ALLTCH/ALLTIMA C-18 55:45-15:85 H2O/CH3CN + 0.05% TFA): rentention time=4.80 min,
94.36%o purity.
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3,78,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 2-naphthalenyImethyl ester Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-2-carboxylic acid, 3,78,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-naphthalenylmethyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy- 2-methyl-lH-indole-3-carboxylic acid naphthalen-2-ylmethyl ester (0.620 g,
1.62 mmol) and recrystallized from ethyl acetate/hexanes to give 0.690 g (59.0%>) ofgranular a white solid: mp 141-143°C; IR (KBr) 3177, 3056, 2929, 1702, 1430, 1 146, 1079 cm"1 ; }H NMR (400 MHz, CDC13) δ 1.19-1.45 (m, 4H, aliphatic CH)
1.55-1.78 (m, 6H, aliphatic CH), 2.07 (d, 7=13.99 Hz, IH, aliphatic CH), 2.43-2.46 (m, IH, aliphatic CH), 2.52-2.55 (m, IH, aliphatic CH), 2.58 (s, 3H,
CCH3), 2.77-2.86 (m, 2Η, aliphatic CH), 3.01-3.07 (m, IH, aliphatic CH),
3.41 (dd, 7=18.08, 6.75 Hz, IH, aliphatic CH), 5.48 (dd, 7=19.53, 10.61 Hz, 2H, OCH2Ar), 6.75 (d, 7=8.68 Ηz, 1Η, ArH), 7.03 (d, 7=8.68 Ηz, 1Η, ArH),
7.48-7.50 (m, 2Η, ArH), 7.55-7.57 (m, 1Η, ArH), 7.82-7.86 (m, 3Η, ArH), 8.11 (s, 1Η, NH); MS(APCI+): m/z 481.3 (MΗ+). Anal. Calcd for C31H32N2O3: C,
77.47; H, 6.71; N, 5.83. Found: C, 77.13; H, 6.84; N, 5.51. Example 60 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl)phenyl]methyl ester
Step A: 5-Hydroxy-2-methyl-lH-indole-3 -carboxylic acid 3-methoxycarbonyl- benzyl ester
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-mefhoxycarbonyl- benzyl ester was synthesized according to Procedure K from 3-bromomethyl- benzoic acid methyl ester (5.49 g, 24.0 mmol) and triturated with ethyl acetate to give 2.01 g (27.0%) of light gray powder: mp 160-162°C; IR (KBr) 3383, 3310,
1721, 1666, 1465, 1289, 1095 cm" 1 ; lU NMR (400 MHz, DMSO-d6) δ 2.56 (s,
3H, CCH3), 3.81 (s, 3Η, OCH3), 5.35 (s, 2Η, OCH2Ar), 6.57 (dd, 7=8.55, 2.20 Ηz, 1Η, ArH), 7.10 (d, 7=8.55 Ηz, 1Η, ArH), 7.25 (d, 7=2.20 Ηz, 1 Η, ArH),
7.53 (t, 7=7.81 Ηz, 1Η, ArH), 7.70 (d, 7=7.81 Ηz , 1Η, ArH), 7.89 (d, 7=7.57 Ηz, 1Η, ArH), 8.01 (s, 1Η, ArH), 8.82 (s, 1Η, OH), 1 1.58 (s, 1Η, NH); MS(APCI+): m/z 340.1 (MΗ+). Anal. Calcd for C^H^N^: C, 67.25; H, 5.05; N, 4.13. Found: C, 67.22; H, 4.75; N, 4.05. Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester
4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3 -carboxylic acid 3-methoxycarbonyl-benzyl ester was synthesized according to Procedure L from
5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester (7.26 g, 21.4 mmol) and triturated with ethyl acetate to give 4.80 g (56.6%) of fine white powder: mp 164-167°C; IR (KBr) 3031 , 2951, 1725, 1683, 1432, 1285, 1077 cm"1 ; lH NMR (400 MHz, DMSO-d6) δ 2.10 (s, 6H, N(CH3)2), 2.49 (s, 3Η, CCH3), 3.81 (s, 3Η, OCH3), 3.96 (s, 2Η, NCH2Ar), 5.31 (s, 2Η, OCH2Ar),
6.55 (d, 7=8.55 Ηz, 1Η, ArH ), 7.06 (d, 7=8.55 Ηz, 1Η, ArH), 7.52 (t, 7=7.81 Ηz, 1Η, ArH), 7.72 (d, 7=7.57 Ηz, 1Η, ArH), 7.90 (d, 7=7.81 Ηz, 1Η, ArH), 8.03 (s,
1Η, ArH), 11.54 (s, 1Η, NH); MS(APCI+): m/z 397.0 (MΗ+). HPLC (ALLTCH/ALLTIMA C-18 65:35-15:85 H2O/CH3CN + 0.05% TFA): rentention time=4.91 min, 92.97% purity.
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl)phenyl]methyl ester Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [3-(methoxycarbonyl)- phenyljmethyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester (2.09 g, 5.27 mmol) and recrystallized from t-butyl methyl ether to give 1.21 g (47.1 %) of fine white powder: mp 169-170°C; IR (KBr) 3380, 2931, 2855, 1721, 1433, 1289, 1076 cm"1 ; !H NMR (400 MHz,
DMSO-dg) δ 1.03-1.21 (m, 3H, aliphatic CH) 1.36-1.63 (m, 7H, aliphatic CH), 1.81 (d, 7=13.43 Hz, IH, aliphatic CH), 2.33 (d, 7=10.50 Hz, IH, aliphatic CH), 2.40-2.42 (m, IH, aliphatic CH), 2.46 (s, 3H, CCH3), 2.56-2.67 (m, 2Η, aliphatic
CH), 2.82-2.88 (m, 1Η, aliphatic CΗ), 3.14 (dd, 7=18.07, 6.84 Ηz, 1Η, aliphatic CΗ), 3.81 (s, 3Η, OCH3), 5.29 (dd, 7=25.15, 12.45 Ηz, 2Η, OCH2Ar), 6.57 (d,
7=8.79 Ηz, 1Η, ArH), 7.02 (d, 7= 8.79 Ηz, 1Η, ArH), 7.52 (t, 7=7.57 Ηz, 1Η, ArH), 7.71 (d, 7=7.57 Ηz, 1Η, ArH), 7.90 (d, 7=7.81 Ηz, 1Η, ArH), 8.02 (s, 1Η,
ArH), 11.55 (s, 1Η, NH); MS(APCI+): m/z 489.2 (MΗ+). Anal. Calcd for 29H32N2°5: C, 71.29; H, 6.60; N, 5.73. Found: C, 71.22; H, 6.91 ; N, 5.43.
Example 61 Pyrrolo[3 ',2' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]methyl ester
Step A: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-hydroxymethyl-benzyl ester
4-Dimethylaminomethyl-5-hydroxy-2-methyl- 1 H-indole-3-carboxylic acid 3-hydroxymethyl-benzyl ester was synthesized according to procedure P from 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methoxycarbonyl-benzyl ester (Example 60, Step B, 2.21 g, 5.58 mmol) and triturated with CH2Cl2 to give 1.11 g (54.0%) of white powder: mp 199-201°C;
IR (KBr) 3065, 2884, 1681, 1586, 1432, 1090 cm"1 ; IH NMR (400 MHz, DMSO- d6) δ 2.25 (s, 3H, CCH3) 2.72 (s, 6Η, N(CH3)2). 4.48 (d, 7=5.37 Ηz, 2Η, ArCH2OH), 4.75 (s, 2H, NCH2Ar), 5.22 (t, 7=5.62 Ηz, 1Η, ArCΗ2OH), 5.28 (s, 2Η, OCH2Ar), 6.87 (d, 7=8.55 Ηz, 1Η, ArH), 7.25-7.34 (m, 4Η, ArH), 7.40 (s, 1Η, ArH ), 8.59 (s, 1Η, ArOH), 12.06 (s, 1Η, NH); MS(APCI+): m/z 369.2 (MΗ+). HPLC (ALLTCH/ALLTIMA C-18 98:2-75:25 H2O/CH3CN +
0.05% TFA): retention time=2.11 min, 98.74%> purity.
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]methyl ester Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(hydroxymethyl)- phenyljmethyl ester was synthesized according to Procedure M from 4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-hydroxymethyl-benzyl ester (0.980 g, 2.66 mmol) and triturated with t-butyl methyl ether to give 0.420 g (44.2%>) of a light yellow green crystal: mp
183-185°C; IR (KBr) 3381, 3197, 2931, 1682, 1430, 1249, 1076 cm" 1 ; !H NMR (400 MHz, DMSO-d6) δ 1.06-1.37 (m, 3H, aliphatic CH) 1.40-1.65 (m, 6H, aliphatic CH), 1.82 (d, 7=13.43 Hz, IH, aliphatic CH), 2.33 (d, 7=10.01 Hz, IH, aliphatic CH), 2.40-2.43 (m, IH, aliphatic CH), 2.46 (s, 3H, CCH3), 2.61 -2.68 (m, 2Η, aliphatic CH), 2.83-2.89 (m, IH, aliphatic CH), 3.12-3.16 (m, IH, aliphatic
CH), 3.18 (dd, 7=18.31, 6.84 Hz, IH, aliphatic CH), 4.46 (d, 7=5.62 Hz, 2H, ArCH2OH), 5.18 (t, 7=6.10 Hz, IH, ArCH2OH), 5.21 (dd, 7=20.27, 12.21 Ηz,
2Η, OCH2Ar), 6.58 (d, 7=8.79 Ηz, 1Η, ArH), 7.01 (d, 7=8.55 Ηz, 1Η, ArH),
7.23-7.32 (m, 3Η, ArH), 7.36 (s, 1Η, ArH), 11.51 (s, 1Η, NH); MS(APCI+): m/z 461.1 (MΗ+). Anal. Calcd for C28H32N2O4: C, 73.02; H, 7.00; N, 6.08. Found:
C, 72.84; H, 7.07; N, 5.91. Example 62
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (3-carboxyphenyl)methyl ester)
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (3-carboxyphenyl)methyl ester was synthesized according to Procedure O from pyrrolo[3',2':5,6][l]- benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15- decahydro-2 -methyl-, [3-(methoxycarbonyl)phenyl]methyl ester (Example 60, Step C, 0.923 g, 1.89 mmol) and triturated with ethyl acetate to give 0.456 g
(50.7%) of white powder: mp 205-208°C; IR (KBr) 2932, 2859, 1693, 1563,
1432, 1076 cm" 1 ; !H NMR (400 MHz, DMSO-dg) δ 1.08-1.36 (m, 3H, aliphatic
CH) 1.39-1.63 (m, 7H, aliphatic CH), 1.81 (d, 7=13.18 Hz, IH, aliphatic CH), 2.33 (d, 7=1 1.23 Hz, IH, aliphatic CH), 2.40-2.43 ( , IH, aliphatic CH), 2.47 (s, 3H, CCH ), 2.56-2.67 (m, 2Η, aliphatic CH), 2.84-2.88 (m, IH, aliphatic CH),
3.15 (dd, 7=17.82, 6.35 Hz, IH, aliphafic CH), 5.28 (dd, 7=24.17, 12.45 Hz, 2H, OCH2Ar), 6.57 (d, 7=8.79 Ηz, 1Η, ArH), 7.02 (d, 7=8.55 Ηz, 1Η, ArH), 7.48 (t, 7=7.57 Ηz, 1Η, ArH), 7.65 (d, 7=7.57 Ηz, 1Η, ArH), 7.87 (d, 7=7.81 Ηz, 1Η,
ArH), 8.00 (s, 1Η, ArH), 1 1.55 (s, 1Η, NH); MS(APCI+): m/z 475.1 (MΗ+). Anal. Calcd for C28H3θN2O5: C, 69.18; H, 6.50; N, 5.75. Found: C, 68.83; H, 6.40; N,
5.63.
Example 63 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (3-carboxypheny)methyl 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][l]- benzopyrano[3,2-i]quinolizine-l -carboxylate (1 :1)
To a suspension of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l- carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (3-carboxyphenyl)methyl ester (Example 62, 0.100 g, 0.211 mmol) in 5 mL of EtOH was added choline carbonate (0.037 mL, 0.211 mmol, 5.66 M). The reaction mixture was heated at reflux for 1 hour resulting in a clear solution. After cooling to room temperature, the mixture was concentrated to give a yellow oil. Triturating this oil with diethyl ether yielded 0.097 g (88.0%) of beige solid: mp
165-170°C; IR (KBr) 2930, 2855, 1685, 1566, 1436, 1077 cm"1 ; lH NMR (400 MHz, DMSO-d6) δ 1.09-1.28 (m, 3H, aliphatic CH) 1.39-1.70 (m, 7H, aliphatic CH), 1.86 (d, 7=13.50 Hz, IH, aliphatic CH), 2.35 (d, 7=10.37 Hz, IH, aliphatic CH), 2.42-2.45 (m, IH, aliphatic CH), 2.47 (s, 3H, CCH3), 2.65-2.72 (m,
2Η, aliphatic CH), 2.87-2.91 (m, IH, aliphatic CH), 3.09 (s, 9H, N(CH3)3),
3.23 (dd, 7=15.19, 8.44 Ηz, 1Η, aliphatic CΗ), 3.35-3.40 (m, 2Η, NCH2CH2OH), 3.81-3.85 (m, 2H, NCH CH2OH), 5.20 (dd, 7=23.63, 12.30 Hz, 2H, OCH^Ar),
6.55 (d, 7=8.44 Ηz, 1Η, ArH), 7.03 (d, 7= 8.44 Ηz, 1Η, ArH), 7.22 (t, 7=7.47 Ηz, 1Η, ArH), 7.29 (d, 7=7.23 Ηz, 1Η, ArH), 7.75 (d, 7=7.48 Ηz, 1Η, ArH), 7.89 (s,
1Η, ArH), 11.55 (s, 1Η, NH); MS(APCI+): m/z 475.1 (MΗ+). Anal. Calcd for C33H43N3O6: C, 65.23; H, 7.68; N, 6.92. Found: C, 64.95; H, 7.68; N, 6.92.
Example 64
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, [3-[(dimethylamino)methyl]phenyl]methyl ester
To a stirred solution of PI13P (0.161 g, 0.616 mmol) and pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]- methyl ester (Example 61, Step B, 0.284 g, 0.616 mmol) in 2.93 mL of anhydrous
THF at -18°C was added dropwise a solution of N-bromosuccinimide (0.110 g, 0.616 mmol) in 2 mL of THF. After 10 minutes, the cold bath was removed, and dimethylamine was introduced in one portion. The reaction was heated at 80°C for 1 hour in a stainless steel vessel. The THF was removed, and the product was purified by flash column chromatography on silica gel (20% MeOH:CH2Cl2) and recrystallized from CH2CI2 to give 1.21 g (40.3%) of coarse off-white powder: mp 87-90°C; IR (KBr) 2930, 2854, 1700, 1589, 1432, 1077 cm"1 ; !H NMR (400 MHz, DMSO-d6) δ 1.06-1.36 (m, 3H, aliphatic CH) 1.39-1.63 (m, 7H, aliphatic CH), 1.82 (d, 7=13.18 Hz, IH, aliphatic CH), 2.11 (s, 6H, N(CH3)2) 2.34 (d, 7=10.74 Ηz, 1Η, aliphatic CΗ), 2.40-2.46 (m, 1Η, aliphatic CΗ), 2.45 (s,
3Η, CCH3), 2.59-2.67 (m, 2Η, aliphatic CH), 2.83-2.89 (m, IH, aliphatic CH),
3.15 (dd, 7=18.31, 6.84 Hz, IH, aliphatic CH), 3.37 (s, 2H, ArCH2N(CH3)2),
5.20 (dd, 7=23.93, 12.21 Hz, 2H, OCH Ar), 6.57 (d, 7=8.79 Ηz, 1Η, ArH),
7.02 (d, 7=8.79 Ηz, 1Η, ArH), 7.22-7.31 (m, 3Η, ArH), 7.34 (s, 1Η, ArH), 11.53 (s, 1Η, NH); MS(APCI+): m/z 488.1 (MΗ+). Anal. Calcd for
C30H3-7N3O3: C, 71.89; H, 7.65; N, 8.62. Found: C, 71.89; H, 7.65; N, 8.20.
Example 65 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [3-[(dimethylamino)carbonyl]phenyl]methyl ester
Step A: 3-Hydroxymethyl-N,N-dimethyl-benzamide
To a mixture of 3-(hydroxymethyl)benzoic acid (9.87 g, 64.9 mmol), dimethylamine (2 M in THF, 32.4 mL, 64.9 mmol), N,N-diisopropyl ethylamine
(22.6 mL, 130 mmol) in 20 mL of DMF was added a solution of HBTU (24.6 g, 64.9 mmol) in 55 mL of DMF at 0°C. After 5 minutes, the yellow solution turned orange. After stirring at 0°C for 1 hour, the reaction mixture was diluted with diethyl ether, washed with 10% HCI, saturated NaHCO3, brine, dried with MgSO4, and concentrated to give a brown oil. The product was purified by flash column chromatography on silica gel (3% MeOH:CH2θ2) to afford 7.5 g (64.5%) of a yellow oil: lH NMR (400 MHz, DMSO-d6) δ 2.88 (s, 3H, NCH3), 2.96 (s, 3Η, NCH3), 4.51 (d, 7=5.55 Ηz, 2Η, OCH2Ar), 5.25 (t, 7=5.79 Ηz, 1Η, OH), 7.21-7.25 (m, 1Η, ArH), 7.31-7.47 (m, 3Η, ArH); MS(APCI+): m/z 180.1 (MΗ+).
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [3-[(dimethylamino)carbonyl]phenyl]methyl ester Pyrrolo[3 ',2 ' : 5 ,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, [3-[(dimethylamino)carbonyl]- phenyljmethyl ester was synthesized according to Procedure N from 3-hydroxymethyl-N,N-dimethyl-benzamide (1.04 g, 5.81 mmol) and triturated with acetone to give 0.250 g (25.7%) of fluffy white powder: mp 112-1 16°C; IR (KBr) 2929, 2854, 1698, 1624, 1432, 1077 cm"1 ; 1 H NMR (400 MHz, DMSO- d6) δ 1.09-1.62 (m, 10H, aliphatic CH), 1.82 (d, 7=14.16 Hz, IH, aliphatic CH),
2.33 (d, 7=10.25 Hz,lH, aliphatic CH), 2.40-2.43 (m, IH, aliphatic CH), 2.45 (s, 3H, CCH3), 2.46 (s, 6Η, N(CH3)2), 2.59-2.67 (m, 2Η, aliphatic CH),
2.86-2.93 (m, IH, aliphatic CH), 3.16 (dd, 7=18.80, 7.81 Hz, IH, aliphatic CH), 5.24 (dd, 7=20.75, 12.45 Hz, 2H, OCH2Ar), 6.57 (d, 7=8.55 Ηz, 1Η, ArH),
7.02 (d, 7=8.55 Ηz, 1Η, ArH), 7.33 (d, 7=7.57 Ηz, 1Η, ArH), 7.40-7.44 (m, 2Η, ArH), 7.49 (d, 7=7.57 Ηz, 1Η, ArH), 11.54 (s, 1Η, NH); MS(APCI+): m/z
502.2 (MΗ+). Anal. Calcd for C30H35N3O4: C, 71.83; H, 7.03; N, 8.38. Found:
C, 71.44; H, 7.05; N, 8.21.
Example 66
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [2-(4-morpholinyl)ethyl ester
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [2-(4-morpholinyl)ethyl ester was synthesized according to Procedure N from 2-morpholin-4-yl-ethanol (0.300 mL, 2.64 mmol) and triturated with CH2Cl2 to give 0.122 g (41.0%) of a white solid: mp 188-190°C; IR (KBr) 2931, 2854, 1696, 1588, 1432, 1148 cm"1; !H NMR (400 MHz, DMSO-d6) δ 1.14-1.75 (m, 10H, aliphatic CH), 1.90 (d, 7=13.18 Hz, IH, aliphatic CH), 2.34-2.46 (m, 2H, aliphatic CH), 2.46 (s, 4H,
N(CH2CH2)2θ), 2.49 (s, 3Η, CCH3), 2.59 (t, 7=5.62 Ηz, 2Η, CO2CH2CH2), 2.64-2.73 (m, 2Η, aliphatic CH), 2.86-2.91 (m, IH, aliphatic CH), 3.29 (dd, 7=19.29, 10.25 Hz, IH, aliphatic CH), 3.52 (s, 4H, N(CH2CH2)2O), 4.18-4.30 (m, 2H, CO2CH2CH ), 6.58 (d, 7= 8.55 Hz, IH, ArH), 7.02 (d, 7=8.55 Ηz, 1Η, ArH), 11.48 (s, 1Η, NH); MS(APCI+): m/z 454.1 (MΗ+). Anal. Calcd for C26H35N3O4: C, 68.60; H, 7.79; N, 9.23. Found: C, 68.23; H, 7.80; N, 9.02.
Example 67 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-[l,l '-biphenyl]-4-ylethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-[l,l '-biphenyl]-4-ylethyl ester was synthesized according to Procedure N from 1 -biphenyl -4-yl-ethanol (2.68 g, 13.5 mmol) and triturated with diethyl ether to give 0.619 g (35.4%) of white powder: mp 132-135°C; IR (KBr) 2929, 2855, 1677, 1432, 1078 cm"1 ; !H NMR (400 MHz, DMSO-d6) δ 1.11-1.67 (m, 1 OH, aliphatic CH), 1.59 (d, 7=6.59 Hz,
2H, OCHCH3), 1.79-1.89 (m, 2Η, aliphatic CH), 2.33-2.47 (m, IH, aliphatic CH),
2.53 & 2.54 (s, 3H, CCH3, diastereomers), 2.60-2.67 (m, 2Η, aliphatic CH), 2.79-2.95 (m, IH, aliphatic CH), 3.14 (dd, 7=28.08, 10.12 Hz, IH, aliphatic CH),
5.96-6.03 (m, IH, OCHCH3), 6.55-6.59 (m, IH, ArH), 7.00-7.03 (m, 1Η, ArH),
7.31-7.34 (m, 1Η, ArH), 7.40-7.51 (m, 4Η, ArH), 7.60-7.64 (m, 4Η, ArH),
11.53 (s, 1Η, NH); MS(APCI+): m/z 521.1 (MΗ+). Anal. Calcd for C34H36N2O3: C, 78.25; H, 7.36; N, 5.14. Found: C, 78.20; H, 7.76; N, 4.85.
Example 68
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, (2,6-difluorophenyl)methyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-,(2,6-difluorophenyl)methyl ester was synthesized according to Procedure N from (2,6-difluoro-phenyl)-methanol (1.50 mL, 13.5 mmol) and triturated with diethyl ether to give 1.07 g (68.0%) of fluffy white powder: mp 219-220°C; IR (KBr) 3330, 2928, 1664, 1473,
1059 cm"1 ; lR NMR (400 MHz, DMSO-d6) δ 1.03-1.35 (m, 3H, aliphatic CH),
1.38-1.56 (m, 7H, cylic CH), 1.78 (d, 7=13.18 Ηz, 2Η, aliphatic CH), 2.32-2.34 (m, 2H, aliphatic CH), 2.41 (s, 3H, CCH3), 2.55-2.66 (m, 2Η, aliphatic CH), 2.83-2.88 (m, IH, aliphatic CH), 3.08 (dd, 7=18.31, 7.08 Hz, IH, aliphatic CH),
5.20 (d, 7=11.96 Hz, IH, OCH Ar), 6.57 (d, 7=8.55 Ηz, 1Η, ArH), 7.01 (d,
7=8.55 Ηz, 1Η, ArH), 7.16 (t, 7=7.81 Ηz, 2Η, ArH), 7.48-7.53 (m, 1Η, ArH),
11.57 (s, 1Η, NH); MS(APCI+): m/z 467.1 (MΗ+). Anal. Calcd for C2 H28N2θ3F2: C, 69.32; H, 6.19; N, 5.80. Found: C, 69.51 ; H, 6.05; N, 6.00.
Example 69
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (l-phenyl-2,2,2-trifluoro)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ( 1 -phenyl-2,2,2-trifluoro)ethyl ester was synthesized according to Procedure N from 2,2,2-trifluoro-l-phenyl- ethanol (1.58 g, 9.00 mmol) and triturated with t-butyl methyl ether to give 0.356 g (31.8%) of fluffy white powder: mp 1 15-1 17°C; IR (KBr) 3382, 2931,
1718, 1432, 1067 cm"1; !H NMR (400 MHz, DMSO-d6) δ 1.07-1.68 (m, 10H, aliphatic CH), 1.87-1.90 (m, 2H, aliphatic CH), 2.35-2.46 (m, 2H, aliphatic CH), 2.58-2.62 (m, IH, aliphatic CH), 2.61 & 2.62 (s, 3H, CCHj, diastereomers), 2.62-2.90 (m, 1Η, aliphatic CΗ), 3.18 (dd, 7=17.82, 6.84 Ηz, 1Η, aliphatic CΗ),
6.52-6.57 (m, 1Η, OCHCF3), 6.61-6.63 (m, 1Η, ArH), 7.05-7.07 (m, 1Η, ArH), .43- .44 (m, 3Η, ArH), 7.55-7.57 (m, 2Η, ArH), 11.83 (s, 1Η, NH); MS(APCI+): m/z 499.1 (MΗ+). Anal. Calcd for C28H29N O3F3: C, 67.46; H, 5.86; N, 5.62. Found: C, 67.40; H, 6.03; N, 5.44.
Example 70
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1 -[3-(trifluoromethyl)phenyl]ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -[3-(trifluoromethyl)phenyl]- ethyl ester was synthesized according to Procedure N from l-(3-trifluoromethyl- phenyl)-ethanol (2.06 mL, 13.5 mmol) and triturated with diethyl ether to give 0.793 g (45.8%) of white solid: mp 102-105°C; IR (KBr) 3380, 2931, 1680, 1432, 1075 cm"1 ; }H NMR (400 MHz, DMSO-dό) δ 1.05-1.59 (m, 10H, aliphatic CH),
1.59 (d, 7=6.59 Hz, 3H, OCHCH3), 1.77-1.88 (m, 1Η, aliphatic CΗ), 2.33 (d,
7=9.03 Ηz, 1Η, aliphatic CΗ), 2.41 (d, 7=8.55 Ηz, 1Η, aliphatic CΗ), 2.51 & 2.52 (s, 3Η, CCH3, diastereomers), 2.51-2.67 (m, 2Η, aliphatic CH), 2.83-2.86
(m, IH, aliphatic CH), 3.06 (dd, 7=18.07, 6.84 Hz, IH, aliphatic CH), 6.01-6.05 (m, IH, OCHCH3), 6.58-6.60 (m, IH, ArH), 7.01-7.04 (m, 1Η, ArH), 7.57-7.67 (m, 2H, ArH), 7.71-7.75 (m, 2Η, ArH), 11.56 (s, 1Η, NH); MS(APCI+): m/z
513.1 (MΗ+). Anal. Calcd for C29H31N2O3F3: C, 67.69; H, 6.08; N, 5.44.
Found: C, 67.34; H, 6.35; N, 5.24.
Example 71 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-(dimethylamino)ethyl ester
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-(dimethylamino)ethyl ester was synthesized according to Procedure N from 2-dimefhylamino-ethanol
(1.36 mL, 13.5 mmol) and triturated with diethyl ether to give 0.489 g (34.9%) of granular off-white solid: mp 190-191 °C; IR (KBr) 3274, 2950, 1653, 1518,
1248 cm"1 ; !H NMR (400 MHz, DMSO-d6) δ 1.13-1.59 (m, 10H, aliphatic CH),
1.71-1.76 (m, IH, aliphatic CH), 1.90 (d, 7=13.43 Hz, IH, aliphatic CH), 2.05 (s, 6H, N(CH3)2), 2.35 (d, 7=10.25 Ηz, 1Η, aliphatic CΗ), 2.48 (s, 3Η, CCH3), 2.52
(t, 7=5.86 Ηz, 2Η, OCH2CH2), 2.64-2.74 (m, 2Η, aliphatic CH), 2.85-2.89 (m,
IH, aliphatic CH), 3.31 (dd, 7=18.56, 7.08 Hz, IH, aliphatic CH), 4.14-4.27 (m, 2H, OCH CH ), 6.58 (d, 7=8.55 Hz, IH, ArH), 7.02 (d, 7=8.79 Ηz, 1Η, ArH),
11.56 (s, 1Η, NH); MS(APCI+): m/z 412.2 (MΗ+). Anal. Calcd for C24H33N3O3: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.01 ; H, 8.20; N, 9.98.
Example 72 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]qumolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-m ethyl-, 2-( 1 -pyrrolidinyl)ethyl ester
Pyrrolo[3 ' ,2 ' : 5 ,6] [ 1 ]benzopyrano [3 ,2-i] quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2 -methyl-, 2-(l-ρyrrolidinyl)ethyl ester was synthesized according to Procedure N from 2-pyrrolidin-l-yl-ethanol (1.02 g, 8.85 mmol) and triturated with t-butyl methyl ether to give 0.253 g (26.0%) of white solid: mp 195-196°C; IR (KBr) 3377, 2930, 1700, 1432, 1081 cm"1 ;
!H NMR (400 MHz, DMSO-d6) δ 1.12-1.78 (m, 10H, aliphatic CH), 1.61-1.69
(m, 8H, cyclic CH2), 1.92 (d, 7=13.26 Hz, IH, aliphatic CH), 2.37 (d, 7=10.61 Hz,
IH, aliphatic CH), 2.47-2.49 (m, IH, aliphatic CH), 2.50 (s, 3H, CH3), 2.66-2.76 (m, 2Η, aliphatic CH), 2.72 (t, 7=6.51 Hz, 2H, OCH2CH2), 2.87-2.93 (m, 1Η, aliphatic CΗ), 3.32 (dd, 7=19.05, 13.02 Ηz, 1Η, aliphatic CΗ), 4.19-4.30 (m, 2Η, OCH2CH2), 6.60 (d, 7=8.68 Hz, IH, ArH), 7.04 (d, 7=8.68 Hz, IH, ArH), 11.49
(s, 1Η, NH); MS(APCI+): m/z 438.2 (MΗ+). Anal. Calcd for C26H35N3O3: C, 71.37; H, 8.06; N, 9.60. Found: C, 70.99; H, 8.13; N, 9.49.
Example 73
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2 -methyl-, 1 -( 1 -naphthalenyl)ethyl ester
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(l-naphthalenyl)ethyl ester was synthesized according to Procedure N from 1-naphthalen-l-yl-ethanol (2.32 g, 13.5 mmol) and triturated with diethyl ether to give 0.707 g (40.9%) of fine white powder: mp 140-145°C; IR (KBr) 3387, 2929, 1682, 1432, 1078 cm'1 ;
ΪH NMR (400 MHz, DMSO-d6) δ 0.94-1.72 (m, 10H, aliphatic CH), 1.72 (d,
7=2.69 Hz, 3H, OCHCH3), 1.83 (d, 7=12.94 Ηz, 1Η, aliphatic CΗ), 2.30-2.63 (m,
3Η, aliphatic CH), 2.50 & 2.52 (s, 3H, CCH3, diastereomers), 2.83-2.88 (m, 2Η, aliphatic CH), 3.21 (dd, 7=32.72, 26.12 Hz, IH, aliphatic CH), 6.52-6.58 (m, IH, ArH), 6.74-6.75 (m, 1Η, OCHCΗ3), 6.98-7.03 (m, IH, ArH), 7.46-7.65 (m, 4Η,
ArH), 7.84-7.89 (m, 1Η, ArH), 7.93-7.96 (m, 1Η, ArH), 8.12-8.14 (m, 1Η, ArH),
11.54 (s, 1Η, NH); MS(APC ): m/z 513.1 (MΗ+). Anal. Calcd for C32H34N2O3: C, 76.66; H, 6.92; N, 5.58. Found: C, 76.29; H, 6.96; N, 5.40.
Example 74 Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -phenylcyclobutyl ester
Step A: 1-Phenyl-cyclobutanol
To a solution of phenylmagnesium bromide (1 M in THF, 148 mL, 148 mmol) in 87 mL of anhydrous diethyl ether was added cyclobutanone (10.0 g, 143 mmol) in 15 mL of ether at 0°C. The reaction mixture was stirred in an ice bath for 1 hour. Saturated ammonium chloride was added and stirred for 10 minutes. The reaction mixture was washed with H O (2 x 250 mL), dried with MgSO4, and concentrated to give a yellow oil. The product was purified by flash column chromatography on silica gel (10% acetone:hexanes) to give 10.1 g (47.7%) of a yellow oil: !H NMR (400 MHz, CDC13) δ 1.62-1.73 (m, IH, CCH2CH2), 1.94-2.09 (m, 1Η, CCΗ2CH2), 2.29-2.38 (m, 2Η, CCH2), 2.50-2.57 (m, 2Η, CCH2), 2.68 (s, 1Η, OH), 7.21-7.29 (m, 1Η, ArH), 7.31-7.38 (m, 2Η,
ArH), 7.38-7.50 (m, 2Η, ArH); MS(APCI+): m/z 171.5 (MΗ+).
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-m ethyl-, 1 -phenylcyclobutyl ester Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -phenylcyclobutyl ester was synthesized according to Procedure N from 1-phenyl-cyclobutanol (1.33 g,
9.00 mmol) and triturated with diethyl ether to give 0.201 g (19.0%) of white powder: mp 218-220°C; IR (KBr) 3328, 2930, 1674, 1434, 1080 cm"1 ; !H NMR (400 MHz, DMSO-d6) δ 1.09-1.84 (m, 10H, aliphatic CH), 1.94-2.00 (m, IH, aliphatic CH), 2.33 (d, 7=9.03 Hz, IH, aliphafic CH), 2.40-2.46 (m, IH, aliphatic CH), 2.46 (s, 3H, CCH3), 2.56 (s, 6Η, cyclic C(CH2)3Ar), 2.52-2.64 (m, 2Η, aliphatic CH), 2.83-2.88 (m, IH, aliphatic CH), 3.15 (dd, 7=18.80, 7.08 Hz, IH, aliphatic CH), 6.56 (d, 7=8.55 Hz, IH, ArH), 7.00 (d, 7=8.55 Ηz, 1 Η, ArH), 7.22 (t, 7=7.08 Ηz, 1Η, ArH), 7.33 (t, 7=7.57 Ηz, 2Η, ArH), 7.47 (d, 7=7.32 Ηz,
2Η, ArH), 1 1.48 (s, 1Η, NH); MS(APCI+): m/z 671.1 (MΗ+). Anal. Calcd for C30H35N2O3: C, 74.72; H, 7.56; N, 5.81. Found: C, 74.43; H, 7.26; N, 5.41.
Example 75 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -phenylcylopropyl ester
Step A: 1 -Phenyl-cyclopropanol
1 -Phenyl-cyclopropanol was synthesized according to the procedure published in Kulinkovich, O.G.; Sviridov, S.N.; Vasilevskii, D.A.; Savchenko, A.I.; Pritytskaya, T.S. 7 Org. Chem. USSR (Engl.) 1991 ;27:250-253.
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-mefhyl-, 1 -phenylcylopropyl ester Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -phenylcylopropyl ester was synthesized according to Procedure Ν from 1 -phenyl-cyclopropanol (1.22 g, 9.00 mmol) and triturated with diethyl ether to give 0.078 g (7.57%) of shiny yellow powder: mp 130-135°C; IR (KBr) 3384, 2929, 1690, 1431, 1069 cm"1 ; ^H ΝMR (400 MHz, DMSO-dg) δ 1.06-1.69 (m, 10H, aliphatic CH), 1.86 (d, 7=13.43 Hz, IH, aliphatic CH), 2.34 (d, 7=10.01 Hz, IH, aliphatic CH),
2.41-2.44 (m, IH, aliphatic CH), 2.46 (s, 3H, CCH3), 2.52 (s, 4Η, cyclic
C(CH2)2Ar), 2.63-2.70 (m, 2Η, aliphatic CH), 2.81 -2.89 (m, IH, aliphatic CH),
3.20 (dd, 7=18.56, 7.33 Hz, IH, aliphatic CH), 6.59 (d, 7=8.55 Hz, IH, ArH), 7.03 (d, 7=8.55 Ηz, 1Η, ArH), 7.15-7.19 (m, 3Η, ArH), 7.26-7.30 (m, 2Η, ArH), 1 1.57 (s, 1Η, ΝH); MS(APCI+): m/z 457.1 (MΗ+). Anal. Calcd for
C29H32Ν2O3: C, 76.29; H, 7.06; N, 6.14. Found: C, 76.12; H, 7.39; N, 5.83.
Example 76 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-m ethyl-, 1 -pyrazinylethyl ester
Step A: l-Pyrazin-2-yl-ethanol
To a solution of l-pyrazin-2-yl-ethanone (5.00 g, 40.9 mmol) in 100 mL of MeOH at 0°C was added NaBH4 (0.774 g, 20.5 mmol) in portions. After stirring at room temperature for 24 hours, the reaction mixture was quenched with 1 N HCI and extracted with CH2C12 (3 x 100 mL). The organic layers were dried with
Na2SO4 and concentrated to give 2.60 g (51.2%) of a yellow oil: *H NMR
(400 MHz, CDC13) δ 1.54 (d, 7=6.59 Hz, 3H, CHCH3), 3.54 (s, 1Η, OH), 4.97 (q,
7=6.59 Ηz, 1Η, CΗ3CH), 8.49 (s, 2Η, NCHCHN), 8.65 (s, IH, CCHN); MS(APCI+): m/z 125.1 (MΗ+).
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 1 -pyrazinylethyl ester Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -pyrazinylethyl ester was synthesized according to Procedure N from 1 -pyrazin-2-yl-ethanol (1.12 g,
9.00 mmol) and triturated with cold acetone to give 0.303 g (30.3%) of coarse white powder: mp 224-225°C; IR (KBr) 3172, 2930, 1704, 1431, 1073 cm"1 ; H NMR (400 MHz, DMSO-d6) δ 1.06-1.63 (m, 10H, aliphatic CH), 1.61 (d, 7=3.17 Hz, 3H, OCHCH3), 1.77-1.98 (m, 1Η, aliphatic CΗ), 2.34 (d, 7=10.25 Ηz, 1Η, aliphatic CΗ), 2.40-2.43 (m, 1Η, aliphatic CΗ), 2.52 & 2.53 (s, 3Η, CCH3, diastereomers), 2.62-2.68 (m, 1Η, aliphatic CΗ), 2.84-2.87 (m, 1Η, aliphatic CΗ), 3.12 (dd, 7=19.04, 6.84 Ηz, 1Η, aliphatic CΗ), 5.99 (q, 7=7.08 Ηz, 1Η, OCHCΗ3), 6.56-6.60 (m, IH, ArH), 7.01-7.04 (m, IH, ArH), 8.57 (s, 1Η, ArH),
8.62 (s, 1Η, ArH), 8.71 & 8.73 (s, 1Η, ArH, diastereomers), 1 1.56 (s, 1Η, NH); MS(APCI+): m/z 441 (MΗ+). Anal. Calcd for C26H30N4O3: C, 69.90; H, 6.79;
N, 12.50. Found: C, 69.51; H, 6.78; N, 12.35. Example 77 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(4-quinolinyl)ethyl ester
Step A: l-Quinolin-4-yl-ethanol
To a solution of quinoline-4-carbaldehyde (5.00 g, 31.8 mmol) in 127 mL of anhydrous THF at -40°C was added methylmagnesium bromide (13.8 mL, 41.4 mmol). After stirring for 5 hours, the reaction mixture was quenched with saturated NH4CI and extracted with ethyl acetate (5 x 100 mL). The organic layers were washed with brine, dried with Na2SO4, and concentrated to give a purple solid. The solid was triturated with acetone to yield 4.52 g (82.2%) of light purple solid: ]H NMR (400 MHz, CDCI3) δ 1.60 (d, 7=6.35 Hz, 3H, CHCH3),
3.70 (s, 1Η, OH), 5.62 (q, 7=6.35 Ηz, 1Η, CHCΗ3), 7.50 (t, 7=7.57 Hz, IH, CCCHCH), 7.56 (d, 7=4.40 Ηz, 1Η, NCΗCH), 7.63 (t, 7=7.32 Ηz, 1Η,
NCCΗCH), 7.97 (d, 7=8.55 Ηz, 1Η, CCCHCΗ), 8.05 (d, 7=8.30 Ηz, 1Η,
NCCHCΗ), 8.73 (d, 7=4.39 Ηz, 1Η, NCHCΗ), MS(APCI+): m/z 174.1 (MΗ+).
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(4-quinolinyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -(4-quinolinyl)ethyl ester was synthesized according to Procedure N from l-quinolin-4-yl-ethanol (1.56 g, 9.00 mmol) and triturated with acetone to give 0.192 g (17.1%>) of pale yellow po deπ mp 165- 168°C; IR (KBr) 2930, 2853, 1690, 1429, 1074 cm"1; ]H NMR (400 MHz, DMSO-d6) δ 1.00-1.46 (m, 10H, aliphatic CH), 1.70 (d, 7=6.35 Hz, 3H, OCHCH3), 1.85 (d, 7=13.18 Ηz, 1Η, aliphatic CΗ), 2.32-2.63 (m, 3Η, aliphatic CH), 2.57 & 2.58 (s, 3H, CCH3, diastereomers), 2.83-2.86 (m, 2Η, aliphatic CH), 3.20 (dd, 7=18.31, 6.84 Hz, IH, aliphatic CH), 6.55-6.58 (m, IH,
ArH), 6.65 (q, 7=6.59 Ηz, 1Η, OCHCΗ3), 7.01-7.05 (m, IH, ArH), 7.50-7.54 (m,
1Η, ArH), 7.63-7.67 (m, 1Η, ArH), 7.75-7.79 (m, 1Η, ArH), 8.04-8.06 (m, 1Η, ArH), 8.21-8.23 (m, 1Η, ArH), 8.84-8.88 (m, 1Η, ArH), 11.61 (s, 1Η, NH);
MS(APCI+): m/z 496.2 (MΗ+). Anal. Calcd for C31H33N3O3: C, 74.12; H, 7.00; N, 7.83. Found: C, 73.73; H, 7.09; N, 7.44.
Example 78 Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(2-pyrimidinyl)ethyl ester
Step A: l-Pyrimidin-2-yl-ethanone
l-Pyrimidin-2-yl-ethanone was synthesized according to the procedure published in Naumenko, I. I.; Mikhaleva, M. A.; Mamaev, V. P. Chem. Het.Cmpds. 1981;17:710-714.
Step B: 1 -Pyrimidin-2-yl-ethanol
To a solution of l-pyrimidin-2-yl-ethanone (2.34 g, 19.2 mmol) in 65 mL of MeOH at 0°C was added NaBH4 (0.726 g, 19.2 mmol) in portions. After stirring at room temperature for 4 hours, the reaction mixture was quenched with IN HCI and extracted with CH2CI2 (3 x 100 mL). The organic layers were dried with Na2SO4 and concentrated to afford 0.984 g (41.3%) of a yellow oil: ]H
NMR (400 MHz, DMSO-dg) δ 1.36 (d, 7=6.59 Hz, 3H, CHCH3), 4.73 (q,
7=6.59 Ηz, 1Η, CΗ3CH), 5.21 (s, 1Η, OH), 7.33-7.36 (m, 1Η, NCΗCH),
8.73-8.77 (m, 2Η, NCHCH); MS(APCI+): m/z 125.1 (MH+).
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(2-pyrimidinyl)ethyl ester Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -(2-pyrimidinyl)ethyl ester was synthesized according to Procedure N from 1 -pyrimidein-2-yl-ethanol (1.01 g, 8.10 mmol) and triturated with acetone to give 0.360 g (29.9%) of fine off-white powder: mp 220-222°C; IR (KBr) 3176, 2932, 1686, 1426, 1078 c "1 ; 1 H NMR (400 MHz, DMSO-d6) δ 1.06-1.54 (m, 10H, aliphatic CH), 1.59 (d, 7=6.59 Hz, 3H, OCHCH3), 1.84 (d, 7=13.92 Ηz, 1Η, aliphatic CΗ), 2.34-2.55 (m, 2Η, aliphatic CH), 2.58 (s, 3H, CCH3), 2.64-2.69 (m, 2Η, aliphatic CH), 2.81-2.86 ( , IH, aliphatic CH), 3.17 (dd, 7=18.31, 6.59 Hz, IH, aliphatic CH), 5.84 (q,
7=6.84 Hz, IH, OCHCH3), 6.57 (d, 7=8.79 Hz, IH, ArH), 7.02 (d, 7=9.03 Ηz, 1Η,
ArH), 7.37-7.38 (m, 1Η, ArH), 8.76-8.77 (m, 2Η, ArH), 11.53 (s, 1Η, NH); MS(APCI+): m/z 447.1 (MΗ+). Anal. Calcd for C26H30N4O3: C, 69.86; H, 7.04; N, 12.07. Found: C, 69.50; H, 6.94; N, 11.71.
Example 79
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-chloro- 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester
Step A: 6-Chloro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester
To a solution of 3-amino-but-2-enoic acid benzyl ester (10.1 g, 52.9 mmol) in 21 1 mL of EtOH was added 2-chloro- 1,4-benzoquinone (9.04 g, 63.4 mmol).
After heating at 50°C for 24 hours, the mixture was cooled to room temperature and concentrated to afford a brown oil. The product was purified by flash column chromatography on silica gel (20% ethyl acetate:hexanes) and recrystallized from ethyl acetate to give 1.02 g (5.12%) of light yellow powder: mp 221-224°C; IR (KBr) 3409, 3226, 1642, 1461, 1181 cm" 1 ; !H NMR (400 MHz, DMSO-dg) δ
2.55 (s, 3H, CCH3), 5.29 (s, 2Η, OCH2Ar), 7.27 (s, 1Η, ArH), 7.30 (d, 7=6.84 Ηz,
1Η, ArH), 7.36 (t, 7=8.30 Ηz, 2Η, ArH), 7.42 (d, 7=7.57 Ηz, 2Η, ArH), 7.50 (s,
1Η, ArH), 9.56 (s, 1Η, OH), 1 1.67 (s, 1Η, NH); MS(APCI+): m/z 316.1 (MΗ+). HPLC (ALLTCH/ALLTIMA C-18 50:50-2:98 H2O/CH3CN + 0.05% TFA): rentention time=5.47 min, 95.86% purity.
Step B: 6-Chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester
6-Chloro-4-dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole- 3-carboxylic acid benzyl ester was synthesized according to Procedure L from 6-chloro-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (7.77 g, 24.6 mmol) and triturated with cold EtOH to give 6.77g (73.8%.) of a white solid: mp 178-180°C; IR (KBr) 3298, 2951, 1687, 1425, 1437, 1264, 1078 cm"1; H NMR (400 MHz, DMSO-d6) δ 2.14 (s, 6H, N(CH3)2) 4.06 (s, 2Η, NCH2Ar), 5.23 (s, 2Η, OCH2Ar), 7.22 (s, 1Η, ArH), 7.31 -7.39 (m, 3Η, ArH), 7.44 (d,
7=6.84 Ηz, 2Η, ArH), 1 1.85 (s, 1Η, NH); MS(APCI+): m/z 373.1 (MΗ+). HPLC (ALLTCH/ALLTIMA C-18 50:50-2:98 H2O/CH3CN + 0.05% TFA): retention time=3.10 min, 99.09% purity.
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-chloro-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-chloro-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2mefhyl-, phenylmethyl ester was synthesized according to Procedure M from 6-chloro-4-dimethylaminomethyl- 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid benzyl ester (6.77 g, 18.2 mmol) and triturated with acetone to give 6.05 g (71.7%) of shiny white powder: mp
90-93°C; IR (KBr) 3291, 2933, 2858, 1673, 1427, 1076 cm"1 ; ]H NMR
(400 MHz, DMSO-d6) δ 1.01-1.71 (m, 10H, aliphatic CH), 1.75 (d, 7=13.43 Hz,
IH, aliphatic CH), 2.37 (d, 7=10.50 Hz, IH, aliphatic CH), 2.45-2.46 (m, IH, aliphatic CH), 2.46 (s, 3H, CCH3), 2.64-2.74 (m, 2Η, aliphatic CH), 2.94-2.99 (m,
IH, aliphatic CH), 3.38 (dd, 7=18.56, 7.08 Hz, IH, aliphatic CH), 5.21 (dd, 7=26.12, 12.21 Hz, 2H, OCH2Ar), 7.18 (s, 1Η, ArH), 7.29-7.43 (m, 5Η, ArH),
11.62 (s, 1Η, NH); MS(APCI+): m/z 465.2 (MΗ+). Anal. Calcd for C27H29N2O3CI1: C, 69.74; H, 6.29; N, 6.02. Found: C, 69.45; H, 6.68; N, 5.82.
Example 80
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-chloro- 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl, 1 -(4-fluorophenyl)ethyl ester
Step A: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-chloro-3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl, anhydride with benzoic acid
In a 250 mL, three-necked, round bottom flask was added pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-chloro-
3,7,8,9,10,12,13, 14,14a,15-decahydro-2methyl-, phenylmethyl ester (Example 79,
Step C, 5.44 g, 11.7 mmol), THF (58.6 mL, 0.2 M), Et3N (1.63 mL, 11.7 mmol), and 10%> Pd(OH)2/C (1.26 g) sequentially. The mixture was stirred under a
H2 atmosphere (balloon) for 1 hour. The reaction mixture was filtered through a pad of celite, and the yellow filtrate was carried on the next step. To this yellow filtrate was added benzoyl chloride in a dropwise fashion (1.36 mL, 1 1.7 mmol). The mixture was stirred at room temperature for 48 hours and the solvent removed to give a brown oil. Trituration with acetone afforded 3.50 g (62.4%) of yellow powder: mp 160-165°C; lH NMR (400 MHz, DMSO-d6) δ 1.10-1.58 (m, 10H, aliphatic CH), 1.83 (d, 7=12.94 Hz, IH, aliphatic CH), 2.41-2.46 (m, 2H, aliphatic CH), 2.51 (s, 3H, CCH3), 2.66-2.71 (m, 1Η, aliphatic CΗ), 2.98-3.01 (m, 2Η, aliphatic CH), 3.38 (dd, 7=17.82, 6.59 Hz, IH, aliphatic CH), 7.29 (s, IH, ArH), 7.58 (t, 7=7.57 Ηz, 2Η, ArH), 7.74 (t, 7=7.57 Ηz, 1Η, ArH), 8.07 (d, 7=7.08 Ηz,
2Η, ArH), 12.14 (s, 1Η, NH); MS(APCI+): m/z 479.1 (MΗ+).
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl, 1 -(4-fluorophenyl)ethyl ester Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-chloro-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2methyl-, 1 -(4-fluorophenyl)ethyl ester was synthesized according to Procedure N from 1 -(4-fluoro-phenyl)-ethanol (0.900 g, 7.16 mmol) and pyrrolo[3',2':5,6][l]-benzopyrano[3,2-i]quinolizine-l- carboxylic acid, 5-chloro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl, anhydride with benzoic acid (0.857 g, 1.79 mmol). The product was recrystallized from t-butyl methyl ether to give 0.210 g (23.6%) of white powder: mp
102-107°C; IR (KBr) 2934, 2859, 1674, 1428, 1055 cm"1; ] H NMR (400 MHz, DMSO-d6) δ 1.06-1.81 (m, 11H, aliphatic CH), 1.55 (d, 7=6.59 Hz, 3H, OCHCH3), 2.37 (d, 7=10.25 Ηz, 1Η, aliphatic CΗ), 2.44-2.46 (m, 1Η, aliphatic
CΗ), 2.46 (s, 3Η, CCH3), 2.63-2.75 (m, 2H, aliphatic CH), 2.97-3.14 (m, IH, aliphatic CH), 3.20 (dd, 7=13.18, 6.59 Hz, IH, aliphatic CH), 5.95 (q, 7=6.59 Hz, IH, OCHCH3), 7.15-7.19 (m, 3H, ArH), 7.43-7.49 (m, 2Η, ArH), 1 1.62 (s, 1Η,
NH); MS(APCI+): m/z 497.2 (MΗ+). Anal. Calcd for C28H3oN2O3F1Cli : C, 66.82; H, 6.15; N, 5.57. Found: C, 66.96; H, 6.39; N, 5.46.
Example 81 Quinolizinium, l-[[(4-fluorophenyl)methoxy]carbonyl]-5-hydroxy-2-methyl-lH- indol-4-yl]methyl]- 1 ,2, 3,4,6, 7, 8, 9-octahydro-, chloride
To a solution of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l- carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (4-fluorophenyl)methyl ester (0.500 g, 1.11 mmol) in 125 mL of CH2C12 was added ethereal HCI in portions until the solution turned cloudy. After the solvent was removed, the yellow residue was triturated with acetone to give 0.307 g (61.0%) of white powder: mp 179-185°C; IR (KBr) 3408, 3193, 2934, 1697,
1431, 1152 cm"1 ; !H NMR (400 MHz, CDCI3) δ 1.37-1.52 (m, IH, aliphatic
CH), 1.52-1.77 (m, 8H, aliphatic CH), 2.07-2.15 (m, IH, aliphatic CH), 2.26 (d, 7=14.65 Hz, IH, aliphatic CH), 2.40-2.54 (m, 2H, aliphatic CH), 2.58 (s, 3H, CCH3), 3.10-3.18 (m, 2Η, aliphatic CH), 3.34-3.48 (m, 2H, aliphatic CH),
5.28 (dd, 7=14.65, 12.45 Hz, 2H, OCH Ar), 6.78 (d, 7=14.65 Ηz, 1Η, ArH),
7.05 (t, 7=8.55 Ηz, 1Η, ArH), 7.14 (d, 7=8.79 Ηz, 1Η, ArH), 7.41 (t, 7=5.37 Ηz, 1Η, ArH), 8.58 (s, 1Η, OΗ), 12.52 (s, 1Η, NH); MS(APCI+): m/z 449.3 (MΗ+).
Anal. Calcd for C27H3oN2O3Fi Cli: C, 66.87; H, 6.23; N, 5.78; Cl, 7.31; F, 3.92.
Found: C, 66.37; H, 6.27; N, 5.69; Cl, 7.64; F, 4.02.
Example 82 Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-l,2-dimethyl-, (4-fluorophenyl)methyl ester
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (4-fluorophenyl)methyl ester (0.500 g, 1.11 mol) in 20 mL of DMF was added to NaH (60% dispersion in mineral oil, 0.049 g, 1.23 mmol, washed with hexanes) and was stirred at room temperature for 1 hour. Methyl iodide (0.076 mL, 1.23 mol) was added to the reaction mixture. The reaction was stirred for 2 hours, quenched with 15 mL of H2O and extracted with diethyl ether (5 χ50 mL). The organic layers were concentrated to afford a yellow solid which was triturated with acetone to give 0.274 g (52.7%) of white solid: mp 179-180°C; IR (KBr) 3466, 2932, 2854, 1673,
1482, 1 155 cm"1 ; 1H NMR (400 MHz, CDCI3) δ 1.06-1.21 (m, 3H, aliphatic
CH), 1.36-1.58 (m, 7H, aliphatic CH), 1.79 (d, 7=14.20 Hz, IH, aliphatic CH), 2.34 (d, 7=10.74 Hz, IH, aliphatic CH), 2.42-2.49 (m, 2H, aliphatic CH), 2.49 (s, 3H, CCH3), 2.64 (t, 7=10.74 Ηz, 1Η, aliphatic CΗ), 2.86 (t, 7=1 1.48 Ηz, 1Η, aliphatic CΗ), 3.10 (dd, 7=18.31, 6.84 Ηz, 1Η, aliphatic CΗ), 3.59 (s, 3Η, NCH3),
5.21 (dd, 7=29.05, 1 1.96 Ηz, 2Η, OCH2Ar), 6.64 (d, 7=8.79 Ηz, 1Η, ArH), 7.16-7.22 (m, 3H, ArH), 7.48 (t, 7=7.81 Ηz, 1Η, ArH); MS(APCI+): m/z 463.1
(MΗ+). Anal. Calcd for C28H31N2θ3Fι : C, 72.71; H, 6.76; N, 6.06. Found: C, 72.89; H, 6.72; N, 5.92.
Example 83 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -phenylpropyl ester
Step A: 5-Acetoxy-2-methyl-lH-indole-3-carboxylic acid 1-phenyl-propyl ester
This compound was made according to Procedure A. White solid, mp
144_145.5°C; MS(APCI-): m/z 350.1 (M-H).
Step B: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 1-phenyl-propyl ester
5-Acetoxy-2-methyl-lH-indole-3-carboxylic acid, 1-phenyl-propyl ester (1.36 g, 3.86 mmol) was mixed with 10 mL of methanol, NaOCH3 (0.834 g, 15.4 mmol) was then added. The resulting reaction mixture was stirred at reflux for 1 minute, then allowed to cool to ambient temperature. The reaction mixture was then mixed with 10 mL of water, the resulting reaction mixture was treated with 5% HCI until pH = 1 affording a white precipitate. The mixture was extracted with EtOAc (2 x 60 mL). The combined organic mixture was dried over
Na2SO4 and concentrated in vacuo to give a black thick oil which was further purified by chromatography using 10%> MeOH in HCCI3 as the eluant to give
1.13 g (98%>) of the desired product as a brown solid: H NMR (DMSO-dg) δ
0.917 (t, 7= 7.33 Hz, 3H, CHCH2CH3), 1.84-2.03 (m, 2Η, CHCH2CH3), 2.59 (s, 3H, ArCH3), 5.84 (t, 7= 5.68 Hz, 2H, CHCH2CH3), 6.59 (dd, 7= 8.61, 2.38 Hz,
IH, ArH), 7.12 (d, 7= 8.61 Hz, IH, ArH), 7.23-7.41 (m, 6H, ArH), 8.87 (s, IH, exchangeable proton), 1 1.6 (bs, IH, exchangeable proton).
Step C: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid, 1-phenyl-proρyl ester
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid, 1-phenyl-propyl ester
(1.07 g, 3.60 mmol) and aqueous Me2NH (40%, 0.99 mL, 7.92 mmol) were mixed with 2.4 mL of EtOH, the mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%), 0.35 g, 4.3 mmol) was added. The resulting reaction mixture was stirred at
50°C for 4 hours, then at ambient teperature for 12 hours. The raction mixture was diluted with EtOAc (30 mL), washed with water (2 x 30 mL), and dried over Na2Sθ4- Concentration in vacuo followed by chromatography using 100%
EtOAc, then 10% MeOH in HCCI3 as the eluants gave 0.50 g (38%) of pure titled compound as a yellow foam: mp 50-62°C (dec); MS(APCI+): m/z 367.2 (MH+). Step D: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -phenylpropyl ester
To a mixture of perchlorate salt (0.38 g, 1.6 mmol, Example 3, Step B) and 30 mL of ether was added 30 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solid had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 30 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 10 mL of dioxane, then indole mannich base (0.45 g, 1.2 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a thick oil. The crude product was further purified by chromatography (50%) EtOAc in hexanes) to 0.40 g (71%) of titled compound as a white foam: mp 90-115°C; MS(APCI+): m/z 459.3 (MH+).
Example 84 Quinolizinium, l,2,3,4,6,7,8,9-octahydro-l-[[5-hydroxy-2-methyl- 3-[(phenylmethoxy)carbonyl]-lH-indol-4-yl]methyl]-, chloride
To a solution of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l- carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, phenylmethyl ester (0.209 g, 0.485 mmol) in CH2CI2 was added etheral HCI. After stirring at ambient temperature for 1 minute, the reaction mixture was concentrated in vacuo. The residue was triturated with 2-butanone. Filtration followed by drying under vacuum gave 0.18 g (79%>) of the desired product as a white solid: MS(APCI+): m/z 431.3 (MH+). Anal. Calcd for C2 H3oN2O3-1.0 HC1-0.3H2O: C, 68.65; H,
6.74; N, 5.93; Cl, 7.50; H2O, 1.14. Found: C, 68.62; H, 6.80; N, 6.00; Cl, 7.54;
H2O, 0.93.
Example 85 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (4-nitrophenyl)methyl ester
Pyrrolo[3 ',2 ':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, phenylmethyl ester (0.149 g, 0.341 mmol) was dissolved in 15 mL of THF, to the solution was added NN- dimethylacetamide dimethyl acetal (0.5 mL), and Pd(OH)2/C (20%, 0.125 g). The resulting reaction solution was stirred at ambient temperature under hydrogen atmosphere until the benzyl ester was completely consumed. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo at ambient temperature and used in the next step without further purification.
To a solution of crude product of debenzylation reaction in DMF were added para-nitrobenzylbromide and DBU. The resulting reaction solution was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with 50 mL of EtOAc and washed successively with saturated aqueous ΝaHCθ3 (3 x
50 mL) and water (3 x 50 mL). After drying over Na2SO4, the solution was concentrated in vacuo and purified by chromatography twice using 10% MeOH in HCCL3 and 50%) EtOAc in hexanes to give 28 mg (17%>) of desired product as a yellow solid: mp 240-242°C; MS(APCI+): m/z 476.3 (MH+).
Example 86 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, anhydride with benzoic acid
Pyrrolo[3 ',2 ' :5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester (10.15 g, 23.58 mmol) was dissolved in 110 mL of THF, and the solution was transferred to a round bottom flask equipped with a stir bar and a three-way stopcock connected to a hydrogen balloon. To the solution was added triethylamine (3.287 mL, 23.58 mmol), followed by Pd(OH)2/C (20%, 2.7 g). The flask was purged with hydrogen gas several times. The resulting reaction solution was stirred at ambient temperature under hydrogen atmosphere until the benzyl ester was completely consumed (2 hours in this case). The catalyst was removed by filtration, and the filtrate was used in the next step.
To the filtrate was added benzoyl chloride (2.737 mL, 23.58 mmol). The resulting reaction solution was stirred at ambient temperature for 16 hours under nitrogen. White precipitate formed was removed by filtration. The filtrate was concentrated in vacuo affording thick oil; trituration with Et2O gave 9.18g (88% over two steps) the desired product as a white solid: mp 159-160°C; MS(APCI+): m/z 443.3 (MH+). General procedure Q: ester synthesis from the mixed anhydride
The mixed anhydride (1 eq.) was mixed with the corresponding alcohol (>2 eq.), the resulting slurry was heated at 120-150°C until a clear solution was obtained. After cooling down to ambient temperature, the solution was diluted with EtOAC, then mixed with aqueous NaHCO3 (saturated). The mixture was for
5 minutes. Two layers were separated, and the organic layer was washed with brine and water, then dried over MgSO4. Purification with flash chromatography or recrystalhzation gave the desired product.
Example 87 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (lR)-l-phenylethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lR)-l-phenylethyl ester was synthesized according to procedure Q from (R)-(+)-l-phenylethanol. The crude product was chromatographed on a preparative silica gel plate using 100% acetonitrile as eluant to give 25 mg of the desired product as a white solid: mp
100-112°C; MS(APCI+): m/z 445.3 (MH+).
Example 88 Pyuolo[3',2':5,6][l]benzopvrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1 -(4-fluorophenyl)ethyl ester was synthesized according to procedure Q from l-(para-fluorophenyl)ethanol. The crude product was chromatographed first on a silica gel column (30% of EtOAc in hexanes as eluant) then on a preparative silica gel plate (100% acetonitrile as eluant) to give 54.5 mg (37%) of the desired product as a yellow foam: mp
98-1 10°C; MS(APCI+): m/z 463.1 (MH+).
General procedure R: parallel synthesis of 6 esters from the mixed anhydride The mixed anhydride (1 eq.) and the corresponding alcohol (2 eq.) were mixed in a NWR 60826-202 tube. The tube was loosely capped and submerged in oil-bath at 120°C for 7 minutes. After cooling to ambient temperature, 10 mL of ether and 10 mL of saturated aqueous Νa2Sθ4 were added to the tube. The mixture was stirred for 1 minute, then the ether layer was transferred into a new tube with MgSO4- After 10 minutes, the MgSO4 was removed by filtration. The filtrate was blown down with a nitrogen stream and the residue was re-dissolved in 0.2 mL of ether and transferred onto a SPE cartridge containing 1 g of silica gel. The short column was eluded with 20 mL of a 10% of EtOAc in hexanes solution. The fractions collected contained mainly the corresponding alcohol and were dicarded. The column was then eluded with 5 mL of a 10% of EtOAc in hexanes solution. The fraction collected was concentrated down (blown down with a nitrogen stream) to give the crude product.
Example 89 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, phenyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenyl ester was synthesized according to procedure R from phenol. The crude product was not further purified: white solid; MS(APCI+): m/z 417.1 (MH+).
Example 90 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro- 1 -phenyl- 1 -(trill uoromefhyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 2,2,2-trifluoro-l-phenyl- l-(trifluoromethyl)ethyl ester was synthesized according to procedure R from l,l,l,3,3,3-hexfluoro-2-phenyl-2-propanol. The crude product was not further purified: white solid; MS(APCI-): m/z 565.1 (M-H).
Example 91 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, bicyclo[2.2.1]hept-2-yl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, bicyclo[2.2.1]hept-2-yl ester was synthesized according to procedure R from exo-norborneol. The crude product was not further purified: white solid; MS(APCI-): m/z 433.2 (M-H).
Example 92 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)- 1-methylethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)- 1 -methylethyl ester was synthesized according to procedure Q from 2-(4-fluorophenyl)-2-propanol. The crude product was chromatographed on a silica gel column (50-70%> of ether in hexanes as eluant) to give 0.15 g (9%) of the desired product as a white solid mp 110-112°C; MS(APCI+): m/z 411 (MH+).
Example 93 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-m ethyl-, 1 -phenylcyclopentyl ester
PyπOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7, 8,9, 10,12, 13, 14,14a,15-decahydro-2-methyl-, 1 -phenylcyclopentyl ester was synthesized according to procedure Q from 1 -phenyl- 1-cyclopentanol. The crude product was chromatographed on a silica gel column (50% of ether in hexanes as eluant) to give 0.15 g (6%) of the desired product as a white solid: mp 205-206°C;
MS(APCI+): m/z 483.1 (MH+).
Example 94 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-phenylcyclohexyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -phenylcyclohexyl ester was synthesized according to procedure Q from 1-phenylcyclohexanol. The crude product was chromatographed on a silica gel column (50-70% of ether in hexanes as eluant) to give 0.13 g (5%) of the desired product as a yellow solid: mp 217-219°C; MS(APCI-): m/z 497 (M-H).
Example 95 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-(hydroxymethyl)phenyl ester
PyπOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3, 7,8,9, 10,12,13, 14,14a,15-decahydro-2-methyl-, 3-(hydroxymethyl)phenyl ester was synthesized according to procedure Q from 3-hydroxybenzyl alcohol. The crude product was chromatographed on a silica gel column (50-100%) of EtOAc in hexanes as eluant) to give 0.196 g (16%>) of the desired product as a white foam: mp 138-140°C; MS(APCI+): m/z 447.2 (MH+).
Example 96 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (3-hydroxyphenyl)methyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13,14, 14a, 15-decahydro-2-methyl-, (3-hydroxyphenyl)methyl ester was synthesized according to procedure Q from 3-hydroxybenzyl alcohol. The crude product was chromatographed on a silica gel column (50-100%) of EtOAc in hexanes as eluant) to give 0.4818 g (39%) of the desired product as a white solid: mp 231-233°C; MS(APCI+): m/z 441 (MH+).
Example 97 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (1S)-1 -(4-pyridinyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzoρyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ( 1 S)- 1 -(4-pyridinyl)ethyl ester was synthesized according to procedure Q from (S)-(-)-l-(4-pyridyl)ethanol. The crude product was chromatographed on a silica gel column (100%) EtOAc as eluant) to give 0.09 g of the desired product as a yellow foam: mp 105-115°C;
MS(APCI+): m/z 447.2 (MH+).
Example 98 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [ό-(methoxycarbonyl)- 2-pyridinyl]methyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [6-(methoxycarbonyl)- 2-pyridinyl]methyl ester was synthesized according to procedure Q from 6-(hydroxymethyl)-picolinic acid ethyl ester. The EtOAc solution (40 mL) of the crude product was mixed with 40 mL of 0.5 N HCI solution in a separative funnel and shaken well, then the aqueous phase was basified with 2N NaOH solution to pH = 1 , shaken well. The two layers were then separated. The organic layer was dried over Na2SO4- Chromatography on a silica gel column (50-100% of EtOAc in hexanes as eluant) to give 0.87 g (53%) of the desired product as a white foam: mp 90-100°C; MS(APCI+): m/z 490 (MH+). Example 99 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 2-pyridinylmethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 2-pyridinylmethyl ester was synthesized according to procedure Q from 2-pyridylmethanol. The EtOAc solution (40 mL) of the crude product was mixed with 40 mL of 0.5N HCI solution in a separative funnel and shaken well, then the aqueous phase was basified with 2N NaOH solution to pH = 1, shaken well. The two layers were then separated. After this process was repeated for three times, the organic layer was separated and dried over Na2SO4- Chromatography on a silica gel column
(60-100% of EtOAc in hexanes as eluant) to give 1.39 g (72%) of the desired product as a white foam: mp 85-95°C; MS(APCI+): m/z 432.2 (MH+).
Example 100 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (6-carboxy-2-pyridinyl)methyl ester
To a solution of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3, 7,8, 9,10,12, 13,14,14a, 15-decahydro-2-methyl-, [6-(methoxycarbonyl)-2-pyridinyl]methyl ester (797.4 mg, 1.629 mmol) in MeOH (20 mL) was added IN NaOH (6.5 mL, 6.5 mmol). The resulting reaction mixture was refluxed for 15 minutes, then concentrated in vacuo. The residue was purified by chromatography (10-30%> MeOH in HCCI3 as eluant) to give 0.62 g of a mixture of free acid and the sodium salt. 0.5 g of the mixture was dissolved in MeOH/HCC13, then mixed with 0.64 mL of IN HCI. The mixture was concentrated in vacuo, the residue was purified by chromatography (10-30% MeOH in HCCI3 as eluant) followed by recrystalhzation from MeOH to give
0.25 g of the desired product as a white solid: MS(APCI-): m/z 414 (M-H).
Example 101 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (6-carboxy-2- pyridinyl)methyl 3,7,8,9,10,12,13, 14,14a,15-decahydro-2- methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylate (1 :1)
To a suspension of Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (6-carboxy-
2-pyridinyl)methyl ester (167.5 mg, 0.3522 mmol) in ethanol was added aqueous choline bicarbonate (5.66 M, 0.056 mL, 0.32 mmol). The resulting mixture was refluxed until a clear solution was obtained. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2 mL of ethanol and then diluted with 70 mL of ether. After cooling in an ice-bath, the precipitate was collected by filtration to give 0.15 g (74%) of the desired product as a yellow solid: mp 120-130°C; MS(APCI-): m/z 414 (M-H). Anal. Calcd for C2-7H28N3O5-l .OC5Hi4N2Oj -O.2C5H25N1O2-l .8H2O: C, 62.38; H, 7.71 ; N, 9.26. Found: C, 62.40; H, 7.58; N, 9.03. Example 102 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)- 3-pyridinyl]methyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)- 3-pyridinyl]methyl ester was synthesized according to procedure Q from 5-hydroxymethyl-nicotinic acid methyl ester. The EtOAc solution (40 mL) of the crude product was mixed with 40 mL of 0.5 N HCI solution in a separative funnel and shaken well, then the aqueous phase was basified with 2N NaOH solution to pH = 1, shaken well. The two layers were then separated. After this process was repeated twice, the organic layer was separated and dried over MgSO4-
Chromatography on a silica gel column (50-100%> of EtOAc in hexanes as eluant) followed by crystallization from ether gave 0.4254 g (25%>) of the desired product as a yellow solid: mp 195-197°C; MS(APCI+): m/z 490.1 (MH+).
Example 103 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (5-carboxy-3-pyridinyl)methyl ester
To a solution of Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)-3-pyridinyl]methyl ester (391.6 mg, 0.7999 mmol) in MeOH (30 mL) was added IN NaOH (3.2 mL, 3.2 mmol). The resulting reaction mixture was stirred at 50°C for 60 minutes. After cooling down to ambient temperature, 3.2 mL of IN aqueous HCI was added, then concentrated in vacuo. The residue was purified by chromatography (10-30%> MeOH in HCCI3 as eluant) followed by trituration with ether to give 0.25 g (67%>) of the desired product as a white solid: mp 224-227°C; MS(APCI-): m/z 414 (M-H).
Example 104 Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (5-carboxy- 3-pyridinyl)methyl 3,7,8,9,10,12,13, 14,14a,15-decahydro-
2-methylpyπOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylate (1 : 1)
^ OH
To a suspension of Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (5-carboxy- 3-pyridinyl)methyl ester (170.3 mg, 0.3580 mmol) in ethanol was added aqueous choline bicarbonate (5.66 M, 0.0569 mL, 0.322 mmol). The resulting mixture was refluxed until a clear solution was obtained. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2 mL of ethanol and then diluted with 70 mL of ether. After cooling in an ice-bath, the precipitate was collected by filtration to give 0.163 g (79%>) of the desired product as a beige solid: mp 147-152°C; MS(APCI-): m/z 474 (M-H). Anal. Calcd for 27H28N305-1-o 5H14Nl0l '0-28C4HιoO-1.2Siιθ2-1.4H2O: C, 57.09; H, 6.89; N, 8.04. Found: C, 57.09; H, 6.70; N, 7.77. Example 105 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(4'-methyl[ 1 , 1 '-biphenyl]- 3-yl)ethyl ester
Pyιτolo[3^2^5,6][l]benzopyrano[3,2-i]quinoliz"ine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-(4'-methyl[l,l '-biphenyl]- 3-yl)ethyl ester was synthesized according to procedure Q from l-(4'-methyl- biphenyl-3-yl)-ethanol. The crude product was chromatographed on a silica gel column (40% of EtOAc in hexanes as eluant) to give 0.67 g (36%.) of the desired product as a white foam: mp 105-1 15°C; MS(APCI+): m/z 535 (MH+).
Example 106 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(2,6-dimethylphenyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(2,6-dimethylphenyl)ethyl ester was synthesized according to procedure Q from l-(2,6-dimethyl-phenyl)- ethanol. The crude product was chromatographed on a silica gel column (30-50% of EtOAc in hexanes as eluant) to give 1.02 g of the desired product which was impure as a yellow foam: mp 100-105°C; MS(APCI+): m/z 473.3 (MH+).
Procedure S: procedure for the array synthesis:
The mixed anhydride (1 eq.) and the corresponding alcohol (2-4 eq.) were mixed in a VWR 60826-202 tube. The tube was loosely capped and submerged in oil-bath at 120°C until a clear solution was obtained (generally 5-7 minutes). After cooling to ambient temperature, 6 mL of EtOAc and 5 mL of saturated aqueous Na2SO4 were added to the tube. The mixture was shaken and stiπ-ed for 1 minute, then the organic layer was pipeted out and filtered through a pack of MgSO4
(packed in a syringe filter) followed by washing with 1 mL of EtOAc. The filtrate was collected in a 2-dram vial and sample was blown dry with a stream of nitrogen. The residue was chromatagraphed on a silica gel column using ISCO system to give the desired product.
The Example 107 through Example 142 were made following Procedure S in a parallel fashion:
Example 107 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ( 1 S,2R)-2-(dimethylamino)- 1 -phenylpropyl ester
MS(APCI+): m/z 502 (MH+). Example 108 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, ( 1 R,2S)-2-(dimethylamino)- 1 -phenylpropyl ester
MS(APCI+): m/z 502 (MH+).
Example 109 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 1-naphthalenyl ester
MS(APCI+): m/z 467 (MH+).
Example 110 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, diphenylmethyl ester
MS(APCI+): m/z 507 (MH+).
Example 111 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lR)-2,3-dihydro-lH-inden-l-yl ester
MS(APCI+): m/z 457 (MH+).
Example 112 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-m ethyl-, 1 ,2-dihydro- 1 -acenaphthylenyl ester
MS(APCI+): m/z 493 (MH+).
Example 113 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, cyclohexyl(phenyl)methyl ester
MS(APCI+): m/z 513 (MH+).
Example 1 14 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 9H-fluoren-9-yl ester
MS(APCI+): m/z 505 (MH+). Example 115 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,2,3,4-tetrahydro- 1 -naphthalenyl ester
MS(APCI+): m/z 471 (MH+).
Example 116 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [(2R,3R)- 3-phenyloxiranyl]methyl ester
MS(APCI+): m/z 473 (MH+).
Example 117 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-oxo- 1 ,2-diphenylethyl ester
MS(APCI+): m/z 535 (MH+).
Example 118 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 10,l l-dihydro-5H- dibenzo[a,d]cyclohepten-5-yl ester
MS(APCI+): m/z 533 (MH+).
Example 119 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (2-methylphenyl)phenylmethyl ester
MS(APCI+): m/z 521 (MH+).
Example 120 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, cyclopropyl(4-fluorophenyl)methyl ester
MS(APCI+): m/z 489 (MH+).
Example 121 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3,4-dihydro-2H- l-benzothiopyran-4-yl ester
MS(APCI+): m/z 489 (MH+).
Example 122 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (lS)-l-(2-bromophenyl)ethyl ester
MS(APCI+): m/z 524 (MH+).
Example 123 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 2,2,2-trifluoroethyl ester
MS(APCI+): m/z 423 (MH+).
Example 124 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [(2S,3S)- 3-phenyloxiranyl]methyl ester
MS(APCI+): m/z 475 (MH+).
Example 125 PyrroloP'^'^όJf lJbenzopyrano ^-ijquinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 2,2,2-trifluoro-l-methyl- l-(trifluoromethyl)ethyl ester
MS(APCI+): m/z 505 (MH+).
Example 126 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10,12,13, 14, 14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro- 1 -(4-fluorophenyl)- 1 -(trifluoromethyl)ethyl ester
MS(APCI+): m/z 585 (MH+).
Example 127 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12, 13, 14,14a,15-decahydro-2-methyl-, 1-cyclopentyl-l -phenylethyl ester
MS(APCI+): m/z 513 (MH+).
Example 128 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-[l,l '-biphenyl]-4-yl- 1 -methylethyl ester
MS(APCI+): m/z 535 (MH+).
Example 129 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12, 13, 14,14a,15-decahydro-2-methyl-, 1 -methyl- 1 -phenyl-2-propynyl ester
MS(APCI+): m/z 469 (MH+).
Example 130 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1,1-diphenylethyl ester
MS(APCI+): m/z 521 (MH+). Example 131 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -methyl- 1,2-diphenylethyl ester
MS(APCI+): m/z 535 (MH+).
Example 132 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -(4-fluorophenyl)cyclohexyl ester
MS(APCI+): m/z 517 (MH+).
Example 133 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a, 15-decahydro-2-m ethyl-, 1 ,2-diphenylethyl ester
MS(APCI+): m/z 521 (MH+).
Example 134 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, l-phenyl-2-propynyl ester
MS(APCI+): m/z 455 (MH+).
Example 135 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, [l,l'-biphenyl]-4-ylmethyl ester
MS(APCI+): m/z 507 (MH+). Example 136 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-pyridinylmethyl ester
MS(APCI+): m/z 432 (MH+).
Example 137 Pyrrolo[3,,2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1,2,3,4-tetrahydro- 7,8-dimethoxy-2-methyl-4-isoquinolinyl ester
MS(APCI+): m/z 546 (MH+).
Example 138 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, l-[3-(dimethylamino)phenyl] ethyl ester
MS(APCI+): m/z 488 (MH+).
Example 139 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 , 1 -dimethyl-2-pyrazinyl ethyl ester
MS(APCI+): m/z 475 (MH+).
Example 140 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 4-(dipropylamino)- l,l-dimethyl-2-butynyl ester
MS(APCI+): m/z 520 (MH+).
Example 141 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (l S)-2,3-dihydro-lH-inden-l-yl ester
MS(APCI+): m/z 457 (MH+).
Example 142 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (lS,2S)-2-(dimethylamino)- 1 -phenylpropyl ester
MS(APCI+): m/z 502 (MH+). Example 143 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [4-(trifluoromethyl)phenyl]methyl ester
Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-trifluoromethylbenzyl ester
To a mixture of 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (4.5 g, 23.54 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (3.58 g, 23.54 mmol) in
DMF (50 mL) was added 2'-bromo-2,2,2-trifluoro-p-xylene (6.2 g, 25.89 mmol). The mixture was stirred at room temperature for 2 days and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give a residue, which was recrystallized from ethyl acetate to give 4.26 g (52%) of the desired product as a white solid: mp 224-225°C; MS(APCI+): m/z 350.1 (MH+); Anal. Calcd for Cι8H14F3Nιθ3: C, 61.89; H, 4.04; N, 4.01. Found: C, 61.87; H, 4.00; N, 3.98.
Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-trifluoro-methylbenzyl ester
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-trifluoromethylbenzyl ester (3.0 g, 8.59 mmol) and aqueous dimethylamine (40%>, 2.37 mL, 18.9 mmol) were mixed with 6.7 mL of ethanol. The mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (31%, 0.83 g, 10.31 mmol) was added. The resulting reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated in vacuo to half volume to give a solid, which was filtered. The solid was washed with ethanol- water and dried in vacuo to give 1.8 g (52%) of pure titled compound as an off- white foam: MS(APCI+): m/z 407.2 (MH+).
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, [4-(trifluoromethyl)phenyl]methyl ester
To a mixture of perchlorate salt (1.37 g, 5.75 mmol, Example 3, step B) and 100 mL of ether was added 150 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Two layers were separated, and the aqueous layer was extracted with ether (2 x 50 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 25 mL of dioxane, then indole mannich base (1.8 g, 4.42 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a thick oil. The crude product was further purified by chromatography (10%-30%> ethyl acetate in hexanes) to give 1.21 g (55%>) of titled compound as a white foam: mp 97-99°C; MS(APCI+): m/z 499.2 (MH+); Anal. Calcd for C28H29F3N2O3: C, 67.46; H, 5.86; N, 5.62; F, 11.43. Found: C, 67.13; H, 5.86; N, 5.45; F, 11.32.
Example 144 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (4-chlorophenyl)methyl ester
Step A: 5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-chlorobenzyl ester
To a mixture of 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (5.0 g, 26.15 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (3.98 g, 26.15 mmol) in DMF (50 mL) was added 4-chlorobenzyl bromide (5.9 g, 28.77 mmol). The mixture was stirred at room temperature for 2 days and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give a residue, which was recrystallized from ethyl acetate to give 5.0 g (61%) of the desired product as an off-white solid: mp 236-237°C; MS(APCI-): m/z 314.1 (M-H). Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-chlorobenzyl ester
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 4-chlorobenzyl ester (4.0 g, 12.7 mmol) and aqueous dimethylamine (40%, 3.5 mL, 27.8 mmol) were mixed with 10.4 mL of ethanol. The mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%o, 1.24 g, 15.2 mmol) was added. The resulting reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated in vacuo to give a residue, which was chromatographed using 100%) ethyl acetate as eluant to give 2.3 g (49%>) of pure titled compound as an off-white foam: MS(APCI+): m/z 373.2 (MH+).
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (4-chlorophenyl)methyl ester
To a mixture of perchlorate salt (1.9 g, 8.02 mmol, Example 3, Step B) and 150 mL of ether was added 200 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Two layers were separated and the aqueous layer was extracted with ether (2 x 100 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 30 mL of dioxane, then indole mannich base (2.3 g, 6.17 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give a thick oil. The crude product was further purified by chromatography (20%-25%> ethyl acetate in hexanes) to give 1.7 g (59%>) of titled compound as a white solid: mp 220-221 °C; MS(APCI+): m/z 465.3 (MH+).
Example 145 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-, phenylmethyl ester
Step A: 5-Hydroxy-lH-indole-3-carboxylic acid benzyl ester
To a mixture of 5-hydroxy-lH-indole-3-carboxylic acid (4.5 g, 25.4 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (3.87 g, 25.4 mmol) in DMF (50 mL) was added benzyl bromide (4.78 g, 27.94 mmol). The mixture was stirred at room temperature for 2 days and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give a residue, which was recrystallized from ethyl acetate-hexanes to give 2.4 g (36%>) of the desired product as an off-white solid: mp 184-186°C; MS(APCI-): m/z 266.1 (M-H). Step B: 4-Dimethylaminomethyl-5-hydroxy-lH-indole-3-carboxylic acid benzyl ester
5-Hydroxy-lH-indole-3-carboxylic acid benzyl ester (2.3 g, 8.6 mmol) and aqueous dimethylamine (40%o, 2.37 mL, 18.9 mmol) were mixed with 6.67 mL of ethanol. The mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%, 0.84 g, 10.32 mmol) was added. The resulting reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated in vacuo to give a residue, which was chromatographed using 50%>-100% ethyl acetate in hexanes as eluant to give 2.16 g (77%) of pure titled compound as an off-white foam: MS(APCI+): m/z 325.3 (MH+).
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-, phenylmethyl ester
To a mixture of perchlorate salt (1.91 g, 8.02 mmol, Example 3, Step B) and 150 mL of ether was added 200 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Two layers were separated and the aqueous layer was extracted with ether (2 x 100 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 30 mL of dioxane, then indole mannich base (2.0 g, 6.17 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give a thick oil, which was recrystallized from acetonitrile to give 1.2 g (47%>) of titled compound as an off- white solid: mp 255-257°C; MS(APCI+): m/z 417.3 (MH+).
Example 146 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-, ethyl ester
Step A: 5-Hydroxy-lH-indole-3-carboxylic acid ethyl ester
To a mixture of 5-hydroxy-lH-indole-3-carboxylic acid (4.5 g, 25.4 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (3.87 g, 25.4 mmol) in DMF (50 mL) was added iodoethane (4.36 g, 27.94 mmol). The mixture was stirred at room temperature overnight and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give a residue, which was recrystallized from ethyl acetate-hexanes to give 2.2 g (42%o) of the desired product as a light brown solid:
MS(APCI+): m/z 206.2 (MH+).
Step B: 4-Dimethylaminomethyl-5-hydroxy-lH-indole-3-carboxylic acid ethyl ester
5-Hydroxy-lH-indole-3-carboxylic acid ehtyl ester (2.1 g, 10.23 mmol) and aqueous dimethylamine (40%, 2.83 mL, 22.51 mmol) were mixed with 7.7 mL of ethanol. The mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%, 0.99 g, 12.28 mmol) was added. The resulting reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated in vacuo to give a residue, which was chromatographed using 50%>-100%> ethyl acetate in hexanes as eluant to give 2.1 g (78%) of pure titled compound as a gum: MS(APCI+): m/z 263.1 (MH+).
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-, ethyl ester
To a mixture of perchlorate salt (2.36 g, 9.9 mmol, Example 3, Step B) and 150 mL of ether was added 250 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Two layers were separated and the aqueous layer was extracted with ether (2 x 100 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 30 mL of dioxane, then indole mannich base (2.0 g, 7.6 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours.
The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give a thick oil, which was recrystallized from acetonitrile to give 1.7 g (63%) of titled compound as an off-white solid: mp 242-244°C;
MS(APCI+): m/z 355.3 (MH+).
Example 147 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-hydroxyethyl ester
Step A: 5-Hydroxy-2-mefhyl-lH-indole-3-carboxylic acid hydroxyethyl ester
To a mixture of 5-hydroxy-2-mefhyl-lH-indole-3-carboxylic acid (5.0 g,
26.15 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (3.91 g, 26.15 mmol) in DMF (100 mL) was added 2-bromoethanol (3.6 g, 28.77 mmol). The mixture was stirred at room temperature for 7 days and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give a residue, which was choromatographed using 30%-100%> ethyl acetate in hexanes as eluant to give 2.4 g (39%) of the desired product as a gum: MS(APCI+): m/z 236 A (MH+).
Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid hydroxyethyl ester
5 -Hydroxy-2 -methyl- lH-indole-3 -carboxylic acid hydroxyethyl ester (2.3 g, 9.8 mmol) and aqueous dimethylamine (40%, 2.7 mL, 21.5 mmol) were mixed with 7.4 mL of ethanol. The mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%, 0.95 g, 11.7 mmol) was added. The resulting reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated in vacuo to give a residue, which was chromatographed using 100% ethyl acetate followed by 20% methanol in methylene chloride as eluant to give 2.0 g (70%) of pure titled compound as a gum: MS(APCI+): m/z 293.2 (MH+).
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-hydroxyethyl ester
To a mixture of perchlorate salt (2.1 g, 8.9 mmol, Example 3, step B) and 150 mL of ether was added 250 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Two layers were separated and the aqueous layer was extracted with ether (2 x 100 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 25 mL of dioxane, then indole mannich base (2.0 g, 6.84 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours.
The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give a residue as thick oil, which was recrystallized from acetonitrile to give 1.6 g (61%) of titled compound as a light brown solid: mp 221-223°C;
MS(APCI+): m/z 385.2 (MH+).
Example 148 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (3-methylphenyl)methyl ester
Step A: 5-Hydroxy-2-mefhyl-lH-indole-3-carboxylic acid 3-methylbenzyl ester
To a mixture of 5-hydroxy-2-methyl-lH-indole-3-carboxylic acid (4.0 g,
20.92 mmol) and l ,8-diazabicyclo[5.4.0]undec-7-ene (3.18 g, 20.92 mmol) in DMF (100 mL) was added -bromo-m-xylene (4.28 g, 23.1 mmol). The mixture was stirred at room temperature for 7 days and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give a residue, which was chromatographed using 20%>-50%) ethyl acetate in hexane as eluant to give 3.0 g (48%>) of the desired product as a tan solid: mp 165-167°C; MS(APCI+): m/z 296.2 (MH+).
Step B: 4-Dimethylaminomethyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methylbenzyl ester
5-Hydroxy-2-methyl-lH-indole-3-carboxylic acid 3-methylbenzyl ester (2.7 g, 9.14 mmol) and aqueous dimethylamine (40%>, 2.52 mL, 20.1 mmol) were mixed with 7.4 mL of ethanol. The mixture was heated with a heatgun until a clear solution was obtained. After cooled to ambient temperature, aqueous HCHO (37%o, 0.89 g, 10.97 mmol) was added. The resulting reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated in vacuo to give a residue, which was chromatographed using 50%)-100%> ethyl acetate in hexanes as eluant to give 2.0 g (62%>) of pure titled compound as a gum: MS(APCI+): m/z 353.3 (MH+).
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (3-methylphenyl)methyl ester
To a mixture of perchlorate salt (1.75 g, 7.38 mmol, Example 3, step B) and 100 mL of ether was added 150 mL of aqueous NaOH (2N). The resulting mixture was shaken in a separatory funnel until all solids had dissolved. Two layers were separated and the aqueous layer was extracted with ether (2 x 50 mL). Combined ether layer was dried over Na2SO4 and concentrated in vacuo. The residual oil was dissolved in 25 mL of dioxane, then indole mannich base (2.0 g, 5.67 mmol) was added, the resulting reaction mixture was refluxed under nitrogen for 6 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo affording a thick oil. The crude product was further purified by chromatography (10%>-25% ethyl acetate in hexanes) to give 1.8 g (55%) of titled compound as a white solid: mp 80-82°C; MS(APCI+): m/z 445.4 (MH+).
Example 149 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lS)-l-phenylethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lS)-l-ρhenylethyl ester was synthesized according to procedure Q from (S)-(-)-l-phenylethanol. The crude product was chromatographed using 30% ethyl acetate in hexanes as eluant to give 75 mg of the desired product as a white solid: mp 98-100°C; MS(APCI+): m/z 445.2 (MH+).
Example 150 Pyrrolo[3',2':5,6][l]benzoρyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -phenylethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-m ethyl-, 1 -phenylethyl ester was synthesized according to procedure Q froml-phenylethanol. The crude product was chromatographed using 40%> ether in hexanes followed by 50%> ethyl acetate in hexanes as eluant to give 480 mg of the desired product as a white solid: mp
89-90°C; MS(APCI+): m/z 445.2 (MH+).
Example 151 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carbothioic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, S-(phenylmethyl) ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carbothioic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, S-(ρhenylmethyl) ester was synthesized according to procedure Q from benzyl mercaptan. The crude product was chromatographed using 50% ether in hexanes as eluant to give 150 mg of the desired product as a white solid: MS(APCI+): m/z 441 (MH+).
Example 152 PynOlo^2^5,6][l]benzopyrano[3,2-i]quinohzine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2 -methyl-, 3-pyridinylmethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12, 13, 14,14a,15-decahydro-2-methyl-, 3-pyridinylmethyl ester was synthesized according to procedure Q from 3-pyridylcarbinol. The crude product was chromatographed using 50% ethyl acetate in hexanes followed by 10%> methanol in ethyl acetate as eluant to give 400 mg of the desired product as a white solid: MS(APCI-): m/z 430.1 (M-H).
Example 153 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1 -[4-(trifluoromefhyl)phenyl]ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -[4-(trifluoromethyl)phenyl]- ethyl ester was synthesized according to procedure Q from 4-trifluoro-α- methylbenzyl alcohol. The crude product was chromatographed using 40%-50% ether in hexanes as eluant to give 180 mg of the desired product as a white solid: mp 104-106°C; MS(APCI-): m/z 511.1 (M-H).
Example 154 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -(pentafluorophenyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 1 -(pentafluorophenyl)ethyl ester was synthesized according to procedure Q from pentafluoro-α-methylbenzyl alcohol. The crude product was chromatographed using 40% ether in hexanes as eluant to give 160 mg of the desired product as a white solid: mp 93-95°C;
MS(APCI+): m/z 535.1 (MH+).
Example 155 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(2,6-difluorophenyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -(2,6-difluorophenyl)ethyl ester was synthesized according to procedure Q from 2,6-difluoro- -methylbenzyl alcohol. The crude product was chromatographed using 40% ether in hexanes as eluant to give 180 mg of the desired product as a white solid: mp 85-87°C;
MS(APCI+): m/z 481.1 (MH+). Example 156 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (1S)-1 -(2-furanyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (1S)-1 -(2-furanyl)ethyl ester was synthesized according to procedure Q from S(-)-l-(2-furyl)ethanol. The crude product was chromatographed using 40%)-60%> ether in hexanes as eluant to give 300 mg of the desired product as a white solid: mp 84-86°C; MS(APCI+): m/z 435.1 (MH+).
Example 157 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-(4-morpholinyl)- 1 -phenylethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-(4-morpholinyl)- 1 -phenylethyl ester was synthesized according to procedure Q from -phenyl- 4-morpholineethanol. The crude product was chromatographed using 40%-60%> ether in hexanes as eluant to give 130 mg of the desired product as a white solid: mp 251-252°C; MS(APCI-): m/z 528.2 (M-H).
Example 158 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lR)-l-(2-furanyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ( 1 R)- 1 -(2-furanyl)ethyl ester was synthesized according to procedure Q from R(+)-l-(2-furyl)ethanol. The caide product was chromatographed using 40%-60% ether in hexanes as eluant to give 300 mg of the desired product as a white solid: mp 79-81°C; MS(APCI+): m/z 435.1 (MH+).
Example 159 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-m ethyl-, 2-methoxy-2-oxo- 1 -phenylethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-methoxy-2-oxo- 1 -phenylethyl ester was synthesized according to procedure Q from (S)-(+)-methyl mandelate. The crude product was chromatographed using 40%>-60% ether in hexanes as eluant to give 309 mg of the desired product as a white solid: mp 103-105°C;
MS(APCI+): m/z 489.2 (MH+).
Example 160 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-(3-pyridinyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(3-pyridinyl)ethyl ester was synthesized according to procedure Q from l-(3-pyridyl)ethanol. The crude product was chromatographed using 50%o ether in hexanes followed by 10% methanol in methylene chloride as eluant to give 300 mg of the desired product as a white solid: mp 78-80°C; MS(APCI+): m/z 446.2 (MH+).
Example 161 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, (S)-carboxy(phenyl)methyl ester
To a solution of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-methoxy- 2-oxo-l -phenylethyl ester (650 mg, 1.33 mmol) in methanol (60 mL) was added IN NaOH solution (5.32 mL, 5.32 mmol). The resulting reaction mixture was stirred at 50°C for 1 hour, then concentrated in vacuo. The residue was purified by chromatography (10-30%> methanol in chloroform as eluant) to give 0.58 g of a mixture of free acid and the sodium salt. All of the mixture (0.58g) was dissolved in methanol-chloroform, then mixed with 0.53 mL of IN HCI. The mixture was concentrated in vacuo, the residue was purified by chromatography (10-30% methanol in chloroform as eluant) followed by recrystalhzation from methanol to give 0.35 g of the desired product as a white solid: mp 250-251°C; MS(APCI-): m/z 413 (M-H), Anal. Calcd for C28H3oN2θ5-0.36H2O: C, 69.91 ; H, 6.44; N, 5.82. Found: C, 69.96; H, 6.33; N, 5.59.
Example 162
Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (S)- carboxy(phenyl)methyl, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro- 2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylate (1:1)
To a suspension of pynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (S)-carboxy(phenyl)methyl ester (181 mg, 0.38 mmol) in ethanol (5 mL) was added aqueous choline bicarbonate (5.66 M, 0.06 mL, 0.34 mmol). The resulting mixture was refluxed until a clear solution was obtained. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2 mL of ethanol and then diluted with 70 mL of ether. After cooling in an ice-bath, the precipitate was collected by filtration to give 0.17 g (11%) of the desired product as an off-white solid: mp 223-225°C; MS(APCI+): m/z 475.2 (MH+). Anal. Calcd for C28H29N2°5' 5Hi4NO-1.2H2O: C, 66.13; H, 7.64; N, 7.01. Found: C, 65.96;
H, 7.56; N, 6.78.
Example 163 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (lR)-2-methoxy-2-oxo- 1 -phenylethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (lR)-2-methoxy-2-oxo- 1 -phenylethyl ester was synthesized according to procedure Q from (R)-(-)-methyl mandelate. The crude product was chromatographed using 40%-60% ether in hexanes as eluant to give 750 mg of the desired product as a white solid: mp
106-108°C; MS(APCI+): m/z 489.2 (MH+). Example 164
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-mefhyl-, (R)-carboxy(phenyl)methyl ester
To a solution of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1R)- 2-methoxy-2-oxo-l -phenylethyl ester (670 mg, 1.37 mmol) in methanol (60 mL) was added IN NaOH (5.5 mL, 5.5 mmol). The resulting reaction mixture was stirred at 50°C for 1 hour and IN HCI (5.5 mL) was added. The mixture was concentrated in vacuo to give a residue, which was purified by chromatography (10-30%) methanol in chlorofoπn as eluant) followed by recrystalhzation from methanol to give 0.35 g of the desired product as a white solid: mp 248-250°C; MS(APCI-): m/z 413 (M-H).
Example 165
Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (R)- carboxy(phenyl)methyl, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro- 2-methylpyπOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylate (1 :1)
To a suspension of pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (R)- carboxy(phenyl)methyl ester (210 mg, 0.44 mmol) in ethanol (5 mL) was added aqueous choline bicarbonate (5.66 M, 0.07 mL, 0.40 mmol). The resulting mixture was refluxed until a clear solution was obtained. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 2 mL of ethanol and then diluted with 70 mL of ether. After cooling in an ice-bath, the precipitate was collected by filtration to give 0.2 g (78%) of the desired product as an off-white solid: mp 215-217°C; MS(APCI+): m/z 475.2 (MH+). Anal. Calcd for C28H29N2°5'c5H14NO'1-8H20: C, 64.96; H, 7.7.70; N, 6.89. Found: C, 65.04; H, 7.59; N, 6.55.
Example 166 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 4-pyridinylmethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3, 7,8, 9,10,12,13, 14, 14a,15-decahydro-2-methyl-, 4-pyridinylmethyl ester was synthesized according to procedure Q from 4-pyridylcarbinol. The crude product was chromatographed using 50% ethyl acetate in hexanes followed by 100% ethyl acetate as eluant to give 260 mg of the desired product as a white solid: mp
199-201 °C; MS(APCI+): m/z 432.5 (MH+).
Example 167 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10,12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(4-pyridinyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -(4-pyridinyl)ethyl ester was synthesized according to procedure Q from l-(4-pyridyl)ethanol. The crude product was chromatographed using 50% ethyl acetate in hexanes followed by 100% ethyl acetate as eluant to give 210 mg of the desired product as a white solid: mp 219-22TC; MS(APCI+): m/z 446.2 (MH+).
Example 168 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(2-pyridinyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3, 7,8,9,10,12, 13, 14,14a,15-decahydro-2-methyl-, l-(2-pyridinyl)ethyl ester was synthesized according to procedure Q from l-(2-pyridyl)ethanol. The crude product was chromatographed using 50%o-75%> ethyl acetate in hexanes as eluant to give 200 mg of the desired product as a white solid: mp 87-89°C; MS(APCI+): m/z 446.2 (MH+). Example 169 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-thienylmethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 3-thienylmethyl ester was synthesized according to procedure Q from 3-thiophenemethanol. The crude product was chromatographed using 50% ether in hexanes as eluant to give
330 mg of the desired product as a white solid: mp 1 15-116°C; MS(APCI+): m/z
437.5 (MH+).
Example 170 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, (1S)-1 -(4-fluorophenyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (1S)-1 -(4-fluorophenyl)ethyl ester was synthesized according to procedure Q from S(-)-l-(4- florophenyl)ethanol. The crude product was chromatographed using 30%-50%> ether in hexanes as eluant to give 300 mg of the desired product as a white solid: mp 108-110°C; MS(APCI+): m/z 463.3 (MH+). Example 171 Pyιτolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ( 1 R)- 1 -(4-fluorophenyl)efhyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, ( 1 R)- 1 -(4-fluorophenyl)ethyl ester was synthesized according to procedure Q from R(+)-l-(4- florophenyl)ethanol. The crude product was chromatographed using 30%-50% ether in hexanes as eluant to give 300 mg of the desired product as a white solid:
MS(APCI+): m/z 463.3 (MH+).
Example 172 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 3-pyridinylmethyl ester
PyπOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 3-pyridinylmethyl ester was synthesized according to procedure Q from 3-pyridylcarbinol. The crude product was chromatographed (1 :1 hexane/EtOAc) to give 1.43g (49.4%) of desired product as a solid: mp 73-80°C; MS(APCI +): m/z 432.6 (MH+). Example 173 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 2-ethoxy-2-oxoethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-m ethyl-, 2-ethoxy-2-oxoethyl ester was synthesized according to procedure Q from ethyl glycolate. The crude product was chromatographed (1 :1 hexane/EtOAc) to give 0.5287g (36.8%)) of desired product as a solid: mp 60-70°C; MS(APCI +): m/z 427.2 (MH+).
Example 174 Pyridinium, 3-[[[(3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2- methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin-l- yl)carbonyl]oxy]methyl]-l -methyl-, methanesulfonate
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3, 7, 8,9,10,12, 13, 14,14a,15-decahydro-2-mefhyl-, 3-pyridinylmethyl ester (1 eq) and methyl methanesulfonate (4 eq) was mixed together in 1,2 dichloroethane and refluxed at 88°C for 30 minutes. After cooling down to ambient temperature the precipitate was isolated by suction filtration and washed with ether to give 86mg (41.2%) of pure desired product as crystals: mp 228-232°C; MS(APCI +): m/z 446.2 (M+). Some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with the ring nitrogen atom at N-l 1. Further, some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with nitrogen atoms optionally present in RJ Q- These structural forms are within the scope of the present invention.
Example 175 Pyrrolo[3',2':5,6][l]benzoρyrano[3,2-i]quinolizinium, 3,7,8,9,10,12,13, 14,14a,15- decahydro-2, 11 -dimethyl- l-[(S)-(l-phenylethoxy)carbonyl]-, methanesulfonate
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (1S)-1 -phenylethyl ester (0.6 g, 1.349 mmol) and methyl methanesulfonate (1.089 g, 10.7964 mmol) were mixed together in 1,2 dichloroethane (8ml) and refluxed at 88°C for 18 hours. The reaction mixture was concentrated in vacuo. The crude product was chromatographed (2:10 MeOH/CH2Cl2) to give 0.41 g (61.5%) of desired product as a solid: mp 160-170°C;
MS(APCI +): m/z 459.3 (M+).
Some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with the ring nitrogen atom at N-l 1. Further, some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with nitrogen atoms optionally present in RI Q. These structural forms are within the scope of the present invention. Example 176 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-furanylmethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 3-furanylmethyl ester was synthesized according to procedure Q from furan-3-yl-methanol. The crude product was chromatographed (1 :1 hexane/EtOAc) to give 0.40 g (42.4%>) of desired product as a solid: mp 174-177°C; MS(APCI +): m/z 421.4 (MH+).
Example 177 Pyιrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizme-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (2-nitrophenyl)methyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, (2-nitrophenyl)methyl ester was synthesized according to procedure Q from 2-nitrobenzylalcohol. The crude product was chromatographed (1:1 hexane/EtOAc) to give 0.39 g (35.9%) of desired product: mp 200-203°C; MS(APCI +): m/z 476.5 (MH+). Example 178 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-furanylmethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3, 7,8,9, 10,12,13, 14,14a,15-decahydro-2-methyl-, 2-furanylmethyl ester was synthesized according to procedure Q from furan-2-yl-methanol. The crude product was chromatographed (1 :1 hexane/EtOAc) to give 0.24 g (24.8%) of desired product as a solid: mp 65-77°C; MS(APCI +): m/z 421.4 (MH+).
Example 179 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-(2-chlorophenyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(2-chloroρhenyl)ethyl ester was synthesized according to procedure Q from l-(2-chlorophenyl) ethanol. The crude product was chromatographed (1 :1 hexane/ether) to give 80 mg (5.0%) of desired product as a solid: mp 95-105°C; MS(APCI +): m/z 479.2 (MH+). Example 180 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, carboxymethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-ethoxy-2-oxoethyl ester (0.47 g, 0.96 mmol) was mixed with IN NaOH (5.73 mmol, 5.73 mL) in MeOH and kept it in a oil bath at 50°C for 3 hours. Then the reaction mixture was cooled to ambient temperature followed by addition of IN HCI to neutralize. The reaction mixture was concentrated in vacuo, and the crude product was chromatographed (initially 1 :1 hexane/ether, then 10% MeOH in CHCI3) to give 0.374g of crude solid. The crude solid was redissolved in CHCI3 and filtered to get 78 mg (20.6%.) of desired product as a solid: MS(APCI +): mp 260°C; m/z 399.1 (MH+).
Example 181 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-(2,6-dichlorophenyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(2,6-dichlorophenyl)ethyl ester was synthesized according to procedure Q from l-(2,2-dichloro phenyl) ethanol. The crude product was chromatographed (1 :1 hexane/ether) to give
93 mg (5.30%) of desired product as a solid: mp 130-135°C; MS(APCI +): m/z
513.1 (M+).
Example 182 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2 -methyl-, 1 -(2-methoxyphenyl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(2-methoxyphenyl)ethyl ester was synthesized according to procedure Q from l-(2-methoxyphenyl) ethanol.
The crude product was chromatographed (1 :1 hexane/ether) to give 0.90 g (42%>) of desired product as a solid; mp 1 15-125°C; MS(APCI +): m/z 475.2 (MH+).
Example 183 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (lS)-l-ρhenylethyl ester, 1 1 -oxide
Pyιrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (1S)-1 -phenylethyl ester (0.3 g) was mixed with 50%> H2O2 in MeOH and the mixture was stirred at room temperature for 3 hours. Then excess H2O2 was destroyed using Pd/C. The reaction solution was filtered and concentrated in vacuo. The crude product was chromatographed (10%> MeOH in CH2CI2) to give 52 mg (48.2%) of pure desired product as a solid: mp 180-190°C; MS(APCI +): m/z 461.2 (MH+).
Some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with the ring nitrogen atom at N-l 1. Further, some of the compounds of ring close Formula I are capable of further forming N-oxides and N-quaternary alkyl salts with nitrogen atoms optionally present in RI Q- These structural forms are within the scope of the present invention.
Example 184 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, 1 -(5-carboxy-3-pyridinyl)ethyl ester
Step A: l-(5-Bromo-pyridin-3-yl)-ethanone
3-(5-Bromo-pyridin-3-yl)-3-oxo-propionic acid methyl ester (8.75 g, 30 mmol) was mixed with 2N H2SO4 and the mixture was refluxed for 24 hours.
The reaction solution was then neutralized with solid NaHCO3 and extracted with ether. The organic phase was dried and ether was evaporated to give 6.06 g
(89.5%) of the pure desired product as crystals: MS(APCI +): m/z 201 (MH+). Step B: l-(5-Bromo-pyridin-3-yl)-ethanol
Compound l-(5-bromo-pyridin-3-yl)-ethanone (5.85 g, 29.2 mmol) was dissolved in MeOH (100 mL) and NaBH4 (1.104 g, 29.19 mmol) was added slowly. The reaction was monitored by TLC. When the starting material was completely consumed mixture was neutralized by NaHCO3 solution and extracted with ether to give the crude product. Crude product was mixed with 1 : 1 hexane/ ethyl acetate and filtered. The filtrate was concentrated to give the pure desired product. MS(APCI +): m/z 203 (MH+).
Step C: 5-(l-Hydroxy-ethyl)-nicotinic acid methyl ester l-(5-Bromo-pyridin-3-yl)-ethanol (6.0 g), Palladium acetate (0.14 g),
DPPP (0.28 g), Triethylamine(6 mL), DMSO (60 mL), and MeOH (60 mL) were mixed together and the reaction mixture was stirred at 100-1 10°C for 18 hours. End of the reaction mixture was filtered to remove the solids and the filtrate was concentrated under vacuum. The residue was triturated with EtOAc and filtered, the filtrate and the solid were collected. The solid was dissolved in NaHCO3 and extracted with EtOAc. The extracts and the filtrate were combined together and dried over Na2SO4- Concentration in vacuo gave the crude product which was chromatographed with 1 :1 hexane/EtOAc to give 3.32 g (61.8%) of the pure desired product: MS(APCI+): m/z 182 (MH+).
Step D: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid,
3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-[5-(methoxycarbonyl)-3-pyridinyl]ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-t]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-[5-(methoxycarbonyl)- 3-pyridinyl]ethyl ester was synthesized according to procedure Q from 5-(l-hydroxy-ethyl)-nicotinic acid methyl ester. The crude product was chromatographed (1 :1 hexane/EtOAc) to give 0.81 g (37%) of desired product as a solid: MS(APCI +): m/z 504.3 (MH+).
Step E: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(5-carboxy- 3-pyridinyl)ethyl ester Example 184, Step D, pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-
1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-[5-(methoxycarbonyl)-3-pyridinyl]ethyl ester (0.2202 g, 0.4378 mmol) was mixed with IN NaOH (1.75 mmol, 1.75 mL) in MeOH (10 mL). The reaction flask was kept in an oil bath at 50°C for 1 hour. Then the reaction mixture was cooled to ambient temperature followed by addition of IN HCI (2 mL) to neutralize the reaction mixture. Mixture was concentrated in vacuo to give the crude product which was chromatographed (20:10, MeOH/CH2Cl2) to give
0.2665 g (100%) of the desired product as a solid: MS(APCI +): m/z 490.2 (MH+).
Example 185
1 ,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2- methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin-l-yl)carbonyl]oxy]- methyl]-, diethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3, 7,8,9,10,12, 13, 14,14a,15-decahydro-2-methyl-, anhydride with benzoic acid (Example 86) (0.502 g, 1.13 mmol) is combined with diethyl-5- (hydroxymethyl)isophthalate (0.859 g, 3.40 mmol) and placed in a 150°C oil bath for 6 minutes. The reaction is allowed to cool to room temperature, diluted with EtOAc and saturated NaHCO3 ancl stirred until all residue is dissolved. The layers are separated and the organic layer is washed with water and brine, dried (MgSO4) and evaporated. The product is purified by column chromatography eluting with a gradient of ether/hexanes (30% yield). H NMR (CDC13,
300 MHz): δ 8.64 (s, IH), 8.31 (s, 2H), 8.11 (s, IH), 7.03 (d, IH) 6.76 (d, IH),
5.40 (d, 2H), 4.44 (q, 4H), 3.38-3.44 (dd, IH), 3.04 (m, IH), 2.76-2.82 (m, 2H),
2.61 (s, 3H), 2.44-2.56 (m, 2H), 1.40 (t, 6H), 1.23-1.78 (m, 1 IH).
MS (APCI, m/z, M+l): 575.2
C33H38N2O7-0.67 H2O. Calcd: C, 67.50; H, 6.70; N, 4.77. Found: C, 67.19; H
6.54; N, 4.37.
Example 186 1 ,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro- 2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin- 1 -yl)carbonyl]oxy]methyl]-
1 ,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15- decahydro-2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin- l-yl)carbonyl]oxy]methyl]-, diethyl ester (0.4787 g, 0.83 mmol) in 10 mL THF, 2 mL MeOH and 0.83 mL (1.66 mmol) of 2 M NaOH were combined and heated to 50-60°C. Two 0.83 mL portions of 2 M NaOH were added until reaction complete by MS. The reaction was cooled to room temperature and washed with Et2O. The aqueous layer was neutralized and concentrated. The residue was dissolved in hot MeOH and filtered to remove NaCl. The filtrate was concentrated and dissolved in MeOH at room temperature and again filtered. The filtrate was dried over MgSO4, filtered and concentrated. The product was lyophilized to give
362.2 mg (83%). LCMS: 88.17%
Example 187 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (2-chloro-5-nitrophenyl)methyl ester
Step A: 2-Chloro-5-nitrobenzyl alcohol
An oven dried 3 neck flask, fitted with 2 septa and a reflux condenser is charged with 2-chloro-5-nitrobenzoic acid (5.53 g, 27.43 mmol), 14 mL THF and BF3-OEt2 (3.5 mL, 27.62 mmol) is added dropwise. The solution is heated to reflux for 2 hours at which point borane methyl sulfide complex (2M/THF, 18 mL, 36 mmol) is added dropwise over 30 minutes. The refluxing is continued for another 2 hours until the reaction is complete by TLC. The reaction is cooled to room temperature and 4 mL 1:1 THF/H2O is slowly added followed by
20.5 mL 5 M NaOH. The reaction is heated to reflux for 16 hours and filtered through a coarse sintered glass funnel while hot, washing solids with THF (2x). The filtrate is dried (MgSO4), filtered, concentrated and purified by column chromatography eluting with a EtOAc/hexane gradient. The product is triturated with hexanes and filtered to obtain the product in 79% yield. *H NMR (CDCI3, 300 MHz): δ 8.45 (d, IH). 8.11 (dd, IH), 7.52 (d, IH), 8.86 (d, 2H), 2.18 (t, IH) MS (APCL AP-) 186.9 Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (2-chloro-
5-nitrophenyl)methyl ester 2-Chloro-5-nitrobenzyl alcohol (1.0879 g, 5.80 mmol) and pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2 -methyl-, anhydride with benzoic acid (Example 86) (0.512 g, 1.15 mmol) are combined and placed in a 150°C oil bath for 6 minutes. The reaction is cooled to ambient temperature and diluted with EtOAc. The mixture is washed with saturated NaHCO3, water and brine, dried
(MgSO4), filtered, concentrated and purified by column chromatography eluting with a gradient of EtOAc/hexanes to obtain the product in 57% yield. 1H NMR (DMSO, 300 MHz): δ 11.65 (s, IH), 8.39 (s, IH), 8.24 (dd, IH), 7.85 (d, IH), 7.07 (d, IH), 6.63 (d, IH), 5.42 (d, 2H), 3.23 (m, IH), 2.8-3.0 (m, IH), 2.60-2.70 (m, 2H), 2.30-2.60 (m, 3H), 2.37 (s, 3H), 1.82-1.87 (m, IH), 1.0-1.75 (m, 11H)
MS (APCI, AP+): 510.1 LCMS: 98.23 % retention time: 7.627 minutes
Example 188 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (5-amino- 2-chlorophenyl)methyl ester
Step A: 5-Amino-2-chlorobenzoic acid
Raney-Nickel (3 gm) was added to a methanolic solution of 5-nitro- 2-chlorobenzoic acid (10 gm,150 mL), this mixture was then connected to a H2 source, after 4 hours, the reaction was completed by TLC (30% MeOH/CH2Cl2). The catalyst was removed by filtration and the filtrate was evaporated to dryness, collected 8 g of product and it was used in the next step without further purification. MS (APCI, AP+): 172.0
Step B: 5-Amino-2-chlorobenzyl alcohol An oven dried two neck flask fitted with a septum and a reflux condenser is charged with 5-amino-2-chlorobenzoic acid (2.611 g, 15.22 mmol) and 7.5 mL THF. BF3OEt2 is added dropwise and the reaction is heated to reflux for 2 hours. Borane methyl sulfide complex (2M/THF, 10 mL, 20 mmol) is added dropwise. The reaction is refluxed for 3 hours, and an additional 3.8 mL of borane methyl sulfide complex (7.2 mmol) is added. The refluxing is continued for 1 hour, cooled to ambient temperature and 3 mL 1 :1 THF/H2O is added slowly, followed by 11.2 mL 5 M NaOH. The reaction is heated to reflux for 16 hours and filtered hot through a coarse sintered glass funnel, rinsing the solids with THF (2χ). The filtrate is concentrated and the residue partitioned between CH2CI2/H2O. The product is extracted three times into CH2CI2. The tan solid in the organic layer is collected by filtration and dried in a 40°C vacuum oven overnight to give 0.6374 g of product. The organic filtrate is dried (MgSO4), filtered, concentrated and purified by column chromatography eluting with a MeOH/CH2θ2 gradient to give 0.56 g of product. ]H NMR (DMSO, 300 MHz): δ 6.93 (d, IH), 6.75 (d, IH), 6.39 (dd, IH), 5.16 (s, 2H), 4.38 (d, 2H).
MS (APCI, AP+): 158.0
Step C: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (5-amino- 2-chlorophenyl)methyl ester 5-Amino-2-chlorobenzyl alcohol (1.055 g, 6.70 mmol) and pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14, 14a,15-decahydro-2-methyl-, anhydride with benzoic acid (Example 86) (0.7023 g, 1.58 mmol) are combined and placed in a 150°C oil bath for 6 minutes. The reaction is cooled, diluted with EtOAc and saturated NaHCO3 and stirred until all residue is dissolved. The organic layer is washed with water and brine, dried (MgSO4), filtered and concentrated. The product is purified by column chromatography eluting with 5%> MeOH/CH2Cl2. The product is placed under high vacuum for two days to yield 0.260 g (34%>) of a light pink solid. ΪH NMR (DMSO, 300 MHz): δ 11.16 (s, IH), 10.13 (s, IH), 8.02 (d, IH), 7.60 (dd, IH), 7.29 (d, IH), 7.05 (d, IH), 6.60 (d, IH), 5.37 (t, IH), 4.51 (d, 2H), 3.14-3.18
(m, IH), 2.90-3.00 (m, IH), 2.65-2.72 (m, IH), 2.30-3.20 (m, 3H), 2.39 (s, 3H), 1.10-1.75 (m, 11H).
MS (APCI, AP+): 480.1 LCMS: 91.44% retention time: 4.623 minutes
Example 189 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -acetic acid,
3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-.alpha.-oxo-, ethyl ester
2-Methyl-pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine (0.296 gm, 1 mm) and ethyl oxylate (0.123 mL, 1.1 mm) were mixed in 20 mL of THF and this mixture was stirred at ambient temperature for 48 hours. THF was evaporated and residue was redissolved in EtOAc, the organic layer was washed with bicarbonate, brine, and evaporated to dryness. The pure product was isolated by column chromatography eluted with hexanes/EtOAc = 1:1 (50 mg, 12.4%)
MS (APCI, AP+): 397.1. *H NMR (CDCI3, 300 MHz): δ 8.3 (s, NH), 7.05 (d, IH), 6.8 (d, IH), 4.4 (q, 2H), 2.4-3.6 (m, 6H), 2.75 (s, 3H), 1.22-2.15 (m, 1 IH),
1.4 (t, 3H), C23H28N2O4-l/3 H2O. Calc'd: C, 68.69; H, 7.19; N, 6.96. Found: C,
68.85; H 6.98; N, 6.51. MP: 200°C Example 190 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,4,5-trimethyl-, phenylmethyl ester
Step A: 2,3-Dimethyquinone
To a solution of NaOAc (16.4 gm, 60 mm) in 200 mL of water was added 2,3-dimethyl-4-hydroxyphenol (5.526 gm, 20 mm) and a solution of benzyltrimethylammonium tribromide (17.6 gm, 22 mm). The mixture was stirred until the color of the solution was faded (3 hours). The organic layer was separated and washed with brine, dried and evaporated, total weight 5 gm, This material was used for the next step without further purification.
Step B: 5-Hydroxy-2,6,7-trimethyl-lH-indole-3-carboxylic acid ethyl ester To a solution of 2,3-dimethylquinone (3.5 gm, 25.7 mm) in 60 mL of EtOΗ, was added a solution of 3-amino-but-2-enoic acid, benzyl ester (5.41 gm, 28.3 mm) under nitrogen. White solid was filtered, and the filtrate was concentrated and the product was purified by column chromatography eluted with hexanes/EtOAc = 1:1 (0.5 gm, 6.3%)
MS (APCI, AP+): 367.1.
Step C: 4-Dimethylaminomethyl-5-hydroxy-2,6,7-trimethyl- lH-indole-3- carboxylic acid ethyl ester
37.5% formaldehyde solution (0.157 mL, 1.94 mm) and 40% dimethylamine solution were added to a solution of 5-hydroxy-2,6,7-trimethyl- lH-indole-3-carboxylic acid ethyl ester in 11 mL of EtOΗ. The reaction mixture was stirred at 55°C for 48 hours. The solvent was removed, the pure product was isolated by column chromatography eluted with MeOΗ/EtOAc = 1 :4 (0.22 gm,
37.3%) MS (APCI, AP+): 367.1.
Step D: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2,4,5-trimethyl-, phenylmethyl ester The perchlorate salt 1,2,3,4,6,7,8, 9-octahydro-quinolizinylium perchlorate (0.204 gm, 0.855 mm) was dissolved in 10 mL IN NaOH and extracted with 3 x 35 mL ether. The ether was concentrated and the residue was redissolved in 4 mL dioxane. The imine solution solution was added to the 4-dimethylaminomethyl-5- hydroxy-2,6,7-trimethyl-lH-indole-3-carboxylic acid ethyl ester in 8 mL of dioxone. The reaction was refluxed at 110°C for 18 hours. The solvent was evaporated and the pure product was isolated by column chromatography eluted with MeOΗ/EtOAc = 1:4 (0.117 gm, 44.5%)
MS (APCI, AP+): 459.2. MP: 75-80°C
C23Η28N θ4-2/3 H2O. Calc'd: C, 74.11 ; H, 7.52; N, 5.966.96. Found: C, 74.12;
H 7.37; N, 5.77.
Example 191 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 , 1 -dimethyl-2-propynyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 , 1 -dimethyl-2-propynyl ester was synthesized according to procedure Q from 2-methyl-but-3-yn-2-ol. MS: m/z
407.52 (MH+). Example 192 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2,2,2-trichloro- 1 , 1 -dimethylethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 2,2,2-trichloro-l,l- dimethylethyl ester was synthesized according to procedure Q from l,l,l-trichloro-2-methyl-propan-2-ol. MS: m/z 500.86 (MH+).
Example 193 Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, tricyclo[3.3.1.13'7]dec-l-yl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid,
3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, tricyclo[3.3.1.13'7]dec-l-yl ester was synthesized according to procedure Q from adamantan-1-ol. MS: m/z
474.63 (MH+). Example 194 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -methyl- 1 -phenylethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -methyl- 1 -phenylethyl ester was synthesized according to procedure Q from 2-phenyl-propan-2-ol. MS: m/z
459.59 (MH+).
Example 195 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -methylcyclohexyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-mefhyl-, 1 -methylcyclohexyl ester was synthesized according to procedure Q. MS: m/z 437.59 (MH+).
Example 196 Pyτrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,1,2-trimethylpropyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-t]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-m ethyl-, 1 , 1 ,2-trimethylpropyl ester was synthesized according to procedure Q. MS: m/z 425.58 (MH+).
Example 197 Pyrrolo[3',2':5,6] [ 1 ]benzopyrano[3,2-/]quinolizine- 1 -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -methylcyclopentyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-;]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 1-methylcyclopentyl ester was synthesized according to procedure Q. MS: m/z 423.56 (MH+).
Example 198 Pyrrolo[3!,2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -cyclohexyl- 1 -methyl ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 1 -cyclohexyl- 1 -methyl ethyl ester was synthesized according to procedure Q. MS: m/z 465.64 (MH+).
Example 199 Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9, 10,12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 ,4-dimethyl-4-piperidinyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l,4-dimethyl-4-piperidinyl ester was synthesized according to procedure Q. MS: m/z 452.60 (MH+).
Example 200 Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 4- fluorophenyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-t]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-m ethyl-, 4-fluorophenyl ester was synthesized according to procedure Q. MS: m/z 435.50 (MH+).
Example 201 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-t]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-methylphenyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13,14, 14a, 15-decahydro-2-methyl-, 3-methylphenyl ester was synthesized according to procedure Q. MS: m/z 431.54 (MH+).
Example 202 Pyτrolo[3',2':5,6][l]benzopyrano[3,2-.jquinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, phenyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid,
3, 7,8,9,10,12,13, 14, 14a,15-decahydro-2-methyl-, phenyl ester was synthesized according to procedure Q. MS: m/z 417.51 (MH+). Example 203 Pyrrolo[3',2':5,6][l]benzoρyrano[3,2-t]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 3-(methoxycarbonyl)phenyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 3-(methoxycarbonyl)phenyl ester was synthesized according to procedure Q. MS: m/z 475.55 (MH+).
Example 204 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-pyridinyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2---]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 3-pyridinyl ester was synthesized according to procedure Q. MS: m/z 417.50 (MH+).
Example 205 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-(trifluoromethyl)-, ethyl ester
PyπOlo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-(trifluoromethyl)-, ethyl ester was synthesized according to procedure Q. MS: m/z 423.44 (MH+).
Example 206 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, [5-[(dimethylamino)methyl]- 2-furanyl]methyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [5-[(dimethylamino)methyl]- 2-furanyl]methyl ester was synthesized according to procedure Q. MS: m/z
478.60 (MH+).
Example 207 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 2-carboxy-2-methylpropyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-carboxy-2-methylpropyl ester was synthesized according to procedure Q. MS: m/z 441.53 (MH+).
Example 208 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 3-(dimethylamino)- 2,2-dimethylpropyl ester
Pyrrolo[3',2':5,6] [ 1 ]benzopyrano[3,2--']quinolizine- 1 -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 3-(dimethylamino)- 2,2-dimethylpropyl ester was synthesized according to procedure Q. MS: m/z 454.62 (MH+).
Example 209 Propanedioic acid, monoanhydride with 3, 7,8,9, 10,12, 13, 14,14a,15-decahydro-
2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 1,1 -dimethylethyl ester Propanedioic acid, monoanhydride with 3, 7,8,9,10,12, 13, 14,14a,15-decahydro- 2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 1 , 1 -dimethylethyl ester was synthesized according to procedure Q. MS: m/z
483.57 (MH+).
Example 210 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-t]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-(dimethylamino)- 2-methylpropyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 2-(dimethylamino)- 2-methylpropyl ester was synthesized according to procedure Q. MS: m/z
440.59 (MH+).
Example 211
Pyιrolo[3',2':5,6][l]benzopyrano[3,2-.']quinolizine-l -carboxylic acid,
3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-( IH-imidazol- 1 -yl)ethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-( 1 H-imidazol- 1 -yl)ethyl ester was synthesized according to procedure Q. MS: m/z 435.53 (MΗ+).
Example 212 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-benzofuranylmethyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-benzofuranylmethyl ester was synthesized according to procedure Q from benzofuran-2-yl-methanol.
MS(APCI+): m/z 471.2 (MH+).
Example 213 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ( 1 R,2-S 2-(dimethylamino)- 1 - phenylpropyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, ( lR,2S)-2-(dimethylamino)- 1 - phenylpropyl ester was synthesized according to procedure Q from (IR, 2S)- dimethylamino-phenyl-propan-1-ol. MS(APCI+): m/z 502.1 (MH+). Example 214 Pyrrolo[3l,2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lS,2R)-2-(dimethylamino)-l- phenylpropyl ester
Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, ( 1 S,2R)-2-(dimethylamino)- 1 - phenylpropyl ester was synthesized according to procedure Q from (IS, 2R)-2- (dimethylamino-phenyl-propan-1-ol. MS(APCI+): m/z 502.1 (MH+).
Example 215 Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)cyclopropyl ester
Step A: l-(4-Fluorophenyl)cyclopropanol
Following the procedure reported by Kulinkovich, O.G.; Sviridov, SN.; Vasilevskii, D.A.; Savchenko, A.I.; and Pritytskaya, T.S. in J. Org. Chem. USSR (Engl) 1991;27(2):250 for the preparation of 1 -phenylcyclopropanol, 4-fluorobenzoic acid ethyl ester (65.72 mmol, 11.05 g) was converted to l-(4- fluorophenyl)cyclopropanol (5.34 g, 53%) as a yellow liquid; ^H ΝMR (400 MHz, CDC13) δ 0.99-1.02 (m, 2H, cyclopropyl CH2), 1.23-1.26 (m, 2Η, cyclopropyl CH ), 2.22 (bs, 1Η, OH), 6.98-7.05 (m, 2Η, ArH), 7.26-7.32 (m, 2Η, ArH); 19F NMR (CDCI3) δ -117.09 (d, J=15.43 Ηz); MS (APCI+) m/z 152.9 (MΗ+).
Step B: Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid,
3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-(4- fluorophenyl)cyclopropyl ester Following the procedure from Example 47, Step B, l-(4-fluorophenyl)- cyclopropanol (35.1 mmol, 5.34 g) and pyrrolo[3',2':5,6][l]benzopyrano[3,2- i]quinolizine-l -carboxylic acid, 3, 7,8, 9,10,12, 13, 14,14a,15-decahydro-2-methyl-, anhydride with benzoic acid (Example 86), (8.77 mmol, 3.90 g) were converted to pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -(4-fluorophenyl)cyclopropyl ester. The product was purified by silica gel flash column chromatography (25-50% ethyl acetate/hexanes, then 30-50%) ether/hexanes) and recrystallized from 2,2,4-trimethylpentane to afford a light yellow solid (0.364 g, 9%>): mp 130- 135°C; IR (KBr) 3302, 29.31, 2857, 1689, 1515, 1429, 1221, 1194, 1 147, 1068 cm"1 ; 1H NMR (400 MHz, DMSO-d6) δ 1.13-1.60 (m, 13H, aliphatic CH), 1.71-
1.74 (m, 1Η, aliphatic CH), 1.88 (d, J=13.18 Ηz, 1Η, aliphatic CH), 2.36 (d, J=10.74 Ηz, 1Η, aliphatic CH), 2.43-2.49 (m, 1Η, aliphatic CH), 2.53 (s, 3Η,
ArCH3), 2.66-2.71 (m, 2Η, aliphatic CH), 2.87-2.90 (m, IH, aliphatic CH), 3.22
(dd, J=18.31, 6.84 Ηz, 1Η, aliphatic CH), 6.61 (d, J=8.79 Ηz, 1Η, ArH), 7.04 (d, J=8.55 Ηz, 1Η, ArH), 7.1 1-7.15 (m, 2Η, ArH), 7.28-7.32 (m, 2Η, ArH), 11.57 (s,
1Η, NH); 19F NMR (DMSO-d6) δ -1 17.03; MS (APCI+) m/z 475.2 (MΗ+). Anal. Calcd for C29H3 iFjN^: C, 73.40; H, 6.58; F, 4.00; N, 5.90. Found: C, 73.58;
H, 6.79; F, 3.93; N, 5.52.

Claims

A compound of Formula I
ring close πng open
or a pharmaceutically acceptable salt thereof wherein: A is O, S, and additionally A is NR] when X is C-R9;
X is N when A is NRj or
X is C-R9 wherein R9 is halogen, hydrogen, alkyl, -CF3, CH2F, CHF2,
-(CH2)m-OR1 ; aryl, arylalkyl, -(CH2)m-NR7R8, or
(CH2)q wherein m is an integer of from 0 to 2 and each occurrence of m is independently an integer of from 0 to 2, q is an integer of from 0 to 1, and r is an integer of from 0 to 3; Y is hydrogen, alkyl, arylalkyl, aryl, (CH2)m-NR7R8, -N(R1)-(CH2)V- C(R7R8)-aryl, or ORJ Q wherein Rio is hydrogen, alkyl, cycloalkyl, cycloalkyl fused to an aryl ring, aryl, (CH2)saryl- -CH2CF3, (CH2)tC(R7R8)-(CH2)uaryl,
wherein s is an integer of from 1 to 3, t is an integer of from 0 to 3, u is an integer of from 0 to 3, v is an integer of from
1 to 3, and w is an integer of from 0 to 2;
Z is CR or N;
Rj is hydrogen or alkyl and each occurrence of Rj is independently hydrogen or alkyl; R and R2 are each independently selected from: hydrogen, alkyl, halogen,
-CN,
-NO2,
-(CH2)m-NR7R8, "(CH2)m-COOR7,
"(CH2)m-CONR7R8,
O II
"(CH2)mN-S-R7 ,
II
O
"(CH2)m-OR7, -(CH2)m-SO2NR7R8, and
-(CH2)m- (O)pR7 wherein each occurrence of R7 and R8 are each independently hydrogen, alkyl, aryl, arylalkyl, -CF3, or R and R8 may be taken together to form a cyclic ring of from
3 to 7 atoms which ring may have O, S, or NRj and p is an integer of from 0 to 2;
R3 is hydrogen or alkyl;
R4 is hydrogen, alkyl, aryl, or aralkyl;
R5 is alkyl, aryl, arylalkyl, acyl; or
R4 and R5 are taken together with the atoms to which they are attached to form a cyclic ring of from 5 to 7 atoms;
Rg is hydrogen or alkyl;
R5 when not taken together with R4 can be taken together with Rg with the atoms to which they are attached to form a ring of from 5 to 7 atoms; N-R5 is also the corresponding N-oxide;
Rj J is hydrogen or alkyl; n is an integer of from 1 to 3; j is an integer of from 1 to 2, andj is the integer 0 when Y is hydrogen, alkyl, arylalkyl, or aryl; with the proviso that Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2- methyl-, ethyl ester is not included.
2. A compound according to Claim 1 wherein Rj is hydrogen.
3. A compound according to Claim 1 wherein: Rj is hydrogen and
X is C-R9.
4. A compound according to Claim 1 wherein: Rj is hydrogen and
X is C-R9, wherein R9 is alkyl.
5. A compound according to Claim 1 wherein: Rj is hydrogen,
X is C-R9, wherein R9 is alkyl; R4 and R5 are taken together with the atoms to which they are attached to form a ring of from 5 to 7 atoms; and
Y is OR J O-
6. A compound according to Claim 1 wherein: Rj is hydrogen, X is C-R9, wherein R9 is alkyl;
R4 and R5 are taken together to form a 6-membered ring; and
Y is ORJ O wherein RJ Q is alkyl, aryl or -(CH2)saryl,
-(CH2)t-C(R7R8)-(CH2)u-aryl.
7. A compound according to Claim 1 wherein: Rj is hydrogen, X is C-R9, wherein R9 is Me;
R4 and R5 are taken together to form a 6-membered ring; Rg is hydrogen; n is 2; and Y is OR 0 wherein R j 0 is alkyl, aryl or R 0 is -(CH2)t-C(R7R8)-(CH2)u- aryl wherein t is 0, R7 and R8 can each independently be H, alkyl,
-(CH2)vOH or (CH2)uCOOR7, and -(CH2)vNRjR2 where u and v are as defined above.
A compound according to Claim 1 and selected from:
Pyrrolo[3 ',2 ' :5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, methyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-bromo-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, propyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15 -decahydro-2-methyl-, 2-methylpropyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2,2-dimethylpropyl ester;
Pyrrolo[3 ',2 ' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3, 7,8, 9,10,12, 13, 14,14a,15-decahydro-2-methyl-, phenylmethyl ester;
Pyrrolo[3 ',2 ' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -methylethyl ester;
Pyrrolo[3 ',2 ' :5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, cyclopropylmethyl ester; Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-(l- piperidinyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-(phenylmethyl)-, ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 2-ethyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester;
Pyrrolo[3 ',2' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 2-cyclopropyl-3,7,8,9,10,12,13,14,14a,15-decahydro-, ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-propyl-, ethyl ester;
Pyrrolo[3 ',2 ' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-(2-methylρropyl)-, ethyl ester; Pyrrolo[3 ',2' :5,6][ 1 ]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1,1 -dimethyl ethyl ester;
2,6a,7-Trimethyl-7,8,9, 10, 10a, 11 -hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester; 7-Ethyl-2,6a-dimethyl-7,8,9, 10, 10a, 11 -hexahydro-3H,6aH-6-oxa-
3,7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester;
6a-Ethyl-2,7-dimethyl-7,8,9,10,10a,l l-hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l-carboxylic acid ethyl ester;
6a,7-Diethyl-2-methyl-7,8,9, 10, 1 Oa, 11 -hexahydro-3H,6aH-6-oxa- 3, 7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester;
7-Benzyl-2,6a-dimethyl-7,8,9,10,10a,l l -hexahydro-3H,6aH-6-oxa- 3,7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester;
2,7-Dimethyl-6a-phenyl-7,8,9, 10, 1 Oa, 11 -hexahydro-3H,6aH- 6-oxa-3,7-diaza-cyclopenta[a]anthracene-l -carboxylic acid ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-e]indole-l -carboxylic acid,
8,9,11, 12,13, 13a,14,14a-octahydro-2-methyl-, ethyl ester; 3H,7H-Pyrrolizino[l',8':5,6]pyrano[3,2-e]indole-l -acetic acid, 8,9,l l,12,12a,13-hexahydro-2-methyl-, ethyl ester;
2-Methyl-8,9, 10, 1 Oa, 11 , 12, 12a, 13-octahydro-3H,6aH,7H-6-oxa- 3,6b-diaza-benzo[a]cyclopenta[h]anthracene-l -carboxylic acid ethyl ester; 3H-Pyrido[l",2":l'2']azepino[3'2':5,6]pyrano[3,2-e]indole-l- acetic acid, 7,8,9,10,12, 13, 14,15, 15a,16-decahydro-2-methyl-, ethyl ester or 7H-Azepino[l",2":l'2']pyrido[3',2':5,6]pyrano[3,2-e]indole-l-acetic acid, 3,8,9,10,11,13, 14,15, 15a,16-decahydro-2-methyl-, ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxamide, 8,9, 11 , 12, 13, 13a, 14, 14a-octahydro-2-methyl-N-(phenylmethyl)-;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxamide, N-ethyl-8,9, 11 , 12, 13 , 13a, 14, 14a-octahydro-2-methyl-;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l- carboxaldehyde, 8,9,1 l,12,13,13a,14,14a-octahydro-2-methyl-; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l- carboxamide,8,9, 11 , 12, 13, 13a, 14, 14a-octahydro-N,2-dimethyl-;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 8,9,1 l,12,13,13a,14,14a-octahydro-2-methyl-, (4-fluorophenyl)- methyl ester; Indazolo[4',5':5,6]pyrano[3,2-/]quinolizine- 1 -carboxylic acid,
3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2, 12,12-trimethyl-, phenylmethyl ester; PyrrololN^'^όJflJbenzopyrano ^-iJquinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,10,10-trimethyl-, phenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-fluoro-3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-fluoro-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester;
12H-Furo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-fluoro-7,8, 9,10,13, 14,14a,15-octahydro-2-methyl-, ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 4,5-difluoro-3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, phenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 4,5-dichloro-3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-4,5-dimethoxy-2-methyl-, phenylmethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2,5-dimethyl-, phenylmethyl ester;
PynOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2,4-dimethyl-, phenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2,4-dimethyl-, 1 -(4-fluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzoρyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-[3-
(methoxycarbonyl)phenyl] ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a, 15-decahydro-2-m ethyl-, l-(3-carboxyphenyl)ethyl ester; 1 -Propanaminium, N,N,N-trimethyl-, salt with
1 -(3-carboxyρhenyl)ethyl 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl- py-τolo[3\2':5,6][l]-benzopyrano[3,2-i]quinolizine-l -carboxylate (1 :1); Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (3-nitrophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-(3-cyanophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -[3-[(dimethylamino)carbonyl]phenyl]ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -[3-[(dimethylamino)methyl]phenyl]ethyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 1 , 13, 14, 14a, 15-decahydro-2-methyl-,2-phenylethyl ester; Pyrrolo[3 ',2 ' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, [4-(methoxycarbonyl)phenyl]methyl ester;
Pyrrolo[3 ',2': 5, 6] [l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2,-methyl-, (4-carboxyphenyl)methyl ester; l-[3-(4-Carboxy-benzyloxycarbonyl)-5-hydroxy-2-methyl-lH- indol-4-ylmethyl]- 1,2,3,4,6, 7,8, 9-octahydro-quinolizinylium; chloride;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [4-(hydroxymethyl)phenyl]methyl ester;
Pyrrolo[3 ' ,2 ' : 5 ,6] [ 1 ]benzopyrano[3 ,2-i]quinolizine-2-carboxylic acid, 3,78,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-naphthalenylmethyl ester;
Pyrrolo[3 ',2 ' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-,
[3-(methoxycarbonyl)phenyl]methyl ester; Pyrrolo[3 ',2' :5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [3-(hydroxymethyl)phenyl]methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-,
(3-carboxyphenyl)methyl ester);
Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (3-carboxypheny)methyl 3,7,8,9, 10, 12, 13, 14, 14a, 1 -decahydro- 2-methylpyrrolo[3 ',2 ':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylate (1 :1);
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [3-[(dimethylamino)methyl]phenyl]methyl ester;
Pyrrolo[3 ',2 ' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-,
[3-[(dimethylamino)carbonyl]phenyl]methyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, [2-(4-morpholinyl)ethyl ester; Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, l-[l,l '-biphenyl]- 4-ylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (2,6-difluorophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (l-phenyl-2,2,2- trifluoro)ethyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-,
1 -[3-(trifluoromethyl)phenyl]ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-(dimethylamino)ethyl ester;
Pyrrolo[3 ' ,2 ' : 5 ,6] [ 1 Jbenzopyrano [3 ,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-,
2-(l-pyrrolidinyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(l-naphthalenyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -phenylcyclobutyl ester;
Pyrrolo[3 ',2' :5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-m ethyl-, 1 -phenylcylopropyl ester;
Pyrrolo[3 ' ,2 ' :5 ,6] [ 1 ]benzopyrano[3 ,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -pyrazinylethyl ester;
Pyrrolo[3 ',2' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, l-(4-quinolinyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -(2-pyrimidinyl)ethyl ester; Pyrrolo[3 ',2' :5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 5-chloro-3, 7,8,9, 10,12, 13, 14,14a, 15-decahydro-2-methyl-, phenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 5-chloro-3,7, 8,9,10,12, 13, 14,14a, 15-decahydro-2-methyl, l-(4-fluorophenyl)ethyl ester;
Quinolizinium, l-[[(4-fluorophenyl)mefhoxy]carbonyl]-5-hydroxy- 2-methyl-lH-indol-4-yl]methyl]-l,2,3,4,6,7,8,9-octahydro-, chloride; Pyrrolo[3 ',2' :5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-l,2-dimethyl-, (4-fluorophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -phenylpropyl ester;
Quinolizinium, l,2,3,4,6,7,8,9-octahydro-l-[[5-hydroxy-2-methyl- 3-[(phenylmethoxy)carbonyl]-lH-indol-4-yl]methyl]-, chloride;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-,
(4-nitrophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (1R)-1 -phenylethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(4-fluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, phenyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro- 1 -phenyl- 1 -(trifluoromethyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, bicyclo[2.2.1]hept- 2-yl ester;
Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1 -(4-fluorophenyl)- 1 -methylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-,
1 -phenylcyclopentyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1-phenylcyclohexyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-,
3-(hydroxymethyl)phenyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (3-hydroxyphenyl)methyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (1S)- l-(4-pyridinyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-m ethyl-, [6-(methoxycarbonyl)-2-pyridinyl]methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-pyridinylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (6-carboxy-
2-pyridinyl)methyl ester;
Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (6-carboxy- 2-pyridinyl)methyl 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2- methylpyτrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylate (1 :1);
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, [5-(methoxycarbonyl)-3-pyridmyl]methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (5-carboxy-
3-pyridinyl)methyl ester;
Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (5-carboxy- 3-pyridinyl)methyl 3,7,8,9,10,12,13, 14,14a,15-decahydro-2- methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylate
0:1);
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -(4'-methyl[ 1,1'- biphenyl]-3-yl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -(2,6-dimethylphenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S,2R)-
2-(dimethylamino)- 1 -phenylpropyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1R,2S)- 2-(dimethylamino)- 1 -phenylpropyl ester; Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -naphthalenyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, diphenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, ( 1 R)-2,3-dihydro- lH-inden-1-yl ester;
Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1,2-dihydro-
1 -acenaphthylenyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, cyclohexyl(phenyl)methyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 9H-fluoren-9-yl ester; Pyrrolo[3',2':5,6] [ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-mefhyl-, 1 ,2,3,4-tetrahydro- 1 -naphthalenyl ester;
PyπOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [(2R,3R)-
3-phenyloxiranyl]methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-oxo- 1 ,2-diphenylethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 10,11 -dihydro-5H- dibenzo[a,d]cyclohepten-5-yl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (2-methylphenyl)phenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, cyclopropyl(4-fluorophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 3,4-dihydro-2H- l-benzothiopyran-4-yl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S)- l-(2-bromophenyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 2,2,2-trifluoroethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, [(2S.3S)- 3-phenyloxiranyl]methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro- 1 -methyl- 1 -(trifluoromethyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2,2,2-trifluoro- 1 -(4-fluorophenyl)- 1 -(trifluoromethyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1 -cyclopentyl-
1 -phenylethyl ester;
Pyrrolo[3 ',2': 5 ,6] [ 1 Jbenzopyrano [3 ,2-i] quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-[l,l'-biphenyl]- 4-yl-l-methylethyl ester; Pyιrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 -methyl- 1 -phenyl- 2-propynyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1 ,1-diphenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1-methyl- 1 ,2-diphenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-,
1 -(4-fluorophenyl)cyclohexyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 ,2-diphenylethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 1-phenyl- 2-propynyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [1,1 '-biphenylj- 4-ylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]qumolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 4-pyridinylmethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 ,2,3,4-tetrahydro- 7,8-dimethoxy-2-methyl-4-isoquinolinyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-,
1 -[3-(dimethylamino)phenyl]ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1 , 1 -dimethyl- 2-pyrazinylethyl ester; Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 4-(dipropylamino)- 1 , 1 -dimethyl-2-butynyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (lS)-2,3-dihydro- lH-inden-1-yl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (1S,2S)- 2-(dimethylamino)-l -phenylpropyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-,
[4-(trifluoromethyl)phenyl]mefhyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (4-chlorophenyl)methyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-, phenylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-, ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-hydroxyethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizme-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (3-methylphenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S)-1 -phenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 1 -phenylethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carbothioic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, S-(phenylmethyl) ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 3-pyridinylmethyl ester; PyπOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, l-[4-(trifluoromethyl)phenyl]ethyl ester;
Pyιτolo[3^2\-5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, l-(pentafluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -(2,6-difluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (1S)- l-(2-furanyl)ethyl este;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 2-(4-morpholinyl)- 1 -phenylethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1R)- l-(2-furanyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-mefhyl-, 2-methoxy-2-oxo- 1 -phenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(3-pyridinyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (S)- carboxy(phenyl)methyl ester; Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (S)- carboxy(phenyl)methyl, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro- 2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylate
0:1);
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (lR)-2-methoxy-
2-oxo-l -phenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, (R)- carboxy(phenyl)methyl ester; Ethanaminium, 2-hydroxy-N,N,N-trimethyl-, salt with (R)- carboxy(phenyl)methyl, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro- 2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylate
(1:1);
Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 4-pyridinylmethyl ester;
PyπOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(4-pyridinyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a, 15-decahydro-2-methyl-, l-(2-pyridinyl)ethyl ester; Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 3-thienylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1S)- l-(4-fluorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (1R)- l-(4-fluorophenyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 3-pyridinylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, 2-ethoxy- 2-oxoethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-furanylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-,
(2-nitrophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2-furanylmethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, l-(2-chlorophenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a, 15-decahydro-2 -methyl-, carboxymethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -(2,6-dichlorophenyl)ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(2- methoxyphenyl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, l-(5-carboxy-
3-pyridinyl)ethyl ester;
1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15- decahydro-2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin- l-yl)carbonyl]oxy]methyl]-, diethyl ester; 1,3-Benzenedicarboxylic acid, 5-[[[(3,7,8,9,10,12,13,14,14a,15- decahydro-2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin- 1 -yl)carbonyl]oxy]methyl]-;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (2-chloro- 5-nitrophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, (2-chloro- 5-nitrophenyl)methyl ester;
PyπOlo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, (5-amino-
2-chlorophenyl)methyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -acetic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-.alpha.-oxo-, ethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2,4,5-trimethyl-, phenylmethyl ester;
Pyrrolo[3 ',2': 5,6] [ 1 ]benzopyrano[3 ,2-/]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1,1-dimethyl- 2-propynyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 2,2,2-trichloro- 1,1 -dimethylethyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l-carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, tricyclo[3.3.1.l3.7]ciec-l-yl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-z]quinolizine-l-carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1-methyl-
1 -phenylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 -methylcyclohexyl ester; Pyιτolo[3,,2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 1,1,2-trimethylpropyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 1-methylcyclopentyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, 1 -cyclohexyl- 1-methylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 1 ,4-dimethyl-
4-piperidinyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizme-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 1 -decahydro-2-methyl-, 4-fluorophenyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-methylphenyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-t]qumolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, phenyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-(methoxycarbonyl)phenyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2-t]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 3-pyridinyl ester;
Pyrrolo[3 ',2': 5 ,6] [ 1 ]benzopyrano[3 ,2-i] quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-(trifluoromethyl)-, ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, [5-[(dimethylamino)methyl]-2-furanyl]methyl ester;
PyπOlo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 2-carboxy-
2-methylpropyl ester;
Pyrrolo[3',2':5,6] [ 1 ]benzopyrano[3,2-t]quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, 3-(dimethylamino)- 2,2-dimethylpropyl ester; Propanedioic acid, monoanhydride with
3,7,8,9,10,12,13,14,14a,15-decahydro-2-methylpyrrolo[3',2':5,6][l]- benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 1,1 -dimethylethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2-methyl-, 2-(dimethylamino)- 2-methylpropyl ester;
Pyrrolo[3',2':5,6][ 1 ]benzopyrano[3,2-/']quinolizine- 1 -carboxylic acid, 3,7,8,9,10,12,13, 14,14a,15-decahydro-2-methyl-, 2-(lH-imidazol- 1 -yl)ethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-,
2-benzofuranylmethyl ester;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-/]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (lR,2S)-2- (dimethylamino)-l -phenylpropyl ester; Pyrrolo[3',2':5,6][l]benzopyrano[3,2--']quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13, 14,14a, 15-decahydro-2-methyl-, (lS,2R)-2- (dimethylamino)-l -phenylpropyl ester; and Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-, l-(4- fluorophenyl)cyclopropyl ester.
9. A compound named Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine, 3,7,8,9,10,12,13,14,14a,15-decahydro-, or
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9,10,12,13,14,14a,15-decahydro-2-methyl-.
10. A pharmaceutical composition comprising a compound according to Claim 1 or Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l- carboxylic acid, 3, 7, 8,9,10,12, 13, 14,14a,15-decahydro-2-methyl-, ethyl ester in admixture with a pharmaceutically acceptable excipient, diluent, or carrier.
11. A method for modulation of a chemokine receptor activity in a mammal comprising administering an effective amount of a compound according to Claim 1 or Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l- carboxylic acid, 3, 7, 8,9,10,12, 13, 14,14a,15-decahydro-2-methyl-, ethyl ester or a pharmaceutically acceptable salt thereof.
12. A method for modulation of the CCR-5 chemokine receptor activity in a mammal comprising administering an effect amount of a compound according to Claim 1 or Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]- quinolizine- 1 -carboxylic acid, 3 ,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2- methyl-, ethyl ester or a pharmaceutically acceptable salt thereof.
13. A method for preventing infection by HIV, treating infection by HIV, delaying the onset of AIDS, or treating AIDS comprising administering to a mammal in need of said treatment a therapeutically effective amount of a compound according to Claim 1 or Pyrrolo[3',2':5,6][l]benzopyrano[3,2- i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13, 14, 14a, 15-decahydro-2- methyl-, ethyl ester or a pharmaceutically acceptable salt thereof.
14. A method of treating inflammatory disease comprising administering to a mammal in need of said treatment a therapeutically effective amount of a compound according to Claim 1 or Pyrrolo[3',2':5,6][l]benzopyrano[3,2- i]quinolizine- 1 -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2- methyl-, ethyl ester or a pharmaceutically acceptable salt thereof.
15. A combination of a compound of Formula I with one or more agents useful in the prevention and/or treatment of AIDS.
16. A compound selected from:
Pyridinium, 3-[[[(3,7,8,9,10,12,13,14,14a,15-decahydro- 2-methylpyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizin- l-yl)carbonyl]oxy]methyl]-l -methyl-, methanesulfonate;
Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizinium, 3,7,8,9,10,12,13,14,14a,15-decahydro-2,l l-dimethyl-l-[(S)-(l- phenylethoxy)carbonyl]-, methanesulfonate; and Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine-l -carboxylic acid, 3,7,8,9, 10, 12, 13 , 14, 14a, 15-decahydro-2-methyl-, ( 1 S)- 1 -phenylethyl ester, 11 -oxide.
17. A compound named Pyrrolo[3',2':5,6][l]benzopyrano[3,2-i]quinolizine- 1 -carboxylic acid, 3, 7,8,9,10,12, 13, 14,14a,15-decahydro-2-methyl-, anhydride with benzoic acid.
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