US20160257677A1 - Large substitutent, non-phenolic opioids and methods of use thereof - Google Patents

Large substitutent, non-phenolic opioids and methods of use thereof Download PDF

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US20160257677A1
US20160257677A1 US14/878,526 US201514878526A US2016257677A1 US 20160257677 A1 US20160257677 A1 US 20160257677A1 US 201514878526 A US201514878526 A US 201514878526A US 2016257677 A1 US2016257677 A1 US 2016257677A1
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Mark P. Wentland
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Rensselaer Polytechnic Institute
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
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    • C07D489/09—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems
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    • C07D489/09—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems
    • C07D489/10—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14
    • C07D489/12—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14 the bridge containing only two carbon atoms

Definitions

  • the invention relates to opioid receptor binding compounds containing carboxamides that have large substitutents on the nitrogen of the carboxamide.
  • the compounds are useful as analgesics, anti-diarrheal agents, anticonvulsants, anti-obesity agents, antitussives, anti-cocaine, and anti-addiction medications.
  • Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been identified.
  • Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e.g., naltrexone and cyclazocine) in humans have limited utility due to poor oral bioavailability and a very rapid clearance rate from the body.
  • the compounds of the invention are therefore useful as analgesics, anti-pruritics, anti-diarrheal agents, anticonvulsants, antitussives, anorexics and as treatments for hyperalgesia, drug addiction, respiratory depression, dyskinesia, pain (including neuropathic pain), irritable bowel syndrome and gastrointestinal motility disorders.
  • Drug addiction includes alcohol and nicotine addiction.
  • the compounds may also be useful as immunosuppressants and antiinflammatories and for reducing ischemic damage (and cardioprotection), for improving learning and memory, and for treating urinary incontinence.
  • the invention relates to compounds of formula:
  • A is (CH 2 ) n , wherein one or more CH 2 may be replaced by —O—, cycloalkyl or —CR 1a R 1b ;
  • R 1a and R 1b are chosen independently from hydrogen, halogen, lower alkyl, lower alkoxy and lower alkylthio;
  • R 2 and R 2a are both hydrogen or taken together R 2 and R 2a are ⁇ O;
  • R 3 is chosen from hydrogen, C 1 -C 8 hydrocarbon, heterocyclyl, heterocyclylalkyl and hydroxyalkyl;
  • R 4 is chosen from hydrogen, hydroxy, amino, lower alkoxy, C 1 -C 20 alkyl and C 1 -C 20 alkyl substituted with hydroxy or carbonyl;
  • R 5 is lower alkyl
  • R 6 is lower alkyl
  • R 7 is chosen from hydrogen and hydroxy
  • R 4 , R 5 , R 6 and R 7 may form from one to three rings, said rings having optional additional substitution;
  • R 10 is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkoxy and (C 1 -C 6 )alkylthio;
  • R 11 is H or
  • A′ is (CH 2 ) m , wherein one or more CH 2 may be replaced by —O—, cycloalkyl, —CR 1a R 1b , —C( ⁇ O)— or —NH—;
  • R 12 is chosen from hydrogen and lower alkyl
  • R 15 is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkoxy and (C 1 -C 6 )alkylthio;
  • n is zero or an integer from 1 to 6;
  • n is an integer from 1 to 6.
  • Subclasses of the foregoing structure include:
  • R 3a is chosen from hydrogen, C 1 -C 7 hydrocarbon, heterocyclyl, and hydroxyalkyl
  • R 4 is chosen from hydrogen, hydroxy, lower alkoxy, C 1 -C 20 alkyl and C 1 -C 20 alkyl substituted with hydroxy or carbonyl;
  • R 5 is lower alkyl
  • R 6 is lower alkyl
  • R 7 is hydrogen or hydroxy.
  • R 3a is chosen from hydrogen, C 1 -C 7 hydrocarbon, heterocyclyl, and hydroxyalkyl; and R 7 is H or OH.
  • R 19 is hydrogen or lower alkyl
  • R 20 is chosen from hydrogen, lower alkyl and hydroxy(lower alkyl); or together, R 9 and R 10 form a spiro-fused carbocycle of 5 to 10 carbons;
  • R 21 is hydrogen
  • R 22 is chosen from hydroxy, lower alkoxy and —NR 13 R 14 ; or together, R 21 and R 22 form a carbonyl or a vinyl substituent.
  • the invention relates to a method for preparing a second compound that interacts with an opioid receptor when a first compound that interacts with an opioid receptor is known.
  • the method comprises converting the phenolic hydroxyl to a residue of structure:
  • the invention relates to methods for inhibiting, eliciting or enhancing responses mediated by an opioid receptor comprising:
  • the invention in another aspect, relates to a method for treating a disease by altering a response mediated by an opioid receptor.
  • the method comprises bringing into contact with the opioid receptor a compound having the formula
  • the invention relates to compounds of formula
  • R 11 is
  • R 10 is phenyl
  • R 10 is hydrogen
  • R 11 is
  • R 11 represents pyridinyl, phenyl, halophenyl, methylphenyl, methoxyphenyl (in all of which A′ is a direct bond) and phenoxy (in which A′ is —O—).
  • R 10 is hydrogen, methoxy, halogen or methyl; and R 11 is hydrogen;
  • R 10 is pyridinyl
  • R 10 is hydrogen
  • R 11 is chosen from phenyl, halophenyl, methylphenyl, methoxyphenyl and phenoxy.
  • Opioid receptor ligands having known high affinity are shown in the following charts. Replacement of OH with Q in these compounds produces compounds that exhibit similar activity and better bioavailability.
  • Membrane protein from CHO cells that stably expressed one type of the human opioid receptor were incubated with 12 different concentrations of the compound in the presence of either 1 nM [ 3 H]U69,593 10 ( ⁇ ), 0.25 nM [ 3 H]DAMGO 11 ( ⁇ ) or 0.2 nM [ 3 H]naltrindole 12 ( ⁇ ) in a final volume of 1 mL of 50 mM Tris-HCl, pH 7.5 at 25° C. Incubation times of 60 min were used for [ 3 H]U69,593 and [ 3 H]DAMGO. Because of a slower association of [ 3 H]naltrindole with the receptor, a 3 h incubation was used with this radioligand.
  • Samples incubated with [ 3 H]naltrindole also contained 10 mM MgCl 2 and 0.5 mM phenylmethylsulfonyl fluoride. Nonspecific binding was measured by inclusion of 10 ⁇ M naloxone. The binding was terminated by filtering the samples through Schleicher & Schuell No. 32 glass fiber filters using a Brandel 48-well cell harvester. The filters were subsequently washed three times with 3 mL of cold 50 mM Tris-HCl, pH 7.5, and were counted in 2 mL Ecoscint A scintillation fluid.
  • [ 35 S]GTP ⁇ S Binding Assays In a final volume of 0.5 mL, 12 different concentrations of each test compound were incubated with 15 ⁇ g ( ⁇ ), 10 ⁇ g ( ⁇ ) or 7.5 ⁇ g ( ⁇ ) of CHO cell membranes that stably expressed either the human ⁇ , ⁇ or ⁇ opioid receptor.
  • the assay buffer consisted of 50 mM Tris-HCl, pH 7.4, 3 mM MgCl 2 , 0.2 mM EGTA, 3 ⁇ M GDP, and 100 mM NaCl.
  • the final concentration of [ 35 S]GTP ⁇ S was 0.080 nM. Nonspecific binding was measured by inclusion of 10 ⁇ M GTP ⁇ S.
  • Binding was initiated by the addition of the membranes. After an incubation of 60 min at 30° C., the samples were filtered through Schleicher & Schuell No. 32 glass fiber filters. The filters were washed three times with cold 50 mM Tris-HCl, pH 7.5, and were counted in 2 mL of Ecoscint scintillation fluid. Data are the mean E. and EC 50 values ⁇ S.E.M. from at least three separate experiments, performed in triplicate. For calculation of the E max values, the basal [ 35 S]GTP ⁇ S binding was set at 0%.
  • CHO membranes expressing the ⁇ opioid receptor were incubated with 12 different concentrations of the compound in the presence of 200 nM of the ⁇ agonist DAMGO.
  • CHO membranes expressing the ⁇ opioid receptor were incubated with the compound in the presence of 100 nM of the ⁇ agonist U50,488.
  • CHO membranes expressing the 6 receptor were incubated with 12 different concentrations of the test compound in the presence of 10 nM of the 6-selective agonist SNC 80.
  • Antinociceptive activity is evaluated by the method described in Jiang et al. [ J. Pharmacol. Exp. Ther. 264, 1021-1027 (1993), page 1022].
  • the ED 50 's of compounds of the invention are expected to be under 100 nmol in the mouse acetic acid writhing test when administered i.c.v., and an increase in the duration of action is expected for compounds of the invention compared to their “parents” when given by i.p. administration.
  • Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof.
  • Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, s- and t-butyl, cyclobutyl and the like. Preferred alkyl groups are those of C 20 or below.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.
  • Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.
  • Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S.
  • the aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl and the like. Heteroarylalkyl means an alkyl residue attached to a heteroaryl ring. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.
  • Heterocycle means a cycloalkyl or aryl residue in which one to two of the carbons is replaced by a heteroatom such as oxygen, nitrogen or sulfur. Heteroaryls form a subset of heterocycles. Examples of heterocycles that fall within the scope of the invention include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
  • Substituted alkyl, aryl, cycloalkyl, or heterocyclyl refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, hydroxy, loweralkoxy, carboxy, carboalkoxy, carboxamido, cyano, carbonyl, —NO 2 , —NR 1 R 2 ; alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, heteroaryloxy, or substituted phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.
  • Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
  • a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
  • the compounds of the invention are synthesized by one of the routes described below:
  • N-hydroxysuccinimide ester intermediates (3) shown in scheme 1 are prepared by the processes of U.S. Pat. No. 7,057,0357, the contents of which are incorporated herein by reference.
  • the N-hydroxysuccinimide ester is then reacted with the appropriate arylalkylamine (4) as described below.
  • An alternative, employing direct carbonylation/amidation is shown in Scheme 2.
  • Many diaryl compounds can be prepared by Suzuki coupling, shown in Scheme 3.
  • Proton NMR spectra and in certain cases 13 C NMR were obtained on a Varian Unity-300 or 500 NMR spectrometer with tetramethylsilane as an internal reference for samples dissolved in CDCl 3 . Samples dissolved in CD 3 OD and DMSO-d 6 were referenced to the solvent. Proton NMR multiplicity data are denoted by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), and br (broad). Coupling constants are in hertz. Direct insertion probe chemical ionization mass spectral data were obtained on a Shimadzu GC-17A GC-MS mass spectrometer.
  • Direct infusion electrospray ionization (in positively charged ion mode) mass spectral data were obtained on an Agilent 1100 series LC/MSD system (Germany). Melting points were determined on a Meltemp capillary melting point apparatus and were uncorrected. Infrared spectral data were obtained on a Perkin-Elmer Paragon 1000 FT-IR spectrophotometer. Optical rotation data was obtained from a Perkin-Elmer 241 polarimeter. The assigned structure of all test compounds and intermediates were consistent with the data.
  • the following reagent was purchased from Trans World Chemicals: 2-(4-biphenyl ethylamine).
  • the following reagents were purchased from Strem Chemicals, Incorporated: 1,1′-bis(diphenyl-phosphino)ferrocene (dppf) and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium (II) dichloromethane adduct [PdCl 2 (dppf)].
  • Pyridine was distilled from KOH.
  • DMF and DMSO were distilled over CaH 2 under reduced pressure.
  • Silica gel (Bodman Industries, ICN SiliTech 2-63 D 60A, 230-400 Mesh) was used for all flash chromatography.
  • Amines were purchased from Aldrich Chemical Company and used as received unless otherwise indicated. Toluene and Et 2 O were distilled from sodium metal. THF was distilled from sodium/benzophenone ketyl. Pyridine was distilled from KOH. Methylene chloride was distilled from CaH 2 . DMF and DMSO were distilled from CaH 2 under reduced pressure. Methanol was dried over 3 ⁇ molecular sieves prior to use. Silica gel (Bodman Industries, ICN SiliTech 2-63 D 60A, 230-400 Mesh) was used for flash column chromatography.
  • the reaction was equipped with a condenser and sealed with a septum and a balloon. The whole system was vacuumed and backfilled with nitrogen for three cycles. DMSO (1 mL) was added via syringe. Then it was vacuumed again and backfilled with a mixture of carbon monoxide. The resulting mixture was heated at 70° C. for 8.5 h. The cooled reaction mixture was diluted with ethyl acetate (30 mL), washed with water, and brine.
  • the reaction was equipped with a condenser and sealed with a septum and a balloon. The whole system was vacuumed and backfilled with nitrogen for three cycles. DMF (2 mL) and triethylamine (0.09 mL, 0.62 mmol) were added via syringe. Then it was vacuumed again and backfilled with a mixture of carbon monoxide. The resulting mixture was heated at 70° C. for 18 h. The cooled reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated bicarbonate solution, water, and brine.
  • This compound was prepared using Method B and triflate ester of (+)-cyclazocine.5 Off-white foam (90 mg, 0.19 mmol, 49%).

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Abstract

8-Substituted-2,6-methano-3-benzazocines of general structure
Figure US20160257677A1-20160908-C00001
are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a divisional of allowed U.S. application Ser. No. 14/529,832, filed Oct. 31, 2014; which is a divisional of U.S. application Ser. No. 13/974,216, filed Aug. 23, 2013, and issued as U.S. Pat. No. 8,901,148 on Dec. 2, 2014; which is a divisional of U.S. application Ser. No. 13/215,392, filed Aug. 23, 2011, and issued as U.S. Pat. No. 8,541,586 on Sep. 24, 2013; which is a continuation of U.S. application Ser. No. 12/477,223, filed Jun. 3, 2009, and issued as U.S. Pat. No. 8,026,252 on Sep. 27, 2011; which is a continuation of U.S. application Ser. No. 11/459,203, filed Jul. 21, 2006, and issued as U.S. Pat. No. 7,557,119 on Jul. 7, 2009; and claims priority of U.S. provisional application 60/701,407, filed Jul. 21, 2005. The entire disclosures of each of the prior applications are hereby incorporated herein by reference.
    • FEDERALLY SPONSORED RESEARCH
  • The following invention was made with Government support under contract number 5 R01 DA12180 awarded by U.S. Dept of Health and Human Services. The Government has certain rights in this invention.
    • FIELD OF THE INVENTION
  • The invention relates to opioid receptor binding compounds containing carboxamides that have large substitutents on the nitrogen of the carboxamide. The compounds are useful as analgesics, anti-diarrheal agents, anticonvulsants, anti-obesity agents, antitussives, anti-cocaine, and anti-addiction medications.
    • BACKGROUND OF THE INVENTION
  • Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been identified. Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e.g., naltrexone and cyclazocine) in humans have limited utility due to poor oral bioavailability and a very rapid clearance rate from the body. This has been shown in many instances to be due to the presence of the 8-hydroxyl group (OH) of 2,6-methano-3-benzazocines, also known as benzomorphans [(e.g., cyclazocine and EKC (ethylketocyclazocine)] and the corresponding 3-OH group in morphinanes (e.g., morphine).
  • Figure US20160257677A1-20160908-C00002
  • The high polarity of these hydroxyl groups retards oral absorption of the parent molecules. Furthermore, the 8-(or 3-)OH group is prone to sulfonation and glucuronidation (Phase II metabolism), both of which facilitate rapid excretion of the active compounds, leading to disadvantageously short half-lives for the active compounds. Until the publications of Wentland in 2001, the uniform experience in the art of the past seventy years had been that removal or replacement of the 8-(or 3-) OH group had led to pharmacologically inactive compounds.
  • U.S. Pat. No. 6,784,187 (to Wentland) disclosed that the phenolic OH of opioids could be replaced by CONH2. In the cyclazocine series of opioids, it was shown that 8-carboxamidocyclazocine (8-CAC) had high affinity for μ and κ opioid receptors. In studies in vivo, 8-CAC showed high antinociception activity and a much longer duration of action than cyclazocine (15 h vs. 2 h) when both were dosed at 1 mg/kg ip in mice. Preliminary structure-activity relationship studies for 8-CAC revealed that mono-substitution of the carboxamide nitrogen with methyl or phenyl reduced binding affinity for guinea pig μ receptors 75- and 2313-fold, respectively whereas dimethylation of the carboxamide group reduced binding affinity 9375-fold. The finding that substitution of the carboxamide nitrogen had such a detrimental effect suggested that the NH2 of the amide was critical to opioid binding.
    • SUMMARY OF THE INVENTION
  • We have now found that the nitrogen of the carboxamide can be substituted with fairly large and relatively non-polar groups, and that such compounds exhibit excellent opioid binding and, presumably, good metabolic stability. The compounds of the invention are therefore useful as analgesics, anti-pruritics, anti-diarrheal agents, anticonvulsants, antitussives, anorexics and as treatments for hyperalgesia, drug addiction, respiratory depression, dyskinesia, pain (including neuropathic pain), irritable bowel syndrome and gastrointestinal motility disorders. Drug addiction, as used herein, includes alcohol and nicotine addiction. There is evidence in the literature that the compounds may also be useful as immunosuppressants and antiinflammatories and for reducing ischemic damage (and cardioprotection), for improving learning and memory, and for treating urinary incontinence.
  • In one aspect, the invention relates to compounds of formula:
  • Figure US20160257677A1-20160908-C00003
  • wherein
  • Figure US20160257677A1-20160908-C00004
  • is an aryl or heteroaryl residue of one to three rings;
  • A is (CH2)n, wherein one or more CH2 may be replaced by —O—, cycloalkyl or —CR1aR1b;
  • R1a and R1b are chosen independently from hydrogen, halogen, lower alkyl, lower alkoxy and lower alkylthio;
  • R2 and R2a are both hydrogen or taken together R2 and R2a are ═O;
  • R3 is chosen from hydrogen, C1-C8 hydrocarbon, heterocyclyl, heterocyclylalkyl and hydroxyalkyl;
  • R4 is chosen from hydrogen, hydroxy, amino, lower alkoxy, C1-C20 alkyl and C1-C20 alkyl substituted with hydroxy or carbonyl;
  • R5 is lower alkyl;
  • R6 is lower alkyl;
  • R7 is chosen from hydrogen and hydroxy; or
  • together R4, R5, R6 and R7 may form from one to three rings, said rings having optional additional substitution;
  • R10 is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl and halo(C1-C6)alkoxy and (C1-C6)alkylthio;
  • R11 is H or
  • Figure US20160257677A1-20160908-C00005
  • Figure US20160257677A1-20160908-C00006
  • is an aryl or heteroaryl residue of one to three rings;
  • A′ is (CH2)m, wherein one or more CH2 may be replaced by —O—, cycloalkyl, —CR1aR1b, —C(═O)— or —NH—;
  • R12 is chosen from hydrogen and lower alkyl;
  • R15 is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl and halo(C1-C6)alkoxy and (C1-C6)alkylthio;
  • m is zero or an integer from 1 to 6; and
  • n is an integer from 1 to 6.
  • Subclasses of the foregoing structure include:
  • II. 2,6-methano-3-benzazocines of the structure shown above, in which R4, R5, R6 and R7 do not form additional rings:
  • Figure US20160257677A1-20160908-C00007
  • wherein:
  • R3a is chosen from hydrogen, C1-C7 hydrocarbon, heterocyclyl, and hydroxyalkyl;
  • R4 is chosen from hydrogen, hydroxy, lower alkoxy, C1-C20 alkyl and C1-C20 alkyl substituted with hydroxy or carbonyl;
  • R5 is lower alkyl;
  • R6 is lower alkyl; and
  • R7 is hydrogen or hydroxy.
  • III. morphinans in which R5 and R6 form one ring:
  • Figure US20160257677A1-20160908-C00008
  • wherein
  • R3a is chosen from hydrogen, C1-C7 hydrocarbon, heterocyclyl, and hydroxyalkyl; and R7 is H or OH.
  • IV. morphinans in which R5, R6 and R7 form two rings:
  • Figure US20160257677A1-20160908-C00009
  • wherein
  • R19 is hydrogen or lower alkyl;
  • R20 is chosen from hydrogen, lower alkyl and hydroxy(lower alkyl); or together, R9 and R10 form a spiro-fused carbocycle of 5 to 10 carbons;
  • R21 is hydrogen;
  • R22 is chosen from hydroxy, lower alkoxy and —NR13R14; or together, R21 and R22 form a carbonyl or a vinyl substituent.
  • and
    V. morphinans wherein R4 and R11 form an additional sixth ring, which may be saturated or
  • unsaturated:
  • Figure US20160257677A1-20160908-C00010
  • In another aspect, the invention relates to a method for preparing a second compound that interacts with an opioid receptor when a first compound that interacts with an opioid receptor is known. When the first compound contains a phenolic hydroxyl, the method comprises converting the phenolic hydroxyl to a residue of structure:
  • Figure US20160257677A1-20160908-C00011
  • which will hereinafter be sometimes referred to as Q.
  • In another aspect, the invention relates to methods for inhibiting, eliciting or enhancing responses mediated by an opioid receptor comprising:
      • (a) providing a first compound that inhibits, elicits or enhances an opioid receptor response;
      • (b) preparing a second compound that interacts with an opioid receptor by converting a phenolic hydroxyl group on the first compound to a residue described as Q above; and
      • (c) bringing the second compound into contact with the opioid receptor.
  • In another aspect, the invention relates to a method for treating a disease by altering a response mediated by an opioid receptor. The method comprises bringing into contact with the opioid receptor a compound having the formula
  • Figure US20160257677A1-20160908-C00012
  • wherein
    B represents the appropriate residue of a known compound of formula
  • Figure US20160257677A1-20160908-C00013
  • and the known compound of that formula alters a response mediated by an opioid receptor.
    • DETAILED DESCRIPTION OF THE INVENTION
  • From many years of SAR studies, it is known that the hydroxyl of morphinans and benzomorphans interacts with a specific site in the opiate receptor. We have now surprisingly found that the hydroxyl can be replaced with a very large carboxamide residue. A fairly wide range of secondary carboxamides exhibit binding in the desired range below 25 nanomolar.
  • Since phenolic hydroxyls of benzomorphans and morphinans can be chemically converted to carboxamides by a simple, flexible and convenient route described in U.S. Pat. Nos. 6,784,187 and 7,057,035, the door is opened to a whole family of new therapeutic agents, many of which derive directly from the application of the principles set forth herein to known therapeutic agents that rely on opioid binding for their activity. Moreover, since the receptor seems to tolerate some variation in Q, one may contemplate further modulating receptor specificity, affinity and tissue distribution by varying the properties of the aryl substituents.
  • In one aspect the invention relates to compounds of formula
  • Figure US20160257677A1-20160908-C00014
  • In one major subclass, R11 is
  • Figure US20160257677A1-20160908-C00015
  • and the compounds are biphenyls, diaryl ethers and the like of formula:
  • Figure US20160257677A1-20160908-C00016
  • Preferred values of Q
  • Figure US20160257677A1-20160908-C00017
  • are those in which
    (a)
  • Figure US20160257677A1-20160908-C00018
  • is phenyl, R10 is hydrogen and R11 is
  • Figure US20160257677A1-20160908-C00019
  • so that R11 represents pyridinyl, phenyl, halophenyl, methylphenyl, methoxyphenyl (in all of which A′ is a direct bond) and phenoxy (in which A′ is —O—).
    (b)
  • Figure US20160257677A1-20160908-C00020
  • is chosen from phenyl, naphthyl, fluorenyl, carbazole, dibenzofuran and dibenzothiophene, R10 is hydrogen, methoxy, halogen or methyl; and R11 is hydrogen;
    (c)
  • Figure US20160257677A1-20160908-C00021
  • is pyridinyl, R10 is hydrogen and R11 is chosen from phenyl, halophenyl, methylphenyl, methoxyphenyl and phenoxy.
  • It is known in the art that compounds that are μ, δ and κ agonists exhibit analgesic activity; compounds that are selective μ agonists exhibit anti-diarrheal activity and are useful in treating dyskinesia; μ antagonists and κ agonists are useful in treating heroin, cocaine, alcohol and nicotine addiction; κ agonists are also anti-pruritic agents and are useful in treating hyperalgesia. Recently it has been found [Peterson et al. Biochem. Pharmacol. 61, 1141-1151 (2001)] that κ agonists are also useful in treating retroviral inflections. In general, the dextrorotatory isomers of morphinans of type III above are useful as antitussives and anticonvulsants.
  • Opioid receptor ligands having known high affinity are shown in the following charts. Replacement of OH with Q in these compounds produces compounds that exhibit similar activity and better bioavailability.
  • Figure US20160257677A1-20160908-C00022
    Figure US20160257677A1-20160908-C00023
  • Figure US20160257677A1-20160908-C00024
    Figure US20160257677A1-20160908-C00025
    Figure US20160257677A1-20160908-C00026
  • Figure US20160257677A1-20160908-C00027
    Figure US20160257677A1-20160908-C00028
    Figure US20160257677A1-20160908-C00029
  • Other opioid receptor ligands are described in Aldrich, J. V. “Analgesics” in Burger's Medicinal Chemistry and Drug Discovery, M. E. Wolff ed., John Wiley & Sons 1996, pages 321-44, the disclosures of which are incorporated herein by reference. In all but two of the foregoing compounds, there is a single phenolic OH that is to be replaced by Q according to the present invention. In norbinaltorphimine and 361444-66-8, there are two phenolic OH's, either or both of which are replaced by Q.
  • We have examined the opioid receptor binding of a series of analogs of known compounds that interact at opioid receptors in which the OH is replaced by the Q-group shown in Tables 1-3. Binding assays used to screen compounds are similar to those previously reported by Neumeyer et al., Design and Synthesis of Novel Dimeric Morphinan Ligands for κ and μ Opioid Receptors. J. Med. Chem. 2003, 46, 5162. Membrane protein from CHO cells that stably expressed one type of the human opioid receptor were incubated with 12 different concentrations of the compound in the presence of either 1 nM [3H]U69,59310 (κ), 0.25 nM [3H]DAMGO11 (μ) or 0.2 nM [3H]naltrindole12 (δ) in a final volume of 1 mL of 50 mM Tris-HCl, pH 7.5 at 25° C. Incubation times of 60 min were used for [3H]U69,593 and [3H]DAMGO. Because of a slower association of [3H]naltrindole with the receptor, a 3 h incubation was used with this radioligand. Samples incubated with [3H]naltrindole also contained 10 mM MgCl2 and 0.5 mM phenylmethylsulfonyl fluoride. Nonspecific binding was measured by inclusion of 10 μM naloxone. The binding was terminated by filtering the samples through Schleicher & Schuell No. 32 glass fiber filters using a Brandel 48-well cell harvester. The filters were subsequently washed three times with 3 mL of cold 50 mM Tris-HCl, pH 7.5, and were counted in 2 mL Ecoscint A scintillation fluid. For [3H]naltrindole and [3H]U69,593 binding, the filters were soaked in 0.1% polyethylenimine for at least 60 min before use. IC50 values were-calculated by least squares fit to a logarithm-probit analysis. Ki values of unlabeled compounds were calculated from the equation Ki=(IC50)/1+S where S=(concentration of radioligand)/(Kd of radioligand).13 Data are the mean±SEM from at least three experiments performed in triplicate.
  • [35S]GTPγS Binding Assays. In a final volume of 0.5 mL, 12 different concentrations of each test compound were incubated with 15 μg (κ), 10 μg (δ) or 7.5 μg (μ) of CHO cell membranes that stably expressed either the human κ, δ or μ opioid receptor. The assay buffer consisted of 50 mM Tris-HCl, pH 7.4, 3 mM MgCl2, 0.2 mM EGTA, 3 μM GDP, and 100 mM NaCl. The final concentration of [35S]GTPγS was 0.080 nM. Nonspecific binding was measured by inclusion of 10 μM GTPγS. Binding was initiated by the addition of the membranes. After an incubation of 60 min at 30° C., the samples were filtered through Schleicher & Schuell No. 32 glass fiber filters. The filters were washed three times with cold 50 mM Tris-HCl, pH 7.5, and were counted in 2 mL of Ecoscint scintillation fluid. Data are the mean E. and EC50 values±S.E.M. from at least three separate experiments, performed in triplicate. For calculation of the Emax values, the basal [35S]GTPγS binding was set at 0%. To determine antagonist activity of a compound at the μ opioid receptors, CHO membranes expressing the μ opioid receptor, were incubated with 12 different concentrations of the compound in the presence of 200 nM of the μ agonist DAMGO. To determine antagonist activity of a compound at the κ opioid receptors, CHO membranes expressing the κ opioid receptor, were incubated with the compound in the presence of 100 nM of the κ agonist U50,488. To determine if a compound was an antagonist at 6 receptors, CHO membranes expressing the 6 receptor were incubated with 12 different concentrations of the test compound in the presence of 10 nM of the 6-selective agonist SNC 80.
  • TABLE 1
    Cyclazocine subseries
    Figure US20160257677A1-20160908-C00030
    Example optical [3H] [3H] [3H]
    # isomer Q DAMGO (μ) Naltrindole (δ) U69,593 (κ)
    15 (±)− CONH(CH2)2(4-C6H4C6H5) 0.048 ± 0.0014 0.94 ± 0.045  0.33 ± 0.015
    42 (±)− CONH(CH2)2(4-C6H4C6H5)  0.30 ± 0.036 0.74 ± 0.019  1.8 ± 0.19
    43 (±)− CONH(CH2)2(4-C6H4C6H5)  0.26 ± 0.006 0.70 ± 0.073  2.3 ± 0.048
    16 (−)− CONH(CH2)2(4-C6H4C6H5) 0.017 ± 0.004 0.32 ± 0.08 0.046 ± 0.01
    16 (−) CONH(CH2)2(4-C6H4C6H5)  0.25 ± 0.031 0.24 ± 0.014  0.35 ± 0.009
    17 (+)− CONH(CH2)2(4-C6H4C6H5)  7.8 ± 2.0   21 ± 0.74   11 ± 1.3
    17 (+) CONH(CH2)2(4-C6H4C6H5)  6.4 ± 0.50  9.9 ± 0.44  8.5 ± 1.07
    18 (±)− CONH(CH2)3(4-C6H4C6H5)  5.8 ± 0.31   72 ± 11  2.7 ± 0.21
    19 (±)− CON(CH3)(CH2)2(4-C6H4C6H5)  6.7 ± 1.7   12 ± 2.4   11 ± 0.44
    44 (±)− CONH-c-C3H4-(4-C6H4C6H5)(trans)   13 ± 0.69   20 ± 2.9   36 ± 6.8
    45 (±)− CONH-c-C3H4-(4-C6H4C6H5)(cis)   12 ± 2.4   20 ± 1.4   21 ± 4.8
    46 (±)− CONHCH2CH(CH3)(4-C6H4C6H5)   18 ± 1.1   12 ± 0.11   15 ± 1.0
    47 (±)− CONHCH(CH3)CH2(4-C6H4C6H5)  7.8 ± 0.99  7.6 ± 0.51   11 ± 0.24
    48 (±)− CONH(CH2)2(4-C6H4-4-CH3OC6H4) 0.084 ± 0.012 0.18 ± 0.022  1.5 ± 0.10
    49 (±)− CONH(CH2)2(4-C6H4-4-ClC6H4)  0.20 ± 0.038 0.71 ± 0.046  3.2 ± 0.67
    50 (±)− CONH(CH2)2(4-C6H4-3-ClC6H4)  0.56 ± 0.087  1.3 ± 0.19  3.8 ± 0.13
    51 (±)− CONH(CH2)2(4-C6H4-4-CH3C6H4)  0.29 ± 0.075 0.72 ± 0.027  3.3 ± 0.20
    52 (±)− CONH(CH2)2(2-Br-C6H4)  4.0 ± 0.36  150 ± 6.2   19 ± 1.3
    30 (±)− CONH(CH2)2(3-Br-C6H4)  0.35 ± 0.021  3.5 ± 0.19 0.063 ± 0.006
    29 (±)− CONH(CH2)2(4-Br-C6H4)  2.4 ± 0.33  2.5 ± 0.28  0.38 ± 0.060
    53 (±)− CONH(CH2)2(4-C6H4)CONH(CH2)2(4-BrC6H4)  1.5 ± 0.18   30 ± 1.8  5.0 ± 0.36
    37 (±)− CONH(CH2)2(2-naphthyl)  0.18 ± 0.009 0.90 ± 0.020  0.20 ± 0.056
    38 (±)− CONH(CH2)3(2-naphthyl)  1.9 ± 0.19   18 ± 1.2  0.18 ± 0.016
    40 (±)− CONH(CH2)2(1-naphthyl)  4.2 ± 0.13   24 ± 1.2  2.4 ± 0.46
    41 (±)− CONH(CH2)3(1-naphthyl)  2.4 ± 0.45   18 ± 1.0  1.9 ± 0.077
    25 (±)− CONH(CH2)2(3-C6H4C6H5)  0.95 ± 0.15  5.9 ± 1.2  2.2 ± 0.14
    26 (±)− CONH(CH2)2(2-C6H4C6H5)  6.7 ± 0.49   21 ± 3.1  2.4 ± 0.28
    33 (±)− CONH(CH2)2(4-C6H4-O-C6H5) 0.059 ± 0.017  3.2 ± 0.30  1.6 ± 0.30
    35 (±)− CONH(CH2)2(3-C6H4-O-C6H5)  0.63 ± 0.090   12 ± 1.9  0.85 ± 0.070
    34 (±)− CONH(CH2)2(2-C6H4-O-C6H5)  0.54 ± 0.16   95 ± 6.7   13 ± 0.67
    54 (±)− CONH(CH2)2(4-C6H4-4-pyridinyl) 0.065 ± 0.0089  6.7 ± 0.58  1.8 ± 0.12
    55 (±)− CONH(CH2)2(4-C6H4-3-pyridinyl) 0.064 ± 0.0051  8.2 ± 0.50  2.2 ± 0.043
    56 (±)− CONH(CH2)2(4-C6H4-2-pyridinyl)  0.33 ± 0.032  9.2 ± 1.3  3.3 ± 0.089
    57 (±)− CONH(CH2)2(3-pyridinyl-4-C6H5)  0.61 ± 0.14   14 ± 1.2  2.6 ± 0.12
    58 (±)− CONH(CH2)2(2-pyridinyl-4-C6H5)  0.82 ± 0.095  6.5 ± 0.81  1.4 ± 0.16
    59
    11 (±)− CONH(CH2)2C6H5  3.5 ± 0.27   59 ± 6.6  1.7 ± 0.18
    12 (±)− CONH(CH2)3C6H5  2.5 ± 0.27   47 ± 1.6  3.0 ± 0.35
    60 (±)− CONH(CH2)4C6H5  4.3 ± 0.42  7.1 ± 0.39 0.082 ± 0.0026
    61 (±)− CONH(CH2)5C6H5  1.7 ± 0.15  7.9 ± 0.12  1.5 ± 0.10
    62 (±)− CONH(CH2)6C6H5 NT NT NT
    63 (±)− CONH(CH2)2-4-Cl-C6H4 NT NT NT
    64 (±)− CONH(CH2)2-4-CH3O-C6H4 NT NT NT
    65 (±)− CONH(CH2)2-4-CH3-C6H4 NT NT NT
    66 (±)− CONH(CH2)2-3,4-Cl2-C6H3 NT NT NT
    27 (±)− CONH(CH2)2(4-C6H4CH2C6H5)  0.23 ± 0.032  5.9 ± 0.70  1.6 ± 0.27
    67 (−)− CONHCH(S—CH3)C6H5   28 ± 1.4 >10 μM   130 ± 4.0
    68 (−)− CONHCH(R—CH3)C6H5   62 ± 3.3 >10 μM   64 ± 4.3
    69 (±)− CONHCH2CH2-3-pyr   120 ± 3.6   54 ± 1.3   97 ± 3.1
    13 (±)− CONH(CH2)2(4-Br-3-pyridinyl)
    14 (±)− CONHCH2CH2-(4-Br-2-pyr)
  • TABLE 2
    Keto subseries:
    Figure US20160257677A1-20160908-C00031
    [3H] [3H] [3H]
    DAMGO Naltrindole U69,593
    example Q = (μ) (δ) (κ)
    20 CONH(CH2)2(4- 3.1 ± 1.3  3.9 ± 1.4  1.3 ± 0.072
    C6H4C6H5 (KC)
    21 CONH(CH2)2(4- 4.9 ± 0.20  13 ± 2.5 5.1 ± 0.18
    C6H4C6H5 (EKC)
  • TABLE 3
    Other Opioid Parents
    Figure US20160257677A1-20160908-C00032
    Figure US20160257677A1-20160908-C00033
    Figure US20160257677A1-20160908-C00034
    Figure US20160257677A1-20160908-C00035
    Figure US20160257677A1-20160908-C00036
    Figure US20160257677A1-20160908-C00037
    [3H] [3H] [3H]
    exam- Q = CONH(CH2)2(4- DAMGO Naltrindole U69,593
    ple C6H4C6H5 (μ) (δ) (κ)
    70 naltrexone 0.11 ± 0.006  11 ± 1.1 0.31 ± 0.03
    71 Q-naltrexone 1.4 ± 0.12  34 ± 4.1  22 ± 1.4
    72 naltrindole 13 ± 1.1  0.13 ± 0.02  4.6 ± 0.23
    73 Q-naltrindole NT NT NT
    74 buprenorphine 0.21 ± 0.024  2.9 ± 0.49  0.62 ± 0.073
    75 Q-buprenorphine  1.3 ± 0.072  16 ± 1.9 120 ± 15 
    76 nalbuphine 1.6 ± 0.37 580 ± 80   3.0 ± 0.63
    77 Q-nalbuphine 5.2 ± 0.07  82 ± 3.3  82 ± 5.8
    78 butorphanol 0.12 ± 0.058  12 ± 3.8  0.22 ± 0.023
    79 Q-butorphanol 0.32 ± 0.048  0.45 ± 0.039  3.9 ± 0.47
    80 naltrexone ring opened 17 ± 4.0  130 ± 6.6   2.2 ± 0.16
    81 Q-naltrexone ring 0.71 ± 0.091  3.7 ± 0.20  1.9 ± 0.15
    opened
  • Antinociceptive activity is evaluated by the method described in Jiang et al. [J. Pharmacol. Exp. Ther. 264, 1021-1027 (1993), page 1022]. The ED50's of compounds of the invention are expected to be under 100 nmol in the mouse acetic acid writhing test when administered i.c.v., and an increase in the duration of action is expected for compounds of the invention compared to their “parents” when given by i.p. administration.
    • DEFINITIONS
  • Throughout this specification the terms and substituents retain their definitions.
  • Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, s- and t-butyl, cyclobutyl and the like. Preferred alkyl groups are those of C20 or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.
  • Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.
  • Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S. The aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl and the like. Heteroarylalkyl means an alkyl residue attached to a heteroaryl ring. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.
  • Heterocycle means a cycloalkyl or aryl residue in which one to two of the carbons is replaced by a heteroatom such as oxygen, nitrogen or sulfur. Heteroaryls form a subset of heterocycles. Examples of heterocycles that fall within the scope of the invention include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.
  • Substituted alkyl, aryl, cycloalkyl, or heterocyclyl refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, hydroxy, loweralkoxy, carboxy, carboalkoxy, carboxamido, cyano, carbonyl, —NO2, —NR1R2; alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, heteroaryloxy, or substituted phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.
  • Virtually all of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. In general it has been found that the levo isomer of morphinans and benzomorphans is the more potent antinociceptive agent, while the dextro isomer may be useful as an antitussive or antispasmodic agent. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
  • Abbreviations
  • The following abbreviations and terms have the indicated meanings throughout:
    • Ac=acetyl
    • BNB=4-bromomethyl-3-nitrobenzoic acid
    • Boc=t-butyloxy carbonyl
    • Bu=butyl
    • c-=cyclo
    • DAMGO=Tyr-ala-Gly-NMePhe-NHCH2OH
    • DBU=diazabicyclo[5.4.0]undec-7-ene
    • DCM=dichloromethane=methylene chloride=CH2C12
    • DEAD=diethyl azodicarboxylate
    • DIC=diisopropylcarbodiimide
    • DIEA=N,N-diisopropylethyl amine
    • DMAP=4-N,N-dimethylaminopyridine
    • DMF=N,N-dimethylformamide
    • DMSO=dimethyl sulfoxide
    • DPPF=1,1′-bis(diphenylphosphino)ferrocene
    • DVB=1,4-divinylbenzene
    • EEDQ=2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline
    • Fmoc=9-fluorenylmethoxycarbonyl
    • GC=gas chromatography
    • HATU═O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
    • hexafluorophosphate
    • HOAc=acetic acid
    • HOBt=hydroxybenzotriazole
    • Me=methyl
    • mesyl=methanesulfonyl
    • MTBE=methyl t-butyl ether
    • NMO=N-methylmorpholine oxide
    • PEG=polyethylene glycol
    • Ph=phenyl
    • PhOH=phenol
    • PfP=pentafluorophenol
    • PPTS=pyridinium p-toluenesulfonate
    • PyBroP=bromo-tris-pyrrolidino-phosphonium hexafluorophosphate
    • rt=room temperature
    • sat′ d=saturated
    • s-=secondary
    • t-=tertiary
    • TBDMS=t-butyldimethylsilyl
    • TFA=trifluoroacetic acid
    • THF=tetrahydrofuran
    • TMOF=trimethyl orthoformate
    • TMS=trimethylsilyl
    • tosyl=p-toluenesulfonyl
    • Trt=triphenylmethyl
  • Figure US20160257677A1-20160908-C00038
  • It may happen that residues in the substrate of interest require protection and deprotection during the conversion of the phenol to the desired Q. Terminology related to “protecting”, “deprotecting” and “protected” functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is below, the person of ordinary skill can readily envision those groups that would be suitable as “protecting groups”. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W. Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference.
  • The compounds of the invention are synthesized by one of the routes described below:
  • Figure US20160257677A1-20160908-C00039
  • Figure US20160257677A1-20160908-C00040
  • Figure US20160257677A1-20160908-C00041
  • In general, the intermediate N-hydroxysuccinimide ester intermediates (3) shown in scheme 1 are prepared by the processes of U.S. Pat. No. 7,057,0357, the contents of which are incorporated herein by reference. The N-hydroxysuccinimide ester is then reacted with the appropriate arylalkylamine (4) as described below. An alternative, employing direct carbonylation/amidation is shown in Scheme 2. Many diaryl compounds can be prepared by Suzuki coupling, shown in Scheme 3.
  • Proton NMR spectra and in certain cases 13C NMR were obtained on a Varian Unity-300 or 500 NMR spectrometer with tetramethylsilane as an internal reference for samples dissolved in CDCl3. Samples dissolved in CD3OD and DMSO-d6 were referenced to the solvent. Proton NMR multiplicity data are denoted by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), and br (broad). Coupling constants are in hertz. Direct insertion probe chemical ionization mass spectral data were obtained on a Shimadzu GC-17A GC-MS mass spectrometer. Direct infusion electrospray ionization (in positively charged ion mode) mass spectral data were obtained on an Agilent 1100 series LC/MSD system (Germany). Melting points were determined on a Meltemp capillary melting point apparatus and were uncorrected. Infrared spectral data were obtained on a Perkin-Elmer Paragon 1000 FT-IR spectrophotometer. Optical rotation data was obtained from a Perkin-Elmer 241 polarimeter. The assigned structure of all test compounds and intermediates were consistent with the data. Carbon, hydrogen, and nitrogen elemental analyses for all novel targets were performed by Quantitative Technologies Inc., Whitehouse, N.J., and were within ±0.4% of theoretical values except as noted; the presence of water or other solvents was confirmed by proton NMR. Reactions were generally performed in an argon or nitrogen atmosphere. Commercially purchased chemicals were used without purification unless otherwise noted. The following reagents were purchased from Aldrich Chemical Company: N-hydroxysuccinimide, phenethylamine, 3-phenyl-1-propylamine, 4-aminobiphenyl, palladium acetate, 4-phenylbenzylamine and benzyl amine. The following reagent was purchased from Trans World Chemicals: 2-(4-biphenyl ethylamine). The following reagents were purchased from Strem Chemicals, Incorporated: 1,1′-bis(diphenyl-phosphino)ferrocene (dppf) and dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium (II) dichloromethane adduct [PdCl2(dppf)]. Pyridine was distilled from KOH. DMF and DMSO were distilled over CaH2 under reduced pressure. Silica gel (Bodman Industries, ICN SiliTech 2-63 D 60A, 230-400 Mesh) was used for all flash chromatography. Amines were purchased from Aldrich Chemical Company and used as received unless otherwise indicated. Toluene and Et2O were distilled from sodium metal. THF was distilled from sodium/benzophenone ketyl. Pyridine was distilled from KOH. Methylene chloride was distilled from CaH2. DMF and DMSO were distilled from CaH2 under reduced pressure. Methanol was dried over 3±molecular sieves prior to use. Silica gel (Bodman Industries, ICN SiliTech 2-63 D 60A, 230-400 Mesh) was used for flash column chromatography.
  • (±)-1-[[[3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-yl]carbonyl]oxy]-2,5-Pyrrolidinedione [(3) R3=CH2c-C3H5; R2, R2a, R4 and R7═H; R5 and R6═CH3.] To a flask charged with triflate [(2) R3=CH2c-C3H5; R2, R2a, R4 and R7═H; R5 and R6═CH3] (403 mg, 1.00 mmol), N-hydroxy succinimide (230 mg, 2.00 mmol) palladium acetate (22.4 mg, 0.10 mmol) and dppf (55.4 mg, 0.10 mmol) was added triethyl amine (0.28 mL, 2.00 mmol). The reaction was equipped with a condenser and sealed with a septum and a balloon. The whole system was vacuumed and backfilled with nitrogen for three cycles. DMSO (1 mL) was added via syringe. Then it was vacuumed again and backfilled with a mixture of carbon monoxide. The resulting mixture was heated at 70° C. for 8.5 h. The cooled reaction mixture was diluted with ethyl acetate (30 mL), washed with water, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated to give a brown oil, which was purified by flash chromatography (Ethyl acetate:Acetone:Hexane:Et3N 2:1:0.4:0.03) to give 3 as a white foam (217 mg, 0.55 mmol, 55%): 1H NMR (500 MHz, CDCl3) δ 7.96 (d, 1H, J=1.5 Hz), 7.82 (dd, 1H, J1=1.5 Hz, J2=8.1 Hz), 7.17 (d, 1H, J=8.1 Hz), 3.19 (m, 1H), 2.97 (d, 1H, J=19.5 Hz), 2.85 (s, 4H), 2.73 (m, 2H), 2.44 (dd, 1H, J1=6.4 Hz, J2=12.7 Hz), 2.33 (dd, 1H, J1=6.6 Hz, J2=12.4 Hz), 1.93 (m, 1H), 1.84 (d, 2H, J=8.5 Hz), 1.35 (s, 3H), 1.27 (m, 1H), 0.83 (m, 1H), 0.79 (d, 3H, J=7.1 Hz), 0.48 (m, 2H), 0.08 (m, 2H). MS (ESI) m/z 397 (M+H)+1; Anal. Calcd. for C23H28N2O4. 0.5H2O: C, 68.20; H, 7.20; N; 6.90. Found: C, 68.04; H, 6.92; N, 7.12.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-[1,1′-biphenyl]-4-ylethyl)-2,6-methano-3-benzazocine-8-carboxamide (15).
  • Method A. Conditions similar to those previously reported by Wentland et al. [Bioorgan. Med. Chem. Lett. 2001, 11, 623-626] were used. A solution of (±)-3 (140 mg, 0.35 mmol) and 2-(4-biphenyl ethylamine) (84 mg, 0.42 mmol) in 2.5 mL of dry pyridine was stirred at room temperature for 48 h. The solvent was removed in vacuo and the residue was taken up in methylene chloride (40 mL), washed once with saturated sodium bicarbonate solution, water, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated to give a brown residue, which was purified by flash chromatography (CH2C12:CH3OH:NH4OH 15:1:0.1) to give 15 as an off-white foam (110 mg, 0.23 mmol, 66%). 1H NMR (500 MHz, CDCl3) δ 7.66 (d, 1H, J=1.5 Hz), 7.57 (dd, 2H, J1=1.3 Hz, J2=7.5 Hz), 7.55 (d, 2H, J=8.5 Hz), 7.43 (t, 2H, J=7.75 Hz), 7.39 (dd, 1H, J1=1.8 Hz, J2=7.75 Hz), 7.34 (t, 1H, J=7.5 Hz), 7.31 (d, 2H, J=8 Hz), 7.08 (d, 1H, J=8 Hz), 6.32 (bt, 1H, J=5.75 Hz), 3.72 (q, 2H, J=6.7 Hz), 3.14 (m, 1H), 2.97 (t, 2H, J=1.5 Hz), 2.93 (d, 1H, J=18.5 Hz), 2.70 (m, 2H), 2.45 (dd, 1H, J1=6.3 Hz, J2=12.75 Hz), 2.34 (dd, 1H, J1=6.75 Hz, J2=12.75 Hz), 1.93 (m, 3H), 1.39 (s, 3H), 1.32 (d, 1H, J=9.5), 0.87 (m, 1H), 0.81 (d, 3H, J=7.0 Hz), 0.50 (dd, 2H, J1=1.5 Hz, J2=8.0 Hz), 0.12 (m, 2H). MS (ESI) m/z 479 (M+H)+; Anal. Calcd. for C33H38N2O.1.0H2O: C, 79.80; H, 8.12; N, 5.64. Found: C, 79.72; H, 8.07; N, 5.96.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-phenylethyl)-2,6-methano-3-benzazocine-8-carboxamide (11). This compound was prepared using Method A and phenethylamine. Off-white foam (93 mg, 0.231 mmol, 83%). 1H NMR (500 MHz, CDCl3) δ 7.61 (d, 1H, J=2.0 Hz), 7.35 (m, 3H), 7.26 (m, 3H), 7.08 (d, 1H, J=8 Hz), 6.07 (bt, 1H, J=5.0 Hz), 3.71 (q, 2H, J=6.5 Hz), 3.16 (m, 1H), 2.94 (m, 3H), 2.70 (m, 2H), 2.47 (m, 1H), 2.32 (m, 1H), 1.93 (m, 3H), 1.40 (s, 3H), 1.33 (d, 1H, J=11.5), 0.87 (m, 1H), 0.82 (d, 3H, J=7.0 Hz), 0.52 (d, 2H, J=8.0 Hz), 0.11 (m, 2H); MS (ESI) m/z 403 (M+H)+; Anal. Calcd. for C27H34N2O.0.5H2O: C, 78.79; H, 8.57; N, 6.81. Found: C, 78.90; H, 8.55; N, 6.86.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-phenylpropyl)-2,6-methano-3-benzazocine-8-carboxamide (12). This compound was prepared using Method A and 3-phenyl-1-propylamine. Off-white foam (72 mg, 0.174 mmol, 68%). 1H NMR (500 MHz, CDCl3) δ 7.66 (d, 1H, J=1.5 Hz), 7.30 (m, 3H), 7.21 (m, 3H), 7.09 (d, 1H, J=8 Hz), 6.02 (bt, 1H, J=5.5 Hz), 3.50 (q, 2H, J=6.8 Hz), 3.15 (m, 1H), 2.95 (d, 1H, J=19.0 Hz), 2.71 (m, 4H), 2.46 (m, 1H), 2.32 (m, 1H), 1.94 (m, 5H), 1.42 (s, 3H), 1.34 (d, 1H, J=9.75), 0.87 (m, 1H), 0.82 (d, 3H, J=7.0 Hz), 0.51 (d, 2H, J=8.0 Hz), 0.11 (m, 2H); MS (ESI) m/z 417 (M+H)+; Anal. Calcd. for C28H36N2O.0.33H2O: C, 79.58; H, 8.75; N, 6.63. Found: C, 79.71; H, 8.75; N, 6.66.
  • (−)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-[1,1′-biphenyl]-4-ylethyl)-2,6-methano-3-benzazocine-8-carboxamide [0-16]. Method B. Conditions similar to those previously reported were used. 2-(4-Biphenyl ethylamine) (85 mg, 0.43 mmol) PdCl2(dppf) (16 mg, 0.02 mmol) were added to a two-neck flask charged with triflate ester of (−)-cyclazocine5 (158 mg, 0.39 mmol). The reaction was equipped with a condenser and sealed with a septum and a balloon. The whole system was vacuumed and backfilled with nitrogen for three cycles. DMF (2 mL) and triethylamine (0.09 mL, 0.62 mmol) were added via syringe. Then it was vacuumed again and backfilled with a mixture of carbon monoxide. The resulting mixture was heated at 70° C. for 18 h. The cooled reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated bicarbonate solution, water, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated to give a black oil, which was purified by flash chromatography (CH2C12:CH3OH:NH4OH 25:1:0.1) to give (−)-16 as an off-white foam (100 mg, 0.21 mmol, 53%). 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.57 (m, 4H), 7.43 (m, 3H), 7.33 (m, 3H), 7.08 (d, 1H, J=7.8 Hz), 6.34 (bt, 1H), 3.73 (q, 2H, J=6.0 Hz), 3.16 (m, 1H), 2.94 (m, 3H), 2.71 (m, 2H), 2.48 (m, 1H), 2.31 (m, 1H), 1.93 (m, 3H), 1.40 (s, 3H), 1.32 (m, 1H), 0.87 (m, 1H), 0.82 (d, 3H, J=7.2 Hz), 0.51 (d, 2H, J=6.6 Hz), 0.11 (m, 2H). MS (ESI) m/z 479 (M+H)+; Anal. Calcd. for C33H38N2O.1.25H2O: C, 79.08; H, 8.14; N, 5.59. Found: C, 79.23; H, 7.84; N, 5.57. For (−)-16: [α]25 D=−69.1° (c=0.75, acetone).
  • (+)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-[1,1′-biphenyl]-4-ylethyl)-2,6-methano-3-benzazocine-8-carboxamide [(+)-17]. This compound was prepared using Method B and triflate ester of (+)-cyclazocine.5 Off-white foam (90 mg, 0.19 mmol, 49%). 1H NMR (500 MHz, CDCl3) δ 7.68 (s, 1H), 7.57 (d, 2H, J=7.5 Hz), 7.55 (d, 2H, J=7.5 Hz) 7.42 (m, 3H), 7.32 (m, 3H), 7.07 (d, 1H, J=8.0 Hz), 6.40 (bt, 1H), 3.72 (q, 2H, J=6.0 Hz), 3.13 (m, 1H), 2.94 (m, 3H), 2.69 (m, 2H), 2.45 (dd, 1H, J1=6.5 Hz, J2=13.0 Hz), 2.30 (dd, 1H, J1=6.5 Hz, J2=12.5 Hz), 1.93 (m, 3H), 1.39 (s, 3H), 1.32 (m, 1H), 0.87 (m, 1H), 0.81 (d, 3H, J=7.0 Hz), 0.50 (d, 2H, J=8.0 Hz), 0.11 (m, 2H). MS (ESI) m/z 479 (M+H)−1; Anal. Calcd. for C33H38N2O.0.67H2O: C, 80.78; H, 8.07; N, 5.71. Found: C, 80.96; H, 8.13; N, 5.45. For (+)-17: [α]25D=+81.3° (c=1.02, acetone).
  • 3-[1,1′-biphenyl]-4-propylamine. To a vigorously stirred solution of 4-biphenylacrylamide (440 mg, 1.97 mmol) in 10 mL of THF under nitrogen atmosphere was added 1.0 M lithium alumina hydride solution in THF (4.0 mL, 4.0 mmol). The resulting mixture was stirred for 2 h at reflux. The reaction was then cooled in an ice bath, quenched with water, diluted with ethyl acetate and filtered. The filtrate was washed with saturated bicarbonate solution, water, and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated to give an oil, which was purified by flash chromatography (CH2C12:CH3OH:NH4OH 10:1:0.1) to give 3-[1,1′-biphenyl]-4-propylamine as a clear oil (147 mg, 0.66 mmol, 34%): 1H NMR (300 MHz, CDCl3) δ 7.59 (d, 2H, J=7.5 Hz), 7.53 (d, 2H, J=7.8 Hz), 7.44 (t, 2H, J=7.65 Hz), 7.33 (m, 1H), 7.27 (d, 2H, J=7.5 Hz), 2.77 (b, 2H), 2.71 (t, 2H, J=7.65 Hz), 1.99 (b, 2H), 1.82 (m, 2H); MS (ESI) m/z 212 (M+H)+; Anal. Calcd. for C15H17N.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-[1,1′-biphenyl]-4-ylpropyl)-2,6-methano-3-benzazocine-8-carboxamide (18). This compound was prepared using Method B and 3-[1,1′-biphenyl]-4-propylamine. Off-white foam (250 mg, 0.51 mmol, 63%). 1H NMR (500 MHz, CDCl3) δ 7.68 (s, 1H), 7.57 (d, 2H, J=7.5 Hz), 7.52 (d, 2H, J=7.5 Hz) 7.43 (t, 2H, J=7.75 Hz), 7.32 (m, 4H), 7.05 (d, 1H, J=7.5 Hz), 6.09 (bt, 1H), 3.52 (q, 2H, J=6.7 Hz), 3.13 (m, 1H), 2.93 (d, 1H, J=19 Hz), 2.77 (t, 2H, J=7.75 Hz), 2.67 (m, 2H), 2.45 (dd, 1H, J1=6.0 Hz, J2=12.5 Hz), 2.30 (dd, 1H, J1=6.75 Hz, J2=12.25 Hz), 1.93 (m, 5H), 1.41 (s, 3H), 1.32 (m, 1H), 0.85 (m, 1H), 0.81 (d, 3H, J=7.5 Hz), 0.51 (d, 2H, J=8.0 Hz), 0.10 (m, 2H). MS (ESI) m/z 493 (M+H)+; Anal. Calcd. for C34H40N2O.0.75H2O: C, 80.67; H, 8.26; N, 5.53. Found: C, 80.78; H, 8.12; N, 5.51.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-[1,1′-biphenyl]-4-ylethyl)-N-methyl-2,6-methano-3-benzazocine-8-carboxamide (19). This compound was prepared using Method B and N-methyl-[1,1′-biphenyl]-4-ethanamine. Off-white foam (190 mg, 0.39 mmol, 60%). 1H NMR (500 MHz, CDCl3) δ 7.56 (m, 4H), 7.43 (m, 3H), 7.39 (m, 1H), 7.33 (t, 2H, J=6.75 Hz), 7.22 (s, 1H), 7.05 (d, 1H, J=7.5 Hz), 3.80 (b, 1H), 3.48 (b, 1H), 3.14 (b, 3H), 3.04 (b, 1H), 2.90 (m, 3H), 2.70 (m, 2H), 2.47 (m, 1H), 2.32 (m, 1H), 1.93 (m, 3H), 1.35 (s, 3H), 1.30 (d, 1H, J=12.5), 0.84 (m, 1H), 0.84 (d, 3H, J=6.5 Hz), 0.51 (d, 2H, J=7.5 Hz), 0.12 (m, 2H). MS (ESI) m/z 493 (M+H)+; Anal. Calcd. for C34H40N2O.0.13H2O: C, 82.51; H, 8.20; N, 5.66. Found: C, 82.33; H, 8.07; N, 5.69.
  • (±)-3-(Cyclopropylmethyl)-6-ethyl-1,2,3,4,5,6-hexaahydro-cis-11-methyl-N-(2-[1,1′-biphenyl]-4-ylethyl)-1-oxo-2,6-methano-3-benzazocine-8-carboxamide (21). This compound was prepared using Method B with the triflate ester of EKC and 2-(4-biphenyl ethylamine). Off-white foam (200 mg, 0.39 mmol, 61%). 1H NMR (500 MHz, CDCl3) δ 8.00 (d, 1H, J=8.0 Hz), 7.82 (s, 1H), 7.58 (m, 4H), 7.51 (d, 2H, J=8.0 Hz) 7.44 (t, 2H, J=7.5 Hz), 7.33 (m, 3H), 6.19 (bt, 1H), 3.77 (q, 2H, J=6.5 Hz), 3.32 (d, 1H, J=8.0 Hz), 3.00 (t, 2H, J=6.75 Hz) 2.92 (dd, 1H, J1=3.75 Hz, J2=12.25 Hz), 2.65 (dd, 2H, J1=5.75 Hz, J2=8.25 Hz), 2.36 (m, 1H), 2.29 (m, 1H), 2.10 (m, 1H), 1.97 (dd, 1H, J1=7.5 Hz, J2=13.0 Hz), 1.90 (m, 1H), 1.82 (m, 1H), 1.24 (d, 1H, J=12.0 Hz), 1.05 (t, 3H, J=7.75 Hz), 0.87 (m, 1H), 0.79 (d, 3H, J=7.0 Hz), 0.48 (m, 2H), 0.26 (m, 1H), 0.01 (m, 1H). MS (ESI) m/z 507 (M+H)+; Anal. Calcd. for C34H38N2O2.1.35H2O: C, 76.91; H, 7.73; N, 5.28. Found: C, 76.89; H, 7.48; N, 4.89.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-(biphenyl-3-yl)ethyl)-2,6-methano-3-benzazocine-8-carboxamide (25). Method B Phenylboronic acid (38 mg, 0.31 mmol), 10 (100 mg, 0.21 mmol), palladium acetate (5 mg, 0.02 mmol), triphenylphosphine (21 mg, 0.08 mmol), 4N sodium carbonate (0.52 mmol) and toluene were places in a microwave vial, sealed and heated at 120° C. for 20 min. The cooled reaction mixture was diluted with ethyl acetate (30 mL), washed with saturated bicarbonate solution, water, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated to give a black oil, which was purified by flash chromatography (CH2C12:CH3OH:NH4OH 25:1:0.1) to give 5 as an white foam (80 mg, 80%). 1H NMR (500 MHz, CDCl3) δ 7.61 (s, 1H), 7.56 (d, 2H, J=7.5 Hz), 7.47 (m, 2H), 7.42 (m, 4H), 7.34 (t, 1H, J=7.3 Hz), 7.23 (d, 1H, J=7.5 Hz), 7.07 (d, 1H, J=7.5 Hz), 6.18 (t, 1H, J=5.7 Hz), 3.72 (q, 2H, J=6.7 Hz), 3.14 (s, 1H), 2.97 (t, 2H, J=1.5 Hz), 2.93 (d, 1H, J=18.5 Hz), 2.70 (m, 2H), 2.45 (dd, 1H, J1=6.3 Hz, J2=12.75 Hz), 2.34 (dd, 1H, J1=6.75 Hz, J2=12.75 Hz), 1.93 (m, 3H), 1.39 (s, 3H), 1.27 (d, 1H, J=11.5), 0.87 (m, 1H), 0.81 (d, 3H, J=7.0 Hz), 0.50 (dd, 2H, J1=1.5 Hz, J2=8.0 Hz), 0.12 (m, 2H). MS (ESI) m/z 479 (M+H)+; Anal. Calcd. for C33H38N2O.1.0H2O: C, 79.80; H, 8.12; N, 5.64. Found: C, 79.66; H, 7.85; N, 5.62.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-(biphenyl-2-yl)ethyl)-2,6-methano-3-benzazocine-8-carboxamide (26). Prepared using Method B. White foam (70 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 7.2-7.4 (m, 10H), 7.06 (d, 1H, J=7.8 Hz), 5.97 (t, 1H, J=5.7 Hz), 3.50 (q, 2H, J=6.0 Hz), 3.14 (s, 1H), 2.94 (m, 3H), 2.70 (m, 2H), 2.44 (dd, 1H, J1=6 Hz, J2=13 Hz), 2.31 (dd, 1H, J1=6 Hz, J2=13 Hz), 1.90 (m, 3H), 1.40 (s, 3H), 1.31 (m, 1H), 0.88 (m, 1H), 0.82 (d, 3H, J=7.0 Hz), 0.50 (d, 2H, J=8.1 Hz), 0.12 (m, 2H). MS (ESI) m/z 479 (M+H)+; Anal. Calcd. for C33H38N2O.0.75H2O: C, 80.53; H, 8.09; N, 5.69. Found: C, 80.43; H, 8.10; N, 5.79.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(4-benzylphenethyl)-2,6-methano-3-benzazocine-8-carboxamide (27). Prepared using Method A and 2-(4-benzylphenyl)ethanamine. White foam (83 mg, 42%). 1H NMR (300 MHz, CDCl3) δ 7.60 (s, 1H), 7.35 (d, 1H, J=7.8 Hz), 7.28 (m, 2H), 7.17 (m, 7H), 7.07 (d, 1H, J=8.1 Hz), 6.08 (t, 1H, J=6 Hz), 3.96 (s, 2H), 3.67 (q, 2H, J=6.5 Hz), 3.13 (s, 1H), 2.94 (d, 1H, J=18.3 Hz), 2.89 (t, 2H, J=6.9 Hz), 2.68 (m, 2H), 2.46 (dd, 1H, J1=6.5 Hz, J2=12.5 Hz), 2.31 (dd, 1H, J1=6.6 Hz, J2=12.9 Hz), 1.90 (m, 3H), 1.38 (s, 3H), 1.30 (d, 1H, J=11.1 Hz), 0.85 (m, 1H), 0.82 (d, 3H, J=7.0 Hz), 0.51 (d, 2H, J=8.0 Hz), 0.09 (m, 2H). MS (ESI) m/z 493 (M+H)+; Anal. Calcd. for C34H40N2O.0.4H2O: C, 81.69; H, 8.23; N, 5.60. Found: C, 81.59; H, 8.26; N, 5.57.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(4-bromophenethyl)-2,6-methano-3-benzazocine-8-carboxamide (29). Prepared using Method A and 2-(4-bromophenyl)ethanamine. Off-white foam (60 mg, 50%). 1H NMR (300 MHz, CDCl3) δ 7.63 (s, 1H), 7.42 (d, 2H, J=8.3 Hz), 7.35 (d, 1H, J=8.1 Hz), 7.09 (d, 2H, J=8.3 Hz), 7.07 (d, 1H, J=7.3 Hz), 6.21 (t, 1H, J=6 Hz), 3.65 (q, 2H, J=6.3 Hz), 3.15 (m, 1H), 2.95 (d, 1H, J=19 Hz), 2.87 (t, 2H, J=7.0 Hz), 2.7 (m, 2H), 2.46 (dd, 1H, J1=6.4 Hz, J2=12.7 Hz), 2.31 (dd, 1H, J1=6.8 Hz, J2=12.4 Hz), 1.90 (m, 3H), 1.39 (s, 3H), 1.31 (m, 1H), 0.89 (m, 1H), 0.81 (d, 3H, J=7.2 Hz), 0.50 (m, 2H), 0.10 (m, 2H). MS (ESI) m/z 481, 483 (M+H)+; Anal. Calcd. for C27H33N2OBr.0.1H2O: C, 67.10; H, 6.92; N, 5.80. Found: C, 67.04; H, 6.80; N, 5.74.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-bromophenethyl)-2,6-methano-3-benzazocine-8-carboxamide (20). Prepared using Method A and 2-(3-bromophenyl)ethanamine. Off-white foam (159 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 7.42 (m, 3H), 7.2 (m, 2H), 7.09 (d, 2H, J=7.8 Hz), 6.1 (t, 1H, J=6 Hz), 3.68 (q, 2H, J=6.1 Hz), 3.15 (m, 1H), 2.95 (d, 1H, J=19 Hz), 2.91 (t, 2H, J=7.1 Hz), 2.7 (m, 2H), 2.46 (dd, 1H, J1=6.4 Hz, J2=12.7 Hz), 2.31 (dd, 1H, J1=6.8 Hz, J2=12.4 Hz), 1.90 (m, 3H), 1.41 (s, 3H), 1.32 (m, 1H), 0.89 (m, 1H), 0.82 (d, 3H, J=7.2 Hz), 0.50 (m, 2H), 0.11 (m, 2H). MS (ESI) m/z 481, 483 (M+H)+; Anal. Calcd. for C27H33N2OBr.0.1H2O: C, 67.10; H, 6.92; N, 5.80. Found: C, 67.00; H, 6.94; N, 5.72.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-bromophenethyl)-2,6-methano-3-benzazocine-8-carboxamide (31). Prepared using Method A and 2-(2-bromophenyl)ethanamine. Off-white foam (150 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 7.64 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.40 (d, 1H), 7.28 (m, 2H), 7.1 (m, 2H), 6.16 (t, 1H, J=6 Hz), 3.73 (q, 2H, J=6.6 Hz), 3.15 (m, 1H), 3.11 (t, 2H, J=7.0 Hz), 2.95 (d, 1H, J=19 Hz), 2.7 (m, 2H), 2.46 (dd, 1H, J1=6.4 Hz, J2=12.7 Hz), 2.31 (dd, 1H, J1=6.8 Hz, J2=12.4 Hz), 1.90 (m, 3H), 1.42 (s, 3H), 1.32 (m, 1H), 0.89 (m, 1H), 0.83 (d, 3H, J=7.2 Hz), 0.51 (m, 2H), 0.11 (m, 2H). MS (ESI) m/z 481, 483 (M+H)+; Anal. Calcd. for C27H33N2OBr: C, 67.35; H, 6.91; N, 5.82. Found: C, 67.22; H, 6.91; N, 5.78.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(4-phenoxyphenethyl)-2,6-methano-3-benzazocine-8-carboxamide (33). Prepared using Method A and 2-(4-phenoxyphenyl)ethanamine. Off-white foam (145 mg, 67%). 1H NMR (500 MHz, CDCl3) δ 7.63 (s, 1H), 7.37 (d, 1H, J=8 Hz), 7.33 (t, 2H, J=8 Hz), 7.20 (d, 2H, J=8.5 Hz), 7.09 (m, 2H), 6.99 (d, 2H, J=8 Hz), 6.96 (d, 2H, J=8 Hz), 6.16 (t, 1H, J=6 Hz), 3.68 (q, 2H, J=6.5 Hz), 3.14 (m, 1H), 2.94 (d, 1H, J=20 Hz), 2.91 (t, 2H, J=6.9 Hz), 2.69 (m, 2H), 2.46 (dd, 1H, J1=6.5 Hz, J2=12.5 Hz), 2.31 (dd, 1H, J1=6.5 Hz, J2=12.5 Hz), 1.90 (m, 3H), 1.40 (s, 3H), 1.31 (d, 1H, J=10 Hz), 0.86 (m, 1H), 0.82 (d, 3H, J=7.0 Hz), 0.50 (d, 2H, J=8.0 Hz), 0.10 (m, 2H). MS (ESI) m/z 495 (M+H)+; Anal. Calcd. for C33H38N2O2.0.25H2O: C, 79.40; H, 7.77; N, 5.61. Found: C, 79.37; H, 7.89; N, 5.77.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-phenoxyphenethyl)-2,6-methano-3-benzazocine-8-carboxamide (34). Prepared using Method A and 2-(3-phenoxyphenyl)ethanamine. Off-white foam (124 mg, 63%). 1H NMR (500 MHz, CDCl3) δ 7.63 (s, 1H), 7.35 (d, 1H, J=8 Hz), 7.29 (m, 3H), 7.09 (m, 2H), 6.98 (m, 3H), 6.88 (m, 2H), 6.15 (t, 1H, J=6 Hz), 3.68 (q, 2H, J=6.5 Hz), 3.14 (m, 1H), 2.94 (d, 1H, J=21.5 Hz), 2.89 (t, 2H, J=7.0 Hz), 2.69 (m, 2H), 2.46 (dd, 1H, J1=6.3 Hz, J2=12.8 Hz), 2.31 (dd, 1H, J1=6.5 Hz, J2=12.5 Hz), 1.90 (m, 3H), 1.40 (s, 3H), 1.32 (d, 1H, J=10 Hz), 0.85 (m, 1H), 0.82 (d, 3H, J=7.0 Hz), 0.51 (d, 2H, J=8.0 Hz), 0.10 (m, 2H). MS (ESI) m/z 495 (M+H)+; Anal. Calcd. for C33H38N2O2.0.2H2O: C, 79.55; H, 7.77; N, 5.62. Found: C, 79.65; H, 7.83; N, 5.53.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-phenoxyphenethyl)-2,6-methano-3-benzazocine-8-carboxamide (35). Prepared using Method A and 2-(2-phenoxyphenyl)ethanamine. Off-white foam (152 mg, 65%). 1H NMR (300 MHz, CDCl3) δ 7.65 (s, 1H), 7.40 (d, 1H, J=7.8 Hz), 7.3 (m, 3H), 7.2 (m, 1H), 7.08 (m, 3H), 6.91 (m, 3H), 6.36 (t, 1H, J=6 Hz), 3.71 (q, 2H, J=6.3 Hz), 3.14 (m, 1H), 2.97 (t, 2H, J=6.75 Hz), 2.95 (d, 1H, J=18.9 Hz), 2.7 (m, 2H), 2.46 (dd, 1H, J1=6.2 Hz, J2=12.8 Hz), 2.31 (dd, 1H, J1=6.6 Hz, J2=12.9 Hz), 1.90 (m, 3H), 1.40 (s, 3H), 1.32 (m, 1H), 0.86 (m, 1H), 0.82 (d, 3H, J=7.2 Hz), 0.51 (d, 2H, J=8.1 Hz), 0.11 (m, 2H). MS (ESI) m/z 495 (M+H)+; Anal. Calcd. for C33H38N2O2.0.2H2O: C, 79.55; H, 7.77; N, 5.62. Found: C, 79.54; H, 7.86; N, 5.69.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-(naphthalen-2-yl)ethyl)-2,6-methano-3-benzazocine-8-carboxamide (37). Prepared using Method A and 2-(naphthalen-2-yl)ethanamine. Off-white foam (93 mg, 55%). 1H NMR (300 MHz, CDCl3) δ 7.77 (m, 3H), 7.65 (s, 2H), 7.3-7.5 (m, 4H), 7.04 (d, 1H, J=7.8 Hz), 6.5 (t, 1H, J=6 Hz), 3.75 (q, 2H, J=6.4 Hz), 3.1 (m, 3H), 2.9 (d, 1H, J=19 Hz), 2.65 (m, 2H), 2.45 (dd, 1H, J1=6.5 Hz, J2=12.5 Hz), 2.30 (dd, 1H, J1=6.6 Hz, J2=12.9 Hz), 1.90 (m, 3H), 1.33 (s, 3H), 1.30 (d, 1H, J=11.1 Hz), 0.85 (m, 1H), 0.79 (d, 3H, J=7.2 Hz), 0.51 (d, 2H, J=6.6 Hz), 0.10 (m, 2H). MS (ESI) m/z 453 (M+H)+; Anal. Calcd. for C31H36N2O.1.0H2O: C, 79.11; H, 8.14; N, 5.95. Found: C, 79.31; H, 7.83; N, 5.92.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-(naphthalen-2-yl)propyl)-2,6-methano-3-benzazocine-8-carboxamide (38). Prepared using Method A and 3-(naphthalen-2-yl)propan-1-amine. Off-white foam (85 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 7.8 (m, 3H), 7.66 (s, 2H), 7.4-7.5 (m, 2H), 7.37 (d, 1H, J=8.3 Hz), 7.26 (m, 1H), 7.03 (d, 1H, J=7.8 Hz), 6.08 (t, 1H, J=6 Hz), 3.54 (q, 2H, J=6.5 Hz), 3.15 (m, 1H), 2.94 (d, 1H, J=20 Hz), 2.91 (t, 2H, J=7.5 Hz), 2.65 (m, 2H), 2.44 (dd, 1H, J1=6.5 Hz, J2=12.5 Hz), 2.31 (dd, 1H, J1=6.6 Hz, J2=12.9 Hz), 2.07 (m, 2H), 1.90 (m, 3H), 1.41 (s, 3H), 1.34 (m, 1H), 0.87 (m, 1H), 0.82 (d, 3H, J=7 Hz), 0.52 (m, 2H), 0.11 (m, 2H). MS (ESI) m/z 467 (M+H)+; Anal. Calcd. for C32H38N2O.0.3H2O: C, 81.42; H, 8.24; N, 5.93. Found: C, 81.33; H, 8.19; N, 5.89.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(2-(naphthalen-1-yl)ethyl)-2,6-methano-3-benzazocine-8-carboxamide (40). Prepared using Method A and 2-(naphthalen-1-yl)ethanamine. Off-white foam (77.5 mg, 24%). 1H NMR (300 MHz, CDCl3) δ 8.19 (d, 1H, J=8.1 Hz), 7.89 (d, 1H, J=7.8 Hz), 7.78 (d, 1H, J=7.8 Hz), 7.3-7.6 (m, 6H), 7.08 (d, 1H, J=8 Hz), 6.16 (t, 1H, J=6 Hz), 3.83 (q, 2H, J=6.5 Hz), 3.44 (t, 2H, J=7 Hz), 3.19 (s, 1H), 2.95 (d, 1H, J=19 Hz), 2.7 (m, 2H), 2.49 (dd, 1H, J1=6.4 Hz, J2=12.7 Hz), 2.35 (dd, 1H, J1=6.8 Hz, J2=12.4 Hz), 1.90 (m, 3H), 1.38 (s, 3H), 1.35 (m, 1H), 0.9 (m, 1H), 0.82 (d, 3H, J=7.2 Hz), 0.53 (m, 2H), 0.13 (m, 2H). MS (ESI) m/z 453 (M+H)+; Anal. Calcd. for C31H36N2O.0.4H2O: C, 80.97; H, 8.07; N, 6.09. Found: C, 81.00; H, 7.98; N, 6.03.
  • (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-N-(3-(naphthalen-2-yl)propyl)-2,6-methano-3-benzazocine-8-carboxamide (41). Prepared using Method A and 3-(naphthalen-2-yl)propan-1-amine. White foam (60 mg, 41%). 1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1H, J=8 Hz), 7.86 (d, 1H, J=7.3 Hz), 7.73 (d, 1H, J=7.6 Hz), 7.65 (s, 1H), 7.3 (m, 5H), 7.08 (d, 1H, J=8 Hz), 6.05 (t, 1H, J=6 Hz), 3.57 (q, 2H, J=6.8 Hz), 3.19 (t, 2H, J=7.7 Hz), 3.15 (m, 1H), 2.95 (d, 1H, J=19 Hz), 2.65 (m, 2H), 2.46 (dd, 1H, J1=6.5 Hz, J2=12.6 Hz), 2.31 (dd, 1H, J1=6.6 Hz, J2=12.4 Hz), 2.11 (m, 2H), 1.90 (m, 3H), 1.41 (s, 3H), 1.37 (d, 1H, J=11.5 Hz), 0.87 (m, 1H), 0.82 (d, 3H, J=7 Hz), 0.50 (m, 2H), 0.11 (m, 2H). MS (ESI) m/z 467 (M+H)+; Anal. Calcd. for C32H38N2O.0.5H2O: C, 80.80; H, 8.26; N, 5.89. Found: C, 80.90; H, 8.09; N, 5.87.
  • (−)-Q-naltrexone (71). Prepared using Scheme 2 and 2-(biphenyl-4-yl)ethanamine. White foam (160 mg, 61%). 1H NMR (500 MHz, CDCl3) δ 7.82 (d, 1H, J=7.8 Hz), 7.73 (t, 1H, J=5.6 Hz), 7.58 (d, 2H, J=7.0 Hz), 7.54 (d, 2H, J=8.3 Hz), 7.42 (m, 4H), 7.33 (t, 1H, J=7.5 Hz), 6.81 (d, 1H, J=8.1 Hz), 5.2 (bs, 1H), 4.75 (s, 1H), 3.81 (m, 1H), 3.73 (m, 1H), 3.22 (d, 1H, J=5.9 Hz), 3.12 (d, 1H, J=19.1 Hz), 3.05 (m, 3H), 2.71 (dd, 1H, J1=12.2 Hz, J2=4.6 Hz), 2.63 (dd, 1H, J1=9.1 Hz, J2=6.0 Hz), 2.44 (dt, 1H, J1=5.2 Hz, J2=12.5 Hz), 2.41 (d, 2H, J=6.3 Hz), 2.32 (td, 1H, J1=3.0 Hz, J2=14.4 Hz), 2.08 (dt, 1H, J1=3.6 Hz, J2=12.2 Hz), 1.92 (m, 1H), 1.58 (dt, 1H, J1=3.4 Hz, J2=14.0 Hz), 1.50 (dd, 1H, J1=2.5 Hz, J2=12.9 Hz), 0.87 (m, 1H), 0.57 (m, 2H), 0.15 (m, 2H). MS (ESI) m/z 549 (M+H)+; Anal. Calcd. for C35H36N2O4.0.75H2O: C, 74.78; H, 6.67; N, 4.89. Found: C, 74.71; H, 6.67; N, 4.95. [α]25D=-108.6° (c=0.75, acetone).
  • (−)-Q-buprenorphine (75). Prepared using Scheme 2 and 2-(biphenyl-4-yl)ethanamine. White foam (150 mg, 73%). 1H NMR (500 MHz, CDCl3) δ 7.87 (d, 1H, J=7.8 Hz), 7.56 (d, 2H, J=7.1 Hz), 7.52 (d, 2H, J=8.0 Hz), 7.44 (t, 2H, J=7.6 Hz), 7.37 (t, 1H, J=5.6 Hz), 7.33 (t, 1H, J=7.5 Hz), 7.26 (d, 2H, J=7.8 Hz), 6.74 (d, 1H, J=8.0 Hz), 5.64 (s, 1H), 4.47 (s, 1H), 3.74 (q, 2H, J=6.6 Hz), 3.22 (s, 3H), 2.85-3.1 (m, 5H), 2.63 (dd, 1H, J1=5.0 Hz, J2=11.9 Hz), 2.2-2.4 (m, 4H), 2.12 (t, 1H, J=9.8 Hz), 1.97 (dt, 1H, J1=5.6 Hz, J2=13.0 Hz), 1.80 (t, 1H, J=12.8), 1.61 (m, 2H), 1.32 (s, 3H), 1.29 (m, 1H), 1.06 (m 1H), 1.03 (s, 9H), 0.80 (m, 1H), 0.63 (m, 1H), 0.49 (m, 2H), 0.12 (m, 2H). MS (ESI) m/z 675 (M+H)+; Anal. Calcd. for C44H54N2O4.0.25H2O: C, 77.78; H, 8.09; N, 4.12. Found: C, 77.64; H, 8.03; N, 4.05. [α]25D=−68.3° (c=0.75, acetone).
  • (−)-Q-nalbuphine (77). Prepared using Scheme 2 and 2-(biphenyl-4-yl)ethanamine. White foam (170 mg, 59%). 1H NMR (500 MHz, CDCl3) δ 7.85 (d, 1H, J=8.0 Hz), 7.57 (d, 2H, J=7.3 Hz), 7.53 (d, 2H, J=8.1 Hz), 7.54 (t, 1H, J=5.6 Hz), 7.42 (t, 2H, J=7.2 Hz), 7.33 (t, 1H, J=7.3 Hz), 7.30 (d, 2H, J=8.0 Hz), 6.75 (d, 1H, J=8.1 Hz), 4.9 (bs, 1H), 4.65 (s, 1H), 4.16 (bs, 1H), 3.81 (m, 1H), 3.63 (m, 1H), 3.12 (d, 1H, J=19.1 Hz), 3.00 (m, 1H), 2.95 (m, 1H), 2.81 (d, 1H, J=5.9 Hz), 2.65 (dd, 1H, J1=19.0 Hz, J2=6.3 Hz), 2.47 (m, 4H), 2.17 (m, 2H), 2.06 (m, 2H), 1.91 (m, 1H), 1.86 (m, 1H), 1.55-1.75 (m, 4H), 1.40 (m, 2H), 1.06 (m, 1H). MS (ESI) m/z 565 (M+H)+; Anal. Calcd. for C36H40N2O4.0.0H2O: C, 76.57; H, 7.14; N, 4.96. Found: C, 76.54; H, 7.22; N, 4.92. [α]25D=−109.3° (c=0.75, acetone).
  • (−)-Q-butorphanol (79). Prepared using Scheme 2 and 2-(biphenyl-4-yl)ethanamine. White foam (75 mg, 81%). 1H NMR (500 MHz, CDCl3) δ 7.69 (S, 1H), 7.57 (d, 2H, J=7.0 Hz), 7.54 (d, 2H, J=8.0 Hz), 7.44 (d, 1H, J=7.3 Hz), 7.43 (t, 2H, J=7.8 Hz), 7.33 (t, 1H, J=7.3 Hz), 7.30 (d, 2H, J=8.0 Hz), 7.11 (d, 1H, J=7.8 Hz), 6.4 (bs, 1H), 4.6 (bs, 1H), 3.72 (m, 2H), 3.10 (d, 1H, J=18.8 Hz), 2.96 (t, 2H, J=7.1 Hz), 2.81 (dd, 1H, J1=6.2 Hz, J2=19 Hz), 2.64 (d, 1H, J=6.1 Hz), 2.45 (m, 3H), 2.34 (m, 1H), 1.75-2.10 (m, 9H), 1.65 (m, 2H), 1.50 (m, 1H), 1.2-1.45 (m, 4H), 0.97 (m, 1H). MS (ESI) m/z 535 (M+H)+; Anal. Calcd. for C36H42N2O2. 0.33H2O: C, 79.97; H, 7.95; N, 5.18. Found: C, 79.92; H, 8.03; N, 5.19. [α]25D=−54.8° (c=0.75, acetone).
  • Q-naltrexone ring opened (81). Prepared using the method described in published US application 2006/0111384, which derives from Coop et al., “δ Opioid Affinity and Selectivity of 4-Hydroxy-3-methoxyindolomorphianan Analogues Related to Naltrindole”, J. Med. Chem. 1999, 42, 1673. Zinc dust (65 mg, 3.75 mmol) was added in portions over 20 min to a solution of (−)-71 Q-naltrexone (103 mg, 0.19 mmol), in HCl (37%, 0.2 mL) and AcOH (5 mL) at reflux. After heating at reflux for a further 10 min, the reaction was cooled by the addition of ice/water (50 mL) and basified (pH 9) with NH4OH, and the products were extracted into CH2C12 (3×50 mL). The organic extracts were washed with brine (100 mL), dried, concentrated, and purified by column chromatography (SiO2, CH2C12:CH3OH:NH4OH 25:1:0.1) to give 81 (71.7 mg, 70%): 1H NMR (300 MHz, CDCl3) δ 13.33 (s, 1H), 7.59 (d, 2H, J=7.8 Hz), 7.57 (d, 2H, J=8.1 Hz), 7.45 (t, 2H, J=7.4 Hz), 7.36 (t, 1H, J=7.5 Hz), 7.32 (d, 2H. J=8.1 Hz), 6.93 (d, 1H, J=8.1 Hz), 6.44 (d, 1H, J=8.4 Hz), 6.38 (bt, 1H), 4.70 (bs, 1H), 4.10 (d, 1H, J=13.5 Hz), 3.70 (m, 2H), 3.11 (d, 1H, J=6.0 Hz), 2.9-3.0 (m, 4H), 2.76-2.87 (m, 2H), 2.63 (m, 1H), 2.35 (d, 2H, J=6.5 Hz), 1.5-2.2 (m, 8H), 0.87 (m, 1H), 0.59 (m, 2H), 0.11 (m, 2H). MS (ESI) m/z 551 (M+H)+; Anal. Calcd. for C35H38N2O4.0.3H2O: C, 75.60; H, 7.00; N, 5.04. Found: C, 75.56; H, 6.90; N, 4.87.
  • In general, the chemistry described above works in the presence of the variety of functional groups found on known core structures. The exceptions would be morphine and congeners having a free 6-OH, which can be protected by a TBDPS (t-butyldiphenylsilyl) group [see Wentland et al., “Selective Protection and Functionalization of Morphine . . . ”, J. Med. Chem. 43, 3558-3565 (2000)].

Claims (2)

I claim:
1. A compound of formula:
Figure US20160257677A1-20160908-C00042
Figure US20160257677A1-20160908-C00043
wherein
Q is
Figure US20160257677A1-20160908-C00044
A is (CH2)n, wherein one or more CH2 may be replaced by —O—, cycloalkyl or CR1aR1b;
R1a and R1b are chosen independently from hydrogen, halogen, lower alkyl, lower alkoxy and lower alkylthio;
Figure US20160257677A1-20160908-C00045
is an aryl or heteroaryl residue of one to three rings;
R10 is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl and halo(C1-C6)alkoxy and (C1-C6)alkylthio;
R11 is H or
Figure US20160257677A1-20160908-C00046
Figure US20160257677A1-20160908-C00047
is an aryl or heteroaryl residue of one to three rings;
A′ is (CH2)m wherein one or more CH2 may be replaced by —O—, cycloalkyl, —CR1aR1b, —C(═O)— or —NH—;
R12 is chosen from hydrogen and lower alkyl;
R15 is one or two residues chosen independently from hydrogen, hydroxyl, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl and halo(C1-C6)alkoxy and (C1-C6)alkylthio;
m is zero or an integer from 1 to 6; and
n is an integer from 1 to 6.
2. A method of treating a patient suffering from a disease or condition wherein said disease or condition is chosen from the group consisting of pain, pruritis, diarrhea, irritable bowel syndrome, gastrointestinal motility disorder, obesity, respiratory depression, convulsions, coughing, hyperalgesia, dyskinesia and drug addiction comprising administering to said patient a compound of claim 1 or a pharmaceutically acceptable salt thereof.
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